The Underdog Covid‑19 Vaccines That the World

News in focus clinical-trial holds in future. The transparency individual, but still provides a summary of the released prematurely, it could present a bias bar should be set much higher than this latest clinical issues that arose, and the conclusions to the clinicians involved in them, says Griffin. example, says Kieny. “When, ultimately, a vac- the committee reached about the implications The integrity of the trials is on the line, he adds. cine will be made available, public trust will be for the study, he says. “It is of concern that they Griffin expects the pause to have little impact paramount to ensure public-health impact. sought to avoid doing so,” says Komesaroff. on the UK trials’ overall timeline. And trust needs transparency.” The University of Oxford and AstraZeneca But it has not been reported when trials of have not yet responded to requests for com- the vaccine in the United States and South Leading vaccine ment on this criticism. Africa will restart. A spokesperson for Astra- The vaccine, AZD1222, is one of the leading Although the university and AstraZeneca Zeneca told Nature that the company “will be candidates being developed to protect against have not released information about the guided by health authorities across the globe the virus that causes COVID-19, and one of a adverse event to the public, Pascal Soriot, as to when other clinical trials of the vaccine handful of immunizations in the final stages AstraZeneca’s chief executive, reportedly can resume”. of clinical testing. The pause in global trials told investors on a telephone call last week So far, some 18,000 people globally have sent a shudder around the world. that a person in the UK trials had developed received the vaccine. Phase III efficacy trials in Such a quick resumption of the trials was the symptoms of transverse myelitis, according the United Kingdom, which began in June, aim most likely outcome, says Paul Griffin, an infec- to health-news website STAT. This condition to recruit 10,000 people, and a phase III trial tious-diseases researcher at the University of involves inflammation of the spinal cord, in Brazil hopes to recruit 5,000 participants. Queensland in Brisbane, Australia. In large which can be triggered by viruses. The US trial, which started in August, is aim- trials, adverse medical events in volunteers But other scientists say there is a good rea- ing to recruit 30,000 participants. A phase I/II are common, and trial holds are designed to son why the company hasn’t released more safety and efficacy trial in South Africa wants ensure that such events are investigated and details. If information about the trials is to recruit 2,000 volunteers. volunteers are protected, he says. But, most often, it is later decided that the event was probably not related to participation in the trial and does not pose a safety concern to the rest of the volunteers, says Griffin. That seems to be what has occurred in this case, he says. THE UNDERDOG COVID‑19 It can be difficult to pin down the cause of adverse events, says Jonathan Kimmelman, a VACCINES THAT THE bioethicist who studies clinical trials at McGill University in Montreal, Canada. “Often, the WORLD MIGHT NEED best you can do is say that there is a possible link, and then proceed with collecting more Small developers struggle to get their candidates data and monitoring outcomes,” he says. The University of Oxford said in a press noticed, but they’ll be crucial if front runners stumble. release on 12 September that the pause, which applied to all trials of the vaccine, was neces- By Ewen Callaway companies rush their COVID-19 vaccines sary “to allow the review of safety data by an through clinical trials and eye up fast-track independent safety review committee, and hen it comes to developing regulatory authorization, dozens of underdog the national regulators”. vaccines, Peter Palese is no slouch. vaccines such as Palese’s have stalled, or are “The independent review process has con- A virologist at Icahn School of advancing along a slower, more conventional cluded and following the recommendations Medicine at Mount Sinai in New path. of both the independent safety review com- York City, he pioneered genetics Scientists acknowledge that it would be a mittee and the UK regulator, the MHRA [Med- Wtechniques that are used to make some of the waste of resources to take every candidate to icines and Healthcare products Regulatory billions of influenza vaccine doses produced clinical trials. But they argue that it’s essential Agency], the trials will recommence in the UK,” annually, and his team has won millions of to have a diverse selection of COVID-19 vac- the statement reads. The university also said dollars to develop a universal flu jab. cines in development. Early favourites could that it cannot disclose medical information Palese is developing a COVID-19 vaccine, fail, confer only partial protection or work about the participant’s illness for reasons of too. It consists of a bird virus that has been poorly in certain age groups; high costs and confidentiality. genetically modified to make a protein found other barriers might make some of the front It’s appropriate not to disclose information, on the surface of SARS-CoV-2. The vaccine fully runners unsuitable for wide-scale deployment for patient confidentiality and to ensure valid protects mice from an experimental model in lower-income countries. interpretation of the trial results, says Kristine of COVID-19, according to a preprint1 (the “Everyone is rooting for them to succeed Macartney, the director of Australia’s National research has not yet been peer reviewed). beyond anyone’s expectation, but it’s prudent Centre for Immunisation Research and Surveil- It also grows in chicken eggs, like most flu to think about what happens if they don’t,” says lance in Sydney. vaccines, so manufacturing could be ramped Dave O’Connor, a virologist at the University up using tried-and-tested technology. of Wisconsin–Madison. “We need to make sure Lack of details Despite its potential, Palese’s vaccine has we have back-up plans — and back-up plans to But Paul Komesaroff, a physician and bio struggled to gain the attention and funding those back-up plans.” ethicist at Monash University in Melbourne, needed to progress to human trials. “We Australia, questions the university’s claim thought this would be the best thing after Dozens of candidates that it could not release information about sliced bread, and people would break down There are more than 320 COVID-19 vaccines the adverse event on the basis of confidenti- our doors to get it. That’s not the case. We are in development, according to a tally by the ality. It is possible to provide information in very disappointed,” he says. Coalition for Epidemic Preparedness Innova- a manner that avoids identifying a particular As leading drug and biotechnology tion (CEPI) in Oslo, a fund created to finance

platforms”, says Diamond. “The challenge has been to find partners.” Many of the vaccines gunning for the first approvals won early funding from CEPI, which has so far spent nearly US$900 million on nine COVID-19 candidates. US government agencies including the Biomedical Advanced Research and Development Authority (BARDA) have spent billions of dollars supporting a handful of candidates as part of Operation Warp Speed. But other funders, with their own pri- orities, are stepping in to help academics turn their experimental vaccines into products.

