Science, Technology Assessment, FEBRUARY 2021 and Analytics WHY THIS MATTERS Safe vaccines are critical to fighting diseases, from polio to COVID-19. Research shows that the protection SCIENCE & TECH SPOTLIGHT: provided by U.S. licensed vaccines outweighs their VACCINE SAFETY potential risks. However, misinformation and unjustified safety concerns can cause people to delay or refuse vaccination, which may increase preventable deaths and prolong negative social and economic impacts. /// THE SCIENCE What is known? Vaccine developers assess safety from early research, through laboratory and animal testing, and even after the vaccine is in use What is it? A vaccine is generally considered safe when the benefits of (fig. 2). Researchers may rely on previous studies to inform future vaccine protecting an individual from disease outweigh the risks from potential trials. For example, safety information from preclinical trials of mRNA side effects (fig. 1). The most common side effects stem from the body’s flu vaccine candidates in 2017 allowed for the acceleration of mRNA immune reaction and include swelling at the injection site, fever, and aches. COVID-19 vaccine development. Vaccine candidates shown to be safe in these preclinical trials can proceed to clinical trials in humans. In the U.S., clinical trials generally proceed through three phases of testing involving increasing numbers of volunteers: dozens in phase 1 to thousands in phase 3. Although data may be collected over years, most common side effects are identified in the first 2 months after vaccination in clinical trials. After reviewing safety and other data from vaccine studies, the Food and Drug Administration (FDA) may license a vaccine to be marketed in the U.S. There are also programs to expedite—but not bypass—development and review processes, such as a priority review designation, which shortens FDA’s goal review time from 10 to 6 months. Safety monitoring continues after licensing. For example, health officials are required to report certain adverse events—such as heart problems— following vaccination, in order to help identify potential long-term or rare side effects that were not seen in clinical trials and may or may not be associated with the vaccine. Figure 1. Symptoms of polio and side effects of the polio vaccine. A vaccine is generally considered safe if its benefits (preventing disease) outweigh its risks (side effects). In rare cases, some vaccines may cause more severe side effects. For example, the vaccine for rotavirus—a childhood illness that can cause severe diarrhea, dehydration, and even death—can cause intestinal blockage in one in 100,000 recipients. However, the vaccine is still administered because this very rare side effect is outweighed by the vaccine’s benefits: it saves lives and prevents an estimated 40,000 to 50,000 childhood hospitalizations in the U.S. each year. The two messenger RNA (mRNA) vaccines authorized for COVID- 19—a disease that contributed to more than 415,000 American deaths between January 2020 and January 2021—can cause severe allergic reactions. However, early safety reporting found that these reactions have been extremely rare, with only about five cases per 1 million recipients, according to data from January 2021 reports by the Centers for Disease Control and Prevention. Figure 2. Vaccine safety is assessed at every stage: development through post-licensure. In general, side effects from vaccines are less acceptable to the public than side effects from treatments given to people who already have a Following a declared emergency, FDA can also issue emergency use disease. authorizations (EUA) to allow temporary use of unlicensed vaccines if there is evidence that known and potential benefits of the vaccine GAO-21-342SP Vaccine Safety Science, Technology Assessment, and Analytics outweigh known and potential risks, among other criteria. As of January /// CHALLENGES 2021, two COVID-19 vaccines had received EUAs, after their efficacy and short-term safety were assessed through large clinical trials. However, There are a number of challenges to ensuring safe vaccines: developers must continue safety monitoring and meet other requirements if they intend to apply for FDA licensure to continue distribution of these ■ Public confidence. Vaccine hesitancy, in part due to misinformation vaccines after the emergency period has ended. or historic unethical human experimentation, decreases participation in clinical trials, impeding identification of side effects across What are the knowledge gaps? One knowledge gap that can remain individuals with different racial, ethnic, and socioeconomic after clinical trials is whether side effects or other adverse events may backgrounds. occur in certain groups. For example, because clinical trials usually ■ Mutating viruses. Some viruses, such as those that cause the flu or exclude certain populations, such as people who are pregnant or have COVID-19, may mutate rapidly and thus may require new or updated existing medical conditions, data on potential adverse events related to vaccines, for which ongoing safety monitoring is important. specific populations may not be understood until vaccines are widely administered. ■ Long-term and rare effects. Exceedingly rare or long-term effects may not be identified until after vaccines have been widely In addition, it can be difficult to determine the safety of new vaccines administered. Further study is needed to detect any such effects and if outbreaks end suddenly. For example, vaccine safety studies were confirm they are truly associated with the vaccine. hindered during the 2014-2015 Ebola epidemic when a large increase in the number of cases was followed by a sharp decrease. This disrupted the /// POLICY CONTEXT AND QUESTIONS clinical trials of Ebola vaccine candidates, because the trials require many infected and non-infected people. ■ What steps can policymakers take to improve public trust and understanding of the process of assessing vaccine safety? Furthermore, a lack of understanding and/or misinformation about the ■ How can policymakers convey the social importance of vaccines to steps taken to ensure the safety of vaccines hinders accurate public protect the general public and those who are most vulnerable? knowledge about safety concerns, which may cause people to delay or refuse vaccination. This resulting hesitancy may, in turn, increase deaths, ■ How can policymakers leverage available resources to support social harm, and economic damage. ongoing vaccine development and post-licensure safety monitoring? /// OPPORTUNITIES /// SELECTED GAO WORK Continuing and, where necessary, improving existing vaccine safety GAO has previously issued the following related products: practices offers the following opportunities to society: ■ COVID-19: Federal Efforts Accelerate Vaccine and Therapeutic ■ Herd immunity. Widespread immunity in a population, acquired in Development, but More Transparency Needed on Emergency Use large part through safe and effective vaccines, can slow the spread Authorizations, GAO-21-207. of infection and protect those most vulnerable. ■ Operation Warp Speed: Accelerated COVID-19 Vaccine ■ Health care improvements. Vaccinations can reduce the burden on Development Status and Efforts to Address Manufacturing the health care system by reducing severe symptoms that require Challenges, GAO-21-319. individuals to seek treatment. /// SELECTED REFERENCES ■ Eradication. Safe vaccination programs, such as those combatting smallpox, may eliminate diseases to the point where transmission no Centers for Disease Control and Prevention, Vaccine Safety. Accessed January 12, 2021, longer occurs. https://www.cdc.gov/vaccinesafety/index.html. Food and Drug Administration, Vaccine Safety & Availability. Accessed January 12, 2021, https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics. GAO SUPPORT: This document is not an audit product and is subject to revision based on continued advances in science and technology. It contains information prepared by GAO GAO meets congressional information needs in several ways, including by to provide technical insight to legislative bodies or other external organizations. providing oversight, insight, and foresight on science and technology issues. This document has been reviewed by the Chief Scientist of the U.S. Government GAO staff are available to brief on completed bodies of work or specific reports Accountability Office. and answer follow-up questions. GAO also provides targeted assistance on This is a work of the U.S. government and is not subject to copyright protection in specific science and technology topics to support congressional oversight activities the United States. The published product may be reproduced and distributed in its and provide advice on legislative proposals. entirety without further permission from GAO. However, because this work may Timothy M. Persons, PhD, Chief Scientist, personst@gao.gov contain copyrighted images or other material, permission from the copyright holder may be necessary if you wish to reproduce this material separately. Staff Acknowledgments: Karen Howard (Director), Sarah Harvey (Assistant Director); Caitlin Dardenne (Analyst-in-Charge); Kristy Hammon; Nacole King; Anika McMillon; and Ben Shouse. GAO-21-342SP Vaccine Safety