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

Updated November 7, 2023



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, the rate of febrile seizures in the 7-10 days after vaccination was approximately 2-3 times higher for children who received MMRV as compared to MMR and varicella vaccines administered separately on the same day and 4 times higher as compared to MMR alone, 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 increase the risk of 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 Immunization Schedule, 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 occurred at a rate of 26.4 per 1000 person-years after MMR and 84.6 per 1,000 person-years after MMRV (ProQuad®) in the 7-10 days after vaccination 17. 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®) 17-22. 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 23,24. 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 (VSD) 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.

A randomized trial in France and Belgium during the 2014–2015 influenza season found no difference in rates of symptoms among older adults comparing co-administration of IIV4 and PPV23 with separate administration, with the exception of injection site pain which occurred more frequently in the co-administration group 34. A 2016 report summarizing ten phase 3 and 4 studies found no impact on vaccine reactogenicity or safety when co-administering routine vaccines with MenACWY-CRM 35. A phase II randomized study found that co-administration of bivalent meningococcal B vaccine and DTaP/IPV was safe and well tolerated 36.

Retrospective cohort studies using the VSD found no increase in risk of acute adverse events or adverse birth outcomes among those vaccinated with Tdap or influenza vaccines during pregnancy 37, as well as 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 38. 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 39.

A VSD nested case-control study of nearly half a million children found no significant difference in estimated cumulative vaccine antigen exposure through the first 23 months of life comparing children ages 2 to 4 years with infections not targeted by the vaccines versus children without such infections 40.

* These conclusions do not necessarily consider vaccines recommended only for special populations in the United States such as Yellow Fever vaccine (international travelers) or Smallpox vaccine (military personnel), or vaccines no longer recommended to the public such as the Janssen (J&J) COVID-19 vaccine.


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