UK Prime Minister Boris Johnson has watched a UK resident receive one of the first doses of the AstraZeneca-Oxford COVID-19 vaccine since the country authorized it for emergency use.
STEFAN ROUSSEAU / POOL / AFP via Getty Images
By Jon Cohen
Science‘s COVID-19 reports are supported by the Pulitzer Center and the Heising-Simons Foundation.
As the COVID-19 pandemic grows, fueled in some places by new variants of rapid spread, officials and public health experts are debating strategies to stretch the limited supply of vaccines. And vaccinators were caught in the middle. Last week, the UK’s decision to extend the interval between the initial dose of the priming vaccine and the booster dose to up to 12 weeks was endorsed. Another stepped back. The maker of a third COVID-19 vaccine has so far remained silent about another plan, suggested by the scientist who led the US COVID-19 vaccine effort, but opposed the US Food and Drug Administration (FDA) to stretch the supply in half its primary and booster doses.
Dosage debates broke out on December 30, 2020, when the United Kingdom became the first country to authorize the emergency use of a vaccine made by AstraZeneca and the University of Oxford, which uses a harmless virus as a vector for the coding peak of DNA, the surface protein of SARS -CoV-2. The urgency of the pandemic led most COVID-19 vaccinators to aim for 3 or 4 weeks between vaccines, and most candidate vaccine clinical trials tested these short intervals, but AstraZeneca and Oxford conducted tests with intervals between two injections that ranged from 4 to 26 weeks.
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In order to give more people a first dose of the COVID-19 vaccine and to protect them at least partially from disease, the UK Medicines and Health Products Regulatory Agency (MHRA) decided to offer the flexibility to postpone the second injection of AstraZeneca- Vaccine Oxford for up to 3 months. MHRA conducted an “exploratory analysis” of the results – which combined data from different candidate effectiveness tests – comparing vaccinated people and placebo recipients at least 22 days after receiving the first injection and before receiving the booster. He found 73% efficacy against symptomatic COVID-19 – a number that some found intriguing because the company reported a lower efficacy, 62%, after two full doses.
Adrian Hill of Oxford, who with Sarah Gilbert of Oxford developed the vaccine, points out that MHRA reached 73%. “We didn’t say, ‘Here’s an extra end point that’s exciting,’ says Hill. But, he adds, “now we’re comfortable with that.”
An independent group advising the UK government, the Joint Vaccination and Immunization Committee (JCVI), endorsed MHRA’s decision that day. He also extended the booster schedule from 3 to 12 weeks for a second vaccine, from Pfizer and BioNTech, which is based on the messenger RNA (mRNA) encoding the spike protein and had previously received emergency use authorization from MHRA. “This should maximize the program’s short-term impact,” explained a JCVI report.
The JCVI today updated its report to note that the “need for high and rapid levels of vaccine absorption among vulnerable people” is driven by the spread of a more easily transmitted strain of SARS-CoV-2 that is linked to a marked 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 launch a “robust” monitoring program to determine how different intervals affect effectiveness. Several scientists have also asked for comparisons of more direct clinical trials of dosage ranges for the various COVID-19 vaccines.
Other agencies disagreed with the approach, however. In the United States, the FDA said that delaying the second dose of the Pfizer-BioNTech vaccine would be “premature and have no solid roots in the available evidence”. The European Medicines Agency, which also authorized the Pfizer-BioNTech vaccine for the European Union, basically agreed, but mixed its message by adding that the booster could take place within 42 days after the first injection, noting that this occurred with some people in the Efficacy study of the Pfizer-BioNTech vaccine. And a vaccine advisory group from the World Health Organization, which yesterday recommended that WHO put the Pfizer-BioNTech vaccine on its “emergency use” list, echoed the FDA’s position.
Pfizer and BioNTech released their own statement objecting to the change in the intended dosing schedule, which they say gives the booster injection 3 weeks after the priming injection. “The safety and efficacy of the vaccine have not been evaluated in different dosing schedules, since the majority of trial participants received the second dose within the window specified in the study design,” said the companies. “There is no data to show that protection after the first dose is maintained after 21 days.”
Data released last month, when Pfizer sought FDA authorization for its vaccine, shows that 2 weeks after the second dose of this vaccine, the efficacy was a remarkable 95%. Between the first and the second dose, it was only 52.4%. The actual effectiveness may be greater because most cases of COVID-19 occurred within the first 10 days after the injection, when an effective immune response is still forming. But the levels of so-called neutralizing antibodies to the virus – which many immunologists say are the most powerful immunological warriors – do not increase appreciably until after the booster dose.
Kathleen Neuzil, an epidemiologist at the University of Maryland School of Medicine, points out that longer intervals between initial and booster doses generally improve the strength and durability of the vaccine-induced immune responses. But she fears postponing the second injection for the elderly and others who are particularly vulnerable to disease, as some have weaker immune responses to vaccines. “I can’t be sure that they don’t need the second dose for protection,” says Neuzil.
The Doctors’ Association UK, in a letter this week to UK Health Minister Matt Hancock, raised a number of other concerns about changing gap spacing, including confusing the public. “Confusing messages and a lack of evidence will inevitably undermine public confidence in the vaccine and can have a negative impact on absorption,” warns the association’s letter.
Evolutionary biologists also raised objections to postponing the second dose. They emphasize that a weaker immune response to SARS-CoV-2 in vaccinated people offers an opportunity for the virus to learn how to turn into antibodies that would otherwise be effective.
Moncef Slaoui, scientific head of the US government’s Operation Warp Speed program, which is now testing 30,000 people with the AstraZeneca-Oxford vaccine in the United States, agrees that delaying the second dose of the Pfizer-BioNTech vaccine is a mistake . But he thinks the data favor his own vaccine extension strategy: cut in half the doses of the other vaccine approved in the U.S., an mRNA preparation made by Moderna, for people between 18 and 55 years old. Relatively small phase I and II studies, which evaluated different doses of the Modern vaccine, found that this age group developed similar levels of antibodies against the peak, whether 50 or 100 micrograms were administered. But as the highest dose worked best in people over 55, Moderna chose it for the phase III efficacy trial, which showed almost 95% effectiveness with two injections. When contacted by Science, Moderna said he had no comment on the proposal, but stressed that the FDA authorization for his vaccine is only for doses of 100 micrograms.
Slaoui did not publicly advocate cutting doses of the Pfizer-BioNTech vaccine, but a similar argument could be made. Their dose-varying studies suggest that 30 micrograms of the vaccine, the amount used in the efficacy test, did not trigger higher antibody levels than 20 micrograms, at least in the 18 to 55 range.
For now, the debate on how to stretch supply is debatable in many parts of the United States and Europe, where logistics, not supply, have been shown to be the limiting factor in vaccination campaigns. But the issue will certainly remain controversial as long as vaccine supplies are scarce, the pandemic continues to overwhelm hospitals and the death toll rises.