Vaccine Safety References

This library provides key references regarding vaccine safety to clinicians and others, including those asked to provide expert testimony in legal proceedings involving the benefits and risks of vaccination, and to lawyers who are defending against such claims. It should also be of value to clinicians answering the questions of patients and parents concerning vaccine safety.

This collection of references should counteract the references of dubious scientific validity that allege safety issues regarding vaccination. We hope the library will serve to provide valuable information to those who confront these issues as well as maintain high levels of vaccine acceptance.

For a scientific overview of this topic, please visit the Vaccine Ingredients section of our website.

Squalene (MF59, AS03, AF03)

Weibel D, Sturkenboom M, Black, S, et al. Narcolepsy and adjuvanted pandemic influenza A (H1N1) 2009 vaccines — multi-country assessment. Vaccine 2018; 38:6202.
The authors found no increased risk of narcolepsy in children or adults in Argentina, Canada, Spain, Switzerland, Taiwan and the Netherlands following implementation of squalene-adjuvanted (AS03, MF59) influenza H1N1 vaccines in those countries.

Dos Santos G, Seifert HA, Bauchau V, Shinde V, Barbeau DM, et al. Adjuvanted (AS03) A/H1N1 2009 Pandemic influenza vaccines and solid organ transplant rejection: systematic signal evaluation and lessons learnt. Drug Saf 2017;40:693-702.
In 2010, the European Medicines Agency (EMA) requested an assessment of available data following a signal of solid organ transplant (SOT) rejection after immunization with either of GlaxoSmithKline’s (GSK) two adjuvanted (AS03) pandemic influenza vaccines, Pandemrix^® and Arepanrix^® H1N1. The authors investigated 5,000 patients who received the 2009 A/H1N1 pandemic vaccine and an additional 11,000 subjects who received adjuvanted (AS03) A/H5N1 vaccines. They found that data supported the safety of adjuvanted (AS03) pandemic influenza vaccination in SOT recipients.

Kumar D, Campbell P, Hoschler K, Hildago L, Al-Dabbagh M, et al. Randomized controlled trial of adjuvanted versus non-adjuvanted influenza vaccine in kidney transplant patients. Transplantation 2016;100;662-669.
The authors compared the safety and immunogenicity of the 2012-2013 influenza vaccine with or without MF59 adjuvant in adult patients who had received a kidney transplant within a median time of 8.1 years. They found no significant differences in response to the vaccine between groups and no evidence of HLA upregulation in transplant recipients who received adjuvanted vaccine.

Stassijns J, Bollaerts K, Baay M, Verstraeten T. A systematic review and meta-analysis on the safety of newly adjuvanted vaccines among children. Vaccine 2016; 34:714-722.
The authors conducted a systematic review on the safety of newly adjuvanted vaccines in more than 25,000 children ≤ 10 years of age, specifically those containing AS01, AS02, AS03 and MF59. They found that serious adverse events did not occur more frequently in the groups receiving adjuvanted vaccines.

Vesikari T, Forsten A, Arora A, Tsai T, Clemens R. Influenza vaccination in children primed with MF59-adjuvanted or non-adjuvanted seasonal influenza vaccine. Hum Vaccin Immunother 2015;11(8):2102-2112.
The authors compared the safety and immunogenicity of vaccination with trivalent inactivated influenza vaccine (TIV) versus MF59-adjuvanted TIV (aTIV) in children. They found that aTIV produced a significantly more robust immune response and a slightly higher but acceptable local and systemic reactions compared with TIV.

Rubinstein F, Micone P, Bonotti A, Wainer V, Schwarcz A, et al. Influenza A/H1N1 MF59 adjuvanted vaccine in pregnant women and adverse perinatal outcomes: multicenter study. BMJ 2013;346:f393.
Approximately 30,000 pregnant women, including more than 7,000 vaccinated during pregnancy, and their newborns were evaluated to assess the risk of adverse perinatal events (fetal and maternal) associated with receipt of MF59-adjuvanted influenza vaccine. Vaccinated women had a significantly lower risk of preterm birth (< 37 weeks), low birth weight, early neonatal mortality, perinatal mortality (early neonatal mortality plus fetal mortality), low APGAR scores, infant non-immune jaundice, hospital admission during pregnancy, and first trimester hemorrhage compared with women who were not vaccinated during pregnancy.

Siegrist CA, Ambrosioni J, Bel M, Combescure C, Hadaya K, et al. Responses of solid organ transplant recipients to the AS03-adjuvanted pandemic influenza vaccine. Antivir Ther 2012;17(5):893-903.
During the 2009 H1N1 pandemic, solid organ transplant (SOT) recipients in Switzerland received two doses of an AS03-adjuvanted influenza vaccine (Pandemrix). The authors compared the safety and immunogenicity of two doses of AS03-adjuvanted vaccine in more than 200 SOT recipients (heart, lung, liver, kidney, pancreas/islet of Langerhans) to one dose in healthy family controls. Adverse reactions occurred less frequently in the SOT group and SOT graft function remained unaffected.

Black S, Della Cioppa G, Malfroot A, Nacci P, Nicolay U, et al. Safety of MF59-adjuvanted versus non-adjuvanted influenza vaccines in children and adolescents: an integrated analysis. Vaccine 2010;28:7331-7336.
The authors investigated the safety profile of MF59-adjuvanted and non-adjuvanted seasonal and pandemic influenza vaccines in more than 1,700 subjects aged 6 months to 18 years. Subjects in the MF59-adjuvanted group experienced a higher percentage of local and systemic reactions, such as injection site reactions or irritability. The group receiving adjuvanted influenza vaccines did not experience an increase in the incidence of serious adverse events.

Pellegrini M, Nicolay U, Lindert K, Groth N, Della Cioppa G. MF59-adjuvanted versus non-adjuvanted influenza vaccines: integrated analysis from a large safety database. Vaccine 2009;27:6959-6965.
The authors evaluated safety data from 64 clinical trials involving 20,000 recipients of MF59-containing seasonal and pandemic influenza vaccines. Other than an increased risk of local and systemic reactions such as injection site reactions or irritability, vaccine recipients had a lower risk of cardiovascular events, new onset chronic diseases, or death.

Monophosphoryl lipid A (MPL), saponin (QS21), and related adjuvant systems (AS01, AS02, AS04)

Bigaeva E, van Doorn E, Liu H, Hak E. Meta-analysis on randomized controlled trials of vaccines with QS-21 or ISCOMATRIX adjuvant: safety and tolerability. PLoSONE 2016;11(5):e0154757. 
Saponin is an immunostimulant that is extracted from the bark of a South American tree, Quillaja sapnonaria. Two saponin-based adjuvants are QS21 and ISCOMATRIX. The authors conducted a systematic literature review to assess the safety and tolerability of saponin-based adjuvants and found no increase in the incidence of reported systemic adverse events.

Leroux-Roels G, Leroux-Roels I, Clement F, Ofori-Anyinam O, Lievens M, et al. Evaluation of the immune response to RTS,S/AS01 and RT,S/AS02 adjuvanted vaccines. Hum Vacc Immunother 2014;10(8):2211-2219.
The authors compared the safety and immunogenicity of malaria vaccines adjuvanted with squalene, monophosphoryl lipid A and saponin to a non-adjuvanted malaria vaccine in adults and found greater immune responses with adjuvanted vaccines. Adjuvanted vaccines had a higher rate of injection site reactions and certain generalized reactions (e.g., fatigue, headache) compared with the non-adjuvanted vaccine but within acceptable limits. These side effects typically resolved within seven days.  No serious adverse events were reported for any group.

Toft L, Storgaard M, Muller M, Sehr P, Bonde P, et al. Comparison of the immunogenicity and reactogenicity of Cervarix and Gardasil human papillomavirus vaccines in HIV-infected adults: a randomized, double-blind clinical trial. J Infect Dis 2014;209:1165-1173.
The immune response and safety of Cervarix^®, a monophosphoryl lipid A-containing-HPV vaccine with Gardasil^®, an aluminum-adjuvanted HPV vaccine were compared in HIV infected adults. The authors found that Cervarix induced superior vaccine responses in HIV-infected women. Both vaccines were well tolerated, though Cervarix was associated with a higher rate of injection site reactions. No serious adverse events occurred in either group. 

Wald A, Koelle DM, Fife K, Warren T, Leclair K, et al. Safety and immunogenicity of long HSV-2 peptides complexed with rhHsc70 in HSV-2 seropositive persons. Vaccine 2011;29(47):8520-8529.
A candidate vaccine, HerpV, against herpes simplex virus-2 (HSV-2) was tested for safety and immunogenicity in a phase 1 human adult study. The authors compared HerpV + QS21 (saponin adjuvant), HerpV alone, QS-21 alone and placebo. The vaccine was well tolerated and safe, and adverse events were similar between HerpV and HerpV + QS-21 groups.

Einstein MH, Baron M, Levin MJ, Chatterjee A, Edwards RP, et al. Comparison of the immunogenicity and safety of Cervarix and Gardasil human papillomavirus (HPV) vaccines in healthy women aged 18-45 years. Hum Vaccin 2009;5(10):705-719.
The authors compared the immune response and safety of Cervarix^®, a monophosphoryl lipid A-containing- HPV vaccine with Gardasil^®, an aluminum-adjuvanted HPV vaccine in healthy adult women. They found that both vaccines were well tolerated, though Cervarixwas associated with a higher rate of injection site reactions, fatigue and myalgia, which were transient and resolved spontaneously without sequelae.

Verstraeten T, Descamps D, David MP, Zahaf T, Hardt K, et al. Analysis of adverse events of potential autoimmune aetiology in a large integrated database of AS04 adjuvanted vaccines. Vaccine 2008;26:6630-6638.
The authors assessed the safety of a monophosphoryl lipid A (MPL) containing adjuvant (AS04) in several vaccines (HPV 16/18, HBV, and phase 3 HSV). More than 68,000 patients were evaluated, including more than 39,000 who received HPV-16/18. The authors found a low rate of autoimmune disorders, without evidence of an increased risk associated with ASO4-adjuvanted vaccines versus non-adjuvanted vaccines. 

Tong N, Beran J, Kee S, Miguel J, Sanchez C, et al. Immunogenicity and safety of an adjuvanted hepatitis B vaccine in pre-hemodialysis and hemodialysis patients. Kidney Int 2005;68:2298-2303.
The authors compared the immunogenicity and safety of an AS04-adjuvanted hepatitis B vaccine with a non-adjuvanted hepatitis B vaccine and found the AS04-adjuvanted vaccine produced a more rapid onset and greater overall level of protection, necessitating fewer booster doses. The adjuvanted vaccine was associated with more injection site reactions, but the rates of serious adverse events were similar between groups, with all events determined to be unrelated to vaccination.

CpG

Hyer R, McGuire DK, Xing B, Jackson S, Janssen R. Safety of a two-dose investigational hepatitis B vaccine, HBsAg-1018, using a toll-like receptor 9 agonist adjuvant in adults. Vaccine 2018;36:2604-2611.
The authors describe the safety aspects of three trials comparing a CpG-ODN adjuvanted hepatitis B vaccine with an aluminum-adjuvanted hepatitis B vaccine in more than 13,000 adult subjects. Vaccine–associated adverse events were limited to mild to moderate local and systemic post-injection reactions.  The authors found no differences in immune-mediated adverse events between the two groups. 

Cooper CL, Davis HL, Morris ML, Efler SM, Kreig AM, et al. Safety and immunogenicity of CPG 7909 injection as an adjuvant to Fluarix influenza vaccine. Vaccine 2004;22:3136-3143.
CPG 7909, a CpG oligodeoxynucleotide (ODN), was tested for safety, tolerability and its ability to augment the immune response of a trivalent influenza vaccine. The authors compared Fluarix^® (full or 1/10^th dose) plus CPG 7909 to Fluarix^® (full or 1/10^th dose) plus saline and found all vaccines were generally well tolerated.

For a scientific overview of this topic, please visit the Vaccine Ingredients — Aluminum section of our website.

Goullé JP, Grangeot-Keros L. Aluminum and vaccines: Current state of knowledge. Med Mal Infect 2020 Feb;50:16-21.
Although aluminum at high doses can cause a variety of clinical manifestations, the quantity of aluminum in vaccines is too small to cause a direct toxic effect. Indeed, the quantity of aluminum in biological specimens from those receiving aluminum-containing vaccines is indistinguishable from unvaccinated subjects. The concern that aluminum in vaccines might be associated with a rare autoimmune disease called macrophagic myofasciitis has been refuted by previous studies.

Karwowski MP, Stamoulis C, Wenren LM, et al. Blood and hair aluminum levels, vaccine history, and early infant development: a cross-sectional study. Acad Pediatr 2018;18:161-165.
Children aged 9 to 13 months, excluding those who received aluminum-containing pharmaceuticals, were evaluated for blood and hair aluminum levels, vaccination history, and cognitive, language and motor development scores. The authors found no correlation between infant blood or hair aluminum concentrations and vaccine history or between blood aluminum and overall developmental status.

Ameratunga R, Gills D, Gold M, et al. Evidence refuting the existence of autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA). J Allergy Clin Immunol Pract 2017;5:1551-1555.
The authors identified two studies refuting the claim for autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA) as suggested by Shoenfeld and coworkers. In one study, lupus patients were found to have no increase in exacerbations after receiving a hepatitis B vaccine containing an aluminum adjuvant. A second study evaluated the incidence of autoimmune disease in more than 18,000 patients who received subcutaneous allergen-specific immunotherapy containing large quantities of injected aluminum. Patients receiving injected aluminum were found to have a lower incidence of autoimmune disease compared with controls. The authors concluded that current studies do not support the existence of ASIA.

Mitkus RJ, King DB, Hess MA, et al. Updated aluminum pharmacokinetics following infant exposures through diet and vaccination. Vaccine 2011; 29:9538-9543.
The authors found that the burden of aluminum from diet and from vaccines given according to the CDC schedule within the first year of life was well within levels considered to be safe, even when the infant was small for age (i.e., equal to or less than the 5^thpercentile for weight).

Jefferson T, Rudin M, Di Pietrantonj C. Adverse events after immunization with aluminium-containing DTP vaccines: systematic review of the evidence. Lancet Infect Dis 2004;4:84-90. The authors reviewed the incidence of adverse events after exposure to aluminum-containing diphtheria, tetanus and pertussis (DTP), alone or in combination, compared with identical vaccines, either without aluminum or containing aluminum in different concentrations. In children up to 18 months of age, aluminum-containing vaccines were associated with more erythema and induration than vaccines without aluminum. They were not, however, associated with serious adverse events.

Keith LS, Jones DE, Chou CHSJ. Aluminum toxicokinetics regarding infant diet and vaccinations. Vaccine 2002;20:S13-S17.
The authors determined whether exposure to aluminum in the diet and in vaccines during the first year of life exceeded the minimal risk level (MRL) set by the Agency for Toxic Substances and Disease Registry (ATSDR). They found that the amount of aluminum received from vaccines was greater than that from dietary sources; however, this level was routinely below the MRL with the exception of brief periods immediately following vaccination. Levels of exposure slightly above the MRL were also likely to be safe given the manner in which the MRL is calculated.

For a scientific overview of this topic, please visit the Antibody-dependent Enhancement (ADE) and Vaccines section of our website.

Dengue

Sridhar S, Luedtke A, Langevin E, Zhu M, Bonaparte M, et al. Effect of dengue serostatus on dengue vaccine safety and efficacy. N Engl J Med 2018;379(4):327-40.
The risk of developing severe disease from dengue is higher for individuals with a secondary infection than for those with a primary infection. Previous studies indicated that it is possible that CYD-TDV vaccination could mimic a primary infection in patients who had never been exposed to the virus (seronegative), causing their first true exposure to natural infection to result in a severe secondary infection. In efficacy and safety trials of CYD-TDV, excess hospitalizations for dengue were observed among vaccine recipients 2 to 5 years of age, but baseline serostatus was not obtained for all children. Researchers in this study determined the baseline serostatus of the children, aged 2 to 16 years, enrolled in these trials to assess safety and efficacy results based on serostatus. In seronegative children, the likelihood of hospitalization or severe virologically confirmed dengue was much greater in vaccine recipients than those who received placebo. Seropositive vaccine recipients had a lower likelihood of hospitalization or severe disease compared with placebo recipients.

Hadinegoro SR, Arredondo-Garcia JL, Capeding MR, Deseda C, Chotpitayasunondh T, et al. Efficacy and long-term safety of a dengue vaccine in regions of endemic disease. N Engl J Med 2015;373:1195-1206.
Investigators assessed the long-term safety and efficacy of a tetravalent dengue vaccine (CYD-TDV) in three clinical trials of more than 30,000 children between the ages of 2 and 16 years of age in Asia and Latin America. Seropositive children had vaccine efficacies of 70% (< 9 years) and 82% (≥ 9 years). Seronegative children had much lower efficacy rates of 14% (< 9 years) and 53% (≥ 9 years). Regarding safety, children vaccinated between 2 to 5 years of age in Asia were shown to have an increased risk of hospitalization secondary to dengue three years after the first vaccine dose compared with children who received placebo. However, the risk of hospitalization in the fourth and fifth years after vaccination was the same as that in children who received placebo. Due to this safety signal in younger patients, CYD-TDV was first submitted for approval for use in children over the age of 9 years. However, after completion of this study, an increased risk of hospitalization and severe disease in children who were seronegative prior to vaccine was found. This caused the manufacturer to change the label to restrict vaccination to subjects who are seropositive at the time of vaccination.

Formalin-inactivated measles vaccine

Martin DB, Weiner LB, Nieburg PI, Blair DC. Atypical measles in adolescents and young adults. Ann Intern Med 1979;90:877-81.
In this case series, the authors describe seven patients aged 12 to 19 years who developed atypical measles 10 to 13 years after receipt of formalin-inactivated measles vaccine (FIMV). Similar to previous reports, atypical measles was characterized by unusual rash, high fevers and pulmonary disease.  Additional findings were increased liver enzymes, thrombocytopenia, disseminated intravascular coagulation and possible cardiac involvement.

Fulginiti VA, Eller JJ, Downie AW, Kempe CH. Altered reactivity to measles virus: atypical measles in children previously immunized with inactivated measles virus vaccines. JAMA 1967;202(12):101-6.
Children aged 6 months to 9 years received either three doses of FIMV, or two doses of FIMV followed by one dose of live attenuated vaccine. In this follow-up case series, the authors described 10 children who were hospitalized at the ages of 6 to 8 years with an atypical severe presentation of measles, five to six years after receipt of FIMV. All became abruptly ill with fever (103-105^oF) and a rash that appeared within 48 to 72 hours of fever. Most had edema of the extremities, and nine children were diagnosed with pneumonia. All recovered completely. The inactivated measles vaccine was removed from the market in 1967 due to waning antibody effects and continued reports of atypical measles in vaccine recipients.

Rauh LW and R Schmidt. Measles immunization with killed virus vaccine. Am J Dis Child 1965;109:226-31.
A series of 386 children, aged 6 months to 6 years, were administered three injections of FIMV. Measles antibody titers conferred protection one month after series completion. After one year, 77% of children tested had no detectable antibodies. Booster injections resulted in a rapid rise in virus-specific antibodies, but failed to offer protection the following year. Two-thirds of these children were observed for two to 2 ½ years after receipt of their third dose, during which time a measles epidemic occurred in the community. During that outbreak, 125 previously vaccinated children were exposed to the virus and nearly half developed a measles infection. Atypical forms of measles or severe manifestations were reported in nine children. Atypical measles was characterized by unusual rash, high fevers (e.g., 105^oF), and some experienced severe pulmonary complications. This was the first report of atypical measles presentation among those who received an inactivated measles vaccine.

Formalin-inactivated respiratory syncytial virus vaccine (FIRSV)

De Swart RL, Kuiken T, Timmerman HH, van Amerongen G, van den Hoogen BG, et al. Immunization of macaques with formalin-inactivated respiratory syncytial virus (RSV) induces interleukin-13-associated hypersensitivity to subsequent RSV infection. J Virol 2002;76:11561-11569.
Formalin-inactivated whole-RSV preparations adjuvated with alum (FIRSV) were found in previous studies to predispose infants for enhanced disease following subsequent natural RSV infection. The authors in this study reproduced this pathological phenomenon in infant macaques and identified immunological and pathological correlates. Vaccine-induced RSV-specific T cells predominantly produced the Th2 cytokines interleukin (IL)-13 and IL-5. Intratracheal challenge with a macaque-adapted wild type RSV three months after the third vaccination elicited a hypersensitivity response associated with lung eosinophilia. The authors hypothesize that an IL-13-associated asthma-like mechanism resulted in airway hyperreactivity in these animals.

Kapikian AZ, Mitchell RH, Chanock RM, Shvedoff RA, Stewart CE. An epidemiologic study of altered clinical reactivity to respiratory syncytial (RS) virus infection in children previously vaccinated with an inactivated RS virus vaccine. Am J Epidemiol 1969;89:405-421.
A formalin inactivated respiratory syncytial virus vaccine (FIRSV) precipitated by alum was administered to infants and children. An outbreak of RSV occurred nine months after the vaccine study was initiated. The authors found that significantly more vaccine recipients under 2 years of age exposed to naturally occurring RSV developed pneumonia compared with those who did not receive the vaccine.

Chin J, Magoffin RL, Shearer LA, Schieble JH, Lennette EH. Field evaluation of a respiratory syncytial virus vaccine and a trivalent parainfluenza virus vaccine in a pediatric population. Am J Epidemiol 1969;89(4):449-463.
Two formalin-inactivated viral vaccines — respiratory syncytial virus and parainfluenza — were evaluated in children 4 months to 9 years of age. Both vaccines elicited substantial serum antibody titers in a high proportion of the subjects, but these antibody levels failed to protect against subsequent natural challenge. Infants up to 18 months who received the RSV vaccine and subsequently became infected with RSV tended to have a more severe clinical illness and a much higher rate of eosinophilia than infants who did not receive the RSV vaccine.

Kim HW, Canchola JG, Brandt CD, Pyles G, Chanock RM, et al. Respiratory syncytial virus disease in infants despite prior administration of antigenic inactivated vaccine. Am J Epidemiol 1969;89(4):422-434.
Three vaccines were evaluated in infants between 2 and 7 months of age including formalin-inactivated RSV precipitated in alum, formalin-inactivated parainfluenza type 1, and formalin-inactivated trivalent parainfluenza (types 1, 2 and 3). The RSV vaccine induced virus-specific serum antibodies but failed to protect against natural RSV infection. Worse, 80% of RSV vaccinees required hospitalization at the time of RSV infection whereas only 5% of RSV infections among parainfluenza vaccine recipients resulted in admission to the hospital. Two children died in the RSV vaccine group.

