The news reached Sarah Gilbert on Saturday night that the Covid-19 vaccine she developed with AstraZeneca Plc appeared to work. But the Oxford University professor expected a key number: was it more than 90% effective, as others have been, or less?
Instead, when his colleague Andrew Pollard called with the results, he wanted to show him slides instead of simple figures. “I really didn’t understand why we had to go through slides,” he recalled. “But then it became clear, because it is a lot more complicated in our test.”
That complexity has led to uncertainty swirling around one of the pioneers along with Pfizer Inc. and Moderna Inc. in the race for a chance to end the pandemic. Questions about the most effective dose of the vaccine, its safety record, and partners’ approach to testing it have cast doubt on whether the US Food and Drug Administration will approve it.
AstraZeneca and Oxford reported results early Monday after 131 trial participants in the UK and Brazil contracted Covid 19. Average prevention efficacy of 70% sounded good, within analyst expectations and above standard. of the 50% that the FDA had set for Covid vaccines.
The study also found 16 severe cases, all of them among people who did not get the AstraZeneca vaccine, according to Moncef Slaoui, the former GlaxoSmithKline Plc researcher who runs the US Operation Warp Speed program. It was good news for him. Astra’s vaccine program that had been on hold for six weeks in the US while regulators reviewed a serious adverse event that the company never gave details about. Oxford will report details of these adverse events in its efficacy study which it will present for review in the coming weeks.
The puzzling part of the Astra results was that the larger doses were less effective. The vaccine was only 62% effective in a group that received two full doses about a month apart. But among about 2,700 people who received a half dose followed by a full dose, the number rose to 90%.
Positive data from another vaccine of substantial efficacy with potential advantages in storage, transportation and affordability will be welcome, said Jesse Goodman, a former chief of the FDA’s office of vaccines who later became the agency’s chief scientist.
“What is still unclear is whether this effect is a random observation or reflects something that the higher dose can negatively affect the immune response,” he said in an interview. “We need more details to begin to understand it.”
Geoffrey Porges, an analyst at SVB Leerink, was among the most critical voices, calling the data “premature and insufficient” in a note to clients and predicting that the vaccine would “never be licensed in the United States.” Shares fell 3.8% in London.
Be patient
AstraZeneca and Oxford are conducting trials of the vaccine in different parts of the world and are currently only studying two full doses of the vaccine in their US study, which is expected to enroll 30,000 volunteers. But the company is still recruiting participants and could add another branch to conduct more studies of the regimen using the half dose, said Ruud Dobber, executive vice president and president of biopharmaceuticals at AstraZeneca.
“Let’s be a little more patient and see how the FDA will react before making such harsh statements,” he said in an interview with Bloomberg TV.
The UK Medicines and Healthcare Products Regulatory Agency has already begun its analysis based on the data it has received in ongoing review, Executive Director June Raine said in a statement. Even the lowest efficacy number for the two full-dose regimen reached the World Health Organization benchmark, said chief scientist Soumya Swaminathan. Low- and middle-income nations are looking to the injection, priced much lower than Pfizer and Moderna, as a way out of the pandemic.
But a lower dose that produces a better result has many scratching their heads, including Gilbert herself. The researchers tested a starting half-dose regimen to find the smallest amount that could still elicit a strong immune response, Gilbert said, not to increase effectiveness.
“I was surprised,” he said in an interview. “I really didn’t expect that.”
Its superiority over two full doses could be good news, as it would allow the company to perform more inoculations with the same total volume of vaccine. That could be important with the need to vaccinate billions of people around the world.
The vaccine uses a harmless chimpanzee adenovirus, the cause of some common colds, as a vector that is then inserted with the coronavirus spike protein to elicit an immune response.
Theoretical reasons
In theory, it is possible that a full initial dose raised antibodies against the adenovirus vector itself, which could have limited the immune response to the coronavirus spike protein, Gilbert said. But his team measured antibodies to adenovirus in previous studies and found only a small effect.
“I’m not sure if that’s the complete answer. We will investigate a little more, ”he said. “But it can be a little more subtle in terms of inducing a high-quality immune response by giving just the right amount of vaccine antigen in the first dose and then spreading it out with the second dose.”
One possible explanation for the variable results is that the lower starting dose does a better job of breaking through the body’s defenses, allowing the vaccine to infect cells and build the immune response, said Michael Kinch, an expert in drug development and associate vice chancellor in Washington. St. Louis University.
Another theoretical reason is more complex: the immune system can become immune from the initial high dose of vaccine and then ignore the subsequent dose, a phenomenon known as immune tolerance or desensitization. Either one would have the potential to mitigate the effects of the shot.
“The 90% headline count might finally turn out right,” Kinch said, “but the dose-response reversal could be a sign of concern.”
The Oxford team is still analyzing their data to better understand how the vaccine works. Gilbert said he’s confident that the higher efficiency number will stick around as more data arrives.
“It could go up or down a bit,” he said. “I don’t think it’s going to change massively, but it may differ from that initial 90% in either direction when we get to a little bigger analysis.”
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