Potential Adverse Events Following Immunization

Summaries of the Evidence

This section addresses the numerous potential adverse events that have been studied in order to determine if an association exists with routine immunization in the United States, and supplements the vaccine information summaries for those seeking more information about a specific adverse event.

The independent 2012 report by the Institute of Medicine (IOM), now called the National Academy of Medicine (NAM), entitled Adverse Effects of Vaccines: Evidence and Causality ¹ was relied upon heavily to compile both the list of adverse events and the sources providing the best evidence for each adverse event. The 2014 and 2021 reports by the Agency for Healthcare Research and Quality (AHRQ) entitled Safety of Vaccines Used for Routine Immunization in the United States (Evidence Report/Technology Assessment No. 215) ² and Safety of Vaccines Used for Routine Immunization in the United States: An Update (Comparative Effectiveness Review No. 244) ³ were used to update and supplement the IOM report, as well as our own systematic literature searches and general knowledge. The aforementioned AHRQ reports were also summarized in review articles in the journals Pediatrics ⁴ and Vaccine ⁵, respectively.

In order to consistently and succinctly characterize the frequency of adverse events in this section, definitions used by the World Health Organization are used here, as outlined in the table below.

In order to summarize the evidence regarding potential adverse events in an accurate, concise, practical and standardized manner, we established the categories of causality conclusions outlined the table below.

Categories of Causality Conclusions*

Categories	Definitions
Vaccines can cause the event.	The evidence shows a clear association between the event and at least one vaccine routinely recommended in the U.S.
Vaccines did cause the event.	The evidence showed a clear association between the event and at least one previously recommended vaccine. However, these vaccine(s) are no longer used in the U.S., if they ever were.
Vaccines have not been shown to cause the event.	The evidence of an association between the event and vaccines currently routinely recommended to the general population in the United States is insufficient or non-existent.
Vaccines do not cause the event.	The evidence shows clear lack of association between the event and vaccines currently routinely recommended to the general population in the United States.

Regarding the category, ‘Vaccines have not been shown to cause the event,’ some may misrepresent conclusions such as this to suggest that the adverse event in question has not been examined and therefore is likely, offering personal anecdotes in support of their argument. We caution against such interpretations. In most of these instances, the specific condition in question is quite rare in the general population (for example, affecting fewer than 1 in 10,000 individuals in a given year). Simply because of their rarity, it is very difficult to quantify risk estimates for such conditions. In almost all cases where we conclude “Vaccines have not been shown to cause the event,” if there were a risk greater than our category of ‘very rare,’ (<1:10,000), that risk would have been detected under existing surveillance systems. For rare conditions, it is inherently difficult to quantify very rare risks.

We summarize several special topics of interest related to vaccine safety, as shown in the table below.

Special Topics of Interest Related To Vaccines Currently Routinely Recommended for The General Population in The United States^*

Topic	Conclusion
Combination Vaccines or Simultaneous Vaccination	MMRV can rarely cause febrile seizures in infants and young children, at slightly higher rates than individual administration of MMR and varicella vaccines. Simultaneous administration of influenza and pneumococcal conjugate vaccines can rarely cause febrile seizures in infants and young children, at slightly higher rates than separate administration of these vaccines. No other adverse events have been shown to be caused by combination vaccines or simultaneous vaccination as compared to separate administration of available individual vaccine components.
Vaccine Ingredients	Certain ingredients found in some vaccines, such as gelatin or neomycin, can very rarely cause severe hypersensitivity reactions (e.g. anaphylaxis) in those who are allergic to these specific ingredients.

The summaries of potential adverse events are arranged in alphabetical order. They have also been organized by the conclusions drawn in the tables below for convenience purposes. For the majority of these potential adverse events, there are no studies of quality that show an association with routine immunization in the United States.

Causal Relationship Established With Vaccines Currently Routinely Recommended for The General Population in The United States*

Adverse Event	Conclusion
Anaphylaxis	Vaccine components can very rarely cause anaphylaxis.
Arthralgia/Arthritis (mild, acute, transient – not chronic)	Rubella-containing vaccines can cause mild, acute, transient arthralgia or arthritis, very commonly in adult women but rarely in children. Other U.S. vaccines have not been shown to cause arthralgia or arthritis.   Vaccines have not been shown to cause chronic arthralgia/arthritis, as stated in the table below.
Deltoid Bursitis/Shoulder Injury Related to Vaccination (SIRVA)	Incorrect administration of vaccines can cause deltoid bursitis/SIRVA.
Disseminated Varicella Infection	Varicella vaccine can rarely cause disseminated varicella infection in immune deficient individuals for whom the vaccine is contraindicated.
Encephalitis	Measles vaccine can very rarely cause encephalitis. Mumps vaccine used in other countries did cause encephalitis (but not the vaccine licensed in the U.S.).
Febrile Seizures	Vaccines that induce fever in infants and young children, such as MMRV, influenza, and PCV vaccines, can rarely cause febrile seizures.
Guillain-Barré Syndrome (GBS)	Influenza vaccine can cause GBS very rarely in adults. An old formulation of rabies vaccine (no longer available) did cause GBS. Other vaccines, including current rabies vaccine, have not been shown to cause GBS.
Hepatitis	Varicella vaccine can rarely cause hepatitis if administered to persons with certain immune deficiencies. Vaccines given to immunocompetent persons do not cause hepatitis.
Herpes Zoster	Varicella vaccine can rarely cause herpes zoster due to vaccine-strain viral reactivation.
Immune Thrombocytopenic Purpura (ITP)	MMR vaccine can very rarely cause ITP in children.
Meningitis	Reactivation of varicella vaccine can very rarely cause meningitis. Mumps vaccine used in other countries (but not the vaccine licensed in the U.S.) did cause meningitis.
Syncope	Vaccines (and other injections) can rarely cause syncope.