Fulginiti VA, Eller JJ, Sieber OF, Joyner JW, Miniamitani M, et al. Respiratory virus immunization I: A field trial of two inactivated respiratory virus vaccines; an aqueous trivalent parainfluenza virus vaccine and an alum-precipitated respiratory syncytial virus vaccine. Am J Epidemiol 1969;89(4):435-448.
Infants and children aged 6 months to 7 years received either formalin-inactivated trivalent parainfluenza vaccine or formalin-inactivated RSV vaccine. RSV vaccine recipients experienced rises in serum antibodies, but this did not confer protection. Researchers observed an unexpected increased in RSV illnesses requiring hospitalization among RSV vaccinees compared with control groups. This difference was most significant in the 6- to 11-month-old group where 13.7% were hospitalized with RSV illness as compared to only 0.86% of an aged matched unimmunized control group.

SARS-CoV-2 vaccine in nonhuman primates

Corbett KS, Flynn B, Foulds KE, Francica JR, Boyoglu-Barnum S, et al. Evaluation of the mRNA-1273 vaccine against SARS-CoV-2 in nonhuman primates. N Engl J Med 2020;383(16):1544-1555.
The induction of CD4 type 2 helper T-cell (Th2) (interleukin-4, -5, or -13) responses has previously been associated with vaccine-associated enhanced respiratory disease (VAERD) in some children who were immunized with inactivated respiratory syncytial virus and measles vaccines. To determine whether mRNA-1273 (Moderna) vaccine induced Th2 responses, researchers immunized macaques with two doses of either 10 mcg or 100 mcg of mRNA vaccine at four-week intervals and challenged the animals eight weeks later with SARS-CoV-2. Vaccination with mRNA-1273 induced robust SARS-CoV-2 neutralizing activity, rapid protection in the upper and lower airways, and no pathologic changes in the lung. mRNA-1273 induced Th1 and not Th2 cell responses.

Vogel AB, Kanevsky I, Che Y, Swanson KA, Muik A, et al. A prefusion SARS-CoV-2 spike RNA vaccine is highly immunogenic and prevents lung infection in non-human primates. bioRxiv 2020; https://doi.org/10.1101/2020.09.08.280818
Researchers reported the design, preclinical development, immunogenicity and anti-viral protective effect in rhesus macaques of the SARS-CoV-2 modified mRNA vaccine candidate, BNT162b2 (Pfizer BioNTech). Animals were inoculated with two doses of 100ug of mRNA. Seven days after the second dose, a robust Th1 response was observed, but only a minute Th2 response, consistent with the unlikely occurrence of vaccine-associated enhanced respiratory disease, which is associated with Th2 responses.

Gao Q, Bao L, Mao H, Wang L, Xu K, et al. Development of an inactivated vaccine candidate for SARS-CoV-2. Science 2020;369(6499):77-81.
Researchers developed a purified inactivated SARS-CoV-2 virus vaccine candidate (PiCoVacc), which induced SARS-CoV-2 specific neutralizing antibodies in mice, rats and nonhuman primates. The vaccine candidate was inactivated using β-propiolactone and mixed with alum adjuvant. Three immunizations using two different doses provided partial or complete protection in macaques. After vaccination, macaques were challenged with SARS-CoV-2 without observable antibody-dependent enhancement of infection or immunopathological exacerbation.

Yu J, Tostanoski LH, Peter L, Mercado NB, McMahan K, et al. DNA vaccine protection against SARS-CoV-2 in rhesus macaques. Science 2020;369:806-811.
Researchers developed a series of six DNA vaccine candidates without adjuvant expressing different forms of the SARS-CoV-2 spike (S) protein and evaluated them in 35 rhesus macaques compared with placebo controls. Vaccinated animals developed humoral and cellular immune responses, including neutralizing antibody titers at levels comparable to those found in convalescent humans and macaques infected with SARS-CoV-2. The DNA vaccines induced Th1 rather than Th2 responses. After vaccination, macaques were challenged with SARS-CoV-2 without observable enhanced clinical disease even with the suboptimal vaccine constructs that failed to protect against infection.

For a scientific overview of this topic, please visit the Vaccines and Autism section of our website.

DeStefano, R., T.T. Shimabukuro, The MMR vaccine and autism, Ann Rev Virol (2019) 6: 1.1-1.16.
Autism is a developmental disability that can cause significant social, communication, and behavioral challenges. A report published in 1998, but subsequently retracted by the journal, suggested that measles, mumps, and rubella (MMR) vaccine causes autism. However, autism is a neurodevelopmental condition that has a strong genetic component with genesis before one year of age, when MMR vaccine is typically administered.

Hviid A, Hansen JV, Frisch M, Melbye M. Measles, mumps, rubella vaccination and autism. Ann Int Med 2019; epub ahead of print.
The authors evaluated the relationship between receipt of MMR vaccine and the development of autism in more than 650,000 Danish children born between 1999 and 2010. During the study period, about 6,500 children were diagnosed with autism. The authors found no increased risk of autism in those who received one or two doses of MMR vaccine compared with those who didn’t. The authors also found that MMR vaccine did not increase the risk of autism in children with specific risk factors such as maternal age, paternal age, smoking during pregnancy, method of delivery, gestational age, 5-minute APGAR scores, low birthweight, head circumference, and sibling history of autism. Further, by evaluating specific time periods after vaccination, the authors found no evidence for a regressive phenotype triggered by vaccination. The authors concluded that MMR vaccination did not increase the risk for autism or trigger autism in susceptible children.

Jain A, Marshall J, Buikema A, et al. Autism occurrence by MMR vaccine status among US children with older siblings with and without autism. JAMA 2015;313(15):1534-1540.
The authors evaluated about 100,000 younger siblings who did or did not receive an MMR vaccine when the older sibling had been diagnosed with autism spectrum disorder (ASD). For children with or without older siblings with ASD, there were no differences in the adjusted relative risks of ASD between no doses of MMR, one dose of MMR or two doses of MMR. The authors concluded that receipt of MMR vaccine was not associated with increased risk of ASD even among children whose older siblings had ASD, and, therefore, were presumed to be at higher risk for developing this disorder.

Taylor LE, Swerdfeger AL, Eslick GD. Vaccines are not associated with autism: an evidence-based meta-analysis of case-control and cohort studies. Vaccine 2014;32:3623-3629.

The authors conducted a meta-analysis of case-control and cohort studies that examined the relationship between the receipt of vaccines and development of autism. Five cohort studies involving more than 1.2 million children and five case-control studies involving more than 9,000 children were included in the analysis. The authors concluded that vaccinations, components of vaccines (thimerosal), and combination vaccines (MMR) were not associated with the development of autism or autism spectrum disorder.

Hornig M, Briese T, Buie T, et al. Lack of association between measles virus vaccine and autism with enteropathy: a case-control study. PLoS ONE 2008;3(9):e3140.
The authors evaluated children with GI disturbances with and without autism to determine if those with autism were more likely to have measles virus RNA or inflammation in bowel tissues and to determine if autism or GI symptoms related temporally to receipt of MMR.  The authors found no differences between patients with and without autism relative to measles virus presence in the ileum and cecum or GI inflammation. GI symptoms and autism onset were unrelated to the receipt of MMR vaccine.

Uchiyama T, Kurosawa M, Inaba Y. MMR-vaccine and regression in autism spectrum disorders: negative results presented from Japan. J Autism Dev Disord 2007;37:210-217.
MMR vaccination was only utilized in Japan between 1989 and 1993, given as a single dose between 12 and 72 months of age.  The authors examined the rate of autism spectrum disorders (ASD) involving regressive symptoms in children who did or didn’t receive MMR during that period. No significant differences were found in the incidence of ASD regression between those who did or didn’t receive an MMR vaccine.

Afzal MA, Ozoemena LC, O’Hare A, et al. Absence of detectable measles virus genome sequence in blood of autistic children who have had their MMR vaccination during the routine childhood immunization schedule of UK. J Med Virol 2006;78:623-630.
Investigators obtained blood from 15 children diagnosed with autism with developmental regression and a documented previous receipt of MMR vaccine. Measles virus genome was not present in any of the samples tested. The authors concluded that measles vaccine virus was not present in autistic children with developmental regression.

Honda H, Shimizu Y, Rutter M. No effect of MMR withdrawal on the incidence of autism: a total population study. J Child Psychol Psychiatry 2005;46(6):572-579.
MMR vaccination was only utilized in Japan between 1989 and 1993, given as a single dose between 12 and 72 months of age. The authors found that while MMR vaccination rates declined significantly in the birth cohort of years 1988 through 1992 (~70% in 1988, < 30% in 1991 and < 10% in 1992), the cumulative incidence of ASD up to age 7 years increased significantly. The authors concluded that withdrawal of MMR in countries where it is still being used will not lead to a reduction in the incidence of ASD.

Smeeth L, Cook C, Fombonne E, et al. MMR vaccination and pervasive developmental disorders: a case-control study. Lancet 2004;364:963-969.
The authors reviewed a major United Kingdom database for patients diagnosed with autism or other pervasive developmental disorders (PDD) over a 28-year period and similarly aged patients without those diagnoses to determine if the receipt of MMR vaccination was associated with an increased risk of autism or other PDD. They found no association between MMR vaccine and risk of autism or other PDD.

Madsen KM, Hviid A, Vestergaard M, et al. A population-based study of measles, mumps, and rubella vaccination and autism. N Engl J Med 2002;347(19):1477-1482.
The authors conducted a retrospective review of all children (> 500,000) born in Denmark between 1991 and 1998 to determine if a link existed between receipt of MMR vaccine and diagnosis of autism or autism spectrum disorders. No association was found between ages at the time of vaccination, the time since vaccination, or the date of vaccination and the development of autistic disorder.

Taylor B, Miller E, Farrington CP, et al. Autism and measles, mumps, and rubella vaccine: no epidemiological evidence for a causal association. Lancet 1999;353:2026-2029.
The authors determined whether the introduction of MMR vaccine in the United Kingdom in 1988 affected the incidence of autism by examining children born between 1979 and 1998. They found no sudden change in the incidence of autism after introduction of MMR vaccine and no association between receipt of the vaccine and development of autism.

For a scientific overview of this topic, please visit the Vaccines and Other Conditions – ASIA section of our website.

Ameratunga R, Gills D, Gold M, et al.  Evidence refuting the existence of autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA). J Allergy Clin Immunol Pract 2017;5:1551-1555.
The authors identified two studies refuting the claim for autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA) as suggested by Shoenfeld and co-workers. In one study, lupus patients were found to have no increase in exacerbations after receiving a hepatitis B vaccine containing an aluminum adjuvant. A second study evaluated the incidence of autoimmune disease in more than 18,000 patients who received subcutaneous allergen-specific immunotherapy containing large quantities of injected aluminum. Patients receiving injected aluminum were found to have a lower incidence of autoimmune disease compared with controls. The authors concluded that current studies do not support the existence of ASIA.

For a scientific overview of this topic, please visit the Vaccines and Other Conditions – Diabetes section of our website.

Type 1 diabetes

Klein NP, Goddard K, Lewis E, Ross P, Gee J, et al. Long term risk of developing type-1 diabetes after HPV vaccination in males and females. Vaccine 2019;37(14):1938-1944.
The authors evaluated whether HPV vaccine was associated with an increased risk of type 1 diabetes over a 10-year period by comparing vaccinated males and females to unvaccinated individuals. They found no increased risk for type 1 diabetes following HPV vaccination in males or females.

Frisch M, Besson A, Clemmensen KKB, Valentiner-Branth P, Molbak K, et al. Quadrivalent human papillomavirus vaccination in boys and risk of autoimmune diseases, neurological diseases and venous thromboembolism. International Journal of Epidemiology 2018;47(2):634-641.
The authors investigated the association of quadrivalent HPV (qHPV) vaccination and the risk of 39 autoimmune diseases, 12 neurological diseases, or venous thromboembolism over a 10-year period in more than 7,000 Danish boys who received at least one dose of qHPV vaccination at the age of 10 to 17 years by comparing them to more than 560,000 boys who did not receive the vaccine. Receipt of qHPV in boys aged 10-17 years was not associated with an elevated risk of neurological diseases, venous thromboembolism, or autoimmune diseases including type 1 diabetes.

Beyerlein A, Strobl AN, Winkler C, et al. Vaccinations in early life are not associated with development of islet autoimmunity in type 1 diabetes high-risk children: results from prospective cohort data. Vaccine 2017;35:1735-1741.
The authors examined the relationship between vaccination and the subsequent development of type 1 diabetes in children with a high familial risk for autoimmune diseases. Vaccination records from more than 1,900 children were evaluated. The authors found no evidence that early vaccinations increased the risk of type 1 diabetes in those at highest risk. 

Vaarala O, Jokinen J, Lahdenkari M, et al. Rotavirus vaccination and the risk of celiac disease or type 1 diabetes in Finnish children at early life. Pediatr Infect Dis 2017;36:674-675.
The authors conducted a nationwide cohort study evaluating whether rotavirus vaccination was associated with the development of type 1 diabetes in Finnish children. In a country that has the highest incidence of type 1 diabetes in the world, researchers found that receipt of the rotavirus vaccine early in life did not alter the risk of type 1 diabetes four to six years after vaccination. 

Morgan E, Halliday SR, Campbell GR, et al. Vaccinations and childhood type 1 diabetes mellitus: a meta-analysis of observational studies. Diabetologica 2016;59:237-243.
The authors reviewed studies that compared vaccination rates in 13,000 children with type 1 diabetes with control children, finding no association between receipt of any childhood vaccine and the subsequent development of type 1 diabetes.

Rousseau MC, El-Zein M, Conus F, et al. Bacillus Calmette-Guerin (BCG) vaccination in infancy and risk of childhood diabetes. Paediatr Perinat Epidemiol 2016; 30:141-148.
The authors found no association between receipt of the BCG vaccine in the first year of life and subsequent development of type 1 diabetes during the next 20 years.

Grimaldi-Bensouda L, Guillemot D, Godeau B, et al. Autoimmune disorders and quadrivalent human papillomavirus vaccination of young female subjects. J Int Med 2014;275(4): 398-408.  
The authors reviewed the records of female patients 14-26 years of age to determine if HPV vaccine (Gardasil^®) increased the risk of autoimmune disorders. They found no evidence for an increase in the risk of type 1 diabetes, idiopathic thrombocytopenic purpura, multiple sclerosis, Guillain-Barre syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, juvenile arthritis, or autoimmune thyroiditis.

Hviid A, Stellfeld M, Wohlfahrt J, et al. Childhood vaccination and type 1 diabetes. New Engl J Med 2004;350:1398-1404.
The authors evaluated all children born in Denmark over a 10-year period to determine if there was a causal relation between childhood vaccinations and development of type 1 diabetes. The authors found no correlation with any vaccine studied, including Hib, DT plus inactivated polio virus (IPV), DTaP + IPV, whole cell pertussis, MMR, or oral polio. In addition, development of type 1 diabetes in genetically predisposed children (e.g., siblings with type 1 diabetes) was not significantly associated with vaccination. 

Black SB, Lewis E, Shinefield HR, et al. Lack of association between receipt of conjugate Haemophilus influenzae type b vaccine (HbOC) in infancy and risk of type 1 (juvenile onset) diabetes: long-term follow-up of the HbOC efficacy trial cohort. Pediatr Infect Dis J 2002; 21(6):568-569. 
The authors performed a 10-year follow-up study of 40,000 children to evaluate the incidence of type 1 diabetes in those who did or didn’t receive the Hib vaccine. The authors found no differences in the rates of type 1 diabetes between these two groups.

DeStefano F, Mullooly JP, Okoro CA, et al. Childhood vaccinations, vaccination timing, and risk of type 1 diabetes mellitus. Pediatrics 2001;108(6).
The authors conducted a large-scale epidemiologic study to determine if the receipt of various childhood vaccines, or the timing of vaccines, increased the risk of developing type 1 diabetes.  Investigators found no evidence for an increased risk of type 1 diabetes among those who received the DTaP, DTP, MMR, Hib, hepatitis B, or varicella vaccines when compared with those who didn’t. Further, the authors found no differences in the risk of type 1 diabetes in babies who received the hepatitis B vaccine at birth as compared with 2 months of age or older.

Karvonen M, Cepaitis Z, Tuomilehto J. Association between type 1 diabetes and Haemophilus influenzae type b vaccination: birth cohort study. BMJ 1999;318:1169-1172. 
The authors investigated the relationship between the timing of Hib vaccination and subsequent development of type 1 diabetes. Patients who did not receive the Hib vaccine were compared to those who received the vaccine at 3 months of age and a booster at 14 to 18 months of age, and those who were vaccinated at 24 months of age only. The authors found no significant differences in the risk of type 1 diabetes among these groups during a 10-year follow-up.

Graves PM, Barriga KJ, Norris JM, et al. Lack of association between early childhood immunizations and β-cell autoimmunity. Diabetes Care 1999;22:1694-1697.
The authors investigated the relationship between vaccination and subsequent development of type 1 diabetes in children ≤ 12 years of age with a first-degree relative with the disease. Investigators found no relationship between receipt of hepatitis B, Hib, polio, or DTP vaccines before 9 months of age and the development of type 1 diabetes.

Heijbel H, Chen RT, Dahlquist G. Cumulative incidence of childhood-onset IDDM is unaffected by pertussis immunization. Diabetes Care 1997;20(2):173-175.
The authors found no differences in the incidence of type 1 diabetes in children within the first 12 years of life between those born before or after pertussis vaccination was excluded from the Swedish national immunization program.

Gestational diabetes

Naleway AL, Irving SA, Henninger ML, et al. Safety of influenza vaccination during pregnancy: a review of subsequent maternal obstetric events and findings from two recent cohort studies. Vaccine 2014;32(26): 3122-3127.
The authors evaluated pregnant women for pregnancy-related complications, including gestational diabetes, to determine if development of these conditions was associated with receipt of inactivated influenza vaccine (IIV). Influenza vaccination during pregnancy did not differ between those who developed gestational diabetes and those who did not. 

Kharbanda EO, Vazquez-Benitez G, Lipkind H, et al. Inactivated influenza vaccine during pregnancy and risks for adverse obstetric events. Obstet Gynecol 2013;122(3):659-667.
The authors compared 74,000 vaccinated females with 140,000 unvaccinated females to determine if vaccination increased the risk for adverse obstetric events. They found no increase in the risk of any obstetric event, including gestational diabetes.

For a scientific overview of this topic, please visit the Vaccine ingredients – DNA section of our website.

Yang H, Wei Z, Schenerman M. A statistical approach to determining criticality of residual host cell DNA. J Biopharm Stat 2015;25:234-246.
The authors proposed a method for determining the quantity of residual host cell DNA regarding oncogenicity and infectivity. The authors created an equation to estimate the risk and applied that equation to a cell-based influenza vaccine manufactured using Madin Darby Canine Kidney (MDCK) cells. The calculated probability of having one cancer-causing or infective event based on the WHO/FDA limits is less than 10^-15. If using limits of 800 base pairs and 40 ng DNA/dose, the risk is estimated to be 4.6 x 10^-7.

Yang H. Establishing acceptable limits of residual DNA. PDA J Pharm Sci Technol 2013; 67(2):155-163.
The author conducted a risk assessment on the WHO and FDA guidelines that recommended 10 ng/dose and 200 base pairs as the limits of residual DNA in the final biological product. The safety margin is defined as the number of doses needed to induce a cancer-causing or infective event in recipients. The author suggested that current safety margin estimates do not take into account DNA fractionation or DNA enzymatic inactivation. By incorporating the number of unfragmented potential cancer genes and accounting for DNA enzymatic inactivation, the author suggests that a more accurate safety margin can be calculated and that higher DNA content or base pair size would be acceptable.

Yang H, Zhang L, Galinski M. A probabilistic model for risk assessment of residual host cell DNA in biological products. Vaccine 2010;28:3308-3311.
The authors assessed the cancer-causing and infective potential of residual DNA from a cell-based live, attenuated influenza vaccine that is manufactured in Madin Darby Canine Kidney (MDCK) cells.  They determined that 230 billion doses of vaccine would need to be administered before a potential cancer gene dosage equivalent would be reached, and 83 trillion doses would need to be administered to induce an infective event.

Knezevic I, Stacey G, Petricciani J, et al. WHO Study Group on cell substrates for production of biologicals, Geneva, Switzerland, 11-12 June 2007. Biologicals 2008;36:203-211.
The WHO Expert Committee on Biological Standardization adopted requirements for the use of animal cells as substrates for the production of vaccines and other biologicals in 1996. In 2006, a WHO Study Group on Cell Substrates was formed to initiate revision of WHO requirements. In 2007, the Study Group agreed that data generated on the possibility of cancer or an infection caused by DNA in vaccines were important in defining potential risk for vaccine recipients. It was considered highly likely that reduction of DNA fragment size reduced the risk from DNA and increased the safety margin, as the smaller the DNA fragments, the lower the probability that intact oncogenes and other functional sequences would be present. Studies performed at the Center for Biological Evaluation and Research (CBER) suggest that DNA fragments smaller than 200 base pairs will give substantial safety margins for products that meet the 10 ng/dose limit. Therefore, the margin of safety for vaccines can be found in the high fragmentation, and therefore very small size, of DNA.

WHO requirements for the use of animal cells as in vitro substrates for the production of biologicals. Biologicals 1998;26:175-193. 
Cell lines of human (e.g., WI-38, MRC-5) or monkey (FRhL-2) origin are non-tumorigenic and residual cellular DNA derived from these cells has not been, and is not, considered to pose any risk. Continuous cell line (CCL) substrates of human origin such as HeLa cells (derived from cervical cancer cells) or Namalva cells (derived from Burkett’s lymphoma) could have the potential to confer the capacity for unregulated cell growth or tumorigenic activity upon other cells. Risk assessment based on an animal oncogene model suggested that in vivo exposure to 1 ng (one-billionth of a gram) of cellular DNA —where 100 copies of an activated cancer gene were present in the genome — could give rise to a cancer-causing event 1 per 1 billion recipients. The risk associated with residual CCL DNA in a product is negligible when the amount of such DNA is 100 pg (a picogram is one-trillionth of a gram), which is the current maximal amount of CCL DNA allowed by the FDA.

