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The United States’ long-standing vaccine safety program closely 

and constantly monitors the safety of vaccines. This chapter 

describes how vaccines licensed for use in the United States are 

monitored for safety and presents general information about 

the health care provider’s role in immunization safety. 

Adverse Events Following Immunization 

and Assessment of Causality

An adverse event following immunization refers to any medical 

event that occurs after vaccination. The adverse event may or 

may not be related to immunization. Further assessment is 

needed to determine if an adverse event is caused by a vaccine. 

A vaccine adverse reaction or side effect is an untoward effect 

caused by a vaccine.

Adverse events following immunization can be classified by 

frequency (common, rare), extent (local, systemic), severity 

(mild, moderate, severe), seriousness (life-threatening, 

requiring hospitalization, or causing disability or death), 

causality, and preventability (intrinsic to vaccine, production 

challenge, administration error). Adverse events following 

immunization may be coincidental, or the vaccine may 

have increased the risk of the adverse event. Many adverse 

events following vaccination are coincidental; they are 

temporally related to vaccination but occur by chance 

without a causal relationship. 

To assess causality of an adverse event following immunization, 

a great deal of information is generally needed. An adverse 

health event can be causally attributed to a vaccine more 

readily if: 

• The health problem occurs during a plausible time period

following vaccination.

• The adverse event corresponds to adverse events previously

associated with the vaccine.

• The event is consistent with a specific clinical syndrome

where association with vaccination has strong biologic

plausibility (e.g., anaphylaxis) or where the syndrome is

known to occur following the natural disease.

• A laboratory result confirms the association (e.g., isolation

of vaccine-strain varicella virus from skin lesions of a patient

with rash).

• The event recurs with re-administration of the vaccine in

the same patient.

A. Patricia Wodi, MD and Tom Shimabukuro, MD, MPH, MBA

NOTES

https://www.cdc.gov/vaccines/pubs/pinkbook/safety.html Aug 2021
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• A controlled clinical trial or epidemiologic study shows

greater risk of a specific adverse event among vaccinated

versus unvaccinated groups.

• A finding linking an adverse event to a vaccine has been

confirmed by other studies.

Importance of Vaccine Safety Programs

Like any medical product, no vaccine is completely without 

risk. While most vaccine adverse reactions are minor and 

self-limited, some vaccines have been associated with 

extremely rare but serious health effects. The following key 

considerations underscore the need for an active and ongoing 

vaccine safety program. 

Decreases in Disease Risks

Most vaccine-preventable diseases are at or near record lows. 

Many people no longer see reminders of the severity and 

potential life-threatening complications of these diseases. 

Parents and providers in the United States may be more likely 

to know someone who has experienced an adverse event 

(an event that may or may not be related to vaccination) 

following vaccination than they are to know someone who 

has experienced a vaccine-preventable disease. The success of 

vaccination has led to increased public attention on potential 

health risks associated with vaccines. 

Public Confidence

Maintaining public confidence in vaccines is critical to 

prevent a decline in vaccination coverage that can result in 

outbreaks of disease. While most parents understand the 

benefits of vaccination and have their children vaccinated, 

some parents have concerns about the safety of vaccines. 

Despite high national vaccination coverage, there are local 

areas of low coverage that allow outbreaks of vaccinepreventable diseases to occur, often the result of parents 

refusing or delaying their children’s vaccinations because of 

concerns about vaccine safety. 

A higher standard of safety is generally expected of vaccines 

than of other medical interventions because, in contrast to most 

pharmaceutical products that are administered to ill persons 

for treatment purposes, vaccines are generally administered 

to healthy persons to prevent disease. Public tolerance for 

adverse reactions related to products given to healthy persons, 

especially healthy infants and children, is substantially less 

than for reactions to products administered to persons who 

are already sick. Less tolerance of risk associated with vaccines 

requires close monitoring and timely assessment of vaccine 

adverse events to help distinguish true vaccine adverse 

reactions from coincidental unrelated events and to help 

maintain public confidence in vaccination. 

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Balancing Immunization Recommendations 

with Risk of Disease

Public health recommendations for immunization programs 

and practices represent a dynamic balance of risks and 

benefits. Vaccine safety monitoring is necessary to accurately 

weigh this balance and adjust immunization policy. For 

example, monitoring of smallpox and oral polio vaccines being 

used in the United States as these diseases neared global 

eradication found complications associated with each vaccine 

that exceeded the risks of the diseases. This observation led to 

discontinuation of routine smallpox vaccination in the United 

States prior to global eradication and a shift from the oral 

poliovirus vaccine to a safer, inactivated poliovirus vaccine. 

