Understanding Vaccine Safety

04 October, 2023

How are vaccine safety questions answered and by whom?

The safety of vaccines is evaluated consistently from clinical trials all the way to post-authorization/post-licensure studies. In clinical trials, vaccines are usually assessed for local and systemic events. Vaccines are said to be reactogenic or have high reactogenicity if they elicit substantial inflammation subsequent to immunization. Reactogenic events can include local outcomes such as injection site pain and redness/swelling at the injection site, as well as systemic outcomes including myalgia, arthralgia, fever and headache (Hervé, September 2019).

Sometimes, rare events may occur after vaccination that are too rare to be identified within clinical trials. These could include outcomes such as Guillain-Barré syndrome, ischemic stroke or myocarditis. Because background rates of these outcomes are very low, the only way to appropriately assess differences in risks of these outcomes is to measure relative risks in large populations. Therefore, vaccines continue to be assessed for safety in much larger populations (millions or tens of millions of people) after they are authorized and/or licensed for use. There are several infrastructures in place to investigate vaccine safety outcomes after vaccine authorization or licensure in the United States. These include the Vaccine Adverse Event Reporting System (VAERS) and the Vaccine Safety Datalink (VSD). Additional safety investigations and considerations are performed by FDA’s BEST system and by using information from the Centers for Medicare & Medicaid Services. Each of these systems plays a distinct and important role in COVID-19 vaccine safety investigations in the U.S.

Vaccine safety infrastructure in the U.S.

VAERS is an open database that collects reports of adverse events following vaccination. Health care providers are required to report certain COVID-19 vaccine safety outcomes to VAERS, but anyone can report events to VAERS, including care providers, child care professionals and individual patients/laypeople. VAERS is not structured to formally investigate causal relationships between vaccines and potential safety outcomes (Dusto, May 2022). Instead, it is an early warning system used to generate hypotheses about vaccine safety that can then be investigated using more robust methods.

VSD is composed of several large managed-care organizations in the U.S. Information from the electronic health records of individuals at these managed-care organizations is combined to investigate formally hypothesized relationships between vaccines and specific safety outcomes. These hypotheses may come from VAERS, v-safe or medical literature. VSD has been in existence since 1990 and currently includes electronic health data for approximately 3% of the U.S. population.

Until May 2023, CDC’s v-safe smartphone-based reporting system collected user-input data for COVID-19 vaccines specifically. In addition to common and usually nonserious adverse effects such as injection site pain, fatigue and headache, some more serious safety signals have been identified in relation to COVID-19 vaccination thanks to a combination of the vaccine safety infrastructures described above.

History of COVID-19 vaccine safety investigations in VAERS and VSD

VAERS, v-safe and VSD have all been continuously monitoring the safety of COVID-19 vaccines since they were originally rolled out. Specific U.S.-based safety investigations have included (not an exhaustive list):

Overall assessments

Assessments in children


Immunocompromised populations and pregnant people

How is vaccine safety information used in policy decisions?

At CDC’s Advisory Committee on Immunization Practices meetings, information from published and as-yet-unpublished vaccine safety research is shared and discussed. This information is first discussed, analyzed and synthesized in vaccine-specific workgroups, including the Vaccine Safety Technical Workgroup. After workgroup discussions, the findings of the workgroup are presented more broadly in public discussions with all ACIP members. Additional presentations from vaccine safety research may also occur in broader, public ACIP meetings. The findings of safety studies play an important role in ACIP recommendations for vaccine policy. For example, after updated safety information regarding rare outcomes following the Janssen/Johnson & Johnson vaccine in December 2021, ACIP reviewed the evidence and issued a recommendation that mRNA vaccines were preferred over the Janssen/Johnson & Johnson vaccine.

What is the current status of COVID-19 vaccine safety research?

COVID-19 vaccine safety has been, and continues to be, very thoroughly and consistently investigated throughout the course of the pandemic. For each outcome that has been investigated and analyzed, the findings have been that the benefits of COVID-19 vaccination outweigh any potential risks caused by vaccines. Many outcomes are easily identified using International Classification of Diseases codes found in electronic health records. Some outcomes require further investigation, including manual review of medical records by trained research staff.

Still other outcomes may be extraordinarily challenging to identify using large-scale data. For example, the possibility of autonomic dysfunction after COVID-19 vaccination has recently been raised (Vogel, July 2023). The investigation of dysautonomia and similar syndromes, including postural orthostatic tachycardia syndrome, myalgic encephalomyelitis/chronic fatigue syndrome and complex regional pain syndrome, is challenging because these syndromes often take a long time to develop and a long time to diagnose.

There are additional key concerns surrounding substantial potential inequity in how these syndromes may be diagnosed, according to race, sex and other social determinants of health. Additionally, for some of these syndromes, there are no dedicated ICD codes, meaning that algorithms, manual chart review or direct patient surveys may be required to appropriately identify the outcome. The challenging nature of these outcomes does not outweigh the importance of assessing them for vaccine safety considerations. For such outcomes, additional novel methodology for vaccine safety investigations is being considered and being used, including natural language processing, machine learning methods and artificial intelligence. 

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