Wierenga DE, Cogan J, Petricciani JC. Administration of tumor cell chromatin to immunosuppressed and non-immunosuppressed non-human primates. Biologicals 1995;23:221-224.
The authors addressed the issue of how risky DNA may be as a residual impurity by injecting both normal and immunosuppressed monkeys with 100 million genome equivalents of DNA from a human tumor cell line that is one million times the DNA (1 mg) allowed by WHO in a single dose of biological product (100 pg). DNA from a human tumor, saline, or cyclosporine doses were administered intravenously, intramuscularly, or intracerebrally on either a daily, weekly or one-time basis. Animals were observed for 8 years, none of which showed any evidence of tumor formation.

Lower J.  Risk of tumor induction in vivo residual cellular DNA: quantitative considerations. J Med Virol 1990;31:50-53.
In 1987, the WHO Study Group compiled a list of experiments in which DNA of tumor viruses or DNA of the corresponding cancer genes were injected into experimental animals to determine the amount required to induce tumors in half of those tested. In this study, the author compared that information with the recommended residual cellular DNA limits (100 pg) in CCL biological products. The author determined that the number of cancer genes in 100 picograms cellular DNA is less than one-billionth of the amount needed to induce tumors in experimental animals.

Temin HM. Overview of biological effects of addition of DNA molecules to cells. J Med Virol 1990;31:13-17. 
A maximum cumulative probability of having a harmful effect is calculated to be less than 10^-16 to 10^-19 per DNA molecule from a cell without activated precursor cancer genes or active viral cancer genes.

For a scientific overview of this topic, please visit the Vaccine Ingredients – Egg Products section of our website.

Influenza vaccine

Greenhawt M, Turner PJ, Kelso JM. Administration of influenza vaccines to egg allergic recipients: a practice parameter update 2017. Ann Allergy Asthma Immunol 2018;120:49-52.
The American Academy of Allergy, Asthma and Immunology (AAAAI) and the American College of Allergy, Asthma, and Immunology (ACAAI) jointly established influenza vaccine practice parameters in egg allergic recipients. AAAAI and ACAAI state that there is now strong evidence that individuals with egg allergy, regardless of severity, can safely receive inactivated or live attenuated influenza vaccine and that the presence of egg allergy is not a contraindication to receive either vaccine. Furthermore, influenza vaccine recipients are at no greater risk for a systemic allergic reaction than those without egg allergy, and vaccine providers do not need to ask about the egg allergy status of influenza vaccine recipients.

Turner PJ, Southern J, Andrews NJ, Miller E, Erewyn-Lajeunesse M, et al. Safety of live attenuated influenza vaccine in atopic children with egg allergy. J Allergy Clin Immunol 2015;136:376-81.
The safety of a live attenuated intranasal influenza vaccine (LAIV; Fluenz Tetra 2013-14 season) containing ≤ 0.24 mcg/0.2 mL dose of ovalbumin was investigated in 282 children aged 2-17 years with documented IgE-mediated food allergy to egg or a clinical reaction to egg or both within the past 12 months, including 115 children with reported anaphylaxis to egg and 188 children with asthma or documented wheezing. No systemic allergic reactions occurred. Children with a history of recurrent wheezing or asthma were not more likely to experience any adverse events compared with those without such a history. The authors concluded the use of LAIV appears to be safe for use in children with egg allergy and well tolerated in those with asthma or recurrent wheezing.

Turner PJ, Southern J, Andrews NJ, Miller E, Erewyn-Lajeunesse M, et al. Safety of live attenuated influenza vaccine in young people with egg allergy: multicenter prospective cohort study. BMJ 2015;351:h6291.
The safety of a live attenuated intranasal influenza vaccine (LAIV; Fluenz Tetra 2014-15 season) containing ≤ 0.24 mcg/0.2 mL dose of ovalbumin was investigated in 779 children aged 2-18 years with documented egg allergy, including 157 with reported anaphylaxis to egg, and 445 children with asthma or documented wheezing. No systemic allergic reactions occurred. The authors concluded that the use of LAIV is associated with a low risk of systemic allergic reactions in young people with egg allergy, and well-tolerated in those with well controlled asthma or recurrent wheezing. 

Webb L, Petersen M, Boden S, LaBelle V, Bird JA, et al. Single-dose influenza vaccination of patients with egg allergy in a multicenter study. J Allergy Clin Immunol 2011;128(1):218-219.
The safety of inactivated (TIV; Fluzone) influenza vaccinations was investigated in 152 patients aged 7 months to 30 years (median age 3 years) with egg allergy, including 34 patients with reported anaphylaxis to egg, during the 2009-2010 influenza season. Thirty-eight separate lots of Fluzone^® from 3 different companies were used for vaccination, and up to 50% of the lots may have contained more than 1.2 mcg/mL ovalbumin. No systemic reactions occurred in any patients, including those with severe egg allergy.

James JM, Zeiger RS, Lester MR, Fasano MB, Gern JE, et al. Safe administration of influenza vaccine to patients with egg allergy. J Pediatr 1998; 133(5):624-628.
The safety of inactivated influenza vaccines was evaluated in children aged 6 months and older with egg allergy, including 27 patients with reported anaphylaxis to egg. The influenza vaccines contained three different amounts of egg protein (ovalbumin/ovomucoid; 0.1, 1.2, and 0.02 mcg/mL). No significant allergic reactions occurred. The authors concluded that influenza vaccine containing no more than 1.2 mcg/mL egg protein can be safely administered to patients with severe egg allergy.

Measles-containing vaccine

James JM, Burks AW, Roberson PK, Sampson HA. Safe administration of the measles vaccine to children allergic to eggs. New Engl J Med 1995;332:1262-1266.
The authors administered MMR vaccine, for which measles and mumps components are propagated in chick-embryo-cell cultures, to 54 children aged 12-63 months with documented egg allergy, including 26 with reported anaphylaxis to egg. No immediate or delayed adverse reactions occurred. The authors concluded that MMR vaccine can safely be administered to children with egg allergy, even those with severe hypersensitivity.

Freigang B, Jadavii TP, Freigang DW. Lack of adverse reactions to measles, mumps and rubella vaccine in egg-allergic children. Ann Allergy 1994;73(6):486-488.
MMR vaccine was administered to 500 egg allergic children in an outpatient setting and no anaphylactic reactions occurred. The authors concluded that a history of egg allergy should not be considered a contraindication to receipt of MMR vaccine.

Bruno G, Giampietro PG, Grandolfo ME, Milita O, Businco L. Safety of measles immunization in children with IgE-mediated egg allergy. Lancet 1990;335(8691):739.
The authors administered measles vaccine to 23 children (median age 2 years 5 months) with documented egg allergy. No immediate or delayed systemic adverse reactions occurred.  The authors concluded that measles vaccine can safely be administered to children with documented egg allergy.

Yellow fever vaccine

Smith D, Wong P, Gomez R, White K. Ovalbumin content in the yellow fever vaccine. J Allergy Clin Immunol Pract 2015;3(5):794-795.
Egg hypersensitivity is listed as a contraindication to the receipt of yellow fever vaccine as it is propagated in hen’s eggs, though the ovalbumin content is unknown. The authors tested four lots of the vaccine manufactured in the United States revealing different concentrations of ovalbumin in each lot (2.43-4.42 mcg/mL), all of which were higher than those concentrations contained in influenza vaccines. The authors concluded that skin testing should be performed in patients with egg allergy prior to yellow fever vaccination, as those with a positive skin test should receive the vaccine in graded doses under the close observation of a medical professional trained to recognize and treat anaphylaxis.

Rutkowski K, Ewan PW, Nasser SM. Administration of yellow fever vaccine in patients with egg allergy. Int Arch Allergy Immunol 2013;161:274-278.
Yellow fever vaccine has an anaphylaxis rate that ranges from 0.42 to 1.8 per 100,000 doses with most cases considered to be due to egg allergy. Six subjects with an egg allergy were successfully vaccinated, including four who completed a desensitization. No systemic adverse reactions occurred.

For a scientific overview of this topic, please visit the Vaccine Ingredients – Formaldehyde section of our website.

Mitkus RJ, Hess MA, Schwartz SL. Pharmacokinetic modeling as an approach to assessing the safety of residual formaldehyde in infant vaccines. Vaccine 2013;31:2738-2743. 
The authors estimated the levels of formaldehyde in blood and total body water following exposure to formaldehyde-containing vaccines and compared them with endogenous background levels. (Formaldehyde is a natural product of single-carbon metabolism.) Following a single intramuscular dose of 200 micrograms of formaldehyde, which is equivalent to the amount of formaldehyde received from DTaP, Hib, IPV, and hepatitis B at a single office visit, formaldehyde was completely removed from the site of injection within 30 minutes. Peak concentrations of formaldehyde in blood were estimated to be less than 1 percent of the level of formaldehyde naturally produced by the body. The authors concluded that formaldehyde in vaccines continues is safe.

For a scientific overview of this topic, please visit the Vaccines and Other Conditions – GBS section of our website.

Frisch M, Besson A, Clemmensen KKB, Valentiner-Branth P, Molbak K, et al. Quadrivalent human papillomavirus vaccination in boys and risk of autoimmune diseases, neurological diseases and venous thromboembolism. International Journal of Epidemiology 2018;47(2):634-641.
The authors investigated the association of quadrivalent HPV (qHPV) vaccination and the risk of 39 autoimmune diseases, 12 neurological diseases, or venous thromboembolism over a 10-year period in more than 7,000 Danish boys who received at least one dose of qHPV vaccination at the age of 10 to 17 years by comparing them to more than 560,000 boys who did not receive the vaccine. Receipt of qHPV in boys aged 10-17 years was not associated with an elevated risk of autoimmune diseases, venous thromboembolism, or neurological diseases including Guillain-Barré syndrome.

Grimaldi-Bensouda L, Rossignol M, Kone-Paut I, et al.  Risk of autoimmune diseases and human papilloma virus (HPV) vaccines: six years of case-referent surveillance. J Autoimmun 2017; 19:84-90.
The authors found that HPV vaccine did not increase the risk of autoimmune diseases (ADs) in females 11 to 25 years of age. ADs included central demyelination, multiple sclerosis, connective tissue disease, Guillain-Barre syndrome, type 1 diabetes, autoimmune thyroiditis, and idiopathic thrombocytopenic purpura. 

Andrews N, Stowe J, Miller E. No increased risk of Guillain-Barre syndrome after human papilloma virus vaccine: a self-controlled case-series study in England. Vaccine 2017;35:1729-1732.
The authors found no evidence of an increased risk of GBS following HPV vaccination in females ages 11 to 20 years in the United Kingdom, including no differences in risks following administration of either the bivalent or quadrivalent vaccines.

Gee J, Sukumaran L, Weintraub E, the Vaccine Safety Datalink Team. Risk of Guillain-Barre Syndrome following quadrivalent human papillomavirus vaccine in the Vaccine Safety Datalink. Vaccine 2017;35:5756-5758.
The Vaccine Safety Datalink (VSD) was utilized to conduct a rapid-cycle analysis to monitor the safety of the quadrivalent HPV vaccine (4vHPV) in real-time from August 2006 through October 2009. No cases of GBS were detected following administration of more than 600,000 doses among females 9 to 26 years of age. As GBS is rare, and the power to detect a risk is limited, VSD continued long-term surveillance from 2006 through 2015 in both males and females, following more than 2.7 million doses to determine the risk of GBS after receipt of 4vHPV. The rate of confirmed GBS within 42 days of vaccination was 0.36 cases per million vaccine doses, which was less than the published background rate in the general population of persons aged 11 to 18 years.

Martin Arias LH, Sanz R, Sainz M, Treceno C, Carvajal A. Guillain-Barre syndrome and influenza vaccines: a meta-analysis. Vaccine 2015;33:3773-3778.
The authors performed a meta-analysis of studies published between 1981 and 2014 to determine the risk of GBS following influenza vaccination. They found the receipt of any influenza vaccine (seasonal or pandemic) increased the risk of GBS by 1.4 (relative risk = 1.41). The RR of 1.41 is probably a reasonable average of the short-term (within 42 days) increased risk of GBS following influenza vaccination. An increased risk has been highly variable, detected in some seasons and not in others. In the seasons when an increased risk has been found, the relative risks have been around 2, which translates to an attributable risk of one additional case of GBS per million vaccinees. Of course, this just accounts for the risk side of the equation. Influenza infection is a stronger risk factor for GBS than is influenza vaccine; thus, during an entire influenza season, influenza vaccine actually decreases the risk of GBS by protecting against influenza infection.

Vellozzi C, Iqbal S, Stewart B, Tokars J, DeStefano F. Cumulative risk of Guillain-Barre syndrome among vaccinated and unvaccinated populations during the 2009 H1N1 influenza pandemic. Am J Public Health 2014;104:696-701.
The authors investigated the relative risk of GBS among 45 million people immunized with the influenza A (H1N1) 2009 monovalent vaccine. They found that by the end of the influenza season the vaccinated population had a lower cumulative risk of GBS compared with the unvaccinated population, indicating that vaccination by preventing influenza infection may have a potential protective effect on GBS.

Kwong JC, Vasa PP, Campitelli MA, Hawken S, Wilson K, et al. Risk of Guillain-Barre syndrome after seasonal influenza vaccination and influenza health-care encounters: a self-controlled study. Lancet Infect Dis 2013;13:769-776.
The authors assessed the risk of GBS after influenza infection or vaccination in Ontario, Canada, between 1993 and 2011. They found that the risk of GBS within six weeks of an influenza infection was greater than that following vaccination. The authors identified one GBS admission per million vaccinations compared with 17 GBS admissions per million cases of influenza infection.

Baxter R, Bakshi N, Fireman B, Lewis E, Ray P, et al. Lack of association of Guillain-Barre Syndrome with vaccinations. CID 2013;57(2):197-204.
The authors assessed the risk of GBS after vaccination with polio, MMR, conjugated pneumococcal, varicella, Haemophilus influenzae type b, rabies, influenza, any tetanus diphtheria combination, hepatitis A, or hepatitis B during a 13-year period and more than 30 million person-years. The authors did not find evidence of an increased risk of GBS following vaccination of any kind. Another important finding of this study was that recurrence of GBS following vaccination was extremely rare.

Greene SK, Rett MD, Vellozzi C, Li L, Kulldorff M, et al. Guillain-Barre Syndrome, influenza vaccination, and antecedent respiratory and gastrointestinal infections: a case-centered analysis in the Vaccine Safety Datalink, 2009-2011. PLoS ONE 2013;8(6):e67185.
The Vaccine Safety Datalink (VSD) team previously found GBS was significantly associated with monovalent inactivated (MIV) but not seasonal trivalent inactivated (TIV) influenza A (H1N1) vaccines during the 2009-10 influenza season, though results were possibly confounded by antecedent infections (see Greene SK, et al, 2012 above). In this follow-up study, the authors estimated the association between GBS and receipt of either 2009-10 MIV or 2010-11 TIV vaccines. They found that after adjusting for antecedent infections, there was no evidence for an elevated GBS risk following 1.27 million 2009-10 MIV or 2.8 million 2010-11 TIV doses.

Salmon DA, Proschan M, Forshee R, Garguillo P, Bleser W, et al.  Association between Guillain-Barre syndrome and influenza A (H1N1) 2009 monovalent inactivated vaccines in the USA: a meta-analysis. Lancet 2013;381:1461-1468.
The authors conducted a meta-analysis of data from six adverse-event-monitoring systems encompassing 23 million people vaccinated in the United States with monovalent influenza vaccine (MIV) to determine the risk of GBS. They found the 2009 H1N1 MIVs were associated with a small increased risk of GBS, which translated to about 1.6 excess cases of GBS per million people vaccinated. The authors also noted that the H1N1 disease peaked around the same time the H1N1 vaccine was administered, which likely confounded study findings.

Greene SK, Rett M, Weintraub ES, Li L, Yin R, et al. Risk of confirmed Guillain-Barre Syndrome following receipt of monovalent inactivated influenza A (H1N1) and seasonal influenza vaccines in the Vaccine Safety Datalink Project, 2009-2010. Am J Epidemiol 2012;175:1100-1109.
The Vaccine Safety Datalink (VSD) team determined the risk of GBS following receipt of monovalent inactivated (MIV) and seasonal trivalent inactivated (TIV) influenza A (H1N1) vaccines during the 2009-10 influenza season. The authors found GBS risk was significantly associated with MIV but not TIV within six weeks of vaccine receipt, though a causal association could not be proven as approximately half of the patients who received MIV also had an antecedent respiratory infection within one month of vaccination. Additionally, MIV became available at the same time as the peak of influenza activity during the 2009 H1N1 pandemic, while TIV preceded this peak.

Velentgas P, Amato AA, Bohn RL, Chan KA, Cochrane T, et al. Risk of Guillain-Barre syndrome after meningococcal conjugate vaccination. Pharmacoepidemiol Drug Saf 2012;21:1350-1358.
The authors identified no cases of GBS following receipt of more than 1.4 million doses of the meningococcal conjugate vaccine (MCV4) during a three-year period in the United States. The authors found that MCV4 vaccination was not associated with an increased risk of GBS.

Esteghamati A, Gouya MM, Keshtkar AA, Mahoney F. Relationship between occurrence of Guillain-Barre syndrome and mass campaign of measles and rubella immunization in Iranian 5-14 years old children. Vaccine 2008;26:5058-5061.
The authors investigated the occurrence of GBS after a four-week national immunization campaign in Iran in 2003 where 98 percent of the target population was vaccinated with measles vaccine, rubella vaccine, or both. Similar to other studies, the annual incidence of GBS remained relatively constant during the three-year period following vaccination, indicating that neither measles nor rubella vaccines were causally associated with GBS.

Patja A, Paunio M, Kinnunen E, Junttila O, Hovi T, et al.  Risk of Guillain-Barre syndrome after measles-mumps-rubella vaccination. J Pediatr 2001;138:250-254.
The authors found that the incidence of GBS following MMR vaccine was no higher than that previously reported in unvaccinated patients; they also found no clustering of cases of GBS at any time after vaccination. Additionally, MMR vaccination after recovery from GBS did not cause a relapse of the illness.Chronic Fatigue

For a scientific overview of this topic, please visit the A Look at Each Vaccine – Human Papillomavirus Vaccine section of our website. For answers to more than 80 questions about HPV infection, testing, treatment, and vaccine, visit our Prevent-HPV.org page.

HPV vaccine and autoimmune diseases

Jiang H-y, Shi, Y-d, Zhang X, et al. Human papillomavirus vaccination and the risk of autoimmune disorders: A systematic review and meta-analysis. Vaccine 2019;37:3031-3039.
Of 541 papers located, 137 were reviewed and 20 met all inclusion criteria. Five of 20 were determined to be of “low quality” based on their lack of scientific rigor. Researchers determined that the HPV vaccine did not cause increases in autoimmune disorders, including several neurological, gastrointestinal, musculoskeletal or systemic, hematological or dermatological disorders. Nor did the vaccine cause type 1 diabetes or thyroid disorders.

Bi D, Apter D, Eriksson T, Hokkanen M, Zima J, et al. Safety of the AS04-adjuvanted human papillomavirus (HPV)-16/18 vaccine in adolescents aged 12-15 years: end-of-study results from a community-randomized study up to 6.5 years. Human Vaccines and Immunotherapy 2019;12:1-12 (epub ahead of print).
In this randomized study, the authors evaluated the efficacy and safety of an adjuvanted-HPV 16/18 vaccine in more than 32,000 Finnish adolescent males and females over a 6.5-year period by comparing those who received HPV vaccine to those who received hepatitis B vaccine. The HPV vaccine adjuvant was composed of monophosphoryl-lipid A plus aluminum salts. The incidence of new-onset autoimmune diseases was similar in both vaccine groups. Similarly, those receiving HPV vaccine during pregnancy did not have an increased risk for spontaneous abortion or congenital anomalies.

Frisch M, Besson A, Clemmensen KKB, Valentiner-Branth P, Molbak K, et al. Quadrivalent human papillomavirus vaccination in boys and risk of autoimmune diseases, neurological diseases and venous thromboembolism. International Journal of Epidemiology 2018;47(2):634-641.
The authors investigated the association of quadrivalent HPV (qHPV) vaccination and the risk of 39 autoimmune diseases, 12 neurological diseases, or venous thromboembolism over a 10-year period in more than 7,000 Danish boys who received at least one dose of qHPV vaccination at the age of 10 to 17 years by comparing them to more than 560,000 boys who did not receive the vaccine. Receipt of qHPV in boys aged 10-17 years was not associated with an elevated risk of autoimmune diseases, neurological diseases, or venous thromboembolism.

Liu EY, Smith LM, Ellis A, Whitaker H, Law B, et al. Quadrivalent human papilloma virus vaccination in girls and the risk of autoimmune disorders: the Ontario Grade 8 HPV vaccine cohort study. Canadian Medical Association Journal 2018;190:E648-655.
The authors assessed the risk of autoimmune disorders following quadrivalent HPV (qHPV) vaccine among more than 290,000 eighth-grade girls eligible for Ontario’s school-based HPV vaccination program. There was no significant risk for developing an autoimmune disorder following HPV vaccination and the association was unchanged by a history of immune-mediated disorders and time since vaccination.

Grimaldi-Bensouda L, Rossignol M, Kone-Paut I, et al. Risk of autoimmune diseases and human papilloma virus (HPV) vaccines: six years of case-referent surveillance. Journal of Autoimmunity 2017; 19:84-90.
The authors found that HPV vaccine did not increase the risk of autoimmune diseases in females 11 to 25 years of age. Autoimmune diseases included central demyelination, multiple sclerosis, connective tissue disease, Guillain-Barré syndrome, type 1 diabetes, autoimmune thyroiditis, and idiopathic thrombocytopenic purpura.

Gronlund O, Herweijer E, Sundstrom K, et al. Incidence of new-onset autoimmune disease in girls and women with pre-existing autoimmune disease after quadrivalent human papillomavirus vaccination: a cohort study. Journal of Internal Medicine 2016;280:618-626.
The authors assessed whether HPV vaccination was associated with an increased incidence of new-onset autoimmune disease in more than 70,000 girls and women (10-30 years of age) with pre-existing autoimmune diseases. They found that HPV vaccination did not increase the risk of other autoimmune diseases in this patient population.

