Pandemic vaccines are about to face the real test.

A Chinese company will turn to Brazil for help. The World Health Organization (WHO) is adopting a strategy forged in a war zone during an Ebola outbreak. And the Trump administration plans to lean on existing infrastructure for testing HIV and flu vaccines. These are the disparate strategies about to be employed in the next and most important stage of the COVID-19 vaccine race: the large-scale, placebo-controlled, human trials needed to prove which of the more than 135 candidates are safe and effective.

Two such efficacy trials plan to start next month, even as the United States and global initiatives struggle to answer major questions, from what it means for a COVID-19 vaccine to work to how to find enough people exposed to the virus so a candidate can be put to a real-world test. Populations that have high levels of viral transmission are a moving target—Wuhan, Seattle, or Milan might once have been a good place to test the mettle of a vaccine, but no longer. And quickly enrolling tens of thousands of properly informed people who meet a trial’s entry criteria is a “big lift,” says Susan Buchbinder, an epidemiologist at the San Francisco Department of Public Health who runs vaccine trials.

Competition among trial efforts could hinder the global push, says Wayne Koff, who heads the nonprofit Human Vaccines Project and formerly led the HIV vaccine program at the National Institute of Allergy and Infectious Diseases (NIAID). “It’s absolutely extraordinary how much has been done in 6 months, but there’s an old adage that everybody loves to collaborate unless they want to win.” Others, however, don’t anticipate conflicts, noting that scientists and officials are sharing information about trial designs and plans. “Each one will contribute differently,” says Ana Maria Henao Restrepo, lead representative of WHO’s vaccine effort, Solidarity. “I don’t see competition.”

“Winning,” one of U.S. President Donald Trump’s favorite terms, is the clear goal of Operation Warp Speed, the U.S. project that aims to start to vaccinate millions of Americans in October and offer shots to 300 million people in the United States by January 2021. After winnowing down vaccine candidates in an opaque process over the past month and committing what could be more than $2 billion to its top choices, Warp Speed plans to enter three to five of them into efficacy trials that will have “harmonized” protocols to streamline oversight and will run analyses in central labs so data can more easily be compared.

The first Warp Speed candidate to launch, from the biotech Moderna, is composed of RNA encoding the coronavirus spike protein from SARS-CoV-2, the virus that causes COVID-19. The candidate’s efficacy trial, announced by the company on 11 June, will enroll 30,000 people and take place at established HIV and flu vaccine test sites, primarily at U.S. hospitals and universities, now overseen by Warp Speed. But which of those brick-and-mortar sites will have enough SARS-CoV-2 circulating near them to quickly produce an efficacy signal is uncertain given the shifting distribution of new cases in the United States.

China has an even starker problem: There’s currently little transmission to speak of in the country, which has forced Sinovac Biotech, a company based in Beijing, to stage efficacy trials of its vaccine candidate in Brazil, where the COVID-19 epidemic is now raging. With a product composed of the entire virus, inactivated with chemicals, Sinovac announced this week it is collaborating with the Butantan Institute, a major research institution in São Paulo that manufactures vaccines. “We are working very hard to start the trial in July,” says Sinovac Senior Director Meng Weining.

WHO proposes a different solution for Solidarity’s efficacy trials. The agency hasn’t yet announced which candidates Solidarity will test, but, unlike Warp Speed—which won’t consider Chinese-made vaccines—it is open to products from every country and has made public detailed criteria for how it will prioritize vaccines. To cope with the patchiness of the pandemic, Solidarity will adopt a strategy Henao Restrepo helped develop for Ebola vaccine trials in Guinea in 2015 and, 3 years later, in the Democratic Republic of the Congo (DRC): setting up vaccination teams that can quickly mobilize to localized outbreaks.

“We did this in Congo despite the war,” Henao Restrepo says. “It’s not the traditional way, and some people think that we are crazy, but we have done it not once but twice.” In the DRC, about 20 teams with 15 members each drove around the affected regions and set up temporary sites, vaccinating and following more than 300,000 people.

Warp Speed, which could if needed expand its trials to international sites used for HIV drug and vaccine testing, also plans to form “surge clinics” to quickly recruit people in rural U.S. areas with big outbreaks or pockets of high transmission such as nursing homes. Models driven by machine learning will help Warp Speed forecast where infection will be highest, says Peter Gilbert, a University of Washington, Seattle, biostatistician. “There are risk predictors that account for space and geography and features that are more constant like race, ethnicity, or preexisting conditions,” Gilbert says. “It’s really complicated.”

One of the trickiest issues for trial designers is deciding what, exactly, represents success for a COVID-19 vaccine. “Is it an infection endpoint, a transmission endpoint, preventing moderate disease, or preventing severe disease?” Koff asks.

“There was a lot of debate on that question,” for Warp Speed, notes John Mascola, who heads NIAID’s Vaccine Research Center and contributes to the project. A COVID-19 vaccine that fails to prevent infection might still provide great benefit if it reduces symptomatic disease, so Warp Speed and Solidarity both ultimately chose that as the primary endpoint of the trials. Trial volunteers who develop fever, headache, dry cough, or other symptoms linked to COVID-19 will be tested for SARS-CoV-2, to see whether more people with confirmed infections develop symptomatic disease in the placebo arm of the trial than among those who received the vaccine.

To detect an efficacy signal, both Warp Speed and Solidarity estimate they will need to give each vaccine to 15,000 to 20,000 people in a population that has a 1% per year incidence of SARS-CoV-2 infection. If the vaccine prevents COVID-19 symptoms at least 50% of the time, its efficacy should be clear in 6 months, after about 150 infections have accumulated in the trial.

Both efforts will pit multiple vaccine candidates head to head. One difference is that Solidarity plans to compare all its vaccines against a shared placebo group, an approach that reduces the number of volunteers the researchers need to recruit and follow. “In the Solidarity trial, the philosophy is we have to make this thing really simple,” says Gilbert, who has worked with this effort, too. Solidarity trial sites have the option to do nuanced studies on immunity and other issues, but those are built into Warp Speed’s trials. They will do repeated blood draws and nasal or throat swabs to evaluate immune responses and viral levels. The data might help researchers understand why vaccines succeed or how they might affect transmission.

In addition to Solidarity, WHO is helping the Access to COVID-19 Tools (ACT) Accelerator, another global effort, which may stage its own vaccine efficacy trials if companies do not want to participate in Solidarity. “Companies may or may not be very enthusiastic about head-to-head comparisons,” explains Soumya Swaminathan, WHO’s chief scientist and top liaison to the ACT Accelerator. And the ACT Accelerator has pockets as deep as Warp Speed: Countries and philanthropies in May pledged $8 billion, with a commitment that it would equitably distribute any proven COVID-19 products—vaccines, treatments, diagnostics—to rich and poor alike.

Buchbinder is impressed by the speed at which these massive efforts have gotten underway. “It’s unlike any other research I’ve undertaken,” she says. But she and others are careful to temper expectations. Even though she will oversee a Warp Speed trial site, for example, she doubts the U.S. effort will meet Trump’s goal of having a proven vaccine by October. Koff agrees; the failures of so many HIV vaccine trials have sobered him, he says. “We need to be really careful how we manage expectations,” he concludes.

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