Clinical trials of the Pfizer – BioNTech and Moderna vaccines involved two injections administered 3 to 4 weeks apart. Both vaccines were approximately 95% effective after the second dose – an impressive finding.1-2
Under normal circumstances, vaccines should be distributed according to trial protocols. However, current circumstances – a slow release of the vaccine, a limited supply of vaccine and the recent emergence of more infectious variants of SARS-CoV-2 that threaten to overtake our vaccination program – are anything but normal. This may be a case where the risks of strict adherence to the plan outweigh the risks of modifying it.
Some argue that any deviation from the protocol used in clinical trials is not scientific. But the argument is based on an overly narrow definition of science. In both trials, the cases in the placebo and active vaccine groups began to diverge about 10 days after the first dose, with the vaccine’s increasing effectiveness over time. On the day of injection of the second dose, the effectiveness of the first dose was somewhere in the range of 80 to 90%.1.2
Why postpone the second dose of the vaccine? First, with Covid-19 currently killing about 3,000 people in the United States each day, we face a crucial trade-off: we use our limited vaccination capacity to increase the protection of approximately 85% of people who received the first dose (after dose one) to 95% (after the second dose) by administering a second dose? Or do we use this same ability to move a similar number of people from an unprotected state to another where they are 80 to 90% protected? One model shows that the expected number of Covid-19 cases would be significantly lower if more people received the first dose, even if it cost to postpone the second doses.3
Second, we recently saw the emergence of several viral variants, with one (B.1.1.7, often referred to as the UK variant) that is approximately 50% more infectious than the native coronavirus.4 This variant quickly became the dominant strain in much of England, and the Centers for Disease Control and Prevention (CDC) now predict the same for the United States in the next 6 weeks.5 This perspective further increases the need to vaccinate the population, especially people at high risk, more quickly.
Are there any potential risks of delaying the second dose? Right. It is possible that the second dose will be less effective when administered later, although few scientists believe that will be the case.6 Immunity may begin to decline between the first dose and a delayed second dose, although the rarity of recurrent infections probably means that the immunity, at least that created by the native infection, lasts much longer than 3 months.7 Some people may forget to return to the second dose after a longer delay, although a reminder system that works for a 3-4 week return should work a month or two later. It is possible that some people may be confused by a change in their vaccination schedule, and confusion may lead them to avoid vaccination or believe that they need only a single dose. The likelihood of this is difficult to quantify, although it can be resolved with a strong messaging campaign. Finally, some experts warned that partial vaccination leading to a less robust immune response may increase the risk of mutations, which, as we have seen, can lead to variants with more problematic characteristics.8 This is also difficult to quantify.
While there are risks to the delayed second dose strategy, the benefits of giving many more people a first dose sooner deserve strong consideration of the strategy, especially since the vaccine shortage is likely to decrease in late spring. On December 30, 2020, the UK approved the second deferred approach.6 And on January 21, 2021, the CDC liberalized its guidance on the timing of the second dose, saying for the first time that a delay of up to 6 weeks after the first dose would be acceptable.9 These moves towards a more flexible approach seem wise.
While following the plan is always comforting, our current Covid-19 crisis offers a classic case in which the plan – protecting very few people very slowly in the face of a growing threat – may represent the most risky option. Obviously, any deviation from the protocol must be rigorously and quickly studied, and the second doses must be administered immediately, as the vaccine supply becomes more abundant.
The disclosure forms provided by the author are available with the full text of this article at NEJM.org.
Author Affiliations
From the University of California San Francisco, San Francisco.
We recommend following the standard regime
Nicole Lurie, MD, MSPH
Public health leaders must make the best decisions they can with the science available, balancing the health of the population, social and economic concerns and the need to maintain public confidence. Data for decision making is rarely available when needed, but the “scope review” is always ready to judge the decisions that have been made. US scientific agencies (the National Institutes of Health, the FDA and CDC) and vaccine developers are committed to making recommendations for Covid-19 vaccines that are guided by science.
My recommendation is that at the moment, in the United States, we should not delay the second dose of the mRNA vaccine beyond the intervals evaluated for its emergency use authorization. Although the immune response to the first dose is unlikely to degrade rapidly, it is incomplete and there is no data to indicate how long a second dose can be delayed without compromising effectiveness. We do not even know the duration of immunity produced by the two-dose regimen or how the timing of the dosage affects immunity in the elderly and immunocompromised people, who are responsible for most hospitalizations and deaths. Substantially delaying a second dose can simultaneously leave these people inadequately protected and hinder progress towards the goal of alleviating the increase in hospitalizations.
Populations essential to social and economic functioning, such as frontline health personnel and other essential workers, need to be assured that, if vaccinated, they can expect a high level of protection and can work more safely. Postponing a second dose cannot provide this guarantee and may have an adverse impact on your future desire to work or be vaccinated.
Some models have suggested that using a less effective vaccine or postponing a second dose to deliver the first doses to more people will end the pandemic sooner.10.11 However, these models do not take into account the potential degradation of the immune response or the side effects of such decisions on vaccine acceptance. Many people are skeptical about vaccines, fearing that the speed of development has required alternative solutions and that political pressure has influenced vaccine recommendations. Suddenly changing dosing recommendations puts public confidence at serious risk and prevents the desire to be vaccinated. Covid-19 cases have already occurred in vaccine containers, as seen in phase 3 tests, which will raise questions about the delayed second dose strategy and undermine confidence in the vaccine launch. If these emerging cases appear to occur more frequently before the second dose, confidence will be further compromised, delaying the end of the pandemic and social and economic recovery.
The appearance of variants of SARS-CoV-2 implies that the virus is under evolutionary pressure. Some have postulated – although this is speculative – that subinhibitory levels of antibody response before a second dose, if generalized, could contribute to the selection of antigenic variants that could escape current vaccines.12 While we now know how to make Covid-19 vaccines, designing, testing, manufacturing and administering a vaccine against a new variant will take time and be challenging.
Currently, our nation is unable to rapidly administer the doses it has. Supply restrictions are likely to ease within a month or two as manufacturing becomes more efficient and other vaccines are likely to be available. In the meantime, vaccines are not the only tool to end this pandemic. In the short term, adherence to basic public health measures is projected to save 1.5 times more lives than vaccines.13 As we increase vaccination, I strongly recommend that we use science to quickly assess alternative approaches to expanding vaccine delivery (eg, second dose delayed, half dose and use of adjuvants that can increase dose savings) to answer critical questions for now and in anticipation of new vaccine-resistant strains.
The disclosure forms provided by the author are available with the full text of this article at NEJM.org.
Dr. Lurie is a strategic consultant for the Coalition for Epidemic Preparedness Innovations (CEPI). The views expressed do not represent those of CEPI.
This article was published on February 17, 2021, at NEJM.org.
Author Affiliations
From the Coalition for Epidemic Preparedness Innovations, Oslo.
