Debates Intensify Over Dosage Plans For Authorized COVID-19 Vaccines | Science

By Jon CohenJan. 6, 2021 at 10:30 p.m.

Science‘s COVID-19 reporting is supported by the Pulitzer Center and the Heising-Simons Foundation.

As the COVID-19 pandemic increases, fueled in some places by new, rapidly spreading variants, officials and public health experts are debating strategies to stretch scarce vaccine stocks. And the vaccinators got caught in the middle. Over the past week, a UK decision was approved to extend the interval between an initial priming vaccine dose and the booster up to 12 weeks. Another pushed back. The maker of a third COVID-19 vaccine has so far remained silent on another plan, launched by the scientist leading the US COVID-19 vaccine effort but opposed by the Food and Drug Administration (FDA) from the United States, to stretch the supply by halving the two. its primer and booster doses.

Dosage debates erupted on December 30, 2020 when the UK became the first country to allow emergency use of a vaccine made by AstraZeneca and the University of Oxford, which uses a harmless virus like DNA coding peak vector, the surface protein of SARS -CoV-2. The urgency of the pandemic prompted most COVID-19 vaccinators to aim for 3 or 4 weeks between vaccines, and most clinical trials of candidate vaccines have tested such short intervals, but AstraZeneca and Oxford had conducted trials with intervals between the two injections which ranged from 4 to 26 weeks.

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In order to allow more people to receive a first dose of a COVID-19 vaccine and to at least partially protect them against the disease, the Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom has decided to offer the flexibility to delay second injection of AstraZeneca-Oxford vaccine for up to 3 months. MHRA conducted an ‘exploratory analysis’ of the results – which combined data from different candidate efficacy trials – comparing those vaccinated with those receiving the placebo at least 22 days after receiving the first vaccine and before receiving the booster. . It found 73% efficacy against symptomatic COVID-19 – a figure some found confusing because the company reported lower efficacy, 62%, after two full doses.

Adrian Hill of Oxford, who with Sarah Gilbert of Oxford developed the vaccine, points out that MHRA came in with the figure of 73%. “We didn’t say, ‘Here’s an extra endpoint that’s exciting,” Hill says. But, he adds, “we are now comfortable with it.”

An independent group advising the British government, the Joint Committee on Vaccination and Immunization (JCVI), approved the MHRA’s decision that day. It also extended the booster schedule from 3 to 12 weeks for a second vaccine, from Pfizer and BioNTech, which is based on messenger RNA (mRNA) encoding the spike protein and had previously been approved for use. emergency response from the MHRA. “This should maximize the short-term impact of the program,” a report from JCVI explained.

JCVI today updated its report to note that “the need for high and rapid levels of immunization among vulnerable people” is driven by the spread of a more easily transmissible strain of SARS-CoV-2 which is linked to a sharp increase in cases in the country last month. The British Society for Immunology issued a statement supporting the MHRA’s “pragmatic” dosing schedule, but urged the government to initiate a “robust” monitoring program to determine how different intervals affect efficacy. Several scientists have also called for more direct clinical trial comparisons of dosing intervals for the various COVID-19 vaccines.

Other agencies, however, disagreed with the approach. In the United States, the FDA has said delaying the second dose of Pfizer-BioNTech vaccine would be “premature and not be firmly anchored in the available evidence.” The European Medicines Agency, which also cleared the Pfizer-BioNTech vaccine for the European Union, basically agreed, but mixed its message by adding that the boost could be as late as 42 days after the first vaccine, noting that this happened with some people in the Pfizer-BioNTech vaccine efficacy study. And a vaccine advisory group to the World Health Organization, which yesterday recommended that the WHO put the Pfizer-BioNTech vaccine on its “emergency use” list, echoed the position. from the FDA.

Pfizer and BioNTech released their own statement opposing the change in the planned dosing schedule, which says to give the booster 3 weeks after the prime injection. “The safety and efficacy of the vaccine has not been evaluated over different dosing regimens because the majority of trial participants received the second dose within the window specified in the study design,” said the researchers. companies. “There is no evidence that protection after the first dose is maintained after 21 days.”

Data released last month when Pfizer applied for FDA clearance for its vaccine shows that 2 weeks after the second dose of this vaccine, efficacy was a remarkable 95%. Between the first and second dose, it was only 52.4%. The actual efficacy could be higher because most cases of COVID-19 have occurred within the first 10 days after firing, when an effective immune response is still developing. But the levels of so-called neutralizing antibodies against the virus – which many immunologists consider to be the strongest immune warriors – do not rise appreciably until after the booster dose.

Kathleen Neuzil, an epidemiologist at the University of Maryland School of Medicine, points out that longer intervals between main and booster doses often improve the strength and durability of immune responses induced by the vaccine. But she is concerned about delaying second vaccines for the elderly and others particularly vulnerable to disease, as some have weaker immune responses to vaccines. “I can’t be so sure that they don’t need that second dose to protect themselves,” says Neuzil.

The U.K. Physicians’ Association, in a letter this week to U.K. Health Minister Matt Hancock, expressed several other concerns about the change in interval spacing, including public confusion. “Mixed messages and the lack of evidence will inevitably lead to undermining public confidence in the vaccine and could have a negative impact on adoption,” the association warns.

Evolutionary biologists have also raised an objection to the postponement of the second dose. They point out that a weaker immune response to SARS-CoV-2 in vaccinated people gives the virus an opportunity to learn to mutate around otherwise effective antibodies.

Moncef Slaoui, chief scientist for the US government’s Operation Warp Speed ​​program which is currently running a 30,000-person trial of the AstraZeneca-Oxford vaccine in the US, agrees that delaying the second dose of the Pfizer-BioNTech vaccine is a mistake. But he believes the data supports his own vaccine stretching strategy: halving doses of the other US-approved vaccine, an mRNA preparation made by Moderna, for people ages 18 to 55. . Relatively small Phase I and II studies, which evaluated different doses of the Moderna vaccine, found that this age group developed similar antibody levels against the peak, whether given at 50 or 100 micrograms. But because the higher dose worked better in people over 55, Moderna chose this for the Phase III efficacy trial, which showed almost 95% efficacy from two injections. When contacted by ScienceModerna said he had no comment on the proposal, but pointed out that the FDA clearance of his vaccine is only for doses of 100 micrograms.

Slaoui has not publicly advocated reducing doses of the Pfizer-BioNTech vaccine, but a similar argument could apply. Its dosage studies suggest that 30 micrograms of the vaccine, the amount used in the efficacy trial, did not trigger antibody levels higher than 20 micrograms, at least in the 18 to 55 age group.

At this time, the debate on how to stretch supply is moot in many parts of the United States and Europe, where logistics, not procurement, have been found to be the limiting factor for vaccination campaigns. But the issue will certainly remain controversial as long as vaccine stocks are scarce, the pandemic continues to overwhelm hospitals and the death toll rises.