On the eve of a pivotal FDA advisory committee meeting, BreakingMED reviews the issues

As winter arrived and daylight hours shortened, the nation entered what many realized would be a dark time with cases, hospitalizations, and deaths from Covid-19 all surging. But in the last month of the year, two vaccines were granted Emergency Use Applications — and, while those approvals brought a bit of lightness, many questions remain unanswered. This special report, originally published Dec. 8, reviews those questions and offers some answers.

The Covid-19 vaccines are coming.

We can hear the distant trumpets, but what exactly can we expect when the cavalry finally comes into view? How justified is the optimism? What pitfalls face us in the next few months? What remains unknown?

The experts are, perhaps not surprisingly, bullish on the drugs themselves and indeed on the whole field of vaccinology. This is “an exciting time,” according to Kathleen Neuzil, MD, of the University of Maryland School of Medicine in Baltimore and co-director of the Covid-19 Prevention Network, the NIH network of sites engaged in clinical trials.

The Race

Going from a standing start to having two or three vaccines constructed, tested, and submitted for regulatory approval in less than a year is an “extraordinary achievement,” Neuzil told reporters during a telephone briefing organized by the Infectious Diseases Society of America (IDSA).

And, she said, the speed has not compromised safety: Scientists were able to accelerate what is usually a years-long process by throwing “unprecedented resources” into the fray and eliminating common bottlenecks caused by lack of knowledge, money, or co-operation, not by skipping steps or cutting corners.

Some 48 vaccine candidates are in human trials, 12 of them in phase III, and more than 160 are in pre-clinical evaluation. But as of early December, no vaccine candidate is widely approved, although the United Kingdom has given the go-ahead to a drug made by New York-based Pfizer Inc.

In the U.S., the FDA advisory panel on vaccines is set to discuss Dec. 10 whether the Pfizer drug can be given emergency use authorization (EUA) in advance of full regulatory approval.

Early Leaders

Just three organizations — two using a novel vaccine technology — have reported some data from their pivotal phase III trials.

Pfizer and Moderna Inc., of Cambridge, Mass., both claim efficacy in excess of 90% for vaccine candidates that use messenger RNA (mRNA); the University of Oxford, in partnership with AstraZeneca, is reporting overall efficacy of about 70% for its more traditional viral vector candidate, with different dosing regimens giving lower or higher outcomes.

The most data are available for the Pfizer vaccine candidate: documents prepared by FDA scientists in advance of the Dec. 10 advisory committee meeting and based on submissions from the drugmaker show the two-dose regimen had 95% efficacy in preventing confirmed Covid-19.

Participants were ruled to have Covid-19 if they had at least one of the common symptoms of the disease, such as fever or cough, and a positive PCR test for SARS-CoV-2.

The 95% figure is based on analysis of 36,621 participants with no evidence of previous SARS-CoV-2 infection who were randomized on a 1:1 basis to get either vaccine or placebo. All told, eight cases occurred in the vaccine group, compared with 162 among those getting the placebo, the FDA documents showed.

When people with evidence of prior infection were included, efficacy was much the same, at 94.6%.

Efficacy estimates were “consistently robust” across a range of subgroups, the FDA document said, including older versus younger participants, men versus women, different racial and ethnic groups, and participants with comorbidities, such as obesity, linked to a high risk of severe Covid-19.

Two Shots … Really?

The vaccine is given as two intramuscular injections 21 days apart; a chart of cumulative incidence shows cases in both placebo and vaccine groups occur at about the same rate until 14 days after the first dose, when they begin to diverge.

But the FDA analysis said the data don’t show whether a single dose provides longer-term protection because participants got the second dose at day 21. But the data do suggest vaccination might start to reduce cases — and therefore pressure on health care systems — even before the injection series is complete.

But, the FDA document said, the data leave a central question open: Does the vaccine work by creating immunity to SARS-CoV-2, or does it simply prevent the disease caused by the virus?

It might be that all the vaccines do is prevent symptoms among those infected, possibly creating a dangerous pool of asymptomatic carriers, according to Dial Hewlett, MD, of the Westchester County Department of Health in New York and a spokesman for the IDSA.

That gap in knowledge, he told BreakingMED, “is one of the big concerns that all of the experts in the field have.”

The FDA document said the vaccine has clear benefits in preventing disease, both mild and severe, but there’s not enough information to talk about any possible effect against asymptomatic infection.

On the other hand, according to documents submitted by Pfizer, the vaccine creates robust antibody and T-cell responses to the virus itself, which could mean it is preventing the infection.


The risks are also small and manageable: There are “no specific safety concerns” that would rule out emergency use authorization, the FDA analysis concluded.

As might be expected, injection site reactions were the most common adverse events, followed by fatigue, headache, muscle pain, chills, joint pain, and fever, but most were mild and short-lived.

There were no severe adverse events associated with the vaccine candidate, although there were four cases of Bell’s palsy among vaccine patients and none among those getting placebo during the trial. Investigators noted that’s roughly the expected background rate but will keep on the issue during post-authorization follow-up, the FDA document said.

Whether the safety and efficacy data on the Pfizer vaccine and others in the pipeline are positive enough for the public remains an open question. Indeed, vaccine hesitancy is rife in the U.S., in many cases fueled by online waves of misinformation and conspiracy theories.

Overcoming that hesitancy, and a host of other hurdles, is going to make vaccination programs a “challenge,” according to C. Buddy Creech, MD, of Vanderbilt University School of Medicine in Nashville, TN.

