Do Combination Vaccines or Simultaneous Vaccination Increase the Risk of Adverse Events?

Conclusion | Why This is an Issue | Epidemiological Evidence | Archives | References


Certain combination vaccines or simultaneous administration of vaccines that are known to cause fever can rarely cause febrile seizures in infants and young children beyond the risk presented by individually administered vaccines. Specifically, if MMRV is used instead of MMR as the first dose of measles-containing vaccine, the risk of febrile seizures in infants and young children 7-10 days after vaccination increases from approximately 1 per 2,500 doses of MMR to 1 per 1,250 doses of MMRV, and when influenza and pneumococcal conjugate vaccines are given simultaneously as opposed to separately in children 6-59 months of age, the risk of febrile seizures in the 24 hours after vaccination increases from roughly 5 to 17.5 per 100,000 doses.

Simultaneous administration of Tdap and influenza vaccines during pregnancy does not cause acute adverse events or adverse birth outcomes. Combination vaccines and simultaneous administration of vaccines currently routinely recommended to the general population in the U.S.* have not been shown to cause any other adverse events at a greater rate than their individual vaccine components.

Why This is an Issue

Prior to 1985, vaccines protecting against seven diseases total were recommended for children under two years of age. As new vaccines have been developed, the number of vaccines that are recommended for children and the number of diseases they protect against have increased correspondingly. According to the 2016 Immunization Schedule, available on the website of the Centers for Disease Control and Prevention (CDC) at, the vaccinations recommended by the Advisory Committee on Immunization Practices (ACIP) for children under two has now increased to protect against 14 different diseases. This is good news; it means our children are protected against more serious diseases than before possible. However, it is understandable that this increase has raised some concern regarding the safety of vaccinating infants and young children with multiple immunizations in a short period of time.

Nonetheless, these concerns are unfounded. The immune systems of infants and children encounter millions of antigens in their environment every day; vaccines only contain a tiny fraction of a typical child’s daily exposure to antigens. New vaccines are tested extensively for safety and effectiveness at the recommended ages and with other recommended vaccines for years prior to introduction in the U.S. as part of the rigorous FDA requirements for licensure. The recommended schedule for children is then carefully constructed by the ACIP in collaboration with major physician organizations including the American Academy of Pediatrics and the American Academy of Family Physicians in order to provide the greatest possible safety and protection against disease. Refusing or delaying vaccines, or following alternative schedules, has been shown to increase risk of disease [1-12].

Epidemiological Evidence

Vaccines which may induce fever may also rarely induce febrile seizures. Febrile seizures are a common and typically benign childhood condition, occurring in 2-5% of children at some point during their first five years of life. Febrile seizures have an estimated background incidence of 240–480 per 100,000 person-years in children under five years, although this varies considerably by age, genetics, co-morbidities and environmental risk factors. There are no long-term effects of simple febrile seizures, [13-16]. See the Do Vaccines Cause Seizures summary for more details.

Febrile seizures occur at a rate of about 1 per 2,500 doses of MMR. The risk is increased to approximately 1 per 1,250 doses if the first dose is the combination vaccine MMRV (ProQuad®) [17, 18]. Several studies have confirmed that MMRV combination vaccine has a higher risk of febrile convulsions than simultaneous yet separate administration of the first dose of MMR and varicella vaccine (Varivax®) [19-24]. However, there is no increased risk of fever or febrile seizures in children receiving their second dose of measles-containing vaccine at 4 to 6 years of age, whether given MMR or MMRV [18]. Delaying MMR or MMRV vaccines past 15 months of age results in a higher risk of seizures than vaccinating according to the recommended schedule [25, 26].

Febrile seizures were estimated to occur at a rate of 17.5 per 100,000 doses in children aged 6-59 months after receiving concomitant trivalent inactivated influenza vaccine (abbreviation: TIV) and 13-valent pneumococcal conjugate vaccine (abbreviation: PCV13; trade name: Prevnar13®); lower rates of 4.9 per 100,000 doses and 5.3 per 100,000 doses were estimated in children who received TIV without concomitant PCV13 and in children who received PCV13 without concomitant TIV, respectively. However, these risk differences varied substantially with age due to the age-dependent background rates of febrile seizures, with the highest estimates at 16 months and the lowest at 59 months [16].

