Vial and syringe.

What to Know About the COVID-19 Vaccine Dosing Debate

By Dorit Rubinstein Reiss

Faced with limited COVID-19 vaccine doses and the ever-mounting toll and strain of the pandemic, a new debate has emerged as to the best strategy for allocating the vaccines.

Both COVID-19 vaccines authorized for emergency use in the U.S., which are produced by Pfizer/BioNTech and Moderna, have been studied under two-dose clinical trials. The two-dose regime is thought to accord a more robust immune response against COVID-19.

In the U.K., however, due to concerns about the shortage of COVID-19 vaccines, the government has deviated from established protocols. First, it decided to delay (but not omit) the administration of the second dose of the available vaccines, in order to increase the number of people getting at least one dose; second, it decided to allow mixing and matching of doses across vaccine types.

The United States is considering following the U.K. and moving to give more first doses, at the cost of delaying completion of the series.

Experts are sharply divided on whether that is a good or bad idea.

On one side, respectable experts like immunologist Prof. Akiko Iwasaki from Yale, Dr. Bob Wachter from UCSF, epidemiologist Dr. Ashish Jha from Brown University, and others support delaying the second dose.

Their argument is, in essence, that a small potential drop in effectiveness due to a delayed second dose is counterbalanced the increased coverage associated with giving more vulnerable people their first doses. In other words, they believe that giving more people a first dose will save more lives.

On the other side, similarly respectable experts like vaccine experts Dr. Peter Hotez from Baylor College of Medicine, Dr. Paul Offit from the University of Pennsylvania, and epidemiologist Prof. Gregg Gonsalves from Yale oppose it.

Their argument, in essence, is that while we have data to support effectiveness of the two dose regime, we do not have similar data for a delayed second dose, that there are reasons a two-dose regime was recommended, which include countering the risk of waning immunity, and that current data about antibodies does not tell us whether the vaccine will be effective in preventing diseases with one dose.

It is important to highlight that this is a sincere debate about what to do during an emergency, in conditions of uncertainty. The reality is that 2,000-3,000 people in the United States are dying each day from COVID-19, and January is likely to be very, very bad in terms of loss of life and other harms. Everyone wants to protect people. The question is how to do it.

We do not have data on the effects of delaying the second dose. One side — opponents of delaying the second dose — believes that going forward without that data is gambling with the lives of the people we can protect, and going back on a promise to follow the science. The other side believes that not maximizing first dose recipients is the gamble, and the worse one.

Complicating this debate is the fact that vaccine distribution has been sub-par. Right now, we have unused doses that have been delivered to states, but not administered to individuals. This has led some to say that the problem right now is not availability of doses, or the dosing regime, but distribution. They suggest that instead of changing the dosing regime, we should focus on getting the available vaccines to people under the current two-dose schedule.

Others, however, agree that we should move to distribute doses, but with the goal of getting at least one dose to as many people as possible.

The last debate between experts is the emergency of a new, more contagious variant of COVID-19, B.1.1.7. Because the new variant spreads faster, which means more are at risk of contracting the virus, supporters of the delayed second dose regime argue that this provides all the more reason to move to protect more people, at least partially.

On the other hand, those who support the current dosing regimen say that the lesser immune response spurred by the alternate vaccination schedule could lead to more viral mutations, as viruses have a better chance to evade a less prepared immune system.

On January 4, 2020 the U.S. Food and Drug Administration (FDA) issued a statement strongly supporting adhering to the scheduled two-dose regime, and not delaying the second dose. The FDA stated:

“We have been following the discussions and news reports about reducing the number of doses, extending the length of time between doses, changing the dose (half-dose), or mixing and matching vaccines in order to immunize more people against COVID-19. These are all reasonable questions to consider and evaluate in clinical trials. However, at this time, suggesting changes to the FDA-authorized dosing or schedules of these vaccines is premature and not rooted solidly in the available evidence. Without appropriate data supporting such changes in vaccine administration, we run a significant risk of placing public health at risk, undermining the historic vaccination efforts to protect the population from COVID-19.

The available data continue to support the use of two specified doses of each authorized vaccine at specified intervals.”

Normally physicians can legally use medicine and vaccines off-label. But COVID-19 vaccines were authorized under an Emergency Use Authorization (EUA) and not approved through the regular process. This means they likely cannot be legally prescribed off-label, against their instructions — though physicians that do delay vaccines are unlikely to face consequences.

During the pandemic, situations may arise where sticking to the specified dosing schedule is impossible, especially if delivery problems continue. It remains to be seen how the COVID-19 vaccination rollout may change in the coming weeks and months.

Dorit Reiss

Dorit Reiss

Dorit Rubinstein Reiss is a professor of law at the University of California, Hastings College of the Law. Increasingly, her research and activities are focused on legal issues related to vaccines, including exemption laws and tort liability related to non-vaccination. She published law review and peer reviewed articles and many blog posts on legal issues related to vaccines. She received an undergraduate degree in Law and Political Science (1999, Magna cum Laude) from the Faculty of Law in the Hebrew University of Jerusalem. She received her Ph.D. from the Jurisprudence and Social Policy program in UC Berkeley. She is a member of the Parents Advisory Board of Voices for Vaccines, and active in vaccine advocacy in other ways. She is also a Member of the Vaccine Working Group on Ethics and Policy (http://vaccineworkinggroupethics.org/).

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