In DepthCOVID-19

Dosing debates, transparency issues roil vaccine rollouts

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Science  08 Jan 2021:
Vol. 371, Issue 6525, pp. 109-110
DOI: 10.1126/science.371.6525.109

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

Last-minute vaccine dosing changes that could gamble away proven COVID-19 protection and undermine public trust. Controversial approvals without any efficacy data. Vaccinemakers at odds with countries hosting their clinical trials. The COVID-19 vaccine landscape keeps changing almost daily, simultaneously raising hopes and triggering confusion and scientific debates. “It's crazy,” says vaccine researcher John Moore of Weill Cornell Medicine. “Every morning, it's just, ‘What's going on?’”

Over the past few weeks, COVID-19 vaccines developed in the United Kingdom, China, and India moved toward widespread rollout, offering new weapons in the face of fast-spreading viral variants that threaten to deepen the crisis (see p. 108). But many came with controversies, and U.K. regulators sparked a debate when they endorsed a sharp departure from the expected dosing schedule for a newly authorized vaccine from AstraZeneca and the University of Oxford and one from Pfizer and BioNTech. The pandemic has driven most COVID-19 vaccinemakers to aim for a short 3 or 4 weeks between prime and booster shots, but the U.K. Medicines and Healthcare products Regulatory Agency (MHRA) said second shots can be given up to 12 weeks later.

Biostatistician Natalie Dean of the University of Florida thinks MHRA moved too quickly and without enough explanation of its dosing decision. “Clearly there were deliberations that the U.K. had about this, but we don't have access to those discussions.”

MHRA didn't cite the fast-spreading B.1.1.7 variant of SARS-CoV-2 in its dosing decision, announced last week when the agency authorized the AstraZeneca-Oxford vaccine. But some scientists say the strain's threat, which led this week to a U.K.-wide lockdown, justifies delaying the booster to expand the population that can receive at least one dose of vaccine.

MHRA said an “exploratory analysis” of some participants in AstraZeneca-Oxford phase III trials in Brazil and the United Kingdom found an efficacy of 73% after a single dose of the vaccine, which uses an adenovirus to deliver a gene that codes for the surface protein, spike, of SARS-CoV-2. This, oddly, was higher than the 62% efficacy after two full doses reported in The Lancet. Oxford's Adrian Hill, who co-led the vaccine's development, notes its efficacy trials started earlier than other groups, which may explain the discrepancy. “I'm afraid it's possible that what's happening is efficacy is declining over time,” Hill says. (The 62% figure has itself brought confusion, as the vaccine had a reported 90% efficacy when the first dose was halved.)

For all two-dose vaccines, intervals between a prime and booster are somewhat arbitrary, says pediatrician Paul Offit of the Children's Hospital of Philadelphia, a member of an independent U.S. vaccine advisory committee. But some physicians and scientists worry that last-minute debates on dosing strategies will increase vaccine hesitancy. “Mixed messages and lack of evidence will inevitably lead to undermining the public trust in the vaccine and could negatively impact on uptake,” the Doctors' Association UK wrote in a letter of concern to the U.K. health minister.

The British Society for Immunology issued a statement supporting MHRA's “pragmatic” dosing schedule, but urged the government to launch a “robust” monitoring program to determine how the different intervals affect efficacy. Several scientists also called for more direct clinical trial comparisons of dosing intervals.

The United States seems unlikely to follow the U.K. example. “The MHRA has taken quite a significant risk,” says Moncef Slaoui, chief scientist for the U.S. government's Operation Warp Speed program, which is now staging its own 30,000-person trial of the AstraZeneca-Oxford vaccine. “After the first dose, quite a lot of people actually are not primed,” he adds. The U.S. Food and Drug Administration (FDA) issued a statement that made similar scientific arguments, adding that the move could backfire if people who are not fully protected begin to increase their risk of exposure.

Nor do data on the two U.S. authorized vaccines, which both use messenger RNA encoding spike, clearly support a delayed booster. Made by Pfizer and BioNTech and Moderna, both have a reported efficacy of about 95% after two doses. But data Pfizer provided last month showed an efficacy of just 52.4% between the first and second dose of its vaccine, below FDA's threshold for emergency use given the result's statistical uncertainty.

Slaoui floated a different change to expand supply of the Moderna vaccine: cutting both doses in half. Moderna has data showing its vaccine stimulated a strong immune response in people between ages 18 and 55 at half the usual dose, he notes. But FDA doesn't like that idea, either. “There are some possible challenges with reliability and interpretation of the data that Slaoui based this on,” says Peter Marks, who heads FDA's Center for Biologics Evaluation and Research. And in much of the United States, logistical problems, rather than supply shortages, are currently the main limiting factor in the vaccination campaign.


Embedded Image

Doses of the AstraZeneca-Oxford COVID-19 vaccine, made at the Serum Institute of India, are stored in a cold room.

PHOTO: FRANCIS MASCARENHAS/REUTERS

In India, meanwhile, the Central Drugs Standard Control Organisation (CDSCO) created a furor on 3 January by granting “restricted emergency approval” for a vaccine containing killed, or “inactivated,” SARS-CoV-2, based on early trials showing immune responses but not efficacy, as well as animal data. A phase III trial of the vaccine, produced by Bharat Biotech, hasn't even completed recruiting. Vineeta Bal of India's National Institute of Immunology calls the decision “unconscionable.”

But CDSCO's director, V. G. Somani, said the approval was out of “abundant precaution,” in case it was needed to protect the country against B.1.1.7. CDSCO also approved a local version of the AstraZeneca-Oxford vaccine, even though it hasn't fully analyzed data from a “bridging study” designed to show that the vaccine triggers an immune response in Indians comparable to that seen in trials elsewhere.

China's Sinovac and Sinopharm added to the confusion with their COVID-19 vaccines, which are based on whole, killed copies of SARS-CoV-2. A press release early last month from the United Arab Emirates said that a candidate from Sinopharm's China National Biotec Group was safe and had “86% efficacy against COVID-19 infection” in a UAE trial that involved 31,000 participants. But on 30 December, the state-owned company reported that the vaccine had 79.34% efficacy “against the disease.”

Its statement contained no other important scientific information. Nevertheless, China gave the vaccine “conditional approval,” instructing Sinopharm to complete the efficacy studies it has underway in UAE and several other countries. (The company did not reply to queries from Science.)

A similar muddle surrounds Sinovac's vaccine. On 23 December, investigators in Brazil announced that a trial with 13,000 participants had shown greater than 50% efficacy. But they said a contractual agreement with Sinovac prohibited them from revealing more information and the company wanted to compare results from other countries. One day later, researchers in Turkey revealed interim data, which were far more preliminary, from a Sinovac vaccine trial that suggested an efficacy of 91.25%.

Mauro Schechter, an infectious disease researcher at the Federal University of Rio de Janeiro, College City, says “the perception that Turkish investigators are at liberty to divulge their data but Brazilians are not” contributes to what he calls “an atmosphere of distrust” for Sinovac's vaccine, one of Brazil's only options now. And that's the last thing needed as the pandemic takes its deadly toll.

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