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.

Adjuvants other than aluminum in vaccines

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 nonadjuvanted 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 adjvanted 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 Gardasi®l, 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 Cervarix was 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 1/10th dose) plus CPG 7909 to Fluarix® (full or 1/10th dose) plus saline and found all vaccines were generally well tolerated.

Aluminum and vaccines

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

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 5th percentile 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.

Autism and the MMR vaccine

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

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.

Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) in vaccines

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.

Diabetes and vaccines

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

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.

DNA and vaccines

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 oncogenic 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 an oncogenic 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 oncogenes 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 oncogenic and infective potential of residual host cell 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 an oncogene 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 oncogenicity and infectivity of cell DNA 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 CBER suggest that DNA fragments smaller than 200 base pairs will give substantial safety margins for products that meet the 10 ng/dose limit.

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 oncogene were present in the genome — could give rise to a transformational 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 oncogenes were injected into suitable hosts to determine the amount required to induce tumors in half of the experimental animals. 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 oncogenes in 100 pg 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 proto-oncogenes or active viral oncogenes.

Formaldehyde and vaccines

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.

Guillain-Barre Syndrome (GBS) and Vaccines

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

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 2009-20 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.

Multiple sclerosis and vaccines

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

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.

Thimerosal (mercury) and vaccines

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.

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.

Too many vaccines, too soon

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.

Vaccine ingredients

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.

Contributing authors

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

Reviewed by Paul A. Offit, MD, Heather Monk Bodenstab, PharmD on October 11, 2018

Materials in this section are updated as new information and vaccines become available. The Vaccine Education Center staff regularly reviews materials for accuracy.

You should not consider the information in this site to be specific, professional medical advice for your personal health or for your family's personal health. You should not use it to replace any relationship with a physician or other qualified healthcare professional. For medical concerns, including decisions about vaccinations, medications and other treatments, you should always consult your physician or, in serious cases, seek immediate assistance from emergency personnel.