“If the regulators accept an immune marker that is an established correlate of protection, it will be such a powerful thing, because it would be relatively easy to study vaccines,” says Peter Gilbert, biostatistician at the Fred Hutchinson Cancer Research Center which is part of the Covid-19 prevention network.
But the different ways in which vaccines attack the virus make it difficult to apply for a universal standard. “The big question is whether the correlate translates between vaccine platforms?” Gilbert said. His team, which helped find the correlates, relies on advanced biostatistical methods in the search for other vaccines and HIV. When Covid-19 arrived, the team pivoted.
Hu says Covaxx is exploring the concept of correlation in an effort to shorten the company’s trial in Brazil, but the strategy hinges on a regulatory path that doesn’t yet exist. An FDA spokesperson wrote by email that establishing correlates is “a major focus of investigation by federal and non-federal entities.” She added that the agency “will provide additional information as our discussions with product manufacturers and our international counterparts progress.”
Manufacturers of drugs with vaccines already authorized are also attached to the correlates. In an email, a spokesperson for Pfizer wrote that these immune response markers could help test its vaccine in children and those with weakened immune systems – or control boosters targeting variants.
Separately, the FDA recently announced that modified vaccines adapted to block new variants may be able to forgo lengthy clinical trials. Under this leadership, Novavax is hoping that a booster that has been modified from its own current vaccine candidate could be the subject of a relatively small immune response study of 400 people, a company spokesperson said.
The Covid-19 Prevention Network is looking for correlates of protection for Moderna’s vaccine, with analysis planned for vaccines from Novavax, Johnson & Johnson and AstraZeneca. There is an urgency behind the effort.
“Very soon, it will no longer be possible to conduct a large placebo-controlled trial, at least in the United States,” said Dan Barouch, a virologist at Beth Israel Medical Center in Boston. He contributed to a December study, Posted in Nature, which found certain antibodies in the blood of monkeys predicts protection against Covid-19. The results increased confidence that blood tests could do the same in humans. “The data from our animal models are very encouraging,” says Barouch, but he cautions that variants pose yet another challenge in identifying correlates.
For vaccine manufacturers approaching late stage trials, another potential option might be to compare one vaccine candidate to one that is already licensed. But a head-to-head study would require more participants than a typical trial with 30,000 subjects, which is already a heavy burden. Instead, much of the vaccine makers seem to go overseas, looking for places where residents may be willing to volunteer because licensed vaccines are not yet available.
During the second quarter of this year, San Diego-based Arcturus Therapeutics will conduct a Phase III study of its single-injection RNA vaccine in countries with high Covid prevalence and access to first-class vaccines. intention is low or even nil. “You can’t run a trial like this in the United States,” says CEO Joseph Payne. “But there are over 200 countries in the world, and a strong majority of them have yet to receive vaccines.” (The company has yet to reveal which countries will be involved.)
Submission of vaccine trial data from other countries calls for closer scrutiny by the FDA. But David Curiel, interim CEO of St. Louis-based Precision Virologics, believes that possible test data from his company in India will be fine with the agency, based on a review by a consultant from the. Testing infrastructure, protocols and familiarity of Bharat Biotech, a collaborator based in India. with various regulators. Bharat is overseeing the Phase I trial as part of a larger partnership between the two companies. Curiel said strong ties between Indian government officials and different villages helped recruit test subjects quickly. “They have a network in place that allows for rapid build-up and implementation of vaccine trials,” says Curiel.