Grimaldi-Bensouda L, Guillemot D, Godeau B, et al. Autoimmune disorders and quadrivalent human papillomavirus vaccination of young female subjects. Journal of Internal Medicine 2014;275(4): 398-408.  
The authors reviewed the records of female patients 14-26 years of age to determine if the HPV vaccine increased the risk of autoimmune disorders. HPV vaccine did not increase the risk of type 1 diabetes, idiopathic thrombocytopenic purpura, multiple sclerosis, Guillain-Barré syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, juvenile arthritis, or autoimmune thyroiditis.

Arnheim-Dahlstrom L, Pasternak B, Svanstrom H, Sparen P, Hviid A. Autoimmune, neurological, and venous thromboembolic adverse events after immunisation of adolescent girls with quadrivalent human papillomavirus vaccine in Denmark and Sweden: cohort study. British Medical Journal 2013;347:f5906.
The authors assessed the risk of serious adverse events after vaccination of approximately 300,000 girls ages 10-17 years with quadrivalent HPV vaccine during a four-year period. The authors found no association between exposure to quadrivalent HPV vaccine and autoimmune, neurological or venous thromboembolic adverse events.

HPV vaccine and chronic fatigue syndrome (CFS)/systemic exertion intolerance disease (SEID)

Schurink-van’t Klooster TM, Kemmeren JM, van der Maas NAT, van de Putte EM, ter Wolbeek M, et al. No evidence found for an increased risk of long-term fatigue following human papillomavirus vaccination of adolescent girls. Vaccine 2018;36:6796-6802.
The Dutch National Institute for Public Health and the Environment investigated the relationship between HPV vaccination and chronic fatigue syndrome (CFS). Investigators compared the incidence of CFS before and after HPV vaccine administration among nearly 70,000 females during a six-year period.  HPV vaccine receipt was not associated with an increased incidence of CFS. Further, the incidence of CFS did not differ before and after the introduction of HPV vaccine.

Skufca J, Ollgren J, Artama M, Ruokokoski E, Nohynek H, et al. The association of adverse events with bivalent human papillomavirus vaccination: a nationwide register-based cohort study in Finland. Vaccine 2018;36:5926-5933.
The authors evaluated the association between bivalent HPV vaccine (Cervarix^®) and 65 selected autoimmune diseases and clinical syndromes during a three-year period in Finland among females ages 11-15 years. The authors reported a lower incidence of chronic recurrent pain syndrome (CRPS) and systemic exertion intolerance disease (SEID) in females who received the bivalent HPV vaccine compared with those who did not. The authors reported an increased incidence of CRPS/SEID diagnoses in the post-HPV vaccination era compared to the pre-HPV era; however, this same increased incidence was also observed in the male population who did not receive bivalent HPV vaccination. 

Feiring B, Laake I, Bakken IJ, Greve-Isdahl M, Wyller VB, et al. HPV vaccination and risk of chronic fatigue syndrome/myalgic encephalomyelitis: a nationwide register-based study from Norway. Vaccine 2017;35:4203-4212.
The authors investigated the association between HPV vaccination and risk of chronic fatigue syndrome (CFS), myalgic encephalomyelitis (ME) in more than 175,000 females ages 10-17 years living in Norway during a six-year period. HPV vaccination was not associated with CFS/ME at any time following vaccination. The authors observed an increase in the incidence of CFS/ME within the Norwegian population; however, this increase was similar among girls and unvaccinated boys. 

Donegan K, Beau-Lejdstrom R, King B, Seabroke S, Thomson A, et al. Bivalent human papillomavirus vaccine and the risk of fatigue syndromes in girls in the UK. Vaccine 2013;31:4961-4967.
The authors compared the incidence of fatigue syndromes in girls before and after the start of an HPV vaccination campaign that included at least 1.5 million girls receiving at least one dose. The number of spontaneous chronic fatigue reports following the use of bivalent HPV vaccine was consistent with estimated background rates. The incidence of fatigue syndromes in girls aged 12-20 years did not change after the introduction of the vaccine.

Human papillomavirus (HPV) vaccine and chronic regional pain syndromes (CRPS)

Arana JE, Harrington T, Cano M, Lewis P, Mba-Jonas A, et al. Post-licensure safety monitoring of quadrivalent human papillomavirus vaccine in the Vaccine Adverse Event Reporting System (VAERS), 2009-2015. Vaccine 2018;36:1781-1788.
The authors reviewed reports to VAERS between 2009 and 2015 in females and males aged 9-26 years who received quadrivalent HPV vaccination. More than 60 million doses of quadrivalent HPV vaccine had been distributed during this time period in the United States. The authors concluded that they did not observe any unusual or unexpected patterns of reporting of CRPS, but noted a lack of consistency in the diagnostic criteria used by healthcare providers.

Skufca J, Ollgren J, Artama M, Ruokokoski E, Nohynek H, et al. The association of adverse events with bivalent human papillomavirus vaccination: a nationwide register-based cohort study in Finland. Vaccine 2018;36:5926-5933.
The authors evaluated the association between bivalent HPV vaccine and 65 selected autoimmune diseases and clinical syndromes over a three-year period in Finland among females aged 11-15 years. The authors found no increased incidence of complex regional pain syndrome (CRPS) in those who were vaccinated with bivalent HPV vaccine versus those who did not receive the vaccine. Additionally, the authors found no increase in the incidence of CRPS in the pre- vs. post-HPV vaccine era.

Moreira Jr ED, Block SL, Ferris D, Giuliano AR, Iversen OE, et al. Safety profile of the 9-valent HPV vaccine: a combined analysis of 7 phase III clinical trials. Pediatrics 2016;138(2):e20154387.
The authors investigated the safety profile of the 9-valent human papillomavirus (9vHPV) vaccine in seven phase III studies conducted in more than 15,000 males and females aged 9 to 26 years. The authors found only two reported cases of CRPS, both of which were attributed to a previous injury.

European Medicines Agency. Pharmacovigilance Risk Assessment Committee. Assessment Report. Review under Article 20 of Regulation (EC) No 726/2004 [Internet]. Human Papillomavirus (HPV) vaccines. London: EMA;2015 Nov 11 [cited 2019 Mar 1]. Available from: https://www.ema.europa.eu/en/documents/referral/hpv-vaccines-article-20-procedure-assessment-report_en.pdf
The Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA), in response to a request from Denmark, performed an in-depth review of the safety of HPV vaccine regarding complex regional pain syndrome (CRPS) and postural orthostatic tachycardia syndrome (POTS). The PRAC concluded that the available evidence does not support that CRPS or POTS are caused by HPV vaccines.

Huygen F, Verschueren K, McCabe C, Stegmann JU, Zima J, et al.  Investigating reports of complex regional pain syndrome: an analysis of HPV-16/18-adjuvanted vaccine post-licensure data. EBioMedicine 2015;2:1114-1121.
The authors investigated a potential safety signal for CRPS related to HPV-16/18-adjuvanted vaccine by reviewing six years of spontaneous reports of CRPS within GlaxoSmithKline’s central worldwide safety database in addition to a full literature review. Globally, only five cases of CRPS were confirmed by independent experts, for a reporting rate of 0.1 cases per 100,000 doses distributed. Observed CRPS incidence after HPV-16/18-adjuvanted vaccine was significantly below expected rates in the general population. No reports of CRPS were identified from clinical trials. The authors concluded there is not sufficient evidence to suggest an increased risk of developing CRPS following vaccination with HPV-16/18-adjuvanted vaccine.

HPV vaccine and postural orthostatic tachycardia syndrome (POTS)

Skufca J, Ollgren J, Artama M, Ruokokoski E, Nohynek H, et al. The association of adverse events with bivalent human papillomavirus vaccination: a nationwide register-based cohort study in Finland. Vaccine 2018;36:5926-5933.
The authors evaluated the relationship between receipt of a bivalent HPV vaccine (Cervarix^®) and 65 selected autoimmune diseases during a three-year period in Finland among females ages 11-15 years. The authors found no increased incidence of POTS in those who were vaccinated compared with those who weren’t. Additionally, the authors found no increase in the incidence of POTS when comparing the pre- and post-HPV vaccine era. 

Arana J, Mba-Jonas A, Jankosky C, Lewis P, Moro PL, et al. Reports of postural orthostatic tachycardia syndrome after human papillomavirus vaccination in the Vaccine Adverse Event Reporting System. J Adol Health 2017;61:577-582.
The authors reviewed postural orthostatic tachycardia syndrome (POTS) reports submitted to VAERS following HPV vaccination. Worldwide, more than 200 million doses of HPV vaccine were distributed during the nine-year period and 29 reports met POTS criteria. Within the United States, nearly 85 million HPV vaccine doses were distributed during this same time frame and 13 reports met POTS criteria, with an estimated rate of 1 POTS report for every 6.5 million HPV doses distributed. The authors found no evidence to suggest a safety problem with POTS following HPV vaccination.

European Medicines Agency. Pharmacovigilance Risk Assessment Committee. Assessment Report. Review under Article 20 of Regulation (EC) No 726/2004 [Internet]. Human Papillomavirus (HPV) vaccines. London: EMA;2015 Nov 11 [cited 2019 Mar 1].
The Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) was charged with performing an in-depth review of the safety of HPV vaccine related to complex regional pain syndrome (CRPS) and postural orthostatic tachycardia syndrome (POTS) after Denmark had requested an investigation. The PRAC found that report of POTS cases following HPV vaccines were not greater than would have been expected in the absence of vaccination, supporting the notion that HPV vaccine does not cause POTS.

HPV vaccine and primary ovarian failure

Arana JE, Harrington T, Cano M, Lewis P, Mba-Jonas A, et al. Post-licensure safety monitoring of quadrivalent human papillomavirus vaccine in the Vaccine Adverse Event Reporting System (VAERS), 2009-2015. Vaccine 2018;36:1781-1788.
The authors evaluated reports to the Vaccine Adverse Events Reporting System (VAERS) between 2009 and 2015 in females and males aged 9-26 years who received quadrivalent HPV vaccination. More than 60 million doses of quadrivalent HPV vaccine were distributed during this time frame in the United States. Only two cases of physician-diagnosed primary ovarian insufficiency after quadrivalent HPV vaccination were reported, both in patients with a history of amenorrhea.

Naleway AL, Mittendorf KF, Irving SA, Henninger ML, Crane B, et al. Primary ovarian insufficiency and adolescent vaccination. Pediatrics 2018;142(3):e20180943.
The authors evaluated the incidence of primary ovarian insufficiency (POI) following HPV vaccination, as well as Tdap, MenACWY, and inactivated influenza vaccines, within the Kaiser Permanente Northwest database (United States) during an eight-year period. About 200,000 females were evaluated, including 60,000 who had received at least one dose of HPV vaccine. Only one confirmed case of POI was identified in a patient 23 months after her third dose of HPV vaccine. The authors found no increased risk of primary ovarian insufficiency after HPV vaccination or any other adolescent vaccination.

HPV vaccine and promiscuity

Chua GT, Ho FK, Tung KT, Wong RS, Cheong KN, et al. Sexual behaviors and intention for cervical screening among HPV-vaccinated young Chinese females. Vaccine 2019;pii: S0264-410X(19)31573-7. (epub ahead of print).
In this survey of Chinese females aged 12-27 years, receipt of at least one dose of HPV vaccine was not associated with underage sex, earlier sexual exposure, multiple sex partners or unprotected sex.

Cook EE, Venkataramani AS, Kim JJ, Tamimi RM, Holmes MD. Legislation to increase uptake of HPV vaccination and adolescent sexual behaviors. Pediatrics 2018;142(3):e20180458.
The authors compared the rates of sexual intercourse before and after the implementation of state laws regarding HPV vaccine. They found that implementation of HPV legislation was not associated with changes in adolescent sexual behaviors in the United States. 

Smith LM, Kaufman JS, Strumpf EC, Lévesque LE. Effect of human papillomavirus (HPV) vaccination on clinical indicators of sexual behaviour among adolescent girls: the Ontario Grade 8 HPV Vaccine Cohort Study. CMAJ 2015;187(2):E74-E81.  
The authors determined the effect of HPV vaccination on sexual behavior, including pregnancy and non-HPV-related sexually transmitted infections, in more than 260,000 adolescent girls in Ontario. They found that neither HPV vaccination nor HPV-vaccination program eligibility increased the risk of pregnancy or non-HPV-related sexually transmitted infections or both among females aged 14-17 years. 

Mayhew A, Kowalczyk Mullins TL, Rosenthal SL, Zimet GD, Morrow C, et al. Risk perceptions and subsequent sexual behaviors after HPV vaccination in adolescents. Pediatrics 2014;133:404-411.
The authors determined whether sexual risk perceptions after the first HPV vaccine dose predicted subsequent sexual behaviors. Risk perceptions included perceived risk of non-HPV-related sexually transmitted infections and perceived need for safer sexual behaviors after HPV vaccination. Nearly half of all participants were sexually inexperienced; risk perceptions within this group were not associated with subsequent sexual intercourse. Among all sexually experienced participants, baseline risk perceptions were not associated with the subsequent number of sexual partners or condom use. The authors concluded that HPV vaccination does not change sexual behaviors among adolescents.

Bednarczyk RA, Davis R, Ault K, Orenstein W, Omer SB. Sexual activity-related outcomes after human papillomavirus vaccination of 11- to 12-year-olds. Pediatrics 2012;130(5):798-805.
The authors evaluated changes in the rates of sexual activity-related outcomes, including sexually transmitted infection testing or diagnosis, pregnancy testing or diagnosis, or counseling on contraceptives, in females who received HPV vaccination at the age of 11-12 years compared to similarly aged girls who did not receive the vaccine. There was no increased in the rate of sexual activity indicators in vaccinated versus unvaccinated females.

HPV vaccine and venous thromboembolism (VTE, blood clots)

Frisch M, Besson A, Clemmensen KKB, Valentiner-Branth P, Molbak K, et al. Quadrivalent human papillomavirus vaccination in boys and risk of autoimmune diseases, neurological diseases and venous thromboembolism. International Journal of Epidemiology 2018;47(2):634-641.
The authors investigated the association of quadrivalent HPV (qHPV) vaccination and the risk of 39 autoimmune diseases, 12 neurological diseases, or venous thromboembolism over a 10-year period in more than 7,000 Danish boys who received at least one dose of qHPV vaccination at the age of 10 to 17 years by comparing them to more than 560,000 boys who did not receive the vaccine. Receipt of qHPV in boys aged 10-17 years was not associated with an elevated risk of autoimmune diseases, neurological diseases, or venous thromboembolism.

Skufca J, Ollgren J, Artama M, Ruokokoski E, Nohynek H, et al. The association of adverse events with bivalent human papillomavirus vaccination: a nationwide register-based cohort study in Finland. Vaccine 2018;36:5926-5933.
The authors evaluated the association between bivalent HPV vaccine (Cervarix^®) and 65 selected autoimmune diseases and clinical syndromes over a three-year period in Finland among females aged 11-15 years. The incidence of venous thromboembolism (VTE) was indistinguishable between those who received bivalent HPV and those who did not. Further, incidence of VTE in the pre- and post-bivalent HPV era was the same. 

Naleway AL, Crane B, Smith N, Daley MF, Donahue J, et al. Absence of venous thromboembolism risk following quadrivalent human papillomavirus vaccination. Vaccine Safety Datalink, 2008-2011. Vaccine 2016;34:167-171.
The authors evaluated the risk of developing VTE among 9- to 26-year-old male and female subjects following quadrivalent HPV vaccine exposure. More than 1.24 million doses were administered to more than 650,000 persons during a three-year period. The authors did not find an increased risk of VTE after quadrivalent HPV vaccine receipt, and no temporal relationship was observed when different exposure periods or different age categories were analyzed. Almost all confirmed VTE cases (97 percent) had at least one known risk factor for VTE, and nearly half had three or more risk factors such as hormonal contraceptive use, obesity and hypercoagulability. The authors concluded that the risk of developing VTE among 9- to 26-year-olds was not elevated following quadrivalent HPV vaccination.

Yih Wk, Greene SK, Zichittella L, Kulldorff M, Baker MA, et al. Evaluation of the risk of venous thromboembolism after quadrivalent human papillomavirus vaccination among US females. Vaccine 2016;34:172-178.
The authors evaluated the risk of developing VTE among 9- to 26-year-old females following quadrivalent HPV vaccine. More than 1.4 million doses of vaccine were administered to more than 650,000 subjects during a seven-year period. The authors found no evidence for an increased risk of VTE, even when accounting for hormonal contraceptive use, age, VTE risk factors, and number of doses of HPV vaccines. All confirmed VTE cases had between 1 and 5 risk factors for VTE.

Scheller NM, Pasternak B, Svanstrom H, Hviid A. Quadrivalent human papillomavirus vaccine and the risk of venous thromboembolism. JAMA 2014;312(2):187-188.
The authors investigated the potential association of VTE and HPV vaccination during a seven-year period in more than 1.6 million Danish females 10 to 44 years of age, including more than 500,000 HPV vaccine recipients. No association was observed between receipt of quadrivalent HPV vaccine and VTE during the 42 days following vaccination, even when divided into shorter time periods (e.g., 1-14, 15-28, and 29-42 days) or when analyzed by age subgroup, inclusion of only anticoagulant-treated cases, inclusion of only HPV vaccine-exposed cases, or adjusting for oral contraceptive use. The authors concluded that receipt of quadrivalent HPV vaccine did not increase the risk of VTE.

Arnheim-Dahlstrom L, Pasternak B, Svanstrom H, Sparen P, Hviid A. Autoimmune, neurological, and venous thromboembolic adverse events after immunisation of adolescent girls with quadrivalent human papillomavirus vaccine in Denmark and Sweden: cohort study.  BMJ 2013;347:f5906.
The authors assessed the risk of serious adverse events after vaccination of approximately 300,000 girls ages 10-17 years with quadrivalent HPV vaccine during a 4-year period.  The authors found no association between exposure to quadrivalent HPV vaccine and development of VTE.

Gee J, Naleway A, Shui I, Baggs J, Yin R, et al. Monitoring the safety of quadrivalent human papillomavirus vaccine: findings from the Vaccine Safety Datalink. Vaccine 2011;29:8279-8284.
The authors investigated whether quadrivalent HPV vaccine was associated with an increased risk of 9 pre-specified adverse events, including VTE, in females 9-26 years of age over a 3-year period by comparing vaccinated females to unvaccinated historical controls.  More than 600,000 doses were administered during this time and 5 subjects were found to have a confirmed diagnosis of VTE, all of whom had other risk factors such as hypercoagulable disorders, hormonal contraceptive use, smoking or obesity or both. The authors concluded that HPV vaccination did not increase the risk of VTE. 

For a scientific overview of this topic, please visit the Vaccines and Multiple Sclerosis section of our website.

Hepatitis B vaccine and MS

Mouchet J, Salvo F, Raschi E, et al. Hepatitis B vaccination and the putative risk of central demyelinating diseases—A systematic review and meta-analysis. Vaccine 2018; 36:1548-1555.
The authors conducted a systematic review of the medical and scientific literature through 2017 finding no relationship between receipt of hepatitis B immunization (HBV) and development of central demyelinating diseases.

Mailand MT and JL Frederiksen. Vaccines and multiple sclerosis: a systematic review. J Neurol 2017; 264:1035-1050. 
The authors reviewed the medical literature finding no change in the risk of developing MS after vaccination against HBV, HPV, influenza, MMR, variola, tetanus, BCG, polio or diphtheria.

Langer-Gould A, Qian L, Tartof SY, et al. Vaccines and risk of multiple sclerosis and other central nervous system demyelinating diseases. JAMA 2014;71(12):1506-1513.
The authors investigated whether vaccines against hepatitis B (HBV) and human papillomavirus (HPV) increased the risk of multiple sclerosis or other acquired central nervous system demyelinating syndromes (CNS ADS), including acute disseminated encephalomyelitis (ADEM), idiopathic transverse myelitis (TM), optic neuritis (ON), and monofocal or multifocal clinically isolated syndrome (CIS). They found no associations between HBV, HPV or any vaccination and the risk of MS or CNS ADS up to three years following vaccination. An increased risk of CNS ADS was observed within 30 days after of vaccination in some younger patients; however, this association disappeared after 30 days suggesting that, at most, vaccines revealed but did not cause pre-existing autoimmunity.

Mikaeloff Y, Caridade G, Rossier M, et al. Hepatitis B vaccination and the risk of childhood-onset multiple sclerosis.  Arch Pediatr Adolesc Med 2007;161(12):1176-1182.
The authors found that hepatitis B vaccination (HBV) did not increase the risk of multiple sclerosis (MS) in childhood within the three-year study period.

Ozakbas S, Idiman E, Yulug B, et al. Development of multiple sclerosis after vaccination against hepatitis B: a study based on human leucocyte antigen haplotypes. Tissue Antigens 2006;68: 235-238.
The authors compared the clinical courses of patients who developed MS after HBV with MS patients without a history of HBV. No differences were observed in the clinical features between vaccinated and unvaccinated MS patients. The authors concluded that HBV is safe in MS patients and not involved in the development of MS.

DeStefano F, Verstraeten T, Jackson LA, et al. Vaccinations and risk of central nervous system demyelinating diseases in adults. Arch Neurol 2003; 60:504-509.
The authors evaluated the relationship between vaccination and multiple sclerosis (MS) or optic neuritis (ON) among adults 18-49 years of age within three large health maintenance organizations. They found that hepatitis B, influenza, tetanus, measles or rubella vaccines were not associated with an increased risk of MS or ON.

Ascherio A, Zhang SM, Hernan MA, et al. Hepatitis B vaccination and the risk of multiple sclerosis. N Engl J Med 2001; 344:327-332. 
The authors performed a large case-control study of nurses in the United States finding no association between HBV and the development of MS, including no correlation with total number of doses received.

Confavreux C, Suissa S, Saddier P, et al. Vaccinations and the risk of relapse in multiple sclerosis. New Engl J Med 2001; 344(5):319-326.
The authors found that tetanus, HBV, or influenza vaccination did not increase the short-term risk of relapse in patients with MS.

Sadovnick AD and DW Scheifele. School-based hepatitis B vaccination programme and adolescent multiple sclerosis. Lancet 2000;355:549-550.
The authors investigated MS in adolescents in British Columbia before and after a HBV program was initiated. They found no differences in the incidence of MS for students 11-12 years of age.