Creech is a principal investigator on phase III trials for two candidate vaccines, the mRNA drug being developed by Moderna and a vector-mediated drug under study by Johnson & Johnson (its trial has not finished yet).

The Roll-Out

Creech told BreakingMED, during the same IDSA briefing, that public health officials now wrestling with vaccination roll-outs have a job that in its own way is as hard as running the clinical trials of the drugs — they must persuade a skeptical public that the drugs are safe and effective, while also coping with technical challenges (Pfizer’s drug requires extreme cold-chain storage, for instance) and ensuring fair distribution.

A major stumbling block now is making sure no one feels left out, he said: “How do we ensure equitable access, how do we ensure that with what will initially be a scarce resource we provide access to as many people as possible?”

That issue is especially important, he said, because many U.S. sub-populations that have been hit hard by the disease are also those that face historic health care disparities.

To get them vaccinated will not be easy, commented Westchester’s Hewlett, who is also a member of the COVID-19 task force of the National Medical Association, an organization of physicians of African descent.

“The biggest hurdle,” he told BreakingMED in an interview, “will be convincing people to take it … and then making sure people come back for the second shot.” On a positive note, Hewlett said, the problem of getting people to take their medicine is something all doctors have all the time: “We’re used to it.”

Distrust of vaccines can be overcome, he said, by using “trusted messengers” who are from the affected communities. But other issues are more structural: many poor Americans of all races and ethnicities don’t have cars, have limited access to public transit, and might have jobs that don’t allow them to take time off to travel any distance to get vaccinated.

“We’re going to have to put a number of different coalitions in place” to solve those issues.

Other Questions Abound

For instance, even if the drugs do make people immune to infection, how long will that immunity last? There have been reports of people being re-infected after a natural infection was cleared although it’s not clear how often that happens. So it’s going to be important for public health officials to monitor immunity, perhaps by following people who have been vaccinated.

Some of that is likely to happen in the clinical trials. Neuzil noted that the three trials will continue to monitor participants for two years for safety; presumably that would include catching Covid-19.

If there is a safety signal, such as a surge in cases among vaccinated participants, Neuzil said, it will be apparent “5 or 6 months” ahead of any issue among the general population and health officials could take action.

Another open question is how well the vaccines will work in pregnant women and children. Moderna announced Dec. 2 that it will start testing its vaccine in children and Pfizer’s trial includes some children as young as 12.

But pregnant women, as is the usual case, were not included in the main clinical trials, Neuzil noted, adding that “we really won’t have a vaccine for everyone until we have a vaccine for pregnant women.”

Complicating that issue is that many health care providers — those who will be first in line for vaccination — are women of childbearing age. The CDC’s Advisory Committee on Immunization Practices has noted pregnant women seem to be at risk for more severe disease if they catch Covid-19 but, owing to lack of data, did not make a recommendation one way or the other about their use of vaccines.

Neuzil added the committee argued that women could still get the shots if they wanted, even in the absence of a formal recommendation.

Still on the issue of healthcare workers, Creech said that early side effects of the vaccines appear to be modest and limited but still enough in some cases to force people to take time off work.

So, for hospitals and other medical facilities, he said, “it’s not as easy as just having everyone line up and get a shot.” Vaccinations will have to be scheduled so that any adverse events will have minimal effects on the workplace, he said, and workers will have to be told what to expect.

Unknowns or Unknowable?

The Pfizer drug has to be stored in freezers than can reach below minus 70 Celsius, although it’s stable once out of the fridge for five or six hours. The Moderna vaccine candidate is more forgiving; it only needs a normal freezer.

In clinical trials, such strict requirements are not major obstacles. But in the real world they might pose problems, Neuzil said: “How many minus 80 freezers do we have?”

It’s important to note that the Pfizer and Moderna vaccines are really new: as Creech put it, they involve a “previously unknown virus, a previously unknown immune response, and a previously unknown technology.”

The idea of using messenger RNA to persuade the body to make antigens is not new, but it had never been tested before in the clinic. There was “abject giddiness” in the vaccine community when the two candidates not only worked but appeared to work extremely well, he said.

The mRNA vaccines leapt to the front of the pack because they could be developed very quickly — researchers just needed to have the genetic sequence that codes for an antigen; they don’t have to grow and purify antigens as they do for old-style drugs, such as the flu or measles vaccines.

The success of the technology in this pandemic has “major implications” for future emerging infections, he added, and could usher in a “golden age of vaccinology.”

A subtler question is the ethics of clinical trials. All the current phase III studies are double-blind and placebo-controlled, but if there is an approved vaccine with high efficacy, can those trials continue?

Those now under way will probably be able to continue for the next few months, Neuzil said, but after that they might have to be modified. It’s a “constantly changing field (and) it’s more important to be right than to be consistent,” she said.

But perhaps the first challenge is simply “supply, supply, supply,” Neuzil said. A vaccine that is highly efficacious and safe in clinical trials is useless unless there’s enough to go around. For instance, Pfizer has recently downgraded its production forecasts, citing a shortage of basic materials.

But, she argued, “if we can get enough vaccine out there, we can have an impact (on the pandemic) very quickly.”

Michael Smith, Contributing Writer, BreakingMED™

Neuzil, and Hewlett are spokespersons for the Infectous Disease Society of America.

Creech is a principal investigator for the Moderna/NIH vaccine trial as well as the Johnson & Johnson vaccine trial.

Cat ID: 190

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