FDA could reject AstraZeneca's COVID-19 vaccine on efficacy and manufacturing shortfalls: analyst

It was bad enough when a study released last week concluded that AstraZeneca’s COVID-19 vaccine was largely ineffective against the aggressive B.1.351 variant that recently emerged in South Africa. Now, analysts are wondering whether inconsistent manufacturing of the vaccine for the clinical trials may have muddied the results—concerns that could give the FDA pause when considering the vaccine for emergency use.

That was the conclusion of a note SVB Leerink analysts sent to clients Wednesday, in which they laid out both the bear and bull cases for FDA authorization of AstraZeneca’s COVID vaccine. The bottom line? The bear case is worrisome, they said.

One major concern SVB Leerink cited is that AstraZeneca is manufacturing its vaccine on a “distributed” basis, meaning it’s not centralized, but spread over multiple sites and contract partners. The material used to make the vaccine for the South Africa trial came from a company in India, and it’s not clear where it was manufactured or whether the results from that trial truly reflect the properties of the vaccine that’s being developed for the U.S.

“Changing manufacturing sites for a vaccine is problematic in the best of times, but in pandemic circumstances, without a recognized correlate of protection, or any bridging immunogenicity studies, it can be disastrous,” SVB Leerink wrote.

That uncertainty could be magnified by the fact that for earlier published trials, AstraZeneca’s vaccine was manufactured at different sites and tested at varying dosing schedules. That may not jibe with the FDA’s usually exacting standards.

“Ultimately one source, one dose, and one dose interval need to be studied and established and reviewed by regulators so the product can have a standard label for physicians and other providers to discuss with patients,” the analysts warned.

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Then there’s the question of just how efficacious AstraZeneca’s COVID-19 vaccine actually is, particularly with emerging mutants of the virus spreading rapidly across the world.

Last week’s study concluded that the vaccine was just 22% effective at protecting against mild to moderate COVID symptoms and that neutralization titers against the South Africa variant were “substantially reduced” in comparison to the original virus, said researchers at Oxford University, where the vaccine was originally developed.

Oxford and AstraZeneca are now updating the vaccine so it can tackle the South Africa variant. The reformulated shot could be ready by fall. But officials in South Africa have suspended their rollout of the shot for now.

All in all, FDA officials could very well decide not to clear a sub-par vaccine, even though the demand for vaccination is far outstripping the supply of the two mRNA vaccines on the market, from Moderna and Pfizer/BioNTech. That’s especially true given the fact that the two marketed vaccines—as well as one from Johnson & Johnson that could get emergency use authorization soon—seem to be better at shielding against the novel variants, SVB Leerink said.

“Since one or more of these [mutant] strains is likely to become dominant in the US by early summer, it is hard to imagine the FDA approving a vaccine with zero efficacy against such strains, and which, if widely used, would only accelerate the spread, and perhaps the further adaptation” of the virus, they wrote.

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So what’s the bull case for AstraZeneca’s product? The near-term supply of COVID-19 vaccine doses has come nowhere close to meeting the demand. By SVB Leerink’s calculations, 88% of the U.S. population has yet to start the two-dose vaccination process.

Plus, more reliable data could be on their way. A clinical trial of AstraZeneca's vaccine in the U.S. was put on hold briefly because of safety concerns last year, but it has since resumed, and results could show that manufacturing and other factors were “better controlled than in other geographies,” SVB Leerink said.

“We believe that it is possible that the overwhelming U.S. supply discrepancy with demand could weigh in on the decision to grant a U.S. AstraZeneca vaccine approval, given that data thus far implies efficacy that is above FDA COVID-19 vaccine guidelines,” the analysts wrote.