LONDON – Controversy has erupted over COVID-19 vaccines dosing after the U.K. said it is to prioritize giving as many people as possible a single dose of the two currently approved products, rather than two doses three or four weeks apart, as scheduled on their labels.

The move prompted a sharp rebuke from FDA Commissioner Stephen Hahn and Peter Marks, director of FDA’s Center for Biologics Evaluation, who said any such change “is not rooted in the science.”

The decision in the U.K. to prioritize administering the first dose was made after the Joint Committee on Vaccination and Immunization (JCVI), the independent body that advises on how vaccines are administered, reviewed the safety and efficacy data for Pfizer Inc./Biontech SE and Astrazeneca plc/Oxford University’s vaccines, concluding that “high levels of protection are obtained after the first dose” and that protection “is obtained two weeks after the first dose.”

Given that, JCVI said it “recommends that vaccinating more people with the first dose is prioritized above offering others their second dose.”

Prioritizing administration of the first dose will “help prevent as many deaths as possible,” said Mary Ramsay, head of immunizations at Public Health England.

The second dose is still important to provide longer lasting protection, but rather than after three weeks, the second dose of Pfizer/Biontech vaccine can be administered up to 12 weeks, and for Astrazeneca/Oxford between four and 12 weeks, JCVI said.

In a statement Hahn and Marks hit back at this, saying, “We want to remind the public about the importance of receiving COVID-19 vaccines according to how they’ve been authorized by FDA.” That will ensure people receive the level of protection observed in the phase III trials, they said. The remarks refer to Pfizer/Biontech and Moderna Inc.’s vaccines, the two products approved to date in the U.S.

Hahn and Marks said they have been following the discussions about reducing the number of doses, extending the length of time between doses, changing the 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, but suggesting changes to the FDA-authorized dosing or schedules of these vaccines is premature. “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,” said Hahn and Marks.

They are dismissive of the idea of trying to get as many people protected as quickly as possible with a single dose of vaccine, saying, “We know that some of these discussions about changing the dosing schedule or dose are based on a belief that can help get more vaccine to the public faster. However, making such changes that are not supported by adequate scientific evidence may ultimately be counterproductive to public health.”

According to their reading, the data in the regulatory submissions regarding the first dose are commonly being misinterpreted. In the phase III trials, 98% of participants in the Pfizer/Biontech trial and 92% of participants in the Moderna trial received two doses of the vaccine at either a three- or four-week interval, respectively.

Those participants who did not receive two vaccine doses were generally only followed for a short period of time. As a result, Hahn and Marks said, “We cannot conclude anything definitive about the depth or duration of protection after a single dose of vaccine from the single dose percentages reported by the companies.”

JCVI took a different view of the data, concluding that between days 15 and 21 after the first dose, Pfizer/Biontech’s vaccine was 89% effective in preventing symptomatic COVID-19 infections. The committee reached a similar conclusion for Moderna’s vaccine, which is under review in the U.K.

For the Astrazeneca/Oxford vaccine, JCVI assessed efficacy as 73% from 21 days after the first dose. Unpublished data show that level of protective immunity lasts through to 12 weeks, JCVI said.

The rate of immunization in the U.K. is limited by vaccine supply, rather than workforce capacity. An extended interval between doses and prioritizing the first dose will increase administration in the short term, the committee said.

A crisis situation

JCVI made its recommendations in the face of a rapid increase in the number of SAR-CoV-2 cases in the U.K. during December, as B.1.1.7, a new more transmissible variant spread around the country.

With hospitals reaching saturation point, it is appropriate to consider options for increasing the short-term impact of the vaccination program, said Arne Akbar, president of the British Society of Immunology. “Our country now faces an extremely difficult few weeks with high levels of SARS-CoV-2 circulating within our communities. While our preference is always for an evidence-based approach, we understand the pragmatic approach taken by the JCVI,” Akbar said.

Similarly, Stephen Evans, professor of pharmacoepidemiology at the London School of Hygiene & Tropical Medicine, said, “In an ideal world, decisions about treatments would only be made within the exact parameters of the trials which have been conducted. In the real world, this is never so.”

The question is how much moving outside the exact conditions is acceptable, said Evans. “Pharmaceutical companies are constrained by law and must only make claims that are reflected in the authorization documents set out by regulatory authorities. Clinicians and health authorities have to take the circumstances they are dealing with into account. We have a crisis situation in the U.K. with a new variant spreading rapidly,” he said.

The trials did not compare different dose spacing, or compare one vs. two doses, so the optimal approach is unclear, but Evans said, “When resources of doses and people to [administer vaccines] are limited, then vaccinating more people with potentially less efficacy is demonstrably better than a fuller efficacy in only half.”

In the current U.K. context, there will be many more cases of disease and therefore more deaths by vaccinating fewer people. “There is no doubt that the U.K.’s current advice is focused on public health,” said Evans said.

The U.K. is uniquely placed to follow up all those vaccinated to see if the policy is justified, based on the cases of disease among those vaccinated. Data on that will become available within about a month, and policy will no doubt be changed if the data indicate it should be, Evans noted.