Assessing and Monitoring Vaccine Safety

Prelicensure

Vaccines, like other pharmaceutical products, undergo extensive 

safety and efficacy evaluations in the laboratory, in animals, 

and in sequentially phased human clinical trials prior to 

licensure. Phase I human clinical trials usually involve anywhere 

from 20 to 100 volunteers and focus on detecting serious 

adverse reactions. Phase II trials generally enroll hundreds of 

volunteers and determine the best dose and number of doses 

for effectiveness and safety. Phase I and II trials might take a few 

months or last up to three years. Phase III trials involve a few 

hundred to several thousand volunteers and may last several 

years. Some volunteers receive another vaccine that has already 

been licensed, allowing researchers to compare one vaccine 

with another for adverse health effects, anything from a sore 

arm to a serious reaction. If the vaccine is shown to be safe 

and effective in a Phase III trial, the manufacturer applies for a 

license from the Food and Drug Administration (FDA). During 

the application process, the FDA reviews the clinical trial results, 

product labeling, and manufacturing plant and protocols. If 

approved, the FDA licenses the vaccine itself (product license) 

and licenses the manufacturing plant where the vaccine will be 

produced (establishment license). 

Postlicensure Vaccine Safety Monitoring

Monitoring for adverse reactions is essential even after vaccine 

licensure because rare reactions, delayed reactions, or reactions 

among subpopulations may not be detected before vaccines 

are licensed. While Phase III trials include enough persons to 

identify certain potential adverse reactions, such as injectionsite reactions and fever, the comparatively small number of 

patients enrolled in these trials generally limits detection of rare 

adverse reactions, including those occurring many months after 

the vaccine is administered. For example, in the pentavalent 

NOTES
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rotavirus vaccine trials, 70,000 infants received either vaccine 

or placebo, permitting evaluation of safety with respect to 

intussusception, which occurs so rarely that large trials would be 

needed to detect even a single occurrence. 

The objectives of postlicensure vaccine safety monitoring 

activities are to:

• Identify rare adverse reactions not detected during 

prelicensure studies.

• Monitor increases in known adverse reactions 

after vaccination.

• Identify risk factors or preexisting conditions that may be 

associated with a higher incidence of adverse reactions.

• Identify whether particular vaccine lots have unusually 

high rates or certain types of reactions.

• Identify possible adverse events that might warrant 

further study to establish the association of an 

adverse event with vaccination or affect current 

immunization recommendations. 

To achieve these objectives, as part of the FDA approval process, 

some vaccines enter Phase IV clinical trials (postmarketing 

studies) to obtain information beyond what Phases I through 

III provided. Also, fundamental to preventing safety problems 

is the assurance that all vaccines are made using good 

manufacturing practices and undergo lot testing for purity and 

potency. Manufacturers must submit samples of each vaccine 

lot and results of their own tests for purity and potency to 

the FDA before releasing vaccine lots for public use. Several 

monitoring systems are used in the United States to detect and 

study adverse events following immunization. CDC and the 

FDA use four main systems to monitor the safety of vaccines 

in use: the Vaccine Adverse Event Reporting System (VAERS), 

the Vaccine Safety Datalink (VSD), the Postlicensure Rapid 

Immunization Safety Monitoring System (PRISM), and the 

Clinical Immunization Safety Assessment (CISA) project.

Vaccine Adverse Event Reporting System (VAERS)

The National Childhood Vaccine Injury Act of 1986 mandates 

that vaccine providers and vaccine manufacturers report certain 

adverse events following vaccinations. This led to the creation 

of the Vaccine Adverse Event Reporting System (VAERS) in 1990. 

VAERS is a national, spontaneous surveillance system, jointly 

administered by CDC and the FDA. It receives about 30,000 

reports per year, a seemingly large number, but relatively small 

considering that millions of doses of vaccines are administered 

yearly to adults and children in the United States. 

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Vaccine providers are required by law to report: 

• Any adverse event listed by the vaccine manufacturer as a 

contraindication to further doses of the vaccine 

• Any adverse event listed in the VAERS Table of Reportable 

Events Following Vaccination (vaers.hhs.gov/resources/

VAERS_Table_of_Reportable_Events_Following_

Vaccination.pdf)

Vaccine providers are encouraged to report:

• Any adverse event that occurs after the administration of a 

U.S. licensed vaccine, whether it is or is not clear a vaccine 

caused the adverse event

• Vaccine administration errors

Vaccine manufacturers are required to report all adverse events 

that come to their attention.

