An experimental mRNA coronavirus vaccine developed by pharmaceutical giant Pfizer and German firm BioNTech appeared to be more than 90-percent effective at preventing symptomatic COVID-19 cases in an interim analysis of their large Phase III clinical trial.

The two companies reported the top-line results of the analysis in a press release early Monday but have not yet published or released detailed data from the trial.

The companies said that they could file for an Emergency Use Authorization (EUA) from the US Food and Drug Administration in the third week of November. That’s the point at which the companies will have a median of two months of safety monitoring data on trial participants, a milestone specified by the FDA—at the objection of the Trump administration.

“Today is a great day for science and humanity,” Pfizer CEO Albert Bourla said in the press release.

Outside researchers and experts echoed the optimism but added caution, noting the lack of detailed data.

“This news made me smile from ear to ear,” Peter Horby, professor of emerging infectious diseases and global health at the University of Oxford, said in a press statement. “It is a relief to see such positive results on this vaccine and bodes well for COVID-19 vaccines in general. Of course, we need to see more detail and await the final results, and there is a long, long way to go before vaccines will start to make a real difference, but this feels to me like a watershed moment.”

How the vaccine works

As Ars has reported previously, Pfizer and BioNtech’s vaccine, BNT162b2, is an mRNA-based vaccine. Like Moderna’s vaccine, BNT162b2 uses a fatty nanoparticle wrapping to deliver a fragment of genetic code—in the form of messenger RNA, or mRNA—from the pandemic coronavirus, SARS-CoV-2, into human cells. Specifically, the bit of code delivered is a snippet of the virus’s blueprint for the infamous spike protein, which is what the virus uses to latch onto human cells and initiate an infection.

Once delivered inside human cells, the genetic snippet of the spike protein is read by cellular machinery, which then produces the protein fragment. From there, the fragment is used to train the immune system to detect and destroy the virus. Setting the immune system’s crosshairs to the spike protein is thought to be the most efficient way to defeat the virus, since the spike protein is an extremely conspicuous protein on the outside of the virus—and one critical to initiating an infection. Most vaccines under development focus on the spike protein, and the most potent antibodies known to defeat the virus—neutralizing antibodies—also attack the spike.

Earlier data and scale-up

Pfizer and BioNtech have previously published data on their vaccine, showing that it prompted immune responses against SARS-CoV-2 and was generally safe, with no serious side effects. Common mild side effects included pain at the injection site, fatigue, fever, headache, chills, and muscle pain. They noted that the vaccine appeared to prompt higher levels of antibodies and neutralizing antibodies against SARS-CoV-2 than was seen in people who had recovered from a natural infection with SARS-CoV-2. They also reported that the vaccine spurred strong T-cell responses, which may be critical for longer-term immune protection.

mRNA vaccines have been a hot topic in research for several years, but so far, there are no licensed vaccines that use this method. This has given some experts pause about the ability to quickly scale up production. The vaccines also require extreme cold storage (-70 degrees Celsius in the case of BNT162b2), which adds to the daunting logistical challenges of vaccinating the worldwide population.

Still, the apparent early success of BNT162b2 bodes well for similar vaccines in development. The Coalition for Epidemic Preparedness Innovations (CEPI) celebrated the news, saying in a press statement:

“These are hugely positive and encouraging interim results and are testament to the ingenuity and skill of the scientific community in advancing vaccine candidates against COVID-19… We believe these interim results also increase the probability of success of other COVID-19 candidate vaccines which use a similar approach [pre-fusion spike as their immunogen], including all of the vaccines in the CEPI portfolio.”

CEPI is co-leading an effort to set up a global vaccine alliance, the COVAX Facility, along with the World Health Organization and Gavi, the Vaccine Alliance.

The Phase III trial

Pfizer and BioNTech began their Phase III clinical trial of BNT162b2 on July 27, enrolling 43,538 participants to date. The trial is international, with enrolling sites in the United States, Argentina, Brazil, South Africa, Germany, and Turkey. Of those enrolled already, 38,955 received their second dose of BNT162b2 as of November 8, 2020.

