Unprecedented vaccine trials on track to begin delivering results

And on Thursday, independent advisers to the Food and Drug Administration will convene their first full-day meeting to lay the groundwork for their coming consequential deliberations on whether to recommend specific vaccines for public use. Those votes are not binding, but the FDA typically follows the recommendations of its advisory committees.

“Going from where we were in January and February — where we are going to be hit by this tsunami — to very likely having a vaccine, or more than one vaccine, that is proven safe and effective within a year, is staggeringly impressive, and would only have happened with strong and effective federal action,” said Robert Wachter, the chair of the department of medicine at the University of California at San Francisco.

Wachter has strongly criticized the administration’s response to the pandemic, arguing it has cost tens of thousands of lives. But he called the vaccine effort “nearly flawless” so far — words he said he found difficult to say.

There are no guarantees, of course. No vaccine has yet been proved safe and effective, some trials have been paused, and candidates still may fail. Once a company has gathered what it considers compelling evidence, regulatory review will take a few weeks. Most significant, the challenges of getting successful vaccines to hundreds of millions of people still loom after the science succeeds. So does the job of persuading Americans that vaccines, while powerful tools, are not panaceas and must be regarded as one of several strategies they must use to protect themselves against the novel coronavirus.

Yet Wachter and others say the government’s initiative to speed up vaccines and therapeutics, Operation Warp Speed, may live up to the fantastical moniker plucked from science fiction.

Pfizer, which received a nearly $2 billion preorder of 100 million vaccine doses from the U.S. government, has projected having enough cases of covid-19, the illness caused by the novel coronavirus, among study participants to assess the effectiveness of its vaccine sometime this month and sufficient safety data to seek regulatory approval by mid-November. Before they authorize a vaccine, regulators will require that the vaccine be at least 50 percent effective, that there be at least five severe cases of covid-19 among people who receive a placebo and that there be at least two months of follow-up on half the study participants.

Backed by about $2.5 billion from the federal government, Moderna is likely to have 53 covid-19 cases among participants by November — enough for a first look at the data — with sufficient safety data available just before Thanksgiving.

AstraZeneca, although its U.S. trial is on pause to investigate a possible adverse reaction, still expects enough data from worldwide trials to determine effectiveness by year’s end. Johnson & Johnson has paused its trial pending an investigation into a potential safety issue. But with a one-dose regimen and 60,000 study subjects, its trial is built to move fast if it is restarted. Novavax has begun a trial in the United Kingdom and soon will start one in the United States, followed by a trial launch by Sanofi and GlaxoSmithKline. Other vaccines are in the pipeline.

“The Pfizer and Moderna vaccines could be — albeit with a low probability — approvable in the month of November, when we would have a few single digit million doses of vaccine,” but odds of regulatory clearance rise dramatically in December and January, Moncef Slaoui, the vaccine veteran leading Warp Speed, said in an interview.

If a vaccine is authorized, Slaoui said, the United States will have enough doses to immunize 100 million people, including elderly people and front-line workers at high risk, between November and January.

Operation Warp Speed is a federal initiative, but the concept is grounded in years of global work on emerging pathogens. The idea of taking the financial risks out of vaccine development and rapidly repurposing technologies developed against other diseases builds on a “global intellectual movement, an understanding of what’s needed in these types of situations,” said Nahid Bhadelia, an infectious-disease physician at Boston University School of Medicine.

The irony is that any political meddling in the approval process could erode public trust and undermine faith in vaccines that experts say could otherwise stand as a singular triumph, a vaccine effort that has kept pace with a timeline about which many were skeptical when the efforts began.

“The progress has been pretty amazing,” said Deborah Fuller, a microbiologist at the University of Washington who is working on second generation vaccines for the novel coronavirus. “In January, people were telling me we could have a vaccine within a year, and all of us were like, ‘We’ll believe it when we see it.’ I’m still cautious about that, because, like anything, it’s not here until it’s here.”

The meeting this week of the FDA advisory committee, a panel of experts in infectious diseases, vaccines and biostatistics, will be a milestone in demonstrating that despite the speed, people will be able to trust the vaccine. It may seem technical and arcane to the public, and that would be a good thing, several scientists said. After months of political grandstanding about the vaccine, these are the principles that will determine the fate of a shot.

