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London – AstraZeneca and the University of Oxford on Wednesday admitted a manufacturing error that raised questions about the preliminary results of their experiment Covid-19 vaccine, but an outside expert told CBS News that there was “nothing sinister” about the way the data from the human trials was gathered, and he remains optimistic that the vaccine will be found to be safe and effective. and approved for use.
A statement describing the error came days after the company and the university described the injections as “very effective” and did not mention why some study participants did not receive as much vaccine as provided in the first of two injections.
The group of volunteers who received a lower dose appeared to be much better protected than the volunteers who received two full doses. In the low dose group, AstraZeneca said the vaccine appeared to be 90% effective. In the group that received two full doses, the vaccine appeared to be 62% effective.
Together, the drugmakers said the vaccine appeared to be 70% effective, but the way the results were obtained and reported led to questions from some experts.
The partial results announced on Monday come from large studies underway in the UK and Brazil to determine the optimal dose of vaccine, as well as to examine safety and effectiveness. Multiple combinations and doses have been tried in volunteers. They were compared to others who received a meningitis vaccine or an injection of saline.
Was it a mistake?
Before starting their research, scientists explain all the steps they take and how they will analyze the results. Any deviation from this protocol may call into question the results.
In a statement to CBS News Thursday, the University of Oxford said the dosage in all three stages of the trial was supposed to be the same, but “due to a difference in the manufacturing process” for the By far the largest phase 3 trial, the methods used to measure vaccine concentration in vials overestimated the dose in newer batches, “resulting in half a dose of vaccine given as the first dose.”
The university said it had discussed the issue with UK drug regulators and agreed to complete the advanced stage trial with the two separate subgroups.
Oxford said in its statement that its methods of measuring vaccine concentration had been adjusted to avoid any further discrepancies, “and we can ensure that all batches of vaccine are now equivalent.” AstraZeneca CEO Pascal Soriot told Bloomberg News on Thursday that the company needs to conduct a new trial, but suggested it could be done quickly because the vaccine’s high efficacy meant the new trial would require a smaller number of patients.
And the results?
Some experts say the relatively small number of people in the low-dose subgroup – 2,741 people – makes it difficult to know whether the 90% efficacy seen in this group is real or a statistical oddity. A total of 8,895 people received two full doses, and in this group the efficacy was less than about 60%.
Another factor: none of the people in the low dose group were over 55 years old. Younger people tend to have a stronger immune response than older people, so the young in the low-dose group may make it look more potent, rather than the size of the first dose.
Earlier this month, a peer-reviewed analysis of data from the Oxford Phase 2 trial, published in The Lancet, found that the vaccine “has similar immunogenicity in all age groups” after two full doses, and that in fact it was “better tolerated in the elderly than in young adults. “
This phase of the trial involved 560 adults, including 240 people over 70 years old.
Older patients are known to be at a significantly higher risk of serious illness and death with the coronavirus – these are the patients most likely to fill overburdened hospital wards with intensive care, and they have been designated to receive the vaccine in first.
Why might a lower dose work better?
Oxford researchers say they’re not sure and are working to find out why, but they have some ideas.
Sarah Gilbert, one of the Oxford scientists leading the research, said the response was likely related to providing exactly the right amount of vaccine to trigger the best immune response.
“This is the amount of Goldilocks you want, I think, neither too much nor too little. Too much could give you a shoddy response too, ” she said. So you just want the right amount and it’s a little hit and miss when you’re trying to go fast to get that perfect first time. “
Professor Adrian Hill, director of the Jenner Institute in Oxford, which developed the vaccine, further explained this “Goldilocks” theory to Charlie D’Agata of CBS News, saying the administration of ‘a first dose of the vaccine elicits an immune response at a time. the coronavirus antigen, which protects a person against infection, and against the virus itself.
“If you give a big dose first and a big second dose, when you come up with the second, it doesn’t work as well because you caused some immunity by giving the first dose,” he said. . “By decreasing the size of the first dose, halving it, you are most likely hampering this vector immunity, as we call it, so the second dose works better.”
Hill pointed out that this explanation has yet to be proven, “but it’s something we will be looking into in the weeks and months to come.”
Where do we go from here?
Moncef Slaoui, who heads the U.S. Operation Warp Speed coronavirus vaccine program, said on a call with reporters on Tuesday that U.S. officials were trying to determine what immune response the vaccine produced and may decide to modify the study AstraZeneca in the United States to include a half. dose subgroup.
“There are a number of variables that we need to understand,” Slaoui said, adding that “we want it to be based on data and science”.
Full details of the trial results will be published in medical journals and provided to UK regulators so they can decide whether or not to allow the vaccine for distribution.
These reports will include a detailed breakdown that will include demographic and other information about who has fallen ill in each group and will give a more complete picture of the vaccine’s effectiveness.
“Nothing sinister”
While even AstraZeneca and Oxford would admit that more data analysis is still needed to conclusively determine how their vaccine works and which dosage to use, Danny Altmann, professor of immunology at Imperial College London, told CBS News on Thursday that he was not too concerned about the error behind the test data.
“There is nothing sinister or dangerous or that undermines the veracity of their work,” said Altmann, who has no connection with the Oxford vaccine, and is equally optimistic about himself and the others. leading vaccine candidates in late stage trials, such as Pfizer and Moderna.
Rather than an attempt to distort the data from the trials, Altmann attributes the Oxford team’s characterization of their preliminary success – and its scrutiny – to the unprecedented speed of the vaccine development process amid this pandemic. and the unprecedented public interest it generates.
“It really highlights the weaknesses and pitfalls of ‘press release science’, which is something that almost everyone has been pushed into by circumstances in the current climate,” he told CBS News.
He said preliminary data from medical trials the world was so eager to devour and understand would normally be judged on a long manuscript for peer review.
“We are not used to evaluating real-time data through a short press release,” he said. Asked whether the reasons and details for the half-dose regimen should have been disclosed in full in the Oxford press release sent on Monday, he said: “This is the price we are paying for a streamlined presentation process. “
And most importantly, based on the available data, Altmann is hoping not only that the Oxford vaccine will work, but that it will not be alone.
“My guess is that within a month we would have seen some very strong and large datasets, probably from Pfizer, Moderna and Oxford, and I suspect Novavax as well,” he said. “Then we’ll have to go through them with a fine comb. I suspect they’ll all be very good. I suspect they’ll all be in the right stadium. I think they’ll all be able to save our Bacon.”
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