There are 10 COVID-19 vaccines in Phase III trials so far, but the Pfizer/BioNTech trial is considered the frontrunner, as it was built for speed. For instance, people in the Pfizer/BioNTech trial get their two doses of the vaccine just 21 days apart, whereas other trials space out two doses by 28 days. The Pfizer/BioNTech trial also begins to monitor participants for COVID-19 earlier than other trials, at seven days after the second dose rather than at 14 days.

In addition, Pfizer and BioNTech initially planned to do a first preliminary glimpse—aka an interim analysis—after just 32 volunteers in the trial become ill with COVID-19. That’s in contrast to Moderna’s trial, which planned to conduct an interim analysis after 53 illnesses, and AstraZeneca’s, which will conduct an interim analysis after 75.

The success of the vaccine is gauged by how many of the interim cases fall into the group that received the vaccine compared with the group that received a placebo. If most of the cases fall into the placebo group, for instance, the vaccine appears to be effective. Pfizer’s 32-case interim analysis was the first of four planned for the trial, which will run until 164 cases occur.

The interim analysis

But the plans recently changed, according to Pfizer CEO Bourla, who explained in the press release:

“After discussion with the FDA, the companies recently elected to drop the 32-case interim analysis and conduct the first interim analysis at a minimum of 62 cases. Upon the conclusion of those discussions, the evaluable case count reached 94 and the DMC [an external, independent Data Monitoring Committee] performed its first analysis on all cases,” Bourla said.

The split of COVID-19 cases between the vaccinated and placebo groups indicates a vaccine efficacy rate above 90 percent, at seven days after the second dose, Bourla went on. “This means that protection is achieved 28 days after the initiation of the vaccination, which consists of a two-dose schedule. As the study continues, the final vaccine efficacy percentage may vary. The DMC has not reported any serious safety concerns and recommends that the study continue to collect additional safety and efficacy data as planned. The data will be discussed with regulatory authorities worldwide.”

While the news is certainly positive, there are some significant notes of caution. Without full data, it’s unclear if the vaccine is able to prevent severe or fatal cases of COVID-19. The trial also defined cases as those with at least one pre-determined symptom of COVID-19 and a positive test. Thus, the trial data so far doesn’t indicate if the vaccine prevents asymptomatic infection, which can allow the virus to continue to spread undetected. Last, with such limited study, it’s impossible to know so far how long any protection from the vaccine will last. It’s also too early to know if there are rare but serious side effects that will develop later in some participants.

For now, Pfizer and BioNTech are preparing the data for publication in a scientific, peer-reviewed journal. They also note that they expect to produce up to 50 million vaccine doses globally in 2020 and up to 1.3 billion doses in 2021.

Politics

Like the rest of the efforts to produce a COVID-19 vaccine so far in the US, today’s news quickly became political. In a tweet, Vice President Mike Pence tweeted that the vaccine’s preliminary success so far was “thanks to the public-private partnership forged by President @realDonaldTrump.”

However, Pfizer quickly squashed that link, with Pfizer’s head of vaccine research and development Kathrin Jansen telling The New York Times, “We were never part of the Warp Speed. We have never taken any money from the US government, or from anyone.”

Pfizer and BioNTech did, however, reach a $2 billion deal to rush its vaccine to market in the US if it was found to be effective.

Pfizer has stayed in the political realm throughout its vaccine development. For weeks this summer, Bourla had dangled the possibility—and desperate hope of lame-duck President Trump—to have vaccine results before the end of October and the presidential election.

The positive news, released the Monday after the election was called for President-elect Biden, has raised some eyebrows.

In a call with investors last month, Bourla stressed, “This is not going to be a Republican vaccine or a Democratic vaccine. This is going to be a vaccine for the citizens of the world. I hope that it is going to be effective.”