“A lot of words … may not necessarily appeal to the average listener,” said Francis Collins, the director of the National Institutes of Health. “It’s an important moment, though, to reassure the public this is going to be a transparent decision-making process, and FDA is not going to be pressured into giving an emergency use authorization if the data doesn’t support that.”

Much of the debate over the timeline for a vaccine has been fueled by the unpredictability of the clock in each vaccine trial, which ticks forward according to the accumulation of covid-19 cases among study participants.

The vast majority of coronavirus infections are mild or even cause no symptoms, but regulators will require at least five severe cases of covid-19 in a trial’s placebo group against which to measure the efficacy of the particular vaccine — and also to look for any signal that the vaccine could cause worse cases of disease, as has occurred with vaccines for some other pathogens. The companies have models that are based on the attack rate of the virus, or how fast people in the trials will become infected, but those are just predictions.

“Since we must wait for a certain number of cases to occur, this data may come earlier or later based on changes in the infection rates,” Pfizer chief executive Albert Bourla wrote in an open letter Friday.

The participants, the study investigators and even the companies running the trials do not know who received the real vaccine and who received a jab of saline. It’s only when the trial clock chimes — when a certain number of infections have occurred — that expert committees can peer beyond the firewall to see whether there’s an early signal that the vaccine works. Those experts, who form a data-safety and -monitoring board, can review whether those who received a particular vaccine are protected, exhibiting fewer infections than are observed among those who got a placebo — and they recommend to an oversight group whether the shots are ready for consideration by regulators.

Pfizer’s trial clock is set to allow experts to take earlier and more frequent looks at the data, the first at 32 covid-19 cases. The government created similar protocols for vaccines whose development is funded by Operation Warp Speed, and those trials wait for more people to become ill, with Moderna’s first look coming after 53 cases. Gaming out when those first looks might occur has become its own kind of sport. But all that has obscured the fact that even if the trials allow their clocks to run to midnight — that is, to preset endpoints for the whole trials — it will be only a matter of weeks, not many months.

Larry Corey, a virologist at Seattle’s Fred Hutchinson Cancer Research Center who is co-leading clinical trials under Operation Warp Speed, has projected that in a two-dose vaccine trial with 30,000 participants, it would take 16 weeks to get the first look at the data — sometime in November for the Moderna trial. But it is likely to take only an additional seven weeks to get to the endpoint of the trial, which is 151 infections.

“We designed [the trial] to understand that with 150 endpoints, there was a reasonable balance, in defining whether the vaccine would work in severe disease or mild disease, in elderly or less elderly, whether it would have enough cases among Hispanic and Black people,” Corey said.

A successful first vaccine is far from being the end of the pandemic or even the end of the scientific race. But a scientific problem will quickly morph into a potentially contentious debate about how to distribute and use initially limited numbers of doses. A country that has often stumbled on implementing and communicating basic public health messages will be faced with an unprecedented new challenge.

“It will be an absolute tragedy if we invest $10 billion and hundreds of thousands of volunteers to develop a vaccine that’s truly safe and effective, and people won’t take it because there has been so much noise and misinformation and redirection,” said Stephen Thomas, the chief of the infectious-disease division at SUNY Upstate Medical University, who is working on the Pfizer trial.

The first vaccine will create a cascade of follow-on effects, raising questions about how to test the next generation of vaccines. If an effective vaccine becomes available in the next few months, it may no longer be ethical to test other vaccines against placebos, for example. Even a very large vaccine trial cannot rule out very rare adverse events, and a careful watch will have to be kept for such events after any vaccine is approved, according to strict regulatory requirements that will be debated at Thursday’s meeting.

But with levels of the virus rising, it will not be a long wait to reach the endpoint of the trials. Corey’s projections show that Moderna’s trial could reach its 151-case endpoint around year’s end, and two trials that haven’t even started in the United States could, if all goes as projected, have evidence of effectiveness by spring. Even experts who have been concerned about political interference marvel at what has been accomplished.

“I’m stunned still to think that [from] the virus sequence in January, and we’ll have trials with results in December, in the same year,” said Eric Topol, a physician-scientist at Scripps Research Translational Institute. “Not five years later — and even five years would have been a near record.”