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.

Aluminum and vaccines

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

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.

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.

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.

Autism and the MMR vaccine

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

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.

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.

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.

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.

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.

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.

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. 

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.

DNA and vaccines

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

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.

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.

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.

Thimerosal (mercury) and vaccines

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

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.

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.

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.

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.

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.

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.

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.

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.

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”).

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.

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.

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.

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.

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. 

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. 

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.

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 May 31, 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.