VAERS collects information about the patient, the vaccine(s) 

administered, the adverse event, and the person reporting 

the event. All reports are coded using Medical Dictionary for 

Regulatory Activities (MedDRA) terms and entered into the 

VAERS database. Attempts are made to obtain additional 

medical information for all reports classified as a serious 

adverse event, including hospitalization or prolongation of 

hospitalization (if a vaccine was administered in the hospital), 

life-threatening illness, permanent disability, congenital 

deformity, or death. For these reports, letters to obtain 

information about recovery status are also sent to the persons 

reporting the events. All patient-identifying information 

submitted to VAERS, directly or as part of follow-up activities, is 

protected by strict confidentiality requirements.

VAERS has limitations inherent to spontaneous reporting 

systems. Also, VAERS is not designed to determine if a vaccine 

caused an adverse event, and additional studies are required to 

confirm possible safety signals detected by VAERS. 

Despite these limitations, VAERS has been able to fulfill its 

primary purpose of detecting new or rare vaccine adverse 

events, increases in rates of known adverse reactions, and 

patient risk factors for types of adverse reactions. In addition, 

VAERS often provides early safety data after a vaccine is licensed 

or during a public health emergency. De-identified VAERS 

reports can be viewed on the VAERS web page. 

NOTES
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Vaccine Safety Datalink (VSD)

CDC established the VSD to address gaps in the scientific 

knowledge of rare and serious adverse events following 

vaccination. This project involves partnerships with large, 

integrated health plans to monitor vaccine safety. Each 

participating plan uses its electronic health records and 

immunization information systems to contribute to a large, 

linked database. These participating health plans serve more 

than 10 million people annually, representing nearly 3% of 

the U.S. population, and contain records for more than 180 

million vaccinations, enabling the VSD to study possible rare 

adverse events. Available information includes vaccination data 

(vaccine type, vaccination date, concurrent vaccinations), health 

conditions, medical encounter types (outpatient, inpatient, 

urgent care), birth data, and census data. 

The VSD allows for planned immunization safety studies, 

as well as timely investigations of hypotheses arising from 

review of medical literature, reports to VAERS, changes in 

immunization schedules, or the introduction of new vaccines. 

A rapid cycle analysis conducted by the VSD enables CDC 

and its co-investigators to monitor adverse events following 

vaccination for a specific disease in near real time, so the public 

can be informed quickly of possible risks. 

Data files used in VSD studies remain at each participating site; 

specific data are pulled together for each analysis and do not 

contain personal identifiers.

Clinical Immunization Safety Assessment (CISA) Project

The CISA Project’s mission is to improve the understanding 

of adverse events following immunization at the individual 

patient level. The CISA Project provides consultation to public 

health partners in the United States and conducts high-quality 

clinical research, including clinical trials across life stages, on the 

safety of influenza vaccines and the safety of vaccines in special 

populations. All clinical research studies conducted by the CISA 

Project are registered on clinicaltrials.gov.

The goals of the CISA Project are to: • Serve as a vaccine safety resource for U.S. healthcare 

providers with complex vaccine safety questions 

about a specific patient to assist with immunization 

decision-making 

• Assist CDC / Health and Human Services (HHS) and partners 

in evaluating emerging vaccine safety issues

• Conduct clinical research studies to better understand 

vaccine safety and identify preventive strategies for adverse 

events following immunization

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4

Postlicensure Rapid Immunization Safety Monitoring 

System (PRISM)

FDA’s PRISM uses a computer algorithm to conduct active 

vaccine safety surveillance. A cooperative effort between FDA’s 

Center for Biologics Evaluation and Research and four health 

care and medical insurance organizations, PRISM analyzes 

health insurance claims data for potential vaccine safety signals. 

PRISM is also used to evaluate safety issues in targeted groups 

and to evaluate specific health conditions or outcomes. 

PRISM is part of FDA’s Sentinel Initiative, a national electronic 

system for medical product safety surveillance.

Vaccine Injury Compensation Program (VICP)

A main impact of the National Childhood Vaccine Injury Act 

(NCVIA) was the creation of the VICP. This program, administered 

by the Health Resources and Services Administration, provides 

financial compensation to persons who are found to have 

been injured by a vaccine covered by the program. VICP 

provides liability protection for vaccine manufacturers and 

administrators. Compensation is provided to persons who 

experience certain vaccine adverse reactions on a no-fault 

basis. No fault means persons filing claims are not required to 

prove negligence on the part of either the health care provider 

or manufacturer to receive compensation. The program covers 

most vaccines routinely given in the United States. 