Human papillomavirus (HPV) vaccine and multiple sclerosis/central demyelinating disease

Frisch M, Besson A, Clemmensen KKB, Valentiner-Branth P, Molbak K, et al. Quadrivalent human papillomavirus vaccination in boys and risk of autoimmune diseases, neurological diseases and venous thromboembolism. International Journal of Epidemiology 2018;47(2):634-641.
The authors investigated the association of quadrivalent HPV (qHPV) vaccination and the risk of 39 autoimmune diseases, 12 neurological diseases, or venous thromboembolism over a 10-year period in more than 7,000 Danish boys who received at least one dose of qHPV vaccination at the age of 10 to 17 years by comparing them to more than 560,000 boys who did not receive the vaccine. Receipt of qHPV in boys aged 10-17 years was not associated with an elevated risk of autoimmune diseases, venous thromboembolism, or neurological diseases including multiple sclerosis, optical neuritis, transverse myelitis, and other demyelinating disorders.

Mouchet J, Salvo F, Raschi E, et al. Human papillomavirus vaccine and demyelinating diseases—a systematic review and meta-analysis. Pharmacol Res 2018;132:108-118.
The authors conducted a systematic review of all published literature through May 2017 to assess the risk of developing demyelination after HPV immunization. They found no significant association between HPV vaccination and central demyelination, multiple sclerosis, or optic neuritis.

Mailand MT and JL Frederiksen. Vaccines and multiple sclerosis: a systematic review. J Neurol 2017; 264:1035-1050. 
The authors reviewed the medical literature regarding the role of vaccines in the development of multiple sclerosis (MS) or MS relapse. They found no change in the risk of developing MS after vaccination against HBV, HPV, seasonal influenza, MMR, variola, tetanus, BCG, polio or diphtheria. No change in the risk of relapse was found following influenza vaccination.

Grimaldi-Bensouda L, Rossignol M, Kone-Paut I, et al. Risk of autoimmune diseases and human papilloma virus (HPV) vaccines: six years of case-referent surveillance. J Autoimmun 2017; 19:84-90.
The authors assessed the risk of autoimmune diseases associated with HPV vaccination of females 11-25 years of age over a 6 ½--year period. They found no association between HPV vaccination and central demyelination, multiple sclerosis, connective tissue disease, Guillain-Barré syndrome, type 1 diabetes, autoimmune thyroiditis, and idiopathic thrombocytopenic purpura. 

Dhar JP, Essenmacher L, Dhar R, et al. The safety and immunogenicity of quadrivalent HPV (qHPV) vaccine in systemic lupus erythematosus. Vaccine 2017;35:2642-2646.
The authors evaluated the safety and immunogenicity of HPV vaccine in systemic lupus erythematosus (SLE) in women aged 19-50 years with mild to moderate SLE and minimally active or inactive SLE. Nine serious adverse events occurred, though none were related to vaccine or SLE. No patients experienced an SLE flare, thrombosis, or generation of thrombogenic antibodies. The authors concluded that HPV vaccine was generally safe, well tolerated, and highly immunogenic.

Gronlund O, Herweijer E, Sundstrom K, et al. Incidence of new-onset autoimmune disease in girls and women with pre-existing autoimmune disease after quadrivalent human papillomavirus vaccination: a cohort study. J Int Med 2016;280:618-626.
The authors assessed whether HPV vaccination was associated with an increased incidence of new-onset autoimmune disease in more than 70,000 girls and women (10-30 years of age) with pre-existing autoimmune diseases. They found that HPV vaccination was not associated with new-onset autoimmune diseases in this patient population.

Scheller NM, Svanstrom H, Pasternak B, et al. Quadrivalent HPV vaccination and risk of multiple sclerosis and other demyelinating diseases of the central nervous system. JAMA 2015;313(1):54-61.
The authors investigated the association of HPV vaccination and risk of multiple sclerosis and other demyelinating diseases among females 10-44 years of age in Denmark and Sweden. Nearly 4,000,000 females were evaluated, including more than 789,000 who received HPV vaccine. The authors found no increased risk of multiple sclerosis or other demyelinating diseases such as optic neuritis, neuromyelitis optica, transverse myelitis, or acute disseminated encephalomyelitis following vaccination.

Langer-Gould A, Qian L, Tartof SY, et al. Vaccines and risk of multiple sclerosis and other central nervous system demyelinating diseases. JAMA 2014;71(12):1506-1513.
The authors investigated whether vaccines, particularly HBV and HPV, increased the risk of multiple sclerosis (MS) or other acquired central nervous system demyelinating syndromes including acute disseminated encephalomyelitis (ADEM), idiopathic transverse myelitis (TM), optic neuritis (ON), and monofocal or multifocal clinically isolated syndrome (CIS). They found no associations between HBV, HPV or any vaccination and the risk of MS or acute demyelinating syndromes up to three years later.

Flu vaccine and multiple sclerosis/CNS demyelinating diseases

Mailand MT and JL Frederiksen. Vaccines and multiple sclerosis: a systematic review. J Neurol 2017; 264:1035-1050. 
The authors reviewed the medical literature on the role of vaccines in the development of multiple sclerosis (MS) or relapse. They found no change in the risk of developing MS after vaccination against HBV, HPV, seasonal influenza, MMR, variola, tetanus, BCG, polio or diphtheria. Similarly, no change in the risk of relapse was found following immunization against influenza.

DeStefano F, Verstraeten T, Jackson LA, et al.  Vaccinations and risk of central nervous system demyelinating diseases in adults. Arch Neurol 2003;60:504-509.
The authors evaluated the association between vaccination and the onset of multiple sclerosis (MS) or optic neuritis (ON) among adults 18 to 49 years of age within three large health maintenance organizations by investigating the onset of first symptoms at any time after vaccination and during specified intervals after vaccination. They found that vaccination against hepatitis B, influenza, tetanus, measles or rubella was not associated with an increased risk of MS or ON.

Confavreux C, Suissa S, Saddier P, et al.  Vaccinations and the risk of relapse in multiple sclerosis. New Engl J Med 2001; 344(5):319-326.
The authors found that tetanus, hepatitis B, and influenza vaccines did not increase the short-term risk of relapse in adult patients with MS.

Moriabadi NF, Niewiesk S, Kruse N, Jung S, Weissbrich B, et al.  Influenza vaccination in MS: absence of T-cell response against white matter proteins. Neurol 2001; 56:938-943.
The authors examined influenza A virus-specific and myelin basic protein-specific T-cell frequencies in patients with MS and healthy controls who received influenza vaccine.  Both groups responded to the vaccine as evidenced by an antibody response, but no increase in T-cell frequencies responsive to human myelin basic protein or recombinant human myelin oligodendrocyte protein was observed after immunization. The authors concluded that these data support the clinical observations that influenza vaccination is effective and safe in patients with MS.

Miller AE, Morgante LA, Buchwald LY, Nutile SM, Coyle PK, et al.  A multicenter, randomized, double blind, placebo-controlled trial of influenza immunization in multiple sclerosis. Neurol 1997;48;312-314.
The authors determined the clinical effect of influenza vaccine in patients with relapsing/remitting MS. No differences were found between vaccine and placebo recipients in the attack rate or disease progression over 6 months. They concluded that influenza immunization in MS patients is neither associated with an increased exacerbation rate in the post-vaccination period nor with a change in disease course over the subsequent six months.

Michielsens B, Wilms G, Marchal G, Carton H. Serial magnetic resonance imaging studies with paramagnetic contrast medium: assessment of disease activity in patients with multiple sclerosis before and after influenza vaccination. Eur Neurol 1990;30(5):258-259.
The authors examined patients with a relapsing-remitting form of MS to determine if influenza vaccination affected the clinical course. Patients were examined clinically as well as with MRI scans three weeks before vaccination, the day of vaccination, and three weeks after vaccination. The authors found no exacerbations in the pre- or post-vaccination period. On MRI, a greater number of lesions appeared at the end of the pre-vaccination period as compared with post-vaccination. The authors concluded that influenza vaccine has no clinical or subclinical short-term effect on the activity of MS.

For a scientific overview of this topic, please visit the A Look at Each Vaccine: Diphtheria, Tetanus and Pertussis Vaccines page of our website.

Top KA, Brna P, Ye L, Smith B. Risk of seizures after immunization in children with epilepsy: a risk interval analysis. BMC Pediatr 2018;18:134.
The authors analyzed the risk of seizures after immunization in children with epilepsy less than 7 years of age. Nearly half of the immunization visits that occurred after epilepsy diagnosis were characterized by receipt of DTaP. The risk of seizures was not increased 0-14 days after any vaccine. The authors concluded that children with epilepsy do not appear to be at increased risk of seizures following immunization. These findings suggest that immunization is safe in children with epilepsy.

Lateef TM, Johann-Liang R, Kaulas H, Hasan R, Williams K, et al. Seizures, encephalopathy, and vaccines: experience in the National Vaccine Injury Compensation Program. J Pediatr 2015;166:576-581 
The authors described the demographic and clinical characteristics of children younger than 2 years of age for whom claims were filed with the National Vaccine Injury Compensation Program (VICP) alleging seizure disorder or encephalopathy or both during a one-year period. In 80 percent of these claims, a pertussis-containing vaccine was implicated, and four times more often related to the whole-cell pertussis vaccine. Seizure disorder was the primary condition for which compensation was sought and less than half of the claimants were known to have been febrile at the time of presentation. A significant number of children with alleged vaccine injury had pre-existing neurologic or neurodevelopmental abnormalities. Among those developing chronic epilepsy, many had clinical features suggesting that the epilepsy had a genetic basis.

Daley MF, Yih WK, Glanz JM, Hambidge SJ, Narwaney KJ, et al. Safety of diphtheria, tetanus, acellular pertussis and inactivated poliovirus (DTaP-IPV) vaccine. Vaccine 2014;32:3019-3024.
The authors examined the risk of serious, but uncommon, adverse events after receipt of DTaP-IPV in more than 200,000 children 4-6 years of age during a four-year period via the Vaccine Safety Datalink project. Receipt of DTaP-IPV did not significantly increase the risk of meningitis/encephalitis, seizures, stroke, Guillain-Barré syndrome, Stevens-Johnson syndrome, anaphylaxis, serious allergic reactions, or serious local reactions.

Sun Y, Christensen J, Hviid A, Li J, Vedsted P, et al. Risk of febrile seizures and epilepsy after vaccination with diphtheria, tetanus, acellular pertussis, inactivated poliovirus, and Haemophilus influenzae type b. JAMA 2012;307(8):823-831.
The authors evaluated the risk of febrile seizures and epilepsy in more than 300,000 children who received DTaP-IPV-Hib at ages 3, 5, and 12 months in Denmark during a six-year period. DTaP-IPV-Hib vaccination was not associated with an increased risk of febrile seizures in children within seven days following receipt of vaccine compared with those children beyond seven days of vaccination. Sub-analyses indicated an increased risk of febrile seizures on the day of the first two vaccinations, although absolute risk was small. DTaP-IPV-Hib vaccination was not associated with an increased risk of epilepsy.

Huang WT, Gargiullo PM, Broder KR, Weintraub ES, Iskander JK, et al. Lack of association between acellular pertussis vaccine and seizures in early childhood. Pediatrics 2010;126(2):e263-e269.
The authors investigated the incidence of seizures following receipt of DTaP during a 10-year period in more than 430,000 children aged 6 weeks to 23 months. They found no significant increase in the risk of seizures following receipt of DTaP.

Yih WK, Nordin JD, Kulldorff M, Lewis E, Lieu TA, et al. An assessment of the safety of adolescent and adult tetanus-diphtheria-acellular pertussis (Tdap) vaccine, using active surveillance for adverse events in the Vaccine Safety Datalink. Vaccine 2009;27:4257-4262.
The safety of Tdap was monitored weekly among subjects aged 10-64 years during 2005-2008 with specific attention to encephalopathy-encephalitis-meningitis, paralytic syndromes, seizures, cranial nerve disorders, and Guillain-Barré syndrome (GBS).  No evidence of an association between Tdap and any of these adverse events was found during a three-year-surveillance period that included more than 660,000 Tdap doses. GBS and cranial nerve sub-analyses found no statistically significant temporal clustering within 42 days after vaccination.

Ray P, Hayward J, Michelson D, Lewis E, Schwalbe J, et al. Encephalopathy after whole-cell pertussis or measles vaccination: lack of evidence for a causal association in a retrospective case-control study. Pediatr Infect Dis J 2006;25:768-773.
The authors investigated the possible relationship between whole-cell pertussis (DTP) or measles (MMR) vaccination and encephalopathy, encephalitis, and Reye syndrome by evaluating 15 years of health records from four health maintenance organizations in the United States, which encompassed nearly 2.2 million children. DTP and MMR vaccines were not associated with an increased risk of encephalopathy, encephalitis, or Reye syndrome after vaccination. Additionally, a clinically distinctive pertussis vaccine-induced encephalopathy was not detected, which was consistent with other studies.

Le Saux N, Barrowman NJ, Moore DL, Whiting S, Scheifele D, et al. Decrease in hospital admissions for febrile seizures and reports of hypotonic-hyporesponsive episodes presenting to hospital emergency departments since switching to acellular pertussis vaccine in Canada: a report from IMPACT. Pediatrics 2003;112:e348-e353.
The authors compared the incidence of hospital admissions for febrile seizures and hypotonic-hyporesponsive episodes (HHEs) presenting to hospital emergency departments before and after transition from DTP to DTaP in Canada. Hospital admissions secondary to pertussis vaccine-related febrile seizures and HHEs associated with pertussis vaccine decreased by 79 percent and 60-67 percent %, respectively.

Barlow WE, Davis RL, Glasser JW, Rhodes PH, Thompson RS, et al. The risk of seizures after receipt of whole-cell pertussis or measles, mumps and rubella vaccines. N Engl J Med 2001;345:656-661.
The authors investigated the relationship between DTP and MMR and the risk of a first seizure, subsequent seizures and neurodevelopmental disability in children. During the three-year period, more than 340,000 DTP vaccines and more than 130,000 MMR vaccines were administered. Receipt of DTP vaccine was associated with an increased risk of febrile seizures only on the day of vaccination (six to nine febrile seizures per 100,000 children vaccinated). Receipt of MMR vaccine was associated with an increased risk of febrile seizures eight to 14 days after vaccination (25-34 febrile seizures per 100,000 children vaccinated). DTP and MMR were not associated with an increased risk of non-febrile seizures. Children with febrile seizures after vaccination were not found to be at a higher risk for subsequent seizures or neurodevelopmental disabilities as compared with their unvaccinated counterparts. The authors concluded that the increased risk of febrile seizures secondary to DTP and MMR do not appear to be associated with any long-term, adverse consequences.

Goodwin J, Nash M, Gold M, Heath TC, Burgess MA. Vaccination of children following a previous hypotonic-hyporesponsive episode. J Paediatr Child Health 1999;35:549-552.
Hypotonic-hyporesponsive episodes (HHE) were once considered a contraindication to pertussis vaccination in Australia. In this study, the authors evaluated the safety of further vaccination in children who had experienced an HHE (95 percent  experienced with whole-cell pertussis and 80 percent after the first dose). Researchers found no HHE or serious reactions after subsequent DTaP, DTP, or DT. The authors concluded that previously healthy children who experience HHE reactions can safely continue standard vaccination schedules.

Vermeer-de Bondi PE, Labadie J, Rumke HC. Rate of recurrent collapse after vaccination with whole cell pertussis vaccine: follow up study. BMJ 1998;316:902-903.
The authors conducted a follow-up study of 84 children in the Netherlands with reported collapse after their first whole cell pertussis vaccination (DTP) to determine the rate of recurrence in those who received subsequent doses of DTP. None of the children had recurrent collapse, and other adverse events were only minor.

Greco D, Salmaso S, Mastrantonio P, Giuliano M, Tozzi A, et al. A controlled trial of two acellular vaccines and one whole cell vaccine against pertussis. N Engl J Med 1996;334:341-348.
The authors compared the efficacy and safety of two acellular pertussis vaccines with whole-cell pertussis and DT alone in more than 14,000 children within six to 28 weeks of life. DTwP was found to have a significantly higher rate of local and systemic reactions, including local swelling and tenderness, irritability, fever, persistent crying for ≥ 3 hours, and hypotonic/hyporesponsive episodes with those receiving DTaP. Events following receipt of DTaP were similar to the control group that received DT alone. Seizures were either infrequent or did not occur in the vaccine groups.

Gustafsson L, Hallander HO, Olin P, Reizenstein E, Storsaeter J. A controlled trial of a two-component acellular, a five-component acellular, and a whole-cell pertussis vaccine. N Engl J Med 1996;334:349-356.
The authors compared the efficacy and safety of a two-component acellular pertussis vaccine, a five-component acellular pertussis vaccine, a whole-cell pertussis and DT alone in more than 9,000 children within the first six months of life. DTP was found to have a significantly higher rate of local and systemic reactions, including protracted crying, cyanosis, fever, and local reactions compared with both DTaP vaccines and DT. DTaP rates of these events were similar to the control group who received DT alone. Seizures occurred infrequently in the 48 hours after any vaccine receipt, and rates were similar among all groups.

Rosenthal S, Chen R, Hadler S. The safety of acellular pertussis vaccine vs whole-cell pertussis vaccine. Arch Pediatr Adolesc Med 1996;150:457-460.
In December 1991, the FDA licensed the first diphtheria, tetanus toxoid, and acellular pertussis vaccine (DTaP) for use in children aged 15 months to 7 years. In this study, the authors analyzed post-marketing surveillance data submitted to the Vaccine Adverse Event Reporting System (VAERS) between late 1990 and late 1993 to determine whether serious but uncommon adverse events are less frequent after DTaP as compared with whole-cell pertussis (DTP) vaccine receipt. An estimated 27 million DTP doses (with or without Haemophilus influenzae type b vaccine) and 5 million DTaP doses were administered during this period. DTaP was associated with significantly fewer total adverse event reports, as well as significantly fewer reports of subcategory adverse events (fever, seizures or hospitalization), compared with DTP.

Gale JL, Thapa PB, Wassilak SGF, Bobo JK, Mendelman PM, et al. Risk of serious acute neurological illness after immunization with diphtheria-tetanus-pertussis vaccine. JAMA 1994;271:37-41.
The authors prospectively identified children between mid-1987 and mid-1988 in Washington and Oregon states to evaluate the association between receipt of whole-cell pertussis vaccine and serious acute neurological illness within seven days of vaccination. Among an estimated 368,000 DTP vaccines administered, no increased risk of serious acute neurological illness including complex febrile seizures, afebrile seizures, infantile spasms, or acute encephalitis/encephalopathy was detected.

Blumberg DA, Lewis K, Mink CM, Christenson PD, Chatfield P, et al. Severe reactions associated with diphtheria-tetanus-pertussis vaccine: detailed study of children with seizures, hypotonic-hyporesponsive episodes, high fevers and persistent crying. Pediatrics 1993;91:1158-1165.
The authors prospectively evaluated children in Los Angeles, California, between 1986 and 1990 to determine causes and risk factors for severe DTP reactions within 48 hours of vaccine receipt. Children with seizures had a high rate of personal and family histories of seizures, and 90 percent  had documented fevers. Persistent crying was associated with painful local reactions. Neither lymphocytosis nor hypoglycemia occurred. No biologically active pertussis toxin was found in the acute sera of children experiencing possible severe DTP reactions. As acellular pertussis vaccines have less endotoxin, which is thought to lead to febrile seizures, the authors concluded that use of acellular vaccines should lead to a reduction in DTP-related seizures due to a decrease in febrile events. Acellular pertussis vaccines also have lower local and systemic reaction rates compared with the whole cell vaccine utilized in this study; therefore, persistent crying may also be reduced.

Griffin MR, Ray WA, Mortimer EA, Fenchel GM, Schaffner W. Risk of seizures and encephalopathy after immunization with the diphtheria-tetanus-pertussis vaccine. JAMA 1990;263:1641-1645.
The authors evaluated the risk of seizures and other neurological events, including encephalopathy, following DTP immunization in Denmark in more than 38,000 children who received about 107,000 DTP immunizations in the first three years of life. The authors found no increased risk of febrile or afebrile seizures in the 0- to three-day window following immunization when compared with 30 or more days after vaccine receipt. Two cases of encephalitis were reported, but onset occurred more than two weeks after vaccine receipt.

Griffith AH. Permanent brain damage and pertussis vaccination: is the end of the saga in sight? Vaccine 1989;7:199-210.
The author provides an overview of the pertussis vaccine and controversies surrounding its possible link to permanent brain damage.  Reports of permanent brain damage thought secondary to receipt of the pertussis vaccine were published in the 1950s through 1970s. Most notably, a case series suggesting permanent brain damage secondary to pertussis vaccination out of the National Hospital for Sick Children by Kulenkampff and colleagues was the subject of a United Kingdom television documentary in 1974 that resulted in a significant decline in vaccination rates and a consequent resurgence of pertussis in England. Repercussions from this documentary in the UK included the establishment of expert panels and sponsored research teams by the Department of Health and Social Security to examine existing clinical data and to carry out prospective studies including the North West Thames study (see Pollock, et al, Lancet 1983 data reported below) and the National Childhood Encephalopathy Study (NCES).

The NCES evaluated reported cases of defined serious neurological disorders arising in children between 2 and 36 months of age admitted to the hospital between mid-1976 and mid-1979 in the UK. These researchers estimated the attributable risk of neurological damage after pertussis immunization to be 1 in 310,000-330,000 injections, but the report was limited by certain structural biases and incomplete information; furthermore, these results could not be reproduced in subsequent studies.

