by Berklee Robins, MD, MA & Ashley Sweet, MD, MBE

Vaccines are approved when it is clear that the benefits to the individual and society outweigh the potential risks and side effects of vaccination. Historically this approval has occurred only after years of vaccine development and testing. However, in an effort to quell the COVID-19 pandemic, the FDA may consider accelerated approval of a vaccine based on the limited available evidence regarding the product’s safety and effectiveness. Although the FDA has suggested a minimum threshold of efficacy for COVID-19 vaccine candidates, there has been little public discussion surrounding acceptable safety profiles, despite the fact that a phase 3 trial was recently halted over safety concerns. While efficacy can be quantified, the question of when a vaccine is “safe enough” is both an ethical and public health one. Failure to explicitly address this issue and frame the need for a vaccine, especially on an expedited timeline, will likely lead to public distrust and low vaccine uptake.

The safety and efficacy profile of any COVID-19 vaccine will need to be considered in the context of the evolving knowledge of the virus, disease morbidity, available medical therapies, burdens on health care systems, and the economic impact of the pandemic. These factors all exist on a continuum, are interrelated, and dynamic. Significant impact of one or more of these factors on one side of the continuum could favor accelerated vaccine approval with less robust safety data, or alternatively, could argue for allowing more time to scrutinize and widely test a candidate vaccine. Transparency and community engagement are needed to address wavering public sentiment regarding the safety and necessity of COVID-19 vaccination. Therefore, the following issues should be explicitly addressed prior to approval of any vaccine.

            1) What medical treatments are available for COVID-19? We have seen the rise and fall of multiple candidates for treatment of coronavirus infection, and fortunately there are new prospects on the horizon. If a medical treatment becomes available that can effectively reduce or prevent serious illness, then the threshold for vaccine approval should be high; any candidate vaccine should be widely tested and stringent safety criteria should be met. Alternatively, if the options for treatment remain sub-optimal, expensive, inaccessible, or mutation of the virus makes existing treatments less effective, then a less robust safety profile may need to be tolerated in an effort to prevent significant disease morbidity and mortality. 

            2) What are the long-term outcomes following recovery from COVID-19 infection? We now know more about arange of long-term health effects after SARS-CoV-2 infection, from fatigue to lasting cardiac, pulmonary, and neurologic damage. Though longer-ranging data are needed to better clarify the consequences of COVID-19 infection, reported trends raise concern that large numbers of people may have persistent severe symptoms or even organ damage after infection. Therefore, prevention or modulation of primary disease with a vaccine, even one that has undergone less rigorous or widespread testing, may be warranted.

            3) What is the impact of COVID-19 on health care systems? Another factor to consider prior to vaccine approval is the overall burden of disease on the health care system. We are already seeing a rise in cases as businesses, schools, and universities re-open. Alternatively, we could see a plateau or fall of COVID-19 cases if public health measures are more widely practiced and enforced. It remains unclear how the upcoming flu season or the impact of patients forgoing both acute and preventative care will impact hospital and health system capacities as we move into fall. Accelerated approval of a vaccine with less safety data or less-than-ideal side effect profile may be warranted to help unload a health care system that is at or above capacity. Alternatively, if health care burden is relatively manageable, accelerated approval of such a vaccine may not be warranted.

            4) What is the impact of COVID-19 on the national economy? Economic recovery, and ultimately growth, will be affected by incidence and prevalence of disease, government policy, and public confidence. Wide uptake of an efficacious vaccine could aid economic recovery by allowing businesses to re-open. An accelerated vaccine approval may be required to stave off further economic decline and its ensuing repercussions. However, should such a vaccine have a more concerning side effect profile or less safety data, rapid approval may actually harm the recovery process if adverse events prove to be more frequent or more serious than anticipated. This could deepen public distrust and lead to low vaccination rates. Rather, waiting for a vaccine that has been more extensively studied to ensure that stringent safety criteria are met may be preferable, if economically tolerable.

            5) What is the public sentiment regarding the safety and necessity of COVID-19 vaccination? Despite reassurance from vaccine manufacturers and the FDA that no vaccine will be approved until thoroughly vetted for safety and efficacy, many Americans remain hesitant to adopt a coronavirus vaccine, and this hesitance appears to be growing. Allowing more time to scrutinize and widely test a vaccine may help build public confidence in the approving bodies, assuage safety concerns, and demonstrate that timing of approval is not politically motivated. This will benefit future vaccine roll-outs, and ultimately increase vaccination rates.

Transparency in the FDA review process is necessary to address these and other public concerns, especially in the case of accelerated vaccine approval. Explicit statements should be made regarding how potential safety risks are being weighed against the perceived benefits to individuals and the community. But this transparency alone may not be enough to ensure trust and credibility in the process. Community engagement will be imperative to acknowledge and validate uncertainty, address apprehensiveness, and develop buy-in from the public and community leaders. This is likely best carried out via collaboration among state and local public health officials, federal authorities such as the CDC and FDA, health care professionals, health advocacy organizations, and community leaders embedded in vulnerable and underserved minority populations.

The urgency to develop a COVID-19 vaccine has prompted rapid historic response to the need for vaccine development, approval, production, and distribution. This expedited timeline, as well as evolving knowledge regarding the virus, disease, medical therapies, and burdens on health and economic systems complicates a traditional risk/benefit discussion about vaccine approval. Clear communication is needed about how these factors are being considered when deciding on an acceptable safety and efficacy profile, how much testing data is needed, and whether accelerated approval is warranted. Transparency and community engagement are needed to develop public confidence in the safety and necessity of a vaccine to ensure adequate vaccination rates, and thus community protection from disease – the very goal of vaccination. The public will also need to be reassured that robust post-licensure monitoring will continue. FDA approval of a safe and effective vaccine is a crucial step in putting an end to this pandemic, but it must be done right, and done right the first time.