The knowns and unknowns of COVID-19 vaccines

The knowns and unknowns of COVID-19 vaccines
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COVID-19 rages throughout the United states, leaving in its wake death and victims suffering debilitating long-term effects of the disease. COVID-19 vaccination is our only route to defeating the pandemic. 

Yet many questions around dosing interval, the extent of protection and whether we can mix vaccines increase confusion and hesitancy around the vaccine.

All of these issues derive from a slow rollout due to flawed planning, inadequate supply, inequitable distribution and ever-changing recommendations regarding who is eligible and when. Without doubt, rolling out the vaccines developed in under a year to over 330 million people in the U.S. comes with challenges — particularly without strong national, state and local plans to manage the pandemic and effectively get the vaccine into people.


This unfortunate situation has engendered the need to consider how to make a limited vaccine supply go further, beyond what the science and evidence from clinical trials supports. What we do not know is as important as what we do know. What we do not know defines the questions that scientists continue to seek answers to in their studies of vaccine effectiveness. Here we consider what science knows and what it does not about the COVID-19 vaccines. 

First, it is known that vaccination protects against severe disease. It is not known if it protects from asymptomatic or mild infection. In developing the Moderna and Pfizer/BioNTech vaccines, given the shortened time scale, people vaccinated as part of clinical trials were assessed only for protection against symptomatic disease. However, the possibility remains that those vaccinated, while protected from severe disease, could possibly become asymptomatically infected enough to transmit virus to the unvaccinated. For this reason, vaccinated individuals should continue practices to mitigate spread — distancing, masking and handwashing — until this question is answered.

Second, it is recommended that the second injection of Pfizer and Moderna vaccines be given at a minimum of 21 and 28 days, respectively, after the first injection. This recommendation has been made because this is the interval tested in the clinical trials, and it worked. No maximum interval for the second injection has been established by a scientific study. The Centers for Disease Control and Prevention (CDC) has recently recommended that under exceptional circumstances the administration of the second dose could be extended up to 42 days. Our understanding of vaccines and immune responses suggests that a slightly longer interval may be effective, but we do not yet know how long that interval can be stretched and still achieve adequate protection. 

Third, if shortages arise, it has been suggested that one dose may be adequate or that mismatching the first and second doses with Pfizer and Moderna vaccines could be tried. But these approaches have not yet been adequately tested in controlled clinical trials and so the effectiveness of these practices in inducing immunity to stop severe disease is unknown. Science is based on strict protocols that are highly controlled; the introduction of unvetted alterations in dosing protocols could increase the precariousness of our situation and serve to extend or worsen the pandemic.

Fourth, there is concern regarding how long protection will last following natural infection or vaccination. Current studies suggest that people are protected by natural infection for at least seven months. While immunity will certainly endure more than seven months, we do not yet know how long as we have only been able to study the protection conferred by natural infection for seven months. Ongoing studies will define the full extent of protective immunity and determine if vaccine boosters will be necessary to extend immunity.


Finally, the greatest challenge of SAR-CoV-2 is its ability to generate new variants. Such variants may spread more effectively, be more pathogenic or be able to escape the protection conferred by the vaccine. While the current vaccines will protect against many of the variants emerging, variants with mutations in the spike protein have a greater likelihood of escaping immunity induced by the current vaccines. High rates of virus spread, as is the present situation in the U.S., propels the generation of new variants. Therefore, we must not let our guard down. It is critical that we continue to mitigate spread, otherwise we risk losing all that we have gained by the development of vaccines. 

Over 400,000 of us in the U.S. have been lost to COVID-19. In considering recommendations for any alterations in vaccine protocols it is essential to acknowledge what is not yet known scientifically, as well as what is known. It is important to let science lead in making protocol decisions. To best protect our public, we must slow transmission of the virus by steadfast mitigation and well-organized, scientifically founded vaccination programs and education.

Felicia Goodrum Sterling is a virologist and professor at the University of Arizona, a fellow of the American Academy for Microbiology and president-elect of the American Society of Virology. James Alwine is a virologist and professor emeritus at the University of Pennsylvania, visiting professor at the University of Arizona and a fellow of the American Academy for Microbiology and the American Association for the Advancement of Science.