Global coverage With many wealthy countries snapping up early supplies of the 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

EVA MARIE UZCATEGUI/BLOOMBERG VIA GETTY MARIE UZCATEGUI/BLOOMBERG EVA Washington in Seattle, and his team are ready Dozens of coronavirus vaccine candidates are in clinical trials. ing a nanoparticle vaccine for clinical trials, with support from the Bill & Melinda Gates and coordinate vaccines for outbreaks. Most Diamond’s adenovirus vaccine, unlike any Foundation in Seattle. The effort, which King of these are in the early stages of preclinical of the leading candidates, is designed to be is leading with University of Washington struc- development; several dozen are in clinical administered through the nose. A team led tural biologist David Veesler, has produced a trials, and only a handful have begun final- by Diamond and Washington University can- vaccine consisting of a self-assembling virus- phase tests for efficacy. “Everybody and cer biologist David Curiel found3 that mice like particle that is dotted with 60 copies of their mother has a vaccine. My dogs have given a single dose of the intranasal vaccine the receptor-binding domain of the spike two vaccines,” says one scientist working on were fully protected from SARS-CoV-2, with protein that SARS-CoV-2 uses to enter human a leading candidate. Although on the face of it almost no sign of virus in their upper or lower cells. In a preprint, the team reported that tiny this is good news, it also presents challenges. airways. Mice that received an injection of the doses of the vaccine led to whopping immune One is determining which candidates should same vaccine were only partially protected, responses in mice4. move forward to costly clinical trials: running echoing animal data from some leading can- The jab could be supplied to low- and even a small study to test safety and dosing is didates. This was because the intranasal vac- middle-income countries, says King. It com- beyond the reach of most academic groups, cine summoned potent ‘mucosal’ immune prises ‘recombinant’ proteins made using DNA and smaller teams face an uphill struggle to responses that can block the virus at the site from multiple sources — which are already get their candidates noticed. of infection in the upper airways, the team used as medical products, including insulin, In some cases, the breakneck pace of says. so there is huge global manufacturing capac- COVID‑19 vaccine efforts has created open- ity for them. ‘Virus-like particle’ vaccines that ings for academic groups. One of the leading “We don’t have a billion self-assemble from these proteins also have a candidates is being developed by the Uni- strong track record: existing vaccines against versity of Oxford, UK, and drug company dollars, but we are moving human papillomavirus, a cause of cervical can- AstraZeneca (see page 331). The vaccine is the programme forward cer, and hepatitis B are based on the technol- based on a kind of chimpanzee cold virus, and making sure we don’t ogy. Clinical trials of the nanoparticle vaccine called an adenovirus, that has been used to lose time.” are set to begin in December. “We don’t have a make experimental vaccines against Ebola, billion dollars from BARDA, but we are moving malaria and other diseases, allowing Oxford the programme forward and making sure we vaccinologists to quickly adapt the platform On the basis of such results, Diamond don’t lose time,” says King. to a COVID-19 vaccine. Another technology feels that his team has “a mission” to push its Researchers say that funders need to step comprises RNA instructions for a coronavirus vaccines into human trials, to “see if they’re in to provide guidance and financial sup- protein, and two front-runner vaccines are going to be one of the last ones standing — port for COVID-19 vaccines. But as much as being developed by firms with expertise in even if they’re not the first ones out there”. underdog developers would like to see their that platform. His university has completed a deal to license vaccines help bring the pandemic to an end, But neither technology has yet produced the intranasal vaccine to a manufacturer, but they are still rooting for their better-funded licensed vaccines, and there is no guarantee Diamond hasn’t yet found anyone to advance competitors to succeed. “As a human being, that the candidates will generate strong immu- his team’s livestock-virus vaccine. Pharmaceu- my hope is that none of the candidates fail,” nity against the coronavirus, says Michael tical company Merck is developing its own vac- says King. Diamond, a viral immunologist at Washington cine based on the same virus, which is also the 1. Sun, W. et al. Preprint at bioRxiv https://doi. University in St. Louis, Missouri, who is work- backbone of the Merck Ebola vaccine that was org/10.1101/2020.07.30.229120 (2020). 2 ing on two early-stage vaccines. One is based approved in the United States and the Euro- 2. Case, J. B. et al. Cell Host Microbe 28, 465–474 (2020). on a weakened livestock virus. The other3 is pean Union last year. Many companies “just 3. Hassan, A. O. et al. Cell https://doi.org/10.1016/ j.cell.2020.08.026 (2020). based on a chimpanzee adenovirus, like the don’t have the bandwidth, money, the where- 4. Walls, A. C. et al. Preprint at bioRxiv https://doi. Oxford–AstraZeneca effort. withal or desire to actually pick up additional org/10.1101/2020.08.11.247395 (2020).