It works! Scientists have greeted with cautious optimism a press release declaring positive interim results from a coronavirus vaccine phase III trial — the first to report on the final round of human testing.
New York City-based drug company Pfizer made the announcement on 9 November. It offers the first compelling evidence that a vaccine can prevent COVID-19 — and bodes well for other COVID-19 vaccines in development. But the information released at this early stage does not answer key questions that will determine whether the Pfizer vaccine, and others like it, can prevent the most severe cases or quell the coronavirus pandemic.
“We need to see the data in the end, but that still doesn’t dampen my enthusiasm. This is fantastic,” says Florian Krammer, a virologist at Icahn School of Medicine at Mount Sinai in New York City, who is one of the trial’s more than 40,000 participants. “I hope I’m not in the placebo group.”
The vaccine, which is being co-developed by BioNTech in Mainz, Germany, consists of molecular instructions — in the form of messenger RNA — for human cells to make the coronavirus spike protein, the immune system’s key target for this type of virus. The two-dose vaccine showed promise in animal studies and early-stage clinical trials. But the only way to know whether the vaccine works is to give it to a large number of people and then follow them over weeks or months to see whether they become infected and symptomatic. These results are compared with those for a group of participants who are given a placebo.
In the press release, Pfizer and BioNTech said they had identified 94 cases of COVID-19 among 43,538 trial participants. The companies did not indicate how many of those cases were in the placebo group or among those who got the vaccine. But they said that the split of cases between the groups suggested that the vaccine was more than 90% effective at preventing disease, when measured at least one week after trial participants had received a second vaccine dose 3 weeks after the first. The trial will continue until a total of 164 COVID-19 cases are detected, so initial estimates of the vaccine’s effectiveness could change.
Although the vaccine might not turn out to be quite so effective once the trial is complete and all the data have been analysed, its effectiveness is likely to stay well above 50%, says Eric Topol, a cardiologist and director of the Scripps Research Translational Institute in La Jolla, California. This is the threshold that the US Food and Drug Administration (FDA) says is required for a coronavirus vaccine to be approved for emergency use. “I think this is an extraordinary achievement, even without many details, because there was no assurance of vaccine efficacy before we got the first read-out from a trial,” Topol says.
What’s missing, say Topol and other scientists, are details about the nature of the infections the vaccine can protect against — whether they are mostly mild cases of COVID-19 or also include significant numbers of moderate and severe cases. “I want to know the spectrum of disease that the vaccine prevents,” says Paul Offit, a vaccine scientist at the Children’s Hospital of Philadelphia in Pennsylvania who sits on a US Food and Drug Administration advisory committee that is set to evaluate the vaccine next month. “You’d like to see at least a handful of cases of severe disease in the placebo group,” he adds, because it would suggest that the vaccine has the potential to prevent such cases.
It’s unclear whether the vaccine can prevent people who show no or only very mild symptoms of COVID-19 from spreading the coronavirus. A transmission-blocking vaccine could accelerate the end of the pandemic. But it will be difficult to determine whether the Pfizer vaccine, or others in late-stage trials, can achieve this, says Krammer, because it would involve routinely testing trial participants. “You can’t do that with 45,000 people,” he says.
Another missing detail is how well the vaccine works in different groups of trial participants. “We don’t know yet if it works in the population that needs it most, which is elderly,” says Krammer. Because of the small number of cases it will accrue before ending, the Pfizer trial is unlikely to conclusively determine the vaccine’s efficacy in particular demographic groups, such as over-65s or African Americans, says Offit. But he adds that if the trial enrolled enough participants from such groups, it could be possible to generalize the vaccine’s probable effectiveness in them from its overall efficacy. In the press release, Pfizer and BioNTech reported that 42% of participants had “racially and ethnically diverse backgrounds”.
One key unanswered question is how long the vaccine’s effectiveness will last. On the basis of when the trial started and previously published data on immune responses in early-stage trials, many trial participants are likely to still have high levels of protective antibodies in their blood, says Rafi Ahmed, an immunologist at Emory University in Atlanta, Georgia. “To me, the main question is what about six months later, or even three months later,” he says.
There will be a chance to answer that question if the trial continues for several more months, says Ahmed. Answers could also come from analysis of the immune responses of people who took part in early-stage trials of the Pfizer vaccine, some of whom might have been given the vaccine up to six months ago. And although little is known about the vaccine’s long-term effectiveness, that is unlikely to hold up its use, says Ahmed. “I don’t think we should say, ‘Well, I’ll only take a vaccine that protects me for five years.’ I mean, that could be crazy.”
The results are a boost for other COVID-19 vaccine candidates. That includes an mRNA vaccine being developed by Moderna, a biotechnology company in Cambridge, Massachusetts, and the US National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, says Krammer. “I expect Moderna stocks will go up today.”
Shane Crotty, a vaccine immunologist at the La Jolla Institute for Immunology in California, thinks that Moderna isn’t the only developer that should celebrate Pfizer’s preliminary results. Several other candidate vaccines triggered immune responses similar to those elicited by Pfizer’s vaccine in early-stage trials, so they should work well, too.
One thing about Pfizer’s vaccine is certain: regulators will soon decide whether it’s ready for roll-out. The company said it would seek an emergency use authorization from the FDA around the third week of November, at which point half of the participants will have been followed for two months — an FDA safety requirement for COVID-19 vaccines.
And although researchers want to see the data behind Pfizer’s vaccine trial, they are prepared to accept caveats that come with them. “Right now, we need a vaccine that works,” says Krammer, even if it works for only a few months or doesn’t stop transmission. “That’s what we need in order to get half-way back to normal.”