Scores of coronavirus vaccines are in competition how will scientists choose the best?

Less than five months after the world first learnt about the new coronavirus causing fatal pneumonia in Wuhan, China, there are more than 90 vaccines for the virus at various stages of development, with more announced each week. At least six are already being tested for safety in people.

Now, developers, funders and other stakeholders are laying the groundwork for their biggest challenge yet: determining which vaccines actually work.

This typically involves giving thousands or tens of thousands of people a vaccine or placebo and seeing, over months or even years, whether there is a difference between the two groups in how many people get infected in the course of their daily lives, as well as checking that no safety issues emerge.

But in this pandemic, scientists will have to accelerate and streamline that process. A vaccine may be the only way to generate immunity to the virus across a population: despite the millions of coronavirus cases worldwide, some preliminary studies suggest that only a small fraction of people in even hard-hit regions have been infected with SARS-CoV-2, and their immunity is unclear.

This month, the World Health Organization (WHO) in Geneva, Switzerland, sketched out plans for a clinical trial that will test numerous vaccines in a single study. Some developers and funders have plans for their own efficacy trials. But key questions remain, such as which vaccines will be tested first — or at all — and how their effectiveness will be measured and compared.

“It’s going to require a level of coordination that has never really happened before, and a time frame that’s never really been even imagined,” says Mark Feinberg, president and chief executive of the International AIDS Vaccine Initiative (IAVI) in New York City. “You can’t take 200 vaccines into efficacy trials,” says Seth Berkley, chief executive of Gavi, the Vaccine Alliance in Geneva, which funds immunizations in low and middle-income countries.

Rolling trial

The WHO’s proposed Solidarity Vaccine Trial seeks to speed development with an adaptive design. This allows vaccines to be added to the trial on an ongoing basis. Participants will be enrolled continuously, and vaccines that don’t seem to be working can be dropped from testing.

The WHO still needs to hammer out details, such as how a vaccine’s efficacy will be measured, says Marie-Paule Kieny, research director at the French National Institute of Health and Medical Research in Paris. But she thinks its overall approach makes sense. “One of the challenges is prioritization — which vaccine should you test first,” she says.

The WHO has established an expert panel to prioritize vaccines for inclusion in its trial, but it is unlikely to be the only organization seeking to do this. “Some strategic alignment and coordination in this effort is going to be critically important or otherwise it'll become very chaotic,” says Feinberg. But the WHO plan “by itself may not be sufficient,” he adds.

The US National Institutes of Health (NIH) in Bethesda, Maryland, this month unveiled a partnership with more than a dozen companies that aims to coordinate the development of drugs and vaccines for coronavirus. And the Coalition of Epidemic Preparedness (CEPI), a global foundation that funds vaccine development, is supporting 9 different vaccines. The non-profit hopes to raise US$2 billion to pay for efficacy trials, manufacturing and other costs, says Melanie Saville, the organization’s director of vaccine research and development.

Criteria for prioritizing vaccines for efficacy could include its production capacity and the immune response generated in early human trials and animal studies, says Kieny, as well as regulators’ experience with the specific type of vaccine. Some of the kinds of vaccine being developed, such as RNA vaccines, have not been widely tested in people or used in a vaccine that has won regulatory approval.

A vaccine developed at the Jenner Institute at the University of Oxford, UK, is currently undergoing early-phase trials. “There’s a reasonable chance that we’ll be able to pick up the efficacy of the vaccine over the next couple of months,” Andrew Pollard, an infectious disease researcher at Oxford leading the trial, said at an online press briefing.

A small number of developers with plans and funding to get their vaccine approved and scale up production will likely call the shots with regard to how efficacy trials are done, says Rip Ballou, a program leader at IAVI. “Doing a phase III trial to show efficacy is meaningless if it's not coupled to a plan to actually licence and deliver under some regulatory authority,” he says. “There's only a handful of players that will be able to meet that very high bar. Because otherwise, it's a publication. It's not a vaccine.”

A fair shot

Another challenge will be determining how the different vaccines compare to one another. WHO’s proposal for an efficacy trial could allow the performance of different vaccines to be directly compared, but Kieny thinks that some developers may be unwilling to accept this because it could hurt a vaccine’s commercial prospects.

Swati Gupta, IAVI’s Vice President and Head of Emerging Infectious Diseases and Scientific Strategy, says vaccine developers will want to understand how key decisions are made before committing to trials that involve comparisons with other vaccines, to make sure their vaccines have “a fair shot at being able to show its efficacy”.

But it is essential to be able to compare different vaccines, even if it requires vaccines developers to set aside their short-term interests, says Charlie Weller, vaccine lead at the Wellcome Trust biomedical charity in London. “They work under commercial business models. That's not going to work for the situation we're in now," she says.

Expected global demand for a coronavirus vaccine could make developers more willing to cooperate. “We need more than one vaccine,” says Kieney. “Monopoly is always very bad, and none of the vaccines may have enough production capacity.”

One factor that could encourage such cooperation is the shifting geography of the pandemic. “China would have been a great place in Wuhan to have done efficacy trials two months ago,” says Berkley. “Italy would have would have been a great place to do it a month ago.” As a result, developers have incentive to join initiatives such as the WHO’s or the NIH’s, because of their access to clinical trial infrastructure around the world that could bring vaccines to where there are coronavirus cases. “We need to be nimble,” adds Gupta.

Emergency use

While most experts see large trials as a necessity to ensure that coronavirus vaccines are safe and effective, some developers are examining alternatives.

One option is to look for signs that a vaccine works in early-stage trials involving hundreds of participants, and then seek permission from regulators to deploy the vaccine under ‘emergency use’ rules in high-risk groups, such as health-care workers, who are more likely to be infected with the coronavirus. Regulators such as the US Food and Drug Administration can grant emergency use, while additional data is collected to license a vaccine.

Cansino Biologics in Tianjin, China, which is developing a vaccine comprised of a chemically inactivated form of SARS-CoV-2 virus, will consider this approach, according to a company spokesman. Johnson and Johnson said in a press release that its vaccine could be ready for emergency use in early 2021.

No vaccine has ever been deployed under emergency-use provisions, says Katherine O'Brien, who heads WHO's immunizations, vaccines, and biologicals department. If coronavirus vaccines follow that path, regulators will seek extra reassurance that a vaccine is safe. “There is no compromise that can be made on the safety issues,” O’Brien adds.

Momentum is building for an even more radical proposal to determine which vaccines work: intentionally infecting young, healthy volunteers, negating the need to wait for trial participants to become infected naturally. These ‘human challenge’ studies are already used to study infectious diseases such as malaria and dengue, and some researchers say they should be considered to speed the development of coronavirus vaccines.

Berkley says challenge trials could be used to rapidly determine which vaccines advance to large-scale trials. But he thinks they may be too risky without either an effective drug or a genetic test to identify the rare young individuals who are likely to develop severe disease. “Until you have a recognised treatment, I think that's a pretty tough story,” he says.