Longer interval between doses of COVID-19 vaccines: A gamble worth taking?

Despite the increasing pace of COVID-19 vaccine rollout around the world, one stark reality remains — cases have been on the rise in many countries while vaccine availability still markedly falls short of the required population coverage to warrant mass protection.

“The substantial ongoing surge in cases and fatalities being seen across many countries means that the rollout of vaccination will come too late for many people,” highlighted Professor Paul Hunter and Dr Julii Brainard from The Norwich Medical School, Norwich, UK.

To save more lives, the UK JCVI* took the bold step of recommending a longer interval of up to 12 weeks between the first and second vaccine doses (ie, prime-boost interval).  

“The basis of this decision was that although two injections would give better protection to an individual than would one inoculation, giving twice as many people a single injection as soon as possible was likely to reduce the incidence of severe disease in the most individuals,” explained Hunter and Brainard.

The crux of the matter

The decision to delay the second dose of COVID-19 vaccine, in the absence of solid evidence from dedicated clinical trials, immediately drew flak. Debate raged over whether the decision has been made based on sound science or mere gamble.

For one, the JCVI believed that efficacy from a first dose of vaccine was as high as 89 percent. However, this figure was derived from an unplanned, retrospective analysis of clinical trial data by JCVI — by comparing COVID-19 cases in vaccinated individuals vs controls during a 6-day window (day 15–21) after the first dose.

“Retrospective analyses in therapeutic trials can be hypothesis-generating but should not be used to treat individuals,” commented Professor John Robertson from University of Nottingham, Derby, UK and colleagues in a Lancet correspondence column. [Lancet 2021;397:879-880]

“[In addition, the] delayed second dose could strongly favour the emergence of consequential SARS-CoV-2 variants resulting from suboptimal or partial immunity,” they cautioned. “Suboptimal vaccination will create selective pressure facilitating the emergence of vaccine-resistant variants, which could result in a persisting pandemic.”

They further took issue with JCVI decision to apply the extended prime-boost interval as a blanket policy for both the AZD1222 viral-vectored DNA vaccine and the mRNA vaccines available on the market.

“We have no concerns regarding the second dose of AZD1222 at 12 weeks, as this is supported by evidence,” wrote Robertson and colleagues. “[However,] no scientific data on mRNA vaccines exists to support the assumption [that immune response to mRNA vaccines is similar to that of DNA vaccine.]”

“If escape variants arise due to suboptimal dosing with BNT162b2, they will likely be resistant to other vaccines that target the same viral spike protein,” they warned.

Evidence on DNA vaccine

An updated pooled analysis of four randomized clinical trials on the ChAdOx1 nCoV-19 (AZD1222) vaccine conducted across the UK, Brazil, and South Africa  (n=17,178) showed an overall efficacy of 66.7 percent in preventing symptomatic COVID-19, more than 14 days after the second dose — thus confirming the efficacy of the vaccine for the first 90 days at least. [Lancet 2021;397:881-891]

Also, no additional hospitalizations or severe COVID-19 cases were reported in the vaccine group after the initial 21 days from vaccination, compared with 15 events in the control group.

Interestingly, exploratory analysis revealed that efficacy was higher after two doses given at a longer prime-boost interval of ≥12 weeks than at a shorter interval of <6 weeks apart (81.3 percent vs 55.1 percent) — lending support to a longer-interval immunization strategy.

Importantly, antibody levels were largely maintained with minimal waning during the interval —indicating that the longer prime-boost interval did not compromise protection during the 3-month period before administration of the second dose.

“Although [the longer prime-boost interval] policy was criticised, the latest results reported by Voysey and colleagues provide a necessary evidence-based justification for the decision,” stated Dr Gregory Poland of Mayo Clinic, Rochester, Minnesota, US, and colleague in a linked commentary. “It offers much-needed evidence for the UK policy of extending the dosing interval to 12 weeks and for rapid mass-immunization campaigns worldwide.” [Lancet 2021;397:854-855]

As data were only available up to the follow-up period described in the study, researchers are still unclear on how durable is the protection conferred by just a single dose of vaccine. 

“A second dose of ChAdOx1 nCoV-19 induces increased neutralising antibody levels and is probably necessary for long-lasting protection,” said the researchers. “With the evidence available at this time, it is anticipated that a second dose is still required to potentiate long-lived immunity.”

In addition, whether the findings would hold up with propagation of new viral variants, which are more infectious and lethal, remains unknown.

“Further studies are warranted to assess whether a longer-interval strategy would also offer higher vaccine efficacy against the new variants and could be applicable to other types of COVID-19 vaccines,” wrote Poland and colleague.

mRNA vaccine: the data thus far

In the original report for the BNT162b2 mRNA vaccine, the efficacy was 94.8 percent after two doses. The efficacy after the first dose, but before the second dose was given, was 52.4 percent. [N Engl J Med 2020;383:2603-2615]

“[However,] they included data that were collected during the first 2 weeks after the first dose, when immunity would have still been mounting,” pointed out Drs Danuta Skowronski and Gaston De Serres from British Columbia Centre for Disease Control, Vancouver and Institut National de Santé Publique du Québec, Quebec, Canada, respectively.

As such, they reanalysed the trial data by calculating the efficacy only from 2 weeks onwards after the first dose. They found that BNT162b2 was highly efficacious, even before the second dose, at a rate of 92.6 percent. This figure, they noted, was similar to that of the mRNA-1273 vaccine — at 92.1 percent after the first dose. [N Engl J Med 2021;doi:10.1056/NEJMc2036242#sa1]

“With such a highly protective first dose, the benefits derived from a scarce supply of vaccine could be maximized by deferring second doses until all priority group members are offered at least one dose,” suggested Skowronski and De Serres.

Further support came from real-world data of more than 500,000 people who had received the BNT162b2 vaccine in Israel. Efficacy increased gradually each day from day 14 after the first dose until it peaked at around 90 percent on day 21, before administration of the second dose. [medRxiv (Preprint) 2021;doi:10.1101/2021.02.01.21250957]

“This analysis would suggest that a single dose of the BNT162b2 vaccine is able to deliver very high protection, albeit only from about three weeks after the initial injection,” observed Hunter and Brainard.

The same message was replicated in a retrospective analysis of 9,109 healthcare workers (HCWs) in Israel. Infection rates were reduced by 30 percent during days 1–14 and by 75 percent for the period between days 15–28 in vaccinated vs unvaccinated HCWs. [Lancet 2021;397:875-877]

“Early reductions of COVID-19 rates provide support of delaying the second dose in countries facing vaccine shortages and scarce resources, so as to allow higher population coverage with a single dose,” according to the authors.

Is the gamble worth the risk?

Although accumulating data seem to support that the UK JCVI might have placed the right bet, these were indirect evidence drawn post hoc. Only with dedicated trials prospectively designed will we have definitive answer to whether lengthening the prime-boost interval was the right thing to do, particularly in extrapolating this to the mRNA vaccines.

Meanwhile, the EMA**, the US CDC, and French health authorities have suggested that the dosing interval for the BNT162b2 mRNA vaccine can be extended to a maximum of 42 days (from the initial 21 days). Nonetheless, this extension was still playing safe within the period supported by trial data — in contrast to the maximum 12 weeks allowed by the UK.

On the other hand, at stake were billions of lives should the longer dosing interval lead to the emergence of lethal escape mutants and persisting pandemic. So high is the stake, it is a gamble one cannot afford to lose.    

Will the gamble pay off? Only time will tell.

 

*JCVI: Joint Committee on Vaccination & Immunisation
**EMA: European Medicines Agency