Oxford vaccine that works best with smaller doses raises questions

Sarah Gilbert learned on Saturday evening that the Covid-19 vaccine she developed with AstraZeneca Plc appeared to be working. But the Oxford University professor had expected a key figure: was it more than 90% effective, like others have been – or less?

Instead, when his colleague Andrew Pollard called with the results, he wanted to show him slides instead of just numbers. “I didn’t really understand why we had to go through slides,” she recalls. “But then it became clear – because it’s a little more complicated in our trial.”

This complexity has driven uncertainty to swirl around one of the pioneers with Pfizer Inc. and Moderna Inc. in the shooting race 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 U.S. Food and Drug Administration will wipe it out.

On Monday morning, AstraZeneca and Oxford reported the results after 131 trial participants in the UK and Brazil contracted Covid 19. The average 70% prevention effectiveness sounded good, within analysts’ expectations and above the 50% standard that the FDA had set for Covid vaccines.

The study also revealed 16 severe cases, all of which were people who did not receive the AstraZeneca blow, according to Moncef Slaoui, the former GlaxoSmithKline Plc researcher who heads the US program Operation Warp Speed. This was good news for Astra’s vaccination program which had been on hiatus for six weeks in the United States as regulators examined a serious adverse event the company had never given details about. Oxford will report the details of these adverse events in its efficacy study which it will submit for review in the coming weeks.

The puzzling part of Astra’s results was that higher doses were less effective. The vaccine was only 62% effective in a group that received two full doses about a month apart. But among around 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 benefits in storage, transport and accessibility will be welcome, said Jesse Goodman, former head of the FDA’s vaccine bureau, who was more later the chief scientist of the agency.

“What is not yet clear is that this effect is a coincidental observation or does it reflect something that the higher dose may have a negative effect on the immune response,” he said. stated in an interview. “We need more details to start to understand this.”

Geoffrey Porges, an analyst at SVB Leerink, was among the most critical voices, calling the data “premature and insufficient” in a note to customers and predicting that the vaccine “would never be authorized in the United States.”

Be patient

AstraZeneca and Oxford are conducting trials of the vaccine in different parts of the world and are currently looking at just two full doses of the vaccine in their US study which is expected to recruit 30,000 volunteers. But the company is still recruiting participants and may add another arm to conduct further studies on the half-dose regimen, said Ruud Dobber, executive vice president and president of biopharmaceuticals at AstraZeneca.

“Let’s be a little more patient and see how the FDA reacts before making such harsh statements,” he said in an interview with Bloomberg TV.

The UK Medicines and Health Products Regulatory Agency has already started its analysis based on data received as part of an ongoing review, Chief Executive Officer June Raine said in a statement. Even the lowest efficacy number of the full-dose regimen has reached the World Health Organization benchmark, Chief Scientist Soumya Swaminathan said. Low- and middle-income countries are looking to the coup, at prices well below those of Pfizer and Moderna, as a way out of the pandemic.

But a lower dose producing a better result causes many to scratch their heads, including Gilbert herself. The researchers tested a diet with an initial half-dose to find the smallest amount that could still generate a strong immune response, Gilbert said, so as not to increase effectiveness.

“I was surprised,” she said in an interview. “I really didn’t expect this.”

Its superiority over two full doses could be good news, allowing the company to do more inoculations from the same overall volume of vaccine. This 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 colds – as a vector which is then inserted with the coronavirus spike protein to generate an immune response.

Theoretical reasons

It is theoretically possible that a full initial dose generated 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 really sure that’s the full answer. We’ll look into it a bit more,” she said. “But it can be something 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 expanding it with the second dose.”

One possible explanation for the varying results is that the lower initial dose allows it to pass through the body’s defenses better, allowing the vaccine to infect cells and create the immune response, said Michael Kinch, an expert in drug development and Associate Vice Chancellor in Washington. University of Saint-Louis.

Another theoretical reason is more complex: the immune system can become hardened by the initial high dose of vaccine and then ignore the next dose, a phenomenon known as immune tolerance or desensitization. Either would have the potential to lessen the effects of the shot.

“The overall number of 90% could ultimately prove to be correct,” 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 she was confident the higher efficiency figure would roughly hold when more data came in.

“It could go up or down a bit,” she said. “I don’t think that’s going to change massively, but it may diverge from that initial 90% either way when we get to a slightly larger analysis.”

(Except for the title, this story was not edited by NDTV staff and is posted from a syndicated feed.)