The Kulenkampff and NCES data were reexamined in the High Court of Justice, London, in the wake of neurologic damage claims brought to the court. Regarding the Kulenkampff data, more than half of the cases either could not be linked to pertussis vaccination (e.g., DT given instead of DTP), had normal outcomes, or were found to have alternative causes. Reexamination of the NCES data showed

1. No previously normal child suffered permanent brain damage with an onset within 48 hours of vaccination
2. No evidence supported the notion that previously neurologically abnormal children had a greater risk than normal children of suffering an event within a short period following vaccination
3. Of the 12 previously normal cases of “serious neurological disorder” with onset within the first 48 hours, 10 were cases of febrile convulsions and those with prolonged convulsions were normal at follow-up
4. If the cases of Reye’s syndrome and of viral origin were excluded— given that they are not caused by DTP — no cases of permanent brain damage or death were linked to the vaccine
5. The figure of 1 in 310,000 or 330,000 given as the attributable risk of permanent brain damage following DTP vaccine could not be supported
6. Evidence supports that on rare occasions, DTP causes febrile convulsions

Livengood JR, Mullen JR, White JW, Brink EW, Orenstein WA. Family history of convulsions and use of pertussis vaccine. J Pediatr 1989;115:527-531.
The authors evaluated data from the CDC Monitoring System for Adverse Events Following Immunization during the period of 1979 to 1986 to determine the risk of neurologic events after vaccination with DTP in patients with a family history of convulsions compared with those without a family history. Children with a family history of seizures had an increased risk of neurologic events, primarily febrile convulsions, after DTP receipt, but this increase in risk may reflect a nonspecific familial tendency for convulsions rather than a specific vaccine effect as well as selection bias. Given the rare occurrence of neurologic events after DTP vaccination, the generally benign outcome of febrile convulsions that accounted for more than 75 percent  of the events, and the risk pertussis caused by not vaccinating people with a family history of convulsions, the authors concluded that a history of convulsions in a close relative should not be a contraindication to the pertussis vaccination. Rather, prevention of post-vaccination fever may be warranted in these children.

Baraff LJ, Shields WD, Beckwith L, Strome G, Marcy SM, et al. Infants and children with convulsions and hypotonic-hyporesponsive episodes following diphtheria-tetanus-pertussis immunization: follow up evaluation. Pediatrics 1988;81(6):789-794.
In a previous prospective study (Cody, et al Pediatrics 1981), the authors found that minor reactions (e.g., local redness, swelling, fever, etc.) were more common following DTP immunization than DT. Among more than 15,000 DTP injections, nine children developed seizures and nine developed hypotonic-hyporesponsive episodes though no sequelae were detected following these possible temporal reactions. The authors completed a follow-up evaluation six to seven years later in 16 of these children to determine if any had evidence of neurologic impairment too subtle to have been detected at the time of their initial evaluation.  All 16 children were considered to be normal by their parents and — as determined by their school performance — had no evidence of serious neurologic damage.

Shields WD, Nielsen C, Buch D Jacobsen V, Christenson P, et al. Relationship of pertussis immunization to the onset of neurologic disorders: a retrospective epidemiologic study. J Pediatr 1988;113:801-805.
The authors examined the temporal relationship between onset of neurologic disorders and the time of pertussis vaccine in children immunized with either DTP or monovalent pertussis at different ages. They found no relationship between the age of onset of epilepsy and scheduled age of administration of pertussis vaccine; however, a relationship existed between scheduled age of administration and first febrile seizure, which occurred more commonly with the third dose in the series between 10-15 months of age. No relationship between pertussis immunization and the occurrence of central nervous system infections was noted.

Walker AM, Jick H, Perera DR, Knauss TA, Thompson RS. Neurologic events following diphtheria-tetanus-pertussis immunization. Pediatrics 1988;81(3):345-349.
The authors assessed the frequency of serious neurologic events following administration of 106,000 DTP immunizations in children between 1977 and 1983. They found no cases of acute unexplained encephalopathy temporally associated with vaccination. The onset of one serious seizure disorder occurred within three days of immunization, with 1.13 cases expected on the basis of chance alone.  The incidence of recorded febrile seizures in the immediate post-immunization period was 3.7 times that in the period 30 days or more after immunization.

Bellman MH, Ross EM, Miller DL. Infantile spasms and pertussis immunisation. Lancet 1983;321(8332):1031-1034.
The authors investigated the possible role of pertussis immunization and other factors in the etiology of infantile spasms reported to the National Childhood Encephalopathy Study between 1976 and 1979 in England, Scotland and Wales. No significant association was found between infantile spasms and pertussis immunization in the 28 days following vaccination.  

Corsellis JA, Janota I, Marshall AK. Immunization against whooping cough: a neuropathological review. Neuropathol Appl Neurobiol 1983;9(4):261-270.
The authors examined published data on childhood deaths which were thought to be due to receipt of the pertussis vaccine and identified an additional 29 children in England and Wales whose deaths between 1960 and 1980 had been reported as occurring in relation to DTP and had post-mortem examinations. Deaths occurred within three weeks or up to 12 years after DTP receipt. Upon autopsy, various cerebral abnormalities were found; however, none of the cases in this study or in previous published reports had demonstrated a recurring pattern of inflammatory or other damage that could be accepted as a specific reaction to pertussis immunization. Reactive changes that were occasionally found appear to be indistinguishable from those seen in other infantile encephalopathies.

Pollock TM and J Morris. A 7-year survey of disorders attributed to vaccination in North West Thames Region. Lancet 1983;1(8327):753-757.
The authors examined the relationship between pertussis and other vaccines and neurological problems over a seven-year period. All children reported to have serious or unusual vaccine reactions, regardless of severity, had records investigated and were physically examined by an area health authority medical officer four weeks after the original report; and all children, except for those with mild symptoms, had a developmental examination six months after the report. In a group of hundreds of thousands of children and more than 400,000 DTP immunizations, 20 reports of convulsions within three weeks of DTP were reported and three-quarters of the reports were febrile seizures within 48 hours of immunization; all children were developmentally normal on follow-up. Twelve neurological disorders were reported to have occurred within eight weeks of DTP receipt; 11 of which had either infantile spasms, infectious etiology, or epilepsy, none of which were linked to DTP. The authors concluded that their study does not support the claim that DTP produces a syndrome characterized by a previously healthy child who presents with continuous screaming, collapse, convulsion and arrested mental development.

Melchior JC. Infantile spasms and early immunization against whooping cough: Danish survey from 1970 to 1975. Arch Dis Child 1977;52:134-137.
The authors examined the relationship between immunization and the onset of infantile spasms over a six-year period in Denmark after a change in its immunization program. Previously, DTP vaccine had been administered at 5, 6, and 15 months of age, but was changed in 1970 to monovalent pertussis vaccine at 5 weeks, 9 weeks, and 10 months of age. The authors found no differences in the age at onset of infantile spasms between immunized and non-immunized children; half of all cases in each group began before 5 months of age despite children immunized before 1970 not receiving the first dose until 5 months of age.

For a scientific overview of this topic, please visit the Vaccine Considerations for New and Expectant Moms page of our website.

Infections during pregnancy

Al-Haddad B, Jacobsson B, Chabra S, et al. Long-term risk of neuropsychiatric disease after exposure to infection in utero. JAMA Psychiatry. 2019 Mar 6. doi: 10.1001/jamapsychiatry2019.0029.
In 2019, researchers from the Department of Obstetrics and Gynecology at the University of Washington School of Medicine evaluated the relationship between maternal infections during hospitalization and neuropsychiatric outcome. A total of 1,791,520 Swedish children born between 1973 and 2014 were observed for up to 41 years using linked, population-based registries. Maternal infections while hospitalized during pregnancy included 1) any maternal infection, 2) severe infections such as sepsis, meningitis, encephalitis, pneumonia, influenza, pyelonephritis, or chorioamnionitis, and 3) urinary tract infections.

The authors found that any maternal infection during pregnancy significantly increased the likelihood of diagnosis of autism or depression in their offspring. No evidence was found, however, for an increase in the diagnosis of bipolar disorder or psychosis. The authors concluded “These results emphasize the importance of avoiding infections during pregnancy, which may impart subtle fetal brain injuries contributing to development of autism and depression.”

Hepatitis A vaccine

Groom HC, Smith N, Irving SA, Koppolu P, Vazquez-Benitez G, et al. Uptake and safety of hepatitis A vaccination during pregnancy: a Vaccine Safety Datalink study. Vaccine 2019;37:6648-6655.
The authors evaluated the potential association between maternal hepatitis A vaccination and maternal and infant safety outcomes in more than 1,100 women with live births over an 11-year period. Pregnancies with hepatitis A vaccine exposure were compared to those with other vaccine exposures and to those with no vaccine exposures. Approximately 70% of women received hepatitis A vaccine during the first trimester. There were no significant associations between hepatitis A vaccine exposure during pregnancy and gestational hypertension, gestational diabetes, pre-eclampsia/eclampsia, caesarian-section delivery, preterm delivery, and low birth weight. There was an association between hepatitis A vaccine receipt and delivering an infant who was small for gestational age, but this was likely due to confounding factors.

Panagiotou OA, Befano BL, Rodriguez AC, Herrero R, Schiller JT, et al. Effect of bivalent human papillomavirus vaccination on pregnancy outcomes: long term observational follow-up in the Costa Rica HPV vaccine trial. British Medical Journal 2015;351:h4358.
The authors examined the effect of the bivalent HPV vaccine on miscarriage by comparing women who received HPV vaccine versus those who received either hepatitis A vaccine or no vaccine. The three groups did not differ in their incidence of miscarriage, even after adjusting for age at vaccination and age at conception.

HPV vaccine

Bi D, Apter D, Eriksson T, Hokkanen M, Zima J, et al. Safety of the AS04-adjuvanted human papillomavirus (HPV)-16/18 vaccine in adolescents aged 12-15 years: end-of-study results from a community-randomized study up to 6.5 years. Human Vaccines and Immunotherapy 2019;12:1-12 (epub ahead of print).
In this randomized study, the authors evaluated the efficacy and safety of an adjuvanted-HPV 16/18 vaccine in more than 32,000 Finnish adolescent males and females over a 6.5-year period by comparing those who received HPV vaccine to those who received hepatitis B vaccine. The HPV vaccine adjuvant was composed of monophosphoryl-lipid A plus aluminum salts. The incidence of new-onset autoimmune diseases was similar in both vaccine groups. Similarly, those receiving HPV vaccine during pregnancy did not have an increased risk for spontaneous abortion or congenital anomalies.

Kharbanda EO, Vazquez-Benitez G, Lipkind HS, Sheth SS, Zhu J, et al. Risk of spontaneous abortion after inadvertent human papillomavirus vaccination in pregnancy. Obstet Gynecol 2018;132(1):35-44.
The authors evaluated the risk of spontaneous abortion following quadrivalent HPV vaccination given before and during pregnancy during a 7-year period. No differences in the risk of spontaneous abortion were identified when comparing those who had received vaccine 16 to 22 weeks before their last menstrual period versus those vaccinated either within 6 weeks of last menstrual period or during the first 19 weeks of pregnancy. The authors concluded that HPV vaccine did not increase the risk of spontaneous abortion in the 6 weeks preceding pregnancy or during pregnancy. 

Lipkind HS, Vazquez-Benitez G, Nordin JD, Romitti PA, Naleway AL, et al. Maternal and infant outcomes after human papillomavirus vaccination in the periconceptional period or during pregnancy. Obstet Gynecol 2017;130(3):599-608.
The authors evaluated whether quadrivalent HPV vaccine administered during the periconceptional period or during pregnancy was associated with increased risks for adverse outcomes. The authors compared outcomes between those women vaccinated two weeks before or two weeks after their last menstrual period with women who were vaccinated four to 18 months before their last menstrual period. Administration of quadrivalent HPV vaccine in the periconceptional period or during pregnancy was not associated with an increased risk of preterm delivery, small for gestational age, chorioamnionitis, hypertensive disorders of pregnancy and gestational diabetes, or more than 50 selected major structural birth defects.

Scheller NM, Pasternak B, Molgaard-Nielsen D, Svanstrom H, Hviid A. Quadrivalent HPV vaccination and the risk of adverse pregnancy outcomes. N Engl J Med 2017;376(13):1223-1233.
The authors assessed the risk of adverse pregnancy outcomes after quadrivalent HPV vaccine exposure during pregnancy in Danish women. Exposure to the quadrivalent HPV vaccine was not associated with significantly higher risks for major birth defect, spontaneous abortion, preterm birth, low birth weight, small for gestational age, or still birth.

Moreira ED, Block SL, Ferris D, Giuliano AR, Iversen OE, et al. Safety profile of the 9-valent HPV vaccine: a combined analysis of 7 phase III clinical trials. Pediatrics 2016;138(2):e20154387.
The authors evaluated the safety profile of the 9-valent HPV vaccine in seven phase III studies. Pregnancy outcomes, including those among live births through the first six weeks of life, were analyzed among nearly 3,000 pregnancies that occurred during the study period. The incidence of adverse pregnancy outcomes was compared between quadrivalent HPV and 9-valent HPV vaccines. The authors found no difference in the number of fetal losses (e.g., spontaneous abortion, late fetal death, etc.), or the incidence of congenital anomalies between the groups. Additionally, the proportion of pregnancies with adverse outcome were within ranges reported in the general population. 

Baril L, Rosillon D, Willame C, Angelo MG, Zima J, et al. Risk of spontaneous abortion and other pregnancy outcomes in 15-25 year old women exposed to human papillomavirus-16/18 AS04-adjuvanted vaccine in the United Kingdom. Vaccine 2015;33:6884-6891.
The authors assessed the risk of spontaneous abortion and other adverse pregnancy outcomes after inadvertent exposure to HPV-16/18 vaccine surrounding gestation during a three-year period.  Investigators found no increased risk of spontaneous abortion, still birth, preterm or post-term birth, small or large for gestational age, or infant death before 12 weeks when comparing those women who became pregnant within 30 days before or 45 to 90 days after vaccine receipt versus those who became pregnant 120 days to 18 months after the last HPV vaccine dose. 

Panagiotou OA, Befano BL, Rodriguez AC, Herrero R, Schiller JT, et al. Effect of bivalent human papillomavirus vaccination on pregnancy outcomes: long term observational follow-up in the Costa Rica HPV vaccine trial. BMJ 2015;351:h4358.
The authors examined the effect of the bivalent HPV vaccine on miscarriage by comparing women who received HPV vaccine, hepatitis A vaccine, or no vaccine. The three groups did not differ in their incidence of miscarriage after adjusting for age at vaccination and age at conception.

Wacholder S, Chen BE, Wilcox A, Macones G, Gonzalez P, et al. Risk of miscarriage with bivalent vaccine against human papillomavirus (HPV) types 16 and 18: pooled analysis of two randomized controlled trials. BMJ 2010;340:c712.
The authors evaluated the risk of miscarriage after receipt of AS04-adjuvanted bivalent 16/18 HPV vaccine during pregnancy. More than 3,500 pregnancies occurred in the two multicenter phase III trials where the bivalent vaccine was compared to a control group that received hepatitis A vaccine. No differences in the rate of miscarriage were detected between the two groups.

Garland SM, Ault KA, Gall SA, Paavonen J, Sings HL, et al. Pregnancy and infant outcomes in the clinical trials of a human papillomavirus type 6/11/16/18 vaccine: a combined analysis of five randomized controlled trials. Obstet Gynecol 2009;114(6):1179-1188.
The authors analyzed the outcomes of more than 4,000 pregnancies in women who did or did not receive the quadrivalent HPV vaccine. No significant differences were detected between the two groups regarding the proportion of pregnancies resulting in live birth, fetal loss, spontaneous abortion, and congenital anomalies.

Influenza vaccine

Tavares F, Nazareth I, Monegal JS, Kolte I, Verstraeten T, et al. Pregnancy and safety outcomes in women vaccinated with an AS03-adjuvanted split virion H1N1 (2009) pandemic influenza vaccine during pregnancy: a prospective cohort study. Vaccine 2011;29:6358-6365.
In this prospective, observational study, the authors found that receipt of the AS03-adjuvanted H1N1 pandemic influenza vaccine administered during pregnancy was not associated with an increased risk of spontaneous abortion, stillbirth, congenital anomalies, preterm delivery, low birth weight, or maternal complications including upper respiratory tract infection, urinary tract infection and preeclampsia/hypertension.

Omon E, Damase-Michel C, Hurault-Delarue C, Lacroix I, Montastruc JL, et al. Non-adjuvanted 2009 influenza A (H1N1)v vaccine in pregnant women: the results of a French prospective descriptive study. Vaccine 2011;29:9649-9654.
In this prospective, observational study, the authors described pregnancy outcomes among more than 500 French women who were vaccinated with non-adjuvanted influenza A/H1N1 vaccines. Compared with the general population, vaccination during pregnancy was not associated with an increased risk of maternal complications (e.g., preterm labor, hypertension, gestational diabetes, premature rupture of membranes, infections), congenital malformations (e.g., orthopaedic, renal, genital, cardiologic, ophthalmologic, otologic, among others) or other neonatal disorders (e.g., quadriplegia, hearing impairment, respiratory infection, infectious diseases, among others).

Pasternak B, Svanstrom H, Molgaard-Nielsen D, Krause TG, Emborg HD, et al. Risk of adverse fetal outcomes following administration of a pandemic influenza A (H1N1) vaccine during pregnancy. JAMA 2012;308(2):165-174.
The authors investigated the incidence of adverse fetal outcomes in 7000 Danish women who did or did not receive an adjuvanted influenza A(H1N1)pdm09 vaccine during pregnancy. Exposure to the vaccine, regardless of trimester, was not associated with a significantly increased risk of major birth defects, preterm birth, or fetal growth restriction.

Oppermann M, Fritzsche J, Weber-Schoendorfer C, Keller-Stanislawski B, Allignol A, et al. A(H1N1)v2009: a controlled observational prospective cohort study on vaccine safety in pregnancy. Vaccine 2012;30:4445-4452.
The authors assessed the safety of influenza A/H1N1 vaccination in pregnancy by prospectively following the pregnancies of German women who were vaccinated during pregnancy or ≤ 4 weeks prior to conception and comparing outcomes to unvaccinated pregnant women. The authors found no differences in the risks for spontaneous abortions, preeclampsia, prematurity, or intrauterine growth restriction, or a difference in the rate of major malformations in women who were vaccinated compared with unvaccinated women.

Launay O, Krivine A, Charlier C, Truster V, Tsatsaris V, et al. Low rate of pandemic A/H1N1 2009 influenza infection and lack of severe complication of vaccination in pregnant women: a prospective cohort study. PLoS ONE 2012;7(12):e52303.
In this prospective cohort study, the authors assessed the consequences of maternal receipt of pandemic A/H1N1 2009 influenza on pregnancy outcomes by comparing vaccinated to unvaccinated women. They found no significant difference in pregnancy outcomes (i.e., onset of labor, mode of delivery, gestational age at delivery) and perinatal outcomes (i.e., birth weight, Apgar score, or requirement for neonatal intensive care) between women who received A/H1N1 2009 influenza vaccine and those who didn’t.

Rubinstein F, Bonotti A, Wainer V, Schwarcz A, Augustovski F, et al. Influenza A/H1N1 MF59-adjuvanted vaccine in pregnant women and adverse perinatal outcomes: multicenter study. BMJ 2013;346:f393.
In this multicenter, prospective study, the authors evaluated the risk of adverse perinatal events after vaccination with an MF59-adjuvanted influenza A/H1N1 vaccine in more than 7200 pregnant women. Vaccinated pregnant women were found to have a lower risk of low birthweight, preterm delivery, or fetal or early neonatal death up to seven days postpartum when compared to unvaccinated pregnant women.

Chavant F, Ingrand I, Jonville-Bera AP, Plazanet C, Gras-Champel V, et al. The PREGVAXGRIP study: a cohort study to assess foetal and neonatal consequences of in utero exposure to vaccination against A(H1N1)v2009 influenza. Drug Saf 2013;36:455-465.
In this prospective study, the authors assessed the outcomes of more than 2400 pregnant French women who received the 2009 influenza A/H1N1 pandemic vaccine.  The rate of congenital malformations, spontaneous abortions, still births, preterm deliveries, or neonatal disorders was not higher than the rate reported in the general population.

Chambers CD, Johnson D, Xu R, Luo Y, Louik C, et al. Risks and safety of pandemic H1N1 influenza vaccine in pregnancy: birth defects, spontaneous abortion, preterm delivery and small for gestational age infants. Vaccine 2013;31:5026-5032.
The authors conducted a prospective safety study of women who did or did not receive a pandemic H1N1 monovalent or trivalent influenza vaccine during pregnancy.  No clinically significant differences in the rate of spontaneous abortion, major birth defects, preterm delivery, or small for gestational age were detected.

Kharbanda EO, Vazquez-Benitez G, Lipkind H, Naleway A, Lee G, et al. Inactivated influenza vaccine during pregnancy and risks for adverse obstetric events. Obstet Gynecol 2013;122(3):659-667.
The authors compared the risks of adverse events during pregnancy in women who did or did not receive a trivalent inactivated influenza vaccine. More than 74,000 pregnant women were vaccinated during the 7-year-study period. Vaccine receipt did not confer an increased risk for adverse maternal outcomes such as hyperemesis, chronic hypertension, gestational hypertension, gestational diabetes, proteinuria, urinary tract infection, puerperal infections, venous complications, pulmonary emboli, peripartum cardiomyopathy, preeclampsia or eclampsia.

Ludvigsson JF, Strom P, Lundholm C, Cnattingius S, Ekbom A, et al. Maternal vaccination against H1N1 influenza and offspring mortality: population based cohort study and sibling design. BMJ 2015;351:h5585.
In this Swedish prospective study, the authors investigated the mortality of more than 41,000 pregnancies in mothers who either did or did not receive the influenza A(H1N1)pdm09 vaccine. Mothers vaccinated during pregnancy were not at increased risk of adverse neonatal outcomes such as stillbirth, early neonatal death (first six days of life) or later death (7 days of life up to 4.6 years of age), regardless of the trimester during which they were vaccinated.

Fabiani M, Bella A, Rota M, Clagnan E, Gallo T, et al. A/H1N1 pandemic influenza vaccination: a retrospective evaluation of adverse maternal, fetal, and neonatal outcomes in a cohort of pregnant women in Italy. Vaccine 2015;33:2240-2247.
The authors evaluated the risk of adverse maternal, fetal, and neonatal outcomes in more than 2000 pregnant women in Italy vaccinated during the second or third trimester with the 2009 MF59-adjuvanted A/H1N1 pandemic influenza vaccine. They found no statistically significant association between vaccine receipt and maternal outcomes (i.e., hospital admissions for influenza, pneumonia, hypertension, eclampsia, diabetes, thyroid disease, and anemia), fetal outcomes (i.e, fetal death after the 22nd gestational week), and neonatal outcomes (i.e., preterm birth, low birth weight, low 5-minute Apgar score, and congenital malformations).

