The University of Oxford’s candidate vaccine against COVID-19 is being tested in South Africa, the United Kingdom and Brazil.Credit: Siphiwe Sibeko/AFP via Getty
When it rains, it pours. In the past few days, scientists working at feverish pace to develop vaccines against the coronavirus have released a flood of data from their first human trials.
The results come from phase I and II trials of four promising vaccine candidates and detail how people respond to the jabs. Because the trials were focused on safety and dosing, the data cannot say whether the vaccines will prevent disease or infection — large-scale efficacy trials are needed for this. But they suggest that the candidate vaccines are broadly safe, and offer the first hints that vaccines can summon an immune response that resembles that of people who have been infected with the virus. Crucially, researchers say the data look good enough to merit testing the vaccines in efficacy trials, in which volunteers receive a vaccine or placebo and rates of COVID-19 disease are compared between groups.
“I’m really happy that there are quite diverse vaccine strategies going beyond phase I trials,” says Shane Crotty, a vaccine immunologist at La Jolla Institute for Immunology in California.
But scientists caution against over-interpreting the results, and say the data shouldn’t be used to directly compare the different vaccines. Ultimately such comparisons will be vital for identifying how different vaccines work, or why they fail, and to use this information to prioritize other vaccines at early stages and to develop new ones. But researchers don’t yet know the precise nature of the immune responses that protects against COVID-19 — and there are likely to be multiple ways to fend off infection. And measurements of different immune markers made in one lab are difficult to compare with those performed by another team, say scientists.
“The data are so early and so preliminary, one thing to avoid is saying one is better at this stage because we just don’t know,” says Rafi Ahmed, an immunologist at Emory University in Atlanta, Georgia.
Viral vectors
All four vaccine-makers said that their vaccines elicited some kind of immune response in people, broadly similar to that seen in recovered patients. Trial participants experienced side effects common to other vaccines, such as muscle pain, fevers and headaches, but few participants developed serious reactions to the different vaccines. “Most of them are looking quite safe,” says Crotty.
Two teams — at the University of Oxford, UK, in collaboration with AstraZeneca, and researchers at Cansino Biologics in Tianjin, China — that are developing ‘viral vector’ vaccines published1,2 their results in The Lancet on 20 July.
“The vaccine is inducing the kind of immune responses that we think are inducing protection against coronavirus,” said Sarah Gilbert, an Oxford vaccinologist leading that effort, in a 20 July press briefing announcing their results. Oxford’s vaccine harnesses a genetically modified chimpanzee cold-causing adenovirus that expresses the coronavirus spike protein, which the virus uses to infect human cells. Cansino’s, meanwhile, is comprised of a modified human adenovirus.
Another group, BioNTech in Mainz, Germany, which is developing an RNA-based vaccine drug company with Pfizer, released detailed immune data from people who received a vaccine that contains RNA instructions for the ‘receptor binding domain’ portion of the spike protein3. This followed long-awaited clinical-trial results on 14 July4 from Moderna, a biotech company in Cambridge, Massachusetts, that has developed a competing RNA vaccine made of the entire spike protein, in collaboration with the US National Institute of Allergy and Infectious Disease (NIAID) in Bethesda, Maryland. Some details of the results were announced in a press release in May.
Immune response
The latest data offer the best insight yet on the nature of the immune responses prompted by the vaccine — the only indication, short of an efficacy trial, that they are likely to work.
Vaccines work by exposing the immune systems to components of a virus — the coronavirus spike protein, in the case of nearly all COVID-19 vaccines — in hopes of provoking a reaction against a real infection in the future. The trials looked at two broad types of immune response: antibody molecules made by the body that can recognize and, in some cases, inactivate viral particles; and T-cells that can kill infected cells as well as promote other immune responses including antibody production.
So far, most focus has been on ‘neutralizing antibodies’ circulating in the blood, which can render viral particles uninfectious. “All of these [vaccines] are inducing some antibodies that neutralize, which is better than no neutralizing,” says Ahmed. That’s a decent sign, he says. Most vaccine volunteers produced levels of these potent antibodies that were similar to those made by recovered Covid-19 patients, which can vary widely.
But many of the vaccines might require more than one dose to get this response. “I think two doses will be required for many of these vaccines in order to achieve adequate virus neutralizing antibodies,” says Peter Hotez, a vaccine scientist at the Baylor College of Medicine in Houston, Texas.
T-cell focus
T-cell responses have received less attention from vaccine developers. That’s in part because they are more difficult to measure, especially as the numbers of trial participants pushes into the thousands. But emerging data from natural infections suggest that T cells might have an important role in controlling the coronavirus, says Crotty.
The slew of vaccine trials detected varying degrees of T-cell responses in participants. Crotty’s team detected spike-recognizing CD4 T cells, which support antibody production, in all 10 of the recovered patients they examined. Seventy per cent also had CD8 T cells, which kill virus-infected cells, against spike5.
If a vaccine can elicit a combination of neutralizing antibodies and both kinds of T-cells, it could bode well for protecting against disease, says Crotty. But that’s mostly a hunch. “We don’t know the rules for what’s most important for protective immunity,” he says. “It’s definitely plausible that there’s more than one way to protect against this virus.”
The nature of the immune response that protects — or fails to protect — against COVID-19 will become clearer when efficacy trials deliver their first results. “As soon as someone gets efficacy, we’ll have a better idea of what a vaccine needs to do,” Gilbert said in the briefing. Oxford’s vaccine is being tested for efficacy in the United Kingdom, Brazil and South Africa, and the Moderna-NIAID vaccine is set to begin its phase III trial in the United States this month.
Compare and contrast
Such data — known as a correlate of protection — could make it easier to interpret early-stage trial results like those released in this week. But such comparisons are also thwarted by the fickle nature of the tests researchers use to measure neutralizing antibody and T-cell responses. The same test can return widely different values when performed in different labs or even on different days of the week.
“It’s hard for us to compare our vaccine results to other people’s,” Adrian Hill, an Oxford vaccinologist, said in the briefing. “We would really like to see different vaccines being tested in the same lab by the same people.” The US government’s effort to support COVID-19 vaccines, known as Project Warp Speed, is supposed to be making such comparisons, notes Hotez. The World Health Organization in Geneva and the Coalition for Epidemic Preparedness in Oslo, which has provided financial support to nine vaccine developers, have also announced plans to support this work.
It is vitally important to be able to identify immune correlates of protection and to be able to compare vaccines, says Daniel Altmann, an immunologist at Imperial College London. “The stakes have never been higher,” he says. "We so desperately need it."
Altmann thinks that most of the frontrunner vaccines “could do the trick”, but he worries that there is not enough emphasis on identifying vaccine candidates whose developers are most capable of manufacturing and delivering enough vaccine for much of the world. That could depend on myriad issues from sourcing glass vials to maintaining cold chains. “That’s like organizing a Moon landing or a world war invasion. Whichever candidates we pick, we want them to be the ones that can most optimize that.”
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