A large cohort study found a small increased risk of febrile seizures after the first two doses of the DTaP-IPV-Hib combination vaccine in Denmark, with an absolute risk of less than 4 per 100,000 vaccinations [27]. A large Vaccine Safety Datalink study found no association between seizures and the DTaP-IPV combination vaccine (Kinrix®) among children 4 to 6 years of age [28].

Two methodologically sound, controlled epidemiological studies found no association between autism spectrum disorder (ASD) and simultaneous vaccination with multiple vaccines [29, 30], as well as a meta-analysis [31]. See the Do Vaccines Cause Autism summary for more details.

A 2002 report by the Institute of Medicine (IOM), now called the National Academy of Medicine (NAM), entitled Immunization Safety Review: Multiple Immunizations and Immune Dysfunction, found that the evidence favors rejection of a causal relationship between multiple immunizations and increased risk for infections and for type I diabetes [32].

A 2013 IOM report entitled The Childhood Immunization Schedule and Safety: Stakeholder Concerns, Scientific Evidence, and Future Studies, the most comprehensive examination of the immunization schedule to date, uncovered no evidence of major safety concerns associated with adherence to the childhood immunization schedule [33].

Retrospective cohort studies using the Vaccine Safety Datalink found no increase in risk of acute adverse events or adverse birth outcomes among those vaccinated with Tdap during pregnancy when comparing those who had received a tetanus toxoid containing vaccine relatively recently with those who had not [34]. In addition, no increase in risk of acute adverse events or adverse birth outcomes were found among those vaccinated concurrently with Tdap and influenza vaccines during pregnancy compared to those vaccinated sequentially [35].