Zerbo O, Modaressi S, Chan B, Goddard K, Lewis N, et al. No association between influenza vaccination during pregnancy and adverse birth outcomes. Vaccine 2017;35:3186-3190.
The authors evaluated the association between maternal influenza vaccination during pregnancy and risk of preterm birth, small or large for gestational age, admission to the neonatal intensive care unit, need for mechanical ventilation, respiratory distress syndrome, low birth weight, and low Apgar scores during a 6-year period in more than 145,000 women among whom 64,000 were vaccinated.  The authors found no association between maternal influenza vaccination during pregnancy and increased risk for adverse outcomes.

Kharbanda EO, Vazquez-Benitez G, Romitti PA, Naleway AL, Cheetham TC, et al. First trimester influenza vaccination and risks of major structural birth defects in offspring.  J Pediatr 2017;187:234-239.
The authors examined the risks for major structural defects in infants following receipt of inactivated influenza vaccine in the first trimester during 10 influenza seasons. More than 50,000 mothers received inactivated influenza vaccine in the first trimester during the study period. The authors found no increased risk for cardiac, orofacial, respiratory, neurologic, ophthalmologic, otologic, gastrointestinal, genitourinary and muscular or limb defects in the offspring of women who were vaccinated during the first trimester.

Hviid A, Svanstrom H, Molgaard-Nielsen D, Lambach P. Association between pandemic influenza A(H1N1) vaccination in pregnancy and early childhood morbidity in offspring. JAMA Pediatr 2017;171(3):239-248.
The authors evaluated whether administration of pandemic influenza A(H1N1) vaccination during pregnancy increased the risk for early childhood morbidity. They found that children whose mothers received influenza vaccine during pregnancy were not more likely to be hospitalized in early childhood than those whose mothers weren’t vaccinated, regardless of trimester exposure.

Tetanus, diphtheria, and acellular pertussis vaccines

Fortner KB, Swamy GK, Broder KR, Jimenez-Truque N, Zhu Y, et al. Reactogenicity and immunogenicity of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Tdap) in pregnant and nonpregnant women. Vaccine 2018;36:6354-6360.
In this prospective, observational, cohort study, the authors investigated the reactogenicity and immunogenicity following Tdap vaccination. Moderate or severe reactions were not significantly higher in pregnant compared with non-pregnant women. 

Sukumaran L, McCarthy NL, Kharbanda EO, Vazquez-Benitez G, Lipkind HS, et al. Infant hospitalizations and mortality after maternal vaccination. Pediatrics 2018;141(3):e20173310.
The authors evaluated whether maternal receipt of influenza and Tdap vaccines increased the risk of infant hospitalization or death in the first six months of life during a 10-year period. They found no association between vaccination and infant all-cause hospitalization, hospitalization from respiratory causes, or mortality.  

DeSilva M, Vazquez-Benitez G, Nordin JD, Lipkind HS, Klein NP, et al. Maternal Tdap vaccination and risk of infant morbidity. Vaccine 2017;35:3655-3660.
A slight increase in the risk of chorioamnionitis in women vaccinated with Tdap during pregnancy was previously detected in two previous Vaccine Safety Datalink (VSD) evaluations. In this study, the authors investigated the clinical significance of these findings by reviewing four years of data from seven VSD sites, including more than 45,000 women vaccinated during pregnancy. An increased risk of chorioamnionitis was observed in women vaccinated during pregnancy compared to those who were not vaccinated. Despite these findings, no increased risk of clinically significant outcomes typically associated with chorioamnionitis was found in infants born to Tdap-vaccinated women, including transient tachypnea of the newborn, neonatal sepsis, neonatal pneumonia, respiratory distress syndrome or newborn convulsions. 

Layton JB, Butler Am, Li D, Boggess KA, Weber DJ, et al. Prenatal Tdap immunization and risk of maternal and newborn adverse events. Vaccine 2017;35:4072-4078.
The authors evaluated the relationship between Tdap vaccination during pregnancy and adverse birth outcomes in more than 148,000 women during a five-year period. Vaccination during pregnancy was not associated with an increased risk of preeclampsia, eclampsia, cesarean section or placental abruption compared to unvaccinated women.

DeSilva M, Vazquez-Benitez G, Nordin JD, Lipkind HS, Romitti PA, et al. Tdap vaccination during pregnancy and microcephaly and other structural birth defects in offspring. JAMA 2016;316(17):1823-1824.
Using the Vaccine Safety DataLink, the authors compared the prevalence of birth defects between infants born to more than 41,000 pregnant women who received Tdap vaccine with unvaccinated women. Vaccination at less than 14 weeks gestation, between 27- and 36-week gestation, or at any time during pregnancy was not associated with an increased risk for microcephaly or any structural defect. 

Hoang, HTT, Leuridan E, Maertens, K, et al. Pertussis vaccination during pregnancy in Vietnam: results of a randomized controlled trial. Vaccine 2016;34:151-159.
In this randomized controlled trial, the authors assessed the safety and efficacy of the pertussis vaccine in pregnant women in Vietnam. Both Tdap and tetanus toxoid vaccines were well tolerated.

Kharbanda EO, Vazquez-Benitez G, Lipkind HS, Klein NP, Cheetham TC, et al. Maternal Tdap vaccination: coverage and acute safety outcomes in the Vaccine Safety Datalink, 2007-2013. Vaccine 2016;34;968-973.
The authors evaluated the risks for adverse events following Tdap vaccination in more than 53,000 pregnant women. They found no increased risk of acute adverse events within 3- or 42-days post-vaccination, including neurologic events, thrombotic events, new onset proteinuria, gestational diabetes, cardiac events, venous thromboembolic events or thrombocytopenia.

Maertens K, Cabore RN, Huygen K, Hens N, Van Damme P, et al. Pertussis vaccination during pregnancy in Belgium: results of a prospective controlled cohort study. Vaccine 2016;34:142-150.
In this prospective, controlled cohort study, the authors assessed the immunogenicity and safety of Tdap immunization during pregnancy. Tdap was generally well-tolerated with mild side effects resolving within 72 hours of vaccine receipt. No reported serious adverse events in the mothers were related to vaccine administration. All reported serious adverse events in infants were common conditions that occur in the neonatal/infant period and were not linked to maternal vaccination.

Petousis-Harris H, Walls T, Watson D, Paynter J, Graham P, et al. Safety of Tdap vaccine in pregnant women: an observational study. BMJ Open 2016;6:e010911.
In this prospective study, the authors followed 800 New Zealand women who received Tdap during the third trimester of pregnancy. Immunization was well-tolerated with no serious adverse events occurring at levels greater than background rates. 

Morgan JL, Baggari SR, McIntire DD, Sheffield JS. Pregnancy outcomes after antepartum tetanus, diphtheria and acellular pertussis vaccination Obstet Gynecol 2015;125(6):1433-1438.
The authors retrospectively evaluated pregnancy outcomes in more than 7,100 women who had or had not received Tdap during pregnancy during a 13-month period. They found no differences in pregnancy outcomes (e.g., stillbirth, major malformations, chorioamnionitis, 5-minute Apgar score, or cord blood pH) or neonatal complications (e.g., ventilation requirement, sepsis, intraventricular hemorrhage, or neonatal death). Additionally, no differences in neonatal outcomes were found between women who had received at least two Tdap vaccines in the past five years with those who had received only a single dose.  

Sukumaran L, McCarthy NL, Kharbanda EO, Weintraub E, Vazquez-Benitez G, et al. Safety of tetanus, diphtheria, and acellular pertussis and influenza vaccinations in pregnancy. Obstet Gynecol 2015;126(5):1069-1074.
The authors evaluated the safety of Tdap and influenza vaccines in 36,000 pregnancies during a seven-year period. Concomitant administration of Tdap and influenza vaccines during pregnancy was not associated with a higher risk of acute adverse outcomes (e.g., fever, limb pain, limb swelling, cellulitis, lymphadenitis, Arthus reaction, or allergy) or birth outcomes (e.g., preterm delivery, low birth weight, small for gestational age) compared to sequential vaccination. No cases of Arthus reaction or Guillain-Barre Syndrome were reported.  

Sukumaran L, McCarthy NL, Kharbanda EO, McNeil MM, Naleway AL, et al. Association of Tdap vaccination with adverse birth outcomes among pregnant women with prior tetanus-containing immunizations. JAMA 2015;314(15):1581-1587.
The authors evaluated the safety of Tdap vaccine in more than 29,000 pregnant women. They found no statistically significant differences in acute adverse events (e.g., fever, allergic reactions or local reactions) or adverse birth outcomes (e.g., preterm delivery, low birth weight, small for gestational age) among women who had received their prior tetanus-containing vaccine less than two years before and two to five years before compared with women who had received a tetanus containing vaccine more than five years earlier. No cases of anaphylaxis, Arthus reaction or Guillain-Barre Syndrome were found following vaccination. 

Donegan K, King B, Byran P. Safety of pertussis vaccination in pregnant women in UK: observational study. BMJ 2014;349:g4219.
The authors conducted an observational cohort study to examine the safety of pertussis vaccination during pregnancy following administration of Repevax^®, a low-dose diphtheria, acellular pertussis and inactivated poliomyelitis vaccine. When compared with national historical rates, the authors found no increased risk of stillbirth, maternal or neonatal death, pre-eclampsia, eclampsia, hemorrhage, fetal distress, uterine rupture, placenta or vasa previa, caesarean delivery, low birth weight, or neonatal renal failure. 

Kharbanda EO, Vazquez-Benitez G, Lipkind HS, Klein NP, Cheetham TC, et al. Evaluation of the association of maternal pertussis vaccination with obstetric events and birth outcomes. JAMA 2014;312(18):1897-1904. 
Using the Vaccine Safety Datalink, the authors determined the safety of Tdap vaccination during pregnancy. Vaccination was not associated with increased risks of adverse birth outcomes including preterm delivery, small for gestational age, or hypertensive disorders of pregnancy (e.g., gestational hypertension, preeclampsia, eclampsia, etc.). Although Tdap vaccination during pregnancy was initially associated with a slightly increased risk of chorioamnionitis, chart reviews found that the association between Tdap vaccination at 27- and 36-week gestation was no longer significant.   

Munoz FM, Bond NH, Maccato M, Pinell P, Hammill HA, et al. Safety and immunogenicity of tetanus diphtheria and acellular pertussis (Tdap) immunization during pregnancy in mothers and infants. JAMA 2014;311(17):1760-1769.
In this randomized, double-blind, placebo-controlled clinical trial, the authors evaluated the safety and immunogenicity of Tdap immunization during the third trimester of pregnancy. No Tdap-associated serious adverse events occurred in women or infants. There were no significant differences in the infants’ gestational ages, birth weights, Apgar scores, neonatal examinations, growth, development or complications when comparing those mothers who received Tdap antepartum versus postpartum. 

For a scientific overview of this topic, please visit the section about “Preterm infants” on the VEC webpage, “Vaccine Considerations for New and Expectant Moms.”

Acellular pertussis vaccine and prematurity

Schloesser RL, Fischer D, Otto W, Rettwitz-Volk W, Herden P, et al. Safety and immunogenicity of an acellular pertussis vaccine in premature infants. Pediatrics 1999;103(5):e60.
The authors prospectively evaluated the safety and immunogenicity of an acellular pertussis vaccine in preterm infants compared with full-term infants at 2 months of age, followed by two additional doses at four and eight weeks after the initial dose. Immune responses to the acellular pertussis vaccine were decreased in preterm compared with term infants, but vaccine efficacy was high. Acellular pertussis vaccine was well tolerated in both groups and the incidence of systemic adverse reactions was limited to one patient in each group having a fever > 38.5C.

Concomitant or combination vaccine receipt and prematurity

Omenaca F, Vazquez L, Garcia-Corbeira P, Mesaros N, Hanssens L, et al. Immunization of preterm infants with GSK’s hexavalent combined diphtheria-tetanus-acellular pertussis-hepatitis B virus-inactivated poliovirus and Haemophilus influenzae type b conjugate vaccine: a review of safety and immunogenicity. Vaccine 2018;36:986-996.
The authors reviewed 10 clinical studies and 15 years of post-marketing safety surveillance data regarding immunization with hexavalent vaccine (DTaP/HepB/IPV/Hib) when administered alone or in combination with pneumococcal conjugate, rotavirus, and meningococcal vaccines and respiratory syncytial virus IgG to infants with a history of prematurity or low birthweight (LBW). At least 92% of infants with a history of LBW or as young as 24 weeks gestational age responded to all vaccine antigens after the three-dose vaccination series. Between 13% and 30% of medically stable infants with a history of prematurity or LBW developed apnea after vaccination, typically after the first dose. The occurrence of post-immunization cardiorespiratory events was influenced by the severity of underlying neonatal conditions, though most events resolved spontaneously or required minimal intervention.  The hexavalent vaccine was well tolerated in co-administration regimens.

Montague EC, Hilinski JA, Williams HO, McCracken CE, Giannopoulos HT, et al. Respiratory decompensation and immunization of preterm infants. Pediatrics 2016;137(5):e20154225.
The authors retrospectively evaluated the safety of routine infant vaccinations (DTaP, IPV, HepB, Hib, PCV, and rotavirus) and influenza vaccine to 240 premature infants born at less than 32 weeks of gestation who were immunized during their hospital stay over a 6.5-year period. Fewer than 10% of infants required increased respiratory support within 72 hours of vaccination. Two percent (2%) of infants required reintubation, all of whom had bronchopulmonary dysplasia (BPD) and a birthweight of less than 650 grams (1 pound 6 ounces). An increased incidence of apnea/bradycardia/desaturation events was observed in infants with and without BPD, but no differences existed between groups.  Most infants received three or more vaccines per day, though the number of vaccines administered in a day was not associated with an increase of adverse events after immunization. The authors concluded that respiratory decompensation requiring clinical intervention after immunization of preterm infants both with and without BPD was uncommon and immunization should not be delayed.

DeMeo SD, Raman SR, Hornik CP, Wilson CC, Clark R, et al. Adverse events after routine immunization of extremely low-birth-weight infants. JAMA Pediatr 2015;169(8):740-745.
The authors retrospectively evaluated the incidence of adverse events after vaccination between the ages of 53 and 100 days in more than 13,000 infants born at 28 weeks of gestation or less and birthweight ≤ 1000 grams. More than 90% of infants received three or more vaccines. Infants who were born at 23 to 24 weeks gestation had a higher risk of sepsis evaluation and intubation after immunization. No increase in the incidence of seizures was detected. The post-immunization incidence of adverse events was similar across immunization types, including combination vaccines when compared with single-dose vaccines. 

Faldella G, Galleti S, Corvaglia L, Ancora G, Alessandroni R. Safety of DTaP-IPV-Hib-HBV hexavalent vaccine in very premature infants. Vaccine 2007;25:1036-1042.
In this prospective, observational study, the safety of DTaP-IPV-Hib-HBV hexavalent vaccine was evaluated in 45 preterm newborns less than 31 weeks of gestation admitted to the NICU who received the vaccine between day of life 49 and 112. Vaccination was generally well tolerated, with 11% showing either a transient recurrence of or increase in apnea and bradycardia episodes following immunization, but intervention was limited to tactile stimulation, supplemental oxygen or bag and mask ventilation, and no patients were intubated. All patients with cardiorespiratory events had chronic diseases. The authors also specifically evaluated cardiac disturbances (QTc interval) and cerebral blood flow effects but found no differences in these parameters before and after vaccination or in those infants who experienced cardiorespiratory events.

Lee J, Robinson JL, Spady DW. Frequency of apnea, bradycardia, and desaturations following first diphtheria-tetanus-pertussis-inactivated polio-Haemophilus influenzae type B immunization in hospitalized preterm infants. BMC Pediatr 2006;6:20.
In this retrospective study, the authors investigated the frequency of apnea, bradycardia and desaturations in approximately 250 hospitalized very preterm infants (mean gestational age 26 weeks) to determine if incidences of these events were increased following the first dose of DTP/DTaP-IPV-Hib vaccine. A significant increase in the incidence of cardiorespiratory events was detected after vaccine administration compared with unvaccinated infants, though most events were clinically insignificant and the need for intervention was not different between the groups.

Schulzke S, Heininger U, Lucking-Famira M, Fahnenstich H. Apnea and bradycardia in preterm infants following immunisation with pentavalent or hexavalent vaccines. Eur J Pediatr 2005;164:432-435.
In this retrospective study, the authors investigated the incidence of apnea and bradycardia in respiratory-stable preterm infants (mean gestational age 28 weeks and postnatal age ~ 2 months) following a combination DTaP/Hib/IPV or DTaP/Hib/IPV/HepB. Vaccination was generally well tolerated, with 13% showing either a transient recurrence of or increase in apnea and bradycardia episodes following immunization, but intervention was limited to tactile stimulation, supplemental oxygen or bag and mask ventilation, and no patients were intubated.

DTaP vaccine and prematurity

Carbone T, McEntire B, Kissin D, Kelly D, Steinschneider A, et al. Absence of an increase in cardiorespiratory events after diphtheria-tetanus-acellular pertussis immunization in preterm infants: a randomized, multicenter study. Pediatrics 2008;121(5):e1085-e1090.
In this randomized, controlled, prospective study, the authors examined the relationship between DTaP and cardiorespiratory events in approximately 200 preterm infants (mean post-conception age of 35 weeks) at 2 months of age. Preterm infants who received DTaP at 2 months of age were not more likely to experience prolonged apnea and bradycardia in the 48-hour post-immunization period than infants who did not receive DTaP. 

Pfister RE, Aeschbach V, Niksic-Stuber V, Martin BC, Siegrist CA. Safety of DTaP-based combined immunization in very-low-birth-weight premature infants: frequent but mostly benign cardiorespiratory events. J Pediatr 2004;145:58-66.
The authors evaluated the safety of DTaP-IPV-Hib immunization in very low birthweight preterm infants (mean gestational age 28 ± 2 weeks; range 24-34 weeks) when administered prior to hospital discharge during the first two to four months of life. Nearly half of the infants had a reappearance or increase in either apnea, bradycardia, or desaturations after vaccination, though all infants returned to baseline within 48-72 hours and most events resolved spontaneously or after brief stimulation. No event resulted in a detrimental impact on the infants’ clinical course, reintubation or a delay in discharge. The authors concluded that timely vaccine receipt in this fragile population is safe.

Hib vaccine and prematurity

Omenaca F, Garcia-Sicilia J, Carcia-Corbeira P, Boceta R, Romero A. Response of preterm newborns to immunization with a hexavalent diphtheria-tetanus-acellular pertussis-hepatitis B virus-inactivated polio and Haemophilus influenzae type b vaccine: first experiences and solutions to a serious and sensitive issue. Pediatrics 2005;116(6):1292-1298.
The authors prospectively evaluated the safety and immunogenicity of a hexavalent DTaP/HepB/IPV/Hib vaccine in approximately 200 preterm and full-term infants at 2, 4, and 6 months of age. Preterm and full-term infants displayed good immune responses to all antigens. Protective immune responses against Hib occurred in more than 90% of preterm infants, though these responses were less than those of term infants. An increased risk of oxygen desaturations or bradycardia was observed in preterm infants born < 28 weeks with birth weights less than or equal to 1000 grams in the 72 hours after their first dose of vaccine, and reintubation was not reported.

Pfister RE, Aeschbach V, Niksic-Stuber V, Martin BC, Siegrist CA. Safety of DTaP-based combined immunization in very-low-birth-weight premature infants: frequent but mostly benign cardiorespiratory events. J Pediatr 2004;145:58-66.
The authors evaluated the safety of DTaP-IPV-Hib immunization in very low birthweight preterm infants (mean gestational age 28 ± 2 weeks; range 24-34 weeks) when administered prior to hospital discharge during the first two to four months of life. Nearly half of the infants had a reappearance or increase in either apnea, bradycardia, or desaturations after vaccination, though all infants with increased events returned to baseline within 48-72 hours and most of these events resolved spontaneously or after brief stimulation. No event resulted in a detrimental impact on the infants’ clinical course, reintubation or a delay in discharge. The authors concluded that timely vaccine receipt in this fragile population is safe.

Influenza vaccine and prematurity

Esposito S, Pugni L, Daleno C, Ronchi A, Valzano A, et al. Influenza A/H1N1 MF59-adjuvanted vaccine in preterm and term children aged 6 to 23 months. Pediatrics 2011;127(5):e1161-e1168.
In this prospective, randomized study, the immunogenicity, safety and tolerability of a monovalent 2009 pandemic influenza A/H1N1 MF59-adjuvanted vaccine was evaluated in approximately 100 children aged 6 to 23 months of age, including those born at less than 32 weeks of gestation. Regardless of gestational or postnatal age, all children developed protective immune responses after two doses, and all but one child was protected after the first dose. The vaccine was generally well tolerated, with fever recorded as the only adverse event; no differences were detected when comparing infants with differing gestational ages (< 32 weeks versus 32-36 weeks versus 37-42 weeks). Local reactions were minimal (less than 4% occurrence) and did not differ between gestational age groups, indicating the tolerability of the MF59 adjuvant. No severe adverse events occurred in any patient.

Measles vaccine and prematurity

McClure D, Jacobsen SJ, Klein NP, Naleway AL, Kharbanda EO, et al. Similar relative risks of seizures following measles containing vaccination in children born preterm compared to full-term without previous seizures or seizure-related disorders. Vaccine 2019;37(1):76-79.
The authors retrospectively evaluated the incidence of febrile seizures following measles vaccine at age 12 through 23 months over a 13-year period in more than 530,000 children to determine if the risk is affected by prematurity. The overall incidence of febrile seizures was low and no differences were found in the risk of febrile seizure between children born preterm versus full term. 

Pneumococcal vaccine and prematurity

Martinón-Torres F, Czajka H, Center KJ, Wysocki J, Majda-Stanislawska E, et al. 13-valent pneumococcal conjugate vaccine (PCV13) in preterm versus term infants. Pediatrics 2015;135(4):e876-e886.
In this prospective study, the authors compared the safety and efficacy of PCV13 age when administered with other routine vaccines (e.g., DTaP, hepatitis B, IPV, Hib, meningococcal group C conjugate vaccine) in term and preterm infants. Immune responses to PCV13 were lower in preterm infants, though the majority of subjects in both groups achieved protective antibody levels. PCV13 was well tolerated in both term and preterm infants, with the most common problem being irritability or decreased sleep in the preterm group.

Esposito S, Pugni L, Bosis S, Proto A, Cesati L, et al. Immunogenicity, safety and tolerability of heptavalent pneumococcal conjugate vaccine administered at 3, 5, and 11 months post-natally to pre- and full-term infants. Vaccine 2005;23:1703-1708.

