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There are more than 175 COVID-19 vaccines in development, but only a few are in end-stage clinical trials.Credit: Joe Raedle / Getty
When it comes to developing vaccines, Peter Palese is not far behind. Virologist at the Icahn School of Medicine at Mount Sinai in New York City, he pioneered the genetic techniques used to produce some of the billions of doses of flu vaccines produced annually, and his team has made millions dollars to develop a universal flu vaccine.
Palese is also developing a COVID-19 vaccine. It consists of a bird virus genetically modified to produce a protein found on the surface of the SARS-CoV-2 coronavirus. The vaccine fully protects mice from an experimental model of COVID-19one, according to a recent draft version (the research has not yet been peer-reviewed). It also grows in chicken eggs, like most flu vaccines, so manufacturing could be increased with proven technology.
Despite its potential, the Palese vaccine has struggled to get the attention and funding necessary to advance to human trials. “We thought this would be the best thing after sliced bread, and people would break down our doors to get it. That is not the case. We are very disappointed, ”he says.
As major pharmaceutical and biotech companies accelerate their COVID-19 vaccines through clinical trials and seek fast-track regulatory clearance, dozens of underprivileged vaccines like Palese’s have either stalled or are moving down a slower path and conventional.
Scientists acknowledge that it would be a waste of resources to bring all candidates to clinical trials. But they argue that having a diverse selection of COVID-19 vaccines in development is essential. Top favorites may fail, confer only partial protection, or malfunction in certain age groups; High costs and other barriers may make some of the top finishers unfit for large-scale deployment in low-income countries.
“Everyone is encouraging them to succeed beyond anyone’s expectations, but it’s wise to think about what happens if they don’t,” says Dave O’Connor, a virologist at the University of Wisconsin-Madison. “We need to make sure we have backup plans and backup plans for those backup plans.”
Dozens of candidates
There are more than 320 COVID-19 vaccines in development, according to a recent tally by the Coalition for Epidemic Preparedness Innovation (CEPI) in Oslo, a fund created to finance and coordinate vaccines for outbreaks. Most of these are in the early stages of preclinical development; several dozen are in clinical trials, and only a few have begun end-stage efficacy trials. “Everyone and their mother have a vaccine. My dogs have two vaccinations, ”says a scientist working on a leading candidate. While this is good news at first glance, it also presents challenges. One is determining which candidates should advance to expensive clinical trials: conducting even a small study to test safety and dosing is out of the reach of most academic groups, and smaller teams face an uphill struggle to get their candidates. are noticed.
In some cases, the breakneck pace of COVID-19 vaccine efforts has created opportunities for academic groups. One of the main candidates is being developed by the University of Oxford, UK, and the pharmaceutical company AstraZeneca (trial enrollment was paused after a participant developed a serious health problem, the company said on Sept. 8). The vaccine is based on a type of chimpanzee cold virus, called adenovirus, which has been used for experimental vaccines against Ebola, malaria and other diseases, allowing Oxford vaccinologists to quickly adapt the platform to a COVID vaccine. -19. Another technology comprises RNA instructions for a coronavirus protein, and firms with expertise on that platform are developing two pioneering vaccines.
But no technology has yet produced licensed vaccines, and there is no guarantee that candidates will generate strong immunity to coronavirus, says Michael Diamond, a viral immunologist at Washington University in St. Louis, Missouri, who is working on two initial stages. vaccinations Onetwo it is based on a weakened cattle virus. The other3 it is based on a chimpanzee adenovirus, like the Oxford-AstraZeneca effort.
The Diamond adenovirus vaccine, unlike any of the leading candidates, is designed to be administered through the nose. A team led by Diamond and University of Washington cancer biologist David Curiel found3 that mice that received a single dose of the intranasal vaccine were completely protected from SARS-CoV-2, with virtually no sign of virus in their upper or lower respiratory tract. Mice given an injection of the same vaccine were only partially protected, echoing animal data from some of the leading candidates. This was because the intranasal vaccine elicited powerful ‘mucosal’ immune responses that can block the virus at the site of infection in the upper respiratory tract, the team says.
Based on these results, Diamond feels his team has “a mission” to push their vaccines into human trials, to “see if they are going to be one of the last standing, even if they are not the first out there.” His university has struck a deal to license the intranasal vaccine to a manufacturer, but Diamond has yet to find anyone to advance his team’s cattle virus vaccine. Pharmaceutical Merck is developing its own vaccine based on it. virus, which is also the backbone of the Ebola vaccine the firm had approved in the United States and the European Union last year. Many companies “just don’t have the bandwidth, the money, the means, or the desire to acquire additional platforms, “says Diamond.” The challenge has been finding partners. “
Funder priorities
Many of the vaccines that were prepared for the first approvals got seed funding from CEPI, which has so far spent nearly $ 900 million on nine COVID-19 candidates. US government agencies, including the Advanced Biomedical Research and Development Authority (BARDA), have spent billions of dollars to support a handful of candidates as part of Operation Warp Speed. But other donors, with their own priorities, are stepping in to help academics turn their experimental vaccines into products.
With many rich countries acquiring the first supplies of leading COVID-19 vaccine candidates, some of these teams have set their sights on developing vaccines for the rest of the world.
Neil King, a biochemist at the University of Washington in Seattle, and his team are preparing a nanoparticle vaccine for clinical trials, with support from the Bill and Melinda Gates Foundation in Seattle. The effort, which King is leading with structural biologist David Veessler of the University of Washington, has produced a vaccine consisting of a self-assembling virus-like particle that is peppered with 60 copies of the receptor-binding domain of the peak protein that SARS-CoV-2 uses to enter human cells. In a recent preprint, the team reported that small doses of the vaccine led to huge immune responses in mice.4.
The jab could be supplied to low- and middle-income countries, King says. It comprises ‘recombinant’ proteins made with DNA from multiple sources, which are already used as medical products, including insulin, blood clotting factors, and other vaccines, so there is enormous global manufacturing capacity for them. Vaccines with ‘virus-like particles’ that self-assemble from these proteins also have a strong track record: existing vaccines against human papillomavirus, a cause of cervical cancer, and hepatitis B are based on technology. . Clinical trials of the nanoparticle vaccine are scheduled to begin in December. “We don’t have a billion dollars from BARDA, but we are moving the program forward and making sure we don’t waste time,” says King.
And last month, the Baylor College of Medicine in Houston, Texas, announced that it had granted a non-exclusive license to its protein-based COVID-19 vaccine candidate to an Indian manufacturer, Biological E in Hyderabad. The vaccine, which is estimated to cost about $ 2 per dose, could be used alone or to boost the immune response elicited by other vaccines, says Baylor vaccine scientist Maria Elena Bottazzi, who is leading the effort to develop it. “While we wait for the Warp Speed vaccines to really show us the data, we need to start thinking about second-generation vaccines.”
Researchers say donors must step in to provide guidance and financial support for COVID-19 vaccines. But as much as underprivileged developers would like their vaccines to help end the pandemic, they are still encouraging their better-funded competitors to succeed. “As a human being, my hope is that none of the candidates fail,” says King. “I want each of them to work, and I want this to go away.”