1. Phadke VK, Bednarczyk RA, Salmon DA, Omer SB. Association Between Vaccine Refusal and Vaccine-Preventable Diseases in the United States: A Review of Measles and Pertussis. Jama 2016;315:1149-58.
2. Feikin DR, Lezotte DC, Hamman RF, Salmon DA, Chen RT, Hoffman RE. Individual and community risks of measles and pertussis associated with personal exemptions to immunization. Jama 2000;284:3145-50.
3. Omer SB, Salmon DA, Orenstein WA, deHart MP, Halsey N. Vaccine refusal, mandatory immunization, and the risks of vaccine-preventable diseases. The New England journal of medicine 2009;360:1981-8.
4. Salmon DA, Haber M, Gangarosa EJ, Phillips L, Smith NJ, Chen RT. Health consequences of religious and philosophical exemptions from immunization laws: individual and societal risk of measles. Jama 1999;282:47-53.
5. Smith PJ, Humiston SG, Parnell T, Vannice KS, Salmon DA. The association between intentional delay of vaccine administration and timely childhood vaccination coverage. Public health reports (Washington, DC : 1974) 2010;125:534-41.
6. Luman ET, Barker LE, Shaw KM, McCauley MM, Buehler JW, Pickering LK. Timeliness of childhood vaccinations in the United States: days undervaccinated and number of vaccines delayed. Jama 2005;293:1204-11.
7. Invasive Haemophilus influenzae Type B disease in five young children--Minnesota, 2008. MMWR Morbidity and mortality weekly report 2009;58:58-60.
8. Glanz JM, McClure DL, Magid DJ, Daley MF, France EK, Hambidge SJ. Parental refusal of varicella vaccination and the associated risk of varicella infection in children. Archives of pediatrics & adolescent medicine 2010;164:66-70.
9. Glanz JM, McClure DL, O'Leary ST, et al. Parental decline of pneumococcal vaccination and risk of pneumococcal related disease in children. Vaccine 2011;29:994-9.
10. Omer SB, Pan WK, Halsey NA, et al. Nonmedical exemptions to school immunization requirements: secular trends and association of state policies with pertussis incidence. Jama 2006;296:1757-63.
11. Zipprich J, Winter K, Hacker J, Xia D, Watt J, Harriman K. Measles outbreak--California, December 2014-February 2015. MMWR Morbidity and mortality weekly report 2015;64:153-4.
12. Clemmons NS, Gastanaduy PA, Fiebelkorn AP, Redd SB, Wallace GS. Measles - United States, January 4-April 2, 2015. MMWR Morbidity and mortality weekly report 2015;64:373-6.
13. (AAP) AAoP. Neurodiagnostic evaluation of the child with a simple febrile seizure. Pediatrics 2011;127:389-94.
14. (AAP) AAoP. Febrile seizures: clinical practice guideline for the long-term management of the child with simple febrile seizures. Pediatrics 2008;121:1281-6.
15. Bonhoeffer J, Menkes J, Gold MS, et al. Generalized convulsive seizure as an adverse event following immunization: case definition and guidelines for data collection, analysis, and presentation. Vaccine 2004;22:557-62.
16. Tse A, Tseng HF, Greene SK, Vellozzi C, Lee GM. Signal identification and evaluation for risk of febrile seizures in children following trivalent inactivated influenza vaccine in the Vaccine Safety Datalink Project, 2010-2011. Vaccine 2012;30:2024-31.
17. Epidemiology and Prevention of Vaccine-Preventable Diseases. Washington D.C.: Centers for Disease Control and Prevention; 2015.
18. Vaccine Information Statements (VIS). 2015, at
19. Jacobsen SJ, Ackerson BK, Sy LS, et al. Observational safety study of febrile convulsion following first dose MMRV vaccination in a managed care setting. Vaccine 2009;27:4656-61.
20. Klein NP, Fireman B, Yih WK, et al. Measles-mumps-rubella-varicella combination vaccine and the risk of febrile seizures. Pediatrics 2010;126:e1-8.
21. Klopfer SO, Stek JE, Petrecz M, et al. Analysis of safety data in children after receiving two doses of ProQuad(R) (MMRV). Vaccine 2014;32:7154-60.
22. Macartney KK, Gidding HF, Trinh L, et al. Febrile seizures following measles and varicella vaccines in young children in Australia. Vaccine 2015;33:1412-7.
23. MacDonald SE, Dover DC, Simmonds KA, Svenson LW. Risk of febrile seizures after first dose of measles-mumps-rubella-varicella vaccine: a population-based cohort study. Cmaj 2014;186:824-9.
24. Schink T, Holstiege J, Kowalzik F, Zepp F, Garbe E. Risk of febrile convulsions after MMRV vaccination in comparison to MMR or MMR+V vaccination. Vaccine 2014;32:645-50.
25. Hambidge SJ, Newcomer SR, Narwaney KJ, et al. Timely versus delayed early childhood vaccination and seizures. Pediatrics 2014;133:e1492-9.
26. Rowhani-Rahbar A, Fireman B, Lewis E, et al. Effect of age on the risk of Fever and seizures following immunization with measles-containing vaccines in children. JAMA Pediatr 2013;167:1111-7.
27. Sun Y, Christensen J, Hviid A, et al. Risk of febrile seizures and epilepsy after vaccination with diphtheria, tetanus, acellular pertussis, inactivated poliovirus, and Haemophilus influenzae type B. Jama 2012;307:823-31.
28. Daley MF, Yih WK, Glanz JM, et al. Safety of diphtheria, tetanus, acellular pertussis and inactivated poliovirus (DTaP-IPV) vaccine. Vaccine 2014;32:3019-24.
29. Uno Y, Uchiyama T, Kurosawa M, Aleksic B, Ozaki N. The combined measles, mumps, and rubella vaccines and the total number of vaccines are not associated with development of autism spectrum disorder: the first case-control study in Asia. Vaccine 2012;30:4292-8.
30. DeStefano F, Price CS, Weintraub ES. Increasing exposure to antibody-stimulating proteins and polysaccharides in vaccines is not associated with risk of autism. The Journal of pediatrics 2013;163:561-7.
31. 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;32:3623-9.
32. Institute of Medicine Immunization Safety Review C. In: Stratton K, Wilson CB, McCormick MC, eds. Immunization Safety Review: Multiple Immunizations and Immune Dysfunction. Washington (DC): National Academies Press (US); 2002.
33. Institute of Medicine. The Childhood Immunization Schedule and Safety: Stakeholder Concerns, Scientific Evidence, and Future Studies. Washington (DC): National Academies Press (US); 2013.
34. Sukumaran L, McCarthy NL, Kharbanda EO, et al. Association of Tdap Vaccination With Acute Events and Adverse Birth Outcomes Among Pregnant Women With Prior Tetanus-Containing Immunizations. Jama 2015;314:1581-7.
35. Sukumaran L, McCarthy NL, Kharbanda EO, et al. Safety of Tetanus Toxoid, Reduced Diphtheria Toxoid, and Acellular Pertussis and Influenza Vaccinations in Pregnancy. Obstetrics and gynecology 2015;126:1069-74.