In this prospective study, the authors assessed the immunogenicity, safety and tolerability of PCV7 administered at 3, 5 and 11 months of age in preterm and full-term infants. PCV7 was immunogenic in both groups when given as a three-dose series. PCV7 was generally well tolerated with irritability and drowsiness occurring regardless of gestational age.

Shinefield H, Black S, Ray P, Fireman B, Schwalbe J, et al. Efficacy, immunogenicity and safety of heptavalent pneumococcal conjugate vaccine in low birth weight and preterm infants. Pediatr Infect Dis J 2002;21:182-186.
In this randomized, double bind trial, more than 37,000 infants were given either PCV7 or meningococcal serogroup C conjugate vaccine (MCV), including approximately 6,000 low birth weight or preterm infants. The vaccine was efficacious in 100% of infants. PCV7 was well tolerated by all infants, regardless of gestational age or birthweight. An increased incidence of hives was found in the low birthweight and preterm groups who received PCV compared with those who received MCV. Preterm infants receiving PCV also had an increased risk of vomiting, irritability, loss of appetite, and diarrhea compared with those receiving MCV.

Rotavirus vaccine and prematurity

Omenaca F, Sarlangue J, Szenborn L, Nogueira M, Suryakiran PV, et al. Safety, reactogenicity and immunogenicity of the human rotavirus vaccine in preterm European infants: a randomized phase IIIB study. Pediatr Infect Dis J 2012;31(5):487-493.
In this randomized, placebo-controlled trial, the safety and efficacy of rotavirus vaccine (Rotarix^®) was evaluated in approximately 1,000 preterm infants (mean gestational age 33 weeks). Immunologic responses to the vaccine were comparable to full-term infants evaluated in previous studies. No differences in the incidence of serious adverse events were detected when comparing vaccine and placebo recipients, with the most common reported finding being fever (less than 5%). Gastroenteritis episodes were also similar between vaccine and placebo recipients. No intussusception cases were reported. 

Goveia MG, Rodriguez ZM, Dallas MJ, Itzler RF, Boslego JW, et al. Safety and efficacy of the pentavalent human-bovine (WC3) reassortant rotavirus vaccine in healthy premature infants. Pediatr Infect Dis J 2007;26(12):1099-1104.
In this randomized, placebo-controlled trial, the safety and efficacy of rotavirus vaccine (Rotateq^®) was evaluated in approximately 70,000 healthy infants 6-12 weeks of age, including more than 2,000 born prematurely. Rotavirus vaccine was well tolerated among preterm infants, including those born at less than 32 weeks of gestation. No differences in the incidence of serious adverse events were detected between preterm vaccine and placebo recipients. No cases of intussusception in any premature infant were found during the study. These results support vaccinating healthy premature infants on the same schedule as term infants.

For a scientific overview of this topic, please visit the Vaccines and Sudden Infant Death Syndrome (SIDS) section of our website.

Yang YT and Shaw J. Sudden infant death syndrome, attention-deficit/hyperactivity disorder and vaccines: longitudinal population analyses. Vaccine 2018;36:595-598.
The authors analyzed six years of vaccine uptake data for 3-month-olds from the National Immunization Survey and state-level National Vital Statistics SIDS reports and found vaccination coverage for routinely used childhood vaccines was not associated with an increased risk of SIDS.

Moro PL, Arana J, Cano M, Lewis P, Shimabukuro TT. Deaths reported to the Vaccine Adverse Event Reporting System, United States, 1997-2013. CID 2015;61:980-987.
The authors examined deaths reported to VAERS in the United States during a 16-year period, with nearly half of the deaths attributed to SIDS. As with the previous 2001 study, SIDS reports progressively decreased over time, during which the addition of seven-valent pneumococcal vaccine and rotavirus vaccine were added to the recommended vaccine schedule, and the DTaP-HepB-IPV combination vaccine was licensed for use.

Traversa G, Spila-Alegiani S, Bianchi C, Ciofi degli Atti M, Frova L, et al. Sudden unexpected deaths and vaccinations during the first two years of life in Italy: a case series study. PLoS ONE 2011;6(1):e16363.
The authors found no increased risk for sudden unexplained death (SUD) and any vaccination in the time windows of 0-7 days or 0-14 days after vaccine receipt.

Vennemann, MMT, Butterfab-Bahloul T, Jorch G, et al. Sudden infant death syndrome: no increased risk after immunisation. Vaccine 2007;25: 336-340.
The authors investigated the risk of SIDS with immunization in the first year of life, particularly with a hexavalent vaccine containing 15 different antigens. They found no increased risk of SIDS in the 14 days after immunization. As with previous studies, patients with SIDS were vaccinated less frequently and later than those infants without SIDS.

Eriksen EM, Perlman JA, Miller A, Marcy SM, Lee H, et al. Lack of association between hepatitis B birth immunization and neonatal death: A population-based study from the Vaccine Safety Datalink Project. Pediatr Infect Dis J 2004;23:656-661.
The authors evaluated more than 360,000 births during a five-year period to determine if a correlation existed between hepatitis B vaccine receipt at birth and neonatal death. The authors found no relationship between hepatitis B vaccine receipt at birth and neonatal death, and the proportion of deaths from unexpected causes (e.g., SIDS) was not different between vaccinated and unvaccinated infants.

Fleming PJ, Blair PS, Platt MW, Tripp J, Smith IJ, et al. The UK accelerated immunisation programme and sudden unexpected death in infancy: case-control study. BMJ 2001;322:1-5.
In the early 1990s, the schedule for routine infant immunizations in the United Kingdom was accelerated to give the vaccines at an earlier age. The authors found that the accelerated immunization program did not increase the risk of SIDS in a study population of 17.7 million infants. Immunization uptake was lowest among the infants who died from SIDS.

Jonville-Bera AP, Autret-Leca E, Barbeillon, Paris-Llado J and the French Reference Centers for SIDS. Sudden unexpected death in infants under 3 months of age and vaccination status – a case-control study. Br J Clin Pharmacol 2001;51:271-276.
The authors conducted a two-year prospective study on the vaccination status of infants with SIDS who died between 1 and 3 months of age to assess whether vaccination increased the risk of SIDS in this population in France. The authors found DTPP ± Hib immunization did not increase the risk of SIDS.  

Silvers LE, Ellenberg SS, Wise RP, Varricchio FE, Mootrey GT, et al. The epidemiology of fatalities reported to the Vaccine Adverse Event Reporting System 1990-1997. Pharmacoepidemiol Drug Saf 2001; 279-285.
The authors examined fatalities reported to VAERS in the United States during a seven-year period and found that reports peaked in 1992-1993 and then declined, with nearly half of the deaths attributed to SIDS. The trend in decreasing SIDS rates correlated with the 1992 American Academy of Pediatrics recommendation for infants to sleep on their side or back and the National Institute of Child Health and Human Development “Back to Sleep” campaign in 1994. The authors concluded that these data support findings of past controlled studies showing that the temporal association between infant vaccination and SIDS is coincidental and not causal.

Griffin MR, Ray WA, Livengood JR, Schaffner W. Risk of sudden infant death syndrome after immunization with the diphtheria-tetanus-pertussis vaccine. New Engl J Med 1988;319(10):618-623.
The authors evaluated recent immunization with DTP as a possible risk factor for SIDS during a 10-year period in Tennessee. They found no increase in the risk of SIDS after immunization with DTP vaccine and no correlation between SIDS and age at first immunization. Additionally, the rate of SIDS decreased in the first week after immunization.

Hoffman HJ, Hunter JC, Damus K, Pakter J, Peterson DR, et al. Diphtheria-tetanus-pertussis immunization and sudden infant death: results of the National Institute of Child Health and Human Development Cooperative Epidemiological Study of Sudden Infant Death Syndrome Risk Factors. Pediatrics 1987;79:598-611.
The authors investigated the possible association between diphtheria-tetanus-pertussis (DTP) immunization and subsequent occurrence of sudden infant death in the United States using data from a national SIDS epidemiological database. They found no temporal association between SIDS and DTP vaccine receipt. Infants with SIDS were less likely to have been immunized than infants without SIDS.

Keens TG, Davidson Ward SL, Gates EP, Andree DI, Hart LD. Ventilatory pattern following diphtheria-tetanus-pertussis immunization in infants at risk for sudden infant death syndrome. AJDC 1985;139:991-994.
The authors evaluated the effects of DTP immunization on the ventilatory pattern during sleep in infants at increased risk for SIDS, including those with unexplained apnea and those who were siblings of SIDS victims. Overnight pneumograms were recorded the night before and the night following DTP immunization. The authors found that DTP immunization did not increase abnormalities of the ventilatory pattern in infants at increased risk for SIDS.

For a scientific overview of this topic, please visit the Vaccine Ingredients – Thimerosal section of our website.

Christensen DL, Baio J, Van Naarden Braun K, Charles J, Constantino JN, et al. Prevalence and characteristics of autism spectrum disorder among children aged 8 years—Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2012. MMWR 2016;65(3):1-23.
The Autism and Developmental Disabilities Monitoring Network (ADDM) is an active surveillance system that provides estimates of the prevalence and characteristics of ASD among children aged 8 years whose parents or guardians reside in 11 ADDM Network sites in the United States. Surveillance showed the ASD prevalence rate for children 8 years of age in 2012 (which means they were born after thimerosal removal from childhood vaccines in 2003) was 14.6 per 1,000 children, compared with 11.3 per 1,000 children in 2008, 9 per 1,000 children in 2006, 6.6 per 1,000 children in 2002, and 6.7 per ,1000 children in 2000. The prevalence of autism continues to rise despite the removal of thimerosal from childhood vaccinations.

Mrozek-Budzyn D, Majewska R, Kieltyka A. Early exposure to thimerosal-containing vaccines and children’s cognitive development. A 9-year prospective birth cohort study in Poland. European Journal of Pediatrics 2015;174:383-391.
The authors prospectively investigated the relationship between early exposure to thimerosal-containing vaccines and cognitive development in children during the first nine years of life by evaluating children who were vaccinated between birth and 6 months of age with hepatitis B and DTP vaccines using formulations with or without thimerosal. Children exposed and not exposed to thimerosal during early infancy had similar outcomes of cognitive-developmental tests.

Taylor LE, Swerdfeger AL, Eslick GD. Vaccines are not associated with autism: an evidence-based meta-analysis of case-control and cohort studies. Vaccine 2014;32:3623-3629.
The authors conducted a meta-analysis of case-control and cohort studies that examined the relationship between receipt of vaccines and development of autism. Five cohort studies involving more than 1.2 million children and five case-control studies involving more than 9,000 children were included in the analysis. The authors concluded that vaccinations, components of vaccines (thimerosal), and multiple vaccines (MMR) were not associated with the development of autism or autism spectrum disorder.

Price CS, Thompson WW, Goodson B, et al. Prenatal and infant exposure to thimerosal from vaccines and immunoglobulins and risk of autism. Pediatrics 2010,126:656-664.
The authors examined the relationship between prenatal and infant exposure to thimerosal from vaccines or immunoglobulin preparations and autism spectrum disorder (ASD). They concluded prenatal and early life exposure to thimerosal from vaccines or immunoglobulin was not related to increased risk of ASDs.

Tozzi AE, Bisiacchi P, Tarantino V, et al. Neuropsychological performance 10 years after immunization in infancy with thimerosal-containing vaccines. Pediatrics 2009;123(2):475-482.
The authors compared the neuropsychological performance 10 years after vaccination in two groups of children exposed randomly to different amounts of thimerosal from vaccines. Among the 24 neuropsychological outcomes that were evaluated, only two were significantly associated with thimerosal exposure. Girls with higher thimerosal intake had lower mean scores in the finger-tapping test with the dominant hand and in the Boston Naming Test. The authors concluded that given the large number of statistical comparisons performed, the few associations found between thimerosal exposure and neuropsychological development were likely attributable to chance.

Thompson WW, Price C, Goodson B, et al. Early thimerosal exposure and neuropsychological outcomes at 7 to 10 years. N Engl J Med 2007;357(13):1281-1292.
The authors administered standardized tests to children between 7 and 10 years of age to assess the association between neuropsychological performance and exposure to thimerosal from vaccines or immune globulins during the prenatal period, the neonatal period (0-28 days), and the first 7 months of life. Results did not support an association between early exposure to mercury and deficits in neuropsychological functioning at the age of 7 to 10 years.

Fombonne E, Zakarian R, Bennett A, et al. Pervasive developmental disorders in Montreal, Quebec, Canada: prevalence and links with immunizations. Pediatrics 2006;118(1):e139-e150.
The authors compared the prevalence of pervasive developmental disorder (PDD) in Montreal, Canada, with the cumulative exposure to thimerosal. Ironically, the prevalence of PDD in the thimerosal-free birth cohorts was significantly higher than that in thimerosal-exposed cohorts. Additional analysis showed no significant effect of thimerosal exposure on prevalence of PDD. In addition, no relationship was found between the rates of PDD and exposure to one or two doses of MMR before 2 years of age.

Andrews N, Miller E, Grant A, et al. Thimerosal exposure in infants and developmental disorders: a retrospective cohort study in the United Kingdom does not support a causal association. Pediatrics 2004;114(3):584-591.
The authors performed a retrospective study in the United Kingdom to determine the relationship between the amount of thimerosal that an infant received via diphtheria-tetanus-whole-cell pertussis (DTP) or diphtheria-tetanus (DT) vaccines and subsequent neurodevelopmental disorders. Although tics in males were observed in one subset of children; in another, thimerosal appeared to enhance cognitive skills in females. The authors concluded that thimerosal at the level contained in these vaccines did not cause signs and symptoms consistent with mercury toxicity.

Heron J, Golding J, et al. Thimerosal exposure in infants and developmental disorders: a prospective cohort study in the United Kingdom does not support a causal association. Pediatrics 2004;114(3):577-583.
The authors performed a prospective study comparing the relationship between the quantity of thimerosal exposure from vaccines with several measures of childhood cognitive and behavioral development from 6 to 91 months of age. They found no evidence that early exposure to thimerosal had a deleterious effect on neurologic or psychological outcome.

Stehr-Green P, Tull P, Stellfeld M, et al. Autism and thimerosal-containing vaccines: lack of consistent evidence for an association.  Am J Prev Med 2003;25:101-106.
The authors compared the prevalence and incidence of autism in California, Sweden and Denmark with average exposures to thimerosal-containing vaccines between the mid-1980s and late-1990s. They found that exposure to thimerosal-containing vaccines was not associated with the increase in rates of autism in young children being observed worldwide.

Verstraeten T, Davis RL, DeStefano F, et al. Safety of thimerosal containing vaccines: a two-phased study of computerized health maintenance organization databases. Pediatrics 2003;112(5):1039-1048.
The authors evaluated the relationship between exposure to thimerosal-containing vaccines and neurodevelopmental disorders in more than 124,000 infants born between 1992 and 1999, finding no significant associations.

Madsen KM, Lauritsen MB, Pedersen CB, et al. Thimerosal and the occurrence of autism: negative ecological evidence from Danish population-based data. Pediatrics 2003;112(3):604-606.
The authors assessed the incidence rates of autism in Denmark among children between 2 and 10 years of age before and after removal of thimerosal from vaccines. Ironically, they found that the discontinuation of thimerosal-containing vaccines was followed by an increase in the incidence of autism. 

Hviid A, Stellfeld M, Wohlfahrt J, et al. Association between thimerosal-containing vaccine and autism. JAMA 2003;290:1763-1766. 
The authors evaluated the incidence of autism in children born in Denmark between 1990-1996 who received either thimerosal-containing vaccines or thimerosal-free preparations of the same vaccine.  They found that the incidence of autism or autistic spectrum disorders did not differ significantly between the two groups.

For a scientific overview of this topic, please visit the Vaccine Safety: Immune System and Health section of our website (see subsection titled “Vaccines impact on the immune system”).

Glanz JM, Newcomer SR, Daley MF, DeStefano F, et al. Association between estimated cumulative vaccine antigen exposure through the first 23 months of life and non-vaccine-targeted infections from 24 through 47 months of age. JAMA 2018;319(9):906-913.
The authors determined the relationship between the number of vaccines given in the first two years of life and the occurrence of non-vaccine targeted infections between two and four years of age. They found no difference in either the cumulative number of antigens or the number of antigens received in a single day in children who developed non-vaccine targeted infections.

Sherrid AM, Ruck CE, Sutherland D, et al. Lack of broad functional differences in immunity in fully vaccinated vs. unvaccinated children. Pediatr Res 2017;81(4):601-608.
The authors assessed the immune response to general, non-vaccine specific stimuli in fully vaccinated and entirely unvaccinated children between 3 and 5 years of age. They found that standard childhood vaccines did not cause long-lasting, gross alterations of the immune system.

DeStefano F, Price CS, Weintraub ES. Increasing exposure to antibody-stimulating proteins and polysaccharides in vaccines is not associated with risk of autism. J Pediatr 2013;163:561-567.
The authors evaluated the relationship between the total cumulative vaccine-specific antigen exposure or maximum exposure on a single day and the development of autism spectrum disorder (ASD), autistic disorder (AD) or ASD with regression. They found no association between antigen exposure from vaccines during the first two years of life and the risk of developing ASD, AD, or ASD with regression.

Iqbal S, Barile JP, Thompson WW, DeStefano F. Number of antigens in early childhood vaccines and neuropsychological outcomes at age 7-10 years. Pharmacoepidemiol Drug Saf 2013;22:1263-1270.
The authors compared neuropsychological outcomes in more than 1,000 children aged 7-10 years with the number of vaccine-specific antigens to which they were exposed during the first 24 months of life. They found no correlation between the number of vaccine-specific antigens received and adverse neuropsychological outcomes.

Smith MJ and Woods CR. On-time vaccine receipt in the first year does not adversely affect neuropsychological outcomes. Pediatrics 2010;125;1134-1141.
The authors compared long-term neuropsychological outcomes in children who received vaccines on time with those with delayed or incomplete vaccination during infancy. Timely vaccination was not associated with adverse neuropsychological outcomes 7 to 10 years later. The authors concluded that there was no benefit in delaying immunizations during the first year of life.

Hviid A, Wohlfahrt J, Stellfeld M, et al.  Childhood vaccination and nontargeted infectious disease hospitalization. JAMA 2005;294(6):699-705.
The authors evaluated the relationship between routinely administered childhood vaccines and the occurrence of non-targeted infectious diseases in more than 800,000 children. They found that neither the number of vaccines nor the receipt of multiple-antigen vaccines increased the risk of hospitalizations caused by non-targeted infectious diseases.

Offit PA, Quarles J, Gerber MA, et al.  Addressing parents’ concerns: do multiple vaccines overwhelm or weaken the infant’s immune system? Pediatrics 2002;109(1):124-129.
Given the number of antibody-generating B cells in the circulation, the number of vaccine-specific antigens to which infants are exposed during the first few years of life, and the quantity of antibodies necessary to react to each antigen, the authors estimated that infants have the theoretical capacity to respond to at least 10,000 vaccines at one time. The authors also showed that the number of immunological components in current vaccines is actually less than the one vaccine (smallpox) that children received 100 years ago.

For a scientific overview of this topic, please visit the Vaccine Ingredients section of our website.

Gadzinowski J, Tansey SP, Wysocki J, et al. Safety and immunogenicity of a 13-valent pneumococcal conjugate vaccine manufactured with and without polysorbate 80 given to healthy infants at 2, 3, 4, and 12 months of age. Pediatr Infect Dis J 2015;34:180-185.
The authors investigated the safety and immunogenicity of PCV-13 manufactured with or without polysorbate 80 (P80) in infants at 2, 3, 4 and 12 months of age. Immunogenicity and safety was similar for both formulations.

For a scientific overview of this topic, please visit the Vaccine Ingredients — Yeast section of our website.

Wiedermann G, Scheiner O, Ambrosch F, Kraft D, Kollaritsch H, et al. Lack of induction of IgE and IgG antibodies to yeast in humans immunized with recombinant hepatitis B vaccines. Int Archs Allergy Appl Immun 1988;85:130-132.
Volunteers were inoculated with three doses of yeast-derived hepatitis B vaccines at monthly intervals and compared with plasma derived vaccines. Before and four weeks after  immunizations, blood samples were tested for presence of IgE or IgG antibodies against yeast antigens related to Saccharomyces cerevisiae and Candida albicans, respectively, as cross-reactivity exists between the two genera. No rise in IgE antibodies against Saccharomyces cerevisiae antigens nor in IgG antibodies against Candida albicans antigens was found. The authors concluded that yeast proteins in recombinant hepatitis B vaccines do not cause type I or type III allergic reactions.

Petre J, Van Wijnendaele F, De Neys B, Conrath K, Van Opstal O, et al. Development of a hepatitis B vaccine from transformed yeast cells. Postgrad Med H 1987;63(Suppl 2):73-81.
Researchers tested subjects before and after exposure to the yeast-derived recombinant hepatitis B vaccine for anti-yeast antibodies. All subjects tested positive for anti-yeast IgG antibodies before vaccination, and 1-2% of subjects had low levels of anti-yeast IgE antibodies prior to immunization.  IgG antibody titers fluctuated after immunization, and were not related to any adverse reactions. Yeast-derived vaccine is safe, even in subjects with pre-existing anti-yeast IgE antibodies.

Zajac BA, West DJ, McAleer WJ, Scolnick EM. Overview of clinical studies with hepatitis B vaccine made by recombinant DNA. J Infect 1986;13(Suppl A):39-45.
The antigen used in the yeast-recombinant hepatitis B vaccine is derived from a culture of Saccharomyces cerevisiae (common baker’s yeast) and trace quantities of yeast protein exist within the product. As such, there is a theoretical concern that administration of a vaccine prepared in yeast might induce allergic reactions to yeast proteins. Researchers tested the sera of 133 persons before and after receipt of the recombinant vaccine for anti-yeast antibodies. One-hundred percent of individuals had anti-yeast IgG in both pre- and post-vaccination samples, presumably from exposure through eating bread. Levels fluctuated after receipt. Adverse reactions were not more frequent in persons with rises in yeast antibody titers.

Paul Offit, MD
Director, Vaccine Education Center
Children’s Hospital of Philadelphia

Stanley A  Plotkin, MD
Emeritus Professor of Pediatrics, University of Pennsylvania

Dorit Reiss, JD
Professor, University of California Hastings College of Law

Heather Bodenstab, PharmD
Children’s Hospital of Philadelphia