Claims may be based on a Vaccine Injury Table, which lists 

conditions associated with each vaccine and provides a 

rebuttable presumption of causation, or by proving by 

preponderant evidence that the vaccine caused an injury not 

listed in the table. The Vaccine Injury Table was developed 

initially by Congress to provide swift compensation to persons 

possibly injured by vaccines. The table continues to be 

amended by the Secretary of the Department of Health and 

Human Services (DHHS) to better reflect current science as 

more information becomes available from research on vaccine 

adverse reactions. 

During the 2009 H1N1 influenza pandemic, the federal 

government implemented another compensation program, 

the Countermeasures Injury Compensation Program (CICP). 

This program provides compensation for certain persons 

who are seriously injured by countermeasures as specified 

in a declaration by the Secretary of DHHS. Both bioterrorism 

and pandemic countermeasures are covered. Covered 

countermeasures within the CICP are not limited to vaccines 

and may include certain medications or devices used to 

diagnose, prevent, or treat the covered condition. People have 

one year from receipt of the countermeasure to file a claim with 

the CICP. 

NOTES
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The Vaccination Provider’s Role in 

Vaccine Safety

Even though the testing phases to approve a vaccine can take 

years before the vaccine can be licensed and vaccines are 

monitored continually for safety and effectiveness, 

vaccination providers also play a key role in helping to 

ensure the safety and efficacy of vaccines. Vaccine providers 

are responsible for proper vaccine storage, handling, 

and administration; timing and spacing of vaccine doses; 

observation of contraindications and precautions; and 

reporting of adverse events following vaccination to VAERS. 

Providers are also responsible for communicating with patients 

and parents about vaccine benefits and risks and for managing 

of vaccine adverse reactions.

Benefit and Risk Communication

Patients and parents should be informed of the benefits and 

risks of vaccines in understandable language. An opportunity 

for questions should be provided before each vaccination. 

Discussion of the benefits and risks of vaccination is sound 

medical practice and is required by law. 

The NCVIA legally requires vaccine information statements 

(VISs) be provided to the patient, parent, guardian, or legal 

representative by vaccine providers before each dose of vaccine. 

Documentation that the VIS was provided is also required. 

Copies of VISs are available from state and local immunization 

programs or can be downloaded from https://www.cdc.gov/

vaccines/hcp/vis/index.html. Translations of VISs into languages 

other than English are available from some immunization 

programs and the Immunization Action Coalition and are 

available at https://immunize.org/vis/. 

Vaccine providers should anticipate questions parents 

or patients may have regarding the need for or safety of 

vaccination. Some people may refuse certain vaccines or even 

reject all vaccinations. Some people might have religious 

or personal objections to vaccination. It is essential that 

health care providers have a basic understanding of how 

patients view vaccine risk and develop effective approaches 

to deal with vaccine safety concerns when they arise. When 

a parent or patient initiates discussion of a vaccine concern, 

the provider should discuss the specific concern and use 

appropriate language to provide facts. Effective, empathic 

vaccine risk communication is essential in responding to 

misinformation and concerns. It is important to remind parents 

that state laws for school or childcare entry might require 

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unvaccinated children to stay home from school during 

outbreaks. For patients who question or refuse vaccination, 

identifying common ground and discussing measures 

for deferring vaccination are more effective public health 

strategies than excluding these patients from a practice. 

VISs provide an outline for discussing vaccine benefits and risks. 

While documentation of VIS distribution is required, additional 

information about discussions should be documented in the 

patient’s record, including the refusal to receive certain vaccines 

(i.e., informed refusal). Such documentation might reduce any 

potential liability if a vaccine-preventable disease occurs in the 

unvaccinated patient. 

Managing Adverse Reactions after Vaccination

Health care providers should be familiar with identifying 

immediate-type allergic reactions, including anaphylaxis, and 

be competent in treating these events at the time of vaccine 

administration. While severe allergic reactions to vaccines are 

rare, occurring at an approximate rate of one to two for every 

1 million doses of vaccine administered, all vaccine providers 

should have emergency procedures in place and be prepared 

to provide emergency care for a person who experiences an 

anaphylactic reaction. This includes the ability to administer 

epinephrine and certification in cardiopulmonary resuscitation 

(CPR). Equipment for maintaining an airway should be available 

for immediate use. All health care personnel should be familiar 

with their office emergency plan.

NOTES
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Acknowledgements

The editors would like to acknowledge Jennifer Hamborsky, 

Andrew Kroger, Michael McNeil, Valerie Morelli, John Su, and 

Eric Weintraub for their contributions to this chapter.

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NOTES