FDA guidance eases some Covid-19 vaccine concerns, but others remain

Operation Warp Speed.

That’s the name the Department of Health and Human Services’ chose for its Covid-19 vaccine development program, a reference to the faster-than-light space travel depicted in the popular TV series “Star Trek.” The moniker illustrates the Herculean effort to develop vaccines against the SARS-CoV-2 in the space of a year rather than the multiple years normally required.

Operation Warp Speed’s quick timeline has led to concerns about the potential for the industry to cut corners. A global race to develop vaccines is already on. According to the WHO, there were 23 vaccine candidates in clinical development around the world as of Wednesday. These include ones that have reached Phase III – such as Sinovac’s inactivated virus vaccine and ChAdOx1-S, under development by AstraZeneca and the University of Oxford and Moderna’s messenger RNA vaccine mRNA-1273 – and numerous others under Phase I and Phase II development by commercial and academic organizations. An additional 140 were in preclinical testing.

All of this makes the role of regulatory bodies like the FDA even more important to ensure safety and efficacy of any potential vaccine to combat the virus that caused Covid-19. A recent Food and Drug Administration guidance document assuages many of those concerns. Still, others remain.

On June 8, two respected experts sounded the alarm. In a New York Times op-ed, Dr. Ezekiel Emanuel, a professor of medical ethics and health policy at the University of Pennsylvania and Dr. Paul Offit, director of the Vaccine Education Center at the Children’s Hospital of Philadelphia, laid out the risks. They wrote that President Donald Trump could pressure the FDA to issue an emergency use authorization for a vaccine against SARS-CoV-2 without sufficient clinical data as an October surprise to swing the election. Emanuel is also a member of the cornavirus task force formed by Joe Biden, the presumptive Democratic presidential nominee.

The October surprise, were it to happen as the authors charge, would perhaps not be a surprise. After all, the agency already gave an EUA to the malaria drugs hydroxychloroquine and chloroquine despite shaky data – something it later revoked –  in the face of aggressive promotion by Trump and his media supporters.

As if to allay concerns outlined in the op-ed, FDA provide a guidance announced July 1.

In it, the FDA seemed to try to address such concerns, as Commissioner Stephen Hahn said the agency would not be cutting corners in its assessments of potential vaccines. The guidance said explicitly that it would require randomized, placebo-controlled clinical trials and data showing a vaccine can actually prevent Covid-19 in at least 50% of those receiving it, not just spur the body to produce antibodies against SARS-CoV-2.

Emanuel, for one, still pointed out some lingering issues.

“Just sort of promising it isn’t what assuages my concern,” he said in a recent phone interview. “What assuages my concern is putting down markers for the criteria they’re going to use.”

For example, while 50% is the minimum threshold, one would want to see the protection last for a decent length of time – the World Health Organization sets the bar at six months, though Emanuel said longer would be preferable.

“I think 12 months is a realistic amount of time,” he said, as that would mean annual vaccinations instead of having to receive two vaccinations lasting six months each.

A regulatory attorney, however, feels differently, implying that the agency is going to hold potential vaccines to a high standard.

“The FDA has taken, I think, quite a conservative approach to indicating to industry what the expectations are for full approval of a vaccine, so it’s not giving industry much of a break,” said Kathy Sanzo, an attorney with law firm Morgan Lewis, in a phone interview.

However, the guidance does allow for some instances where it would be willing to grant accelerated approvals on the basis of surrogate endpoints – such as if a vaccine uses a technology platform already established as effective and has positive data on a surrogate endpoint established as indicating long-term efficacy.

While not legally binding, the standards laid out in the FDA guidance stand in contrast to the ease by which the FDA granted the hydroxychloroquine/chloroquine EUA, said Clint Hermes, an attorney with law firm Bass, Berry & Sims.

“I don’t think the hydroxychloroquine thing was a particularly shining moment,” Hermes said in a phone interview.

He added that with the Covid-19 vaccine guidance, the FDA is now pushing back and setting a much higher standard.

In order to adequately test for vaccines’ efficacy, the Phase III trials will require significant enrollment targets: Moderna’s will enroll about 30,000 healthy volunteers in the study it plans to initiate near the end of the month, while Novavax has provided a similar target for the Phase III trial of NVX-CoV2373 that it intends to start in the fall. But one possibility is that there may not be enough people still infected by the start of next year to determine whether the vaccines are protective.

“I am depressingly hopeful that we shouldn’t have any cases by January, which is what happened with China – their first vaccine was stopped because they ran out of cases,” said Barry Bloom, a research professor at Harvard University’s T.H. Chan School of Public Health, in a phone interview. “So my big worry has been whether we will have enough cases to be able to look for efficacy if we test 30,000 people.”

As of Wednesday, the U.S. accounted for one-quarter of the world’s cases and deaths, with more than 3.4 million infected and 136,807 dead.

On the other hand, by some accounts, finding volunteers may not be as much of a problem. Dr. John Ervin, medical director of the Center for Pharmaceutical Research in Kansas City, Missouri, said that when his center did its first Phase I study of a Covid-19 vaccine, 90 people tried to get into the 20 slots the center was allotted. “Subsequently, they’ve expanded that trial and put more people in it,” he said. Due to confidentiality agreements, he could not reveal which trial he was referring to. The center and the Alliance for Multispecialty Research, of which it is part, have been involved with Inovio Pharmaceuticals and Moderna’s Covid-19 vaccine studies.

A more widespread concern is that even when a vaccine becomes available, enough of the public may not even take it thanks to anti-vaccine sentiments, potentially making vaccine-induced herd immunity unachievable.

“I don’t think there’s any question that that’s the case,” Emanuel said. “We’re dealing with a public that is very concerned.”

According to some polls, anywhere between one-quarter to half of respondents have said they would not get a vaccine against SARS-CoV-2, ranging from 26% of respondents in France to as many as 50% in the U.S.

“We live in a world of anti-vaccine advocates that will make this difficult,” Bloom said.

Anti-vaccine sentiment could also pose a risk to the high enrollment targets set by vaccine developers, Ervin said.

“I just don’t understand the antivaxxers,” Ervin said, pointing to how vaccines helped to wipe out smallpox, yellow fever and polio. “Even as a resident, I saw people at the VA on iron lungs.”

Aside from those activists, one potential threat could come from some unforeseen side effect.

“If there were safety issues with a vaccine, it would just be catastrophic, not just for the people that experience adverse effects, but for trust in the scientific establishment,” Hermes said.

Some potential long-term complications really are cause for worry. For instance, the FDA expressed considerable concern for enhanced respiratory disease, or ERD, which happens when people who have been vaccinated contract the virus and, instead of fighting it off, experience heightened symptoms due to a dysfunctional immune response. This occurred in the late 1960s among several children who received vaccines against respiratory syncytial virus and, more recently, has been seen in animal models of vaccines against coronaviruses like the 2002-2004 severe acute respiratory syndrome and Middle East respiratory syndrome.

Fortunately, at least with Moderna’s vaccine, there have not been signs so far of ERD being a problem in humans. According to data from the Phase I study of mRNA-1273 published in The New England Journal of Medicine, CD4 T-cell responses were biased in favor of the cytokine Th1, without elevation of Th2-biased CD4 T-cell responses, the latter of which are associated with ERD.

Nevertheless, ERD and other long-term effects will require vigilance.

“You’re going to take healthy people and give them a vaccine, so you’ve got to be sure that you’re not actually making things worse,” Emanuel said. “That would be a disaster.”

Photo: Teka77, Getty Images