No Causal Relationship Established With Vaccines Currently Routinely Recommended for the General Population in The United States*

Adverse Event	Conclusion
Acute Disseminated Encephalomyelitis (ADEM)	An old formulation of rabies vaccine (no longer available) did cause ADEM.  Other vaccines, including current rabies vaccine, have not been shown to cause ADEM.
Arthralgia/Arthritis (chronic)	Vaccines have not been shown to cause chronic arthralgia/arthritis.
Asthma	Influenza vaccines do not cause asthma. Other vaccines have not been shown to cause asthma.
Ataxia	Vaccines have not been shown to cause ataxia.
Autism	Childhood vaccines do not cause autism. Maternal vaccines have not been shown to cause autism.
Brachial Neuritis	Vaccines have not been shown to cause brachial neuritis.
Chronic Fatigue Syndrome	Vaccines have not been shown to cause chronic fatigue syndrome.
Chronic Inflammatory Disseminated Polyneuropathy (CIDP)	Vaccines have not been shown to cause CIDP.
Chronic Urticaria	Vaccines have not been shown to cause chronic urticaria.
Complex Regional Pain Syndrome (CRPS)	Vaccines have not been shown to cause CRPS.
Diabetes	Vaccines do not cause diabetes.
Epilepsy	Vaccines have not been shown to cause epilepsy.
Erythema Nodosum	Vaccines have not been shown to cause erythema nodosum.
Fibromyalgia	Vaccines have not been shown to cause fibromyalgia.
Hearing Loss	Vaccines have not been shown to cause hearing loss.
Infantile Spasms	Vaccines have not been shown to cause infantile spasms.
Multiple Sclerosis (MS)	Influenza vaccine does not cause MS in adults. Influenza vaccine has not been shown to cause MS in children. Other vaccines have not been shown to cause MS.
Myocardial Infarction (MI)	Vaccines have not been shown to cause MI.
Myocarditis	Smallpox vaccine can very rarely cause myocarditis, but is not routinely recommended to the general population in the U.S. Other vaccines have not been shown to cause myocarditis.
Narcolepsy	Current vaccines have not been shown to cause narcolepsy. AS03-adjuvanted 2009 pandemic H1N1 influenza vaccine used in Europe (not used in the U.S.) did very rarely cause narcolepsy.
Neuromyelitis Optica	Vaccines have not been shown to cause neuromyelitis optica.
Oculorespiratory syndrome (ORS)	Two influenza vaccines used in Canada (but not used in the U.S.) did commonly cause ORS. Changes made to the formulation of these vaccines have resulted in a dramatic decrease in the risk of ORS.
Opsoclonus Myoclonus Syndrome	Vaccines have not been shown to cause opsoclonus myoclonus syndrome.
Optic Neuritis	Vaccines have not been shown to cause optic neuritis.
Polyarteritis Nodosa	Vaccines have not been shown to cause polyarteritis nodosa.
Primary Ovarian Insufficiency (POI)	Vaccines have not been shown to cause POI.
Transverse Myelitis	Vaccines have not been shown to cause transverse myelitis.
Serum Sickness	Vaccines have not been shown to cause serum sickness.
Small Fiber Neuropathy	Vaccines have not been shown to cause small fiber neuropathy.
Spontaneous Abortion	Maternal vaccines have not been shown to cause spontaneous abortion.
Stroke	Vaccines have not been shown to cause stroke.
Sudden Infant Death Syndrome (SIDS)	DTP and hepatitis B vaccines do not cause SIDS. Other vaccines have not been shown to cause SIDS.
Systemic Lupus Erythematosus (SLE)	Vaccines have not been shown to cause SLE.
Vasculitis	Vaccines have not been shown to cause vasculitis.

References

1.         Institute of Medicine. In: Stratton K, Ford A, Rusch E, Clayton EW, eds. Adverse Effects of Vaccines: Evidence and Causality. Washington (DC): National Academies Press (US); 2012.

2.         Maglione MA GC, Das L, Raaen L, Smith A, Chari R, Newberry S, Hempel S, Shanman R, Perry T, Goetz MB. Safety of Vaccines Used for Routine Immunization in the United States. Evidence Report/Technology Assessment No. 215. Rockville, MD: Agency for Healthcare Research and Quality, July 2014. (www.effectivehealthcare.ahrq.gov/reports/final.cfm).

3.         Gidengil C, Goetz MB, Maglione M, et al. Safety of Vaccines Used for Routine Immunization in the United States: An Update. Comparative Effectiveness Review No. 244. Rockville, MD: Agency for Healthcare Research and Quality, May 2021. (https://effectivehealthcare.ahrq.gov/products/safety-vaccines/research).

4.         Maglione MA, Das L, Raaen L, et al. Safety of vaccines used for routine immunization of U.S. children: a systematic review. Pediatrics 2014;134(2):325-37. (In eng). DOI: 10.1542/peds.2014-1079.

5.         Gidengil C, Goetz MB, Newberry S, et al. Safety of vaccines used for routine immunization in the United States: An updated systematic review and meta-analysis. Vaccine 2021;39(28):3696-3716. (In eng). DOI: 10.1016/j.vaccine.2021.03.079.