By Gary Evans, Medical Writer

Although questions and caveats remain, preliminary reports of two new COVID-19 vaccines in the 90% to 95% effectiveness range have bolstered hopes that healthcare workers may soon be protected and potentially large portions of the public immunized in 2021.

“The effectiveness was stunning,” says William Schaffner, MD, a professor of health policy at Vanderbilt University and a national vaccine advocate and expert as medical director of the National Foundation for Infectious Diseases (NFID).

Moderna, Inc. recently announced that an independent, National Institutes of Health-appointed Data Safety Monitoring Board determined its Phase III study of a “messenger RNA vaccine,” mRNA-1273, has achieved efficacy of 94.5%. The study authors enrolled more than 30,000 participants in the United States. They conducted the work in collaboration with the National Institute of Allergy and Infectious Diseases (NIAID).1 This was preceded by an announcement from Pfizer Inc. and BioNTech that a similar messenger RNA vaccine had achieved more than 90% efficacy in a Phase III trial with 43,538 participants.2

Of course, safety and efficacy data of both vaccines must undergo a thorough review by the Food and Drug Administration (FDA), its vaccine and biologic committees, and the CDC’s Advisory Committee on Immunization Practices (ACIP). Should those hurdles be cleared, there remain the logistical challenges of delivering the vaccines and assuring a suspect public that it is safe to be immunized. Still, with the U.S. COVID-19 death toll at 250,000 people as of Nov. 19, 2020, the vaccine breakthroughs provided some respite as a “dark winter” of surging cases began.

“The light at the end of the tunnel just got a little brighter,” says Schaffner, an ACIP liaison member representing NFID. “We will look at all these data, and I think we will all get a chance to see them when they apply for an Emergency Use Authorization [EUA] and it goes to the FDA.”

The companies released some details, but questions remain, including more efficacy data in the elderly and other risk groups, and the longer-term implications for use in pregnancy and children.

“We also don’t have the answer for how long the vaccines will protect someone. That will have to be determined going forward,” Schaffner says. “By that time, there will be a lot more safety data, and that will be very important. There is hesitancy on the part of so many people, including healthcare professionals of all kinds — doctors, nurses, physician assistants, pharmacists, everybody.”

Much of these concerns can be traced to the speed at which vaccines were developed and the fear of political influence during the buildup to the presidential election. Healthcare workers are expected to be the first group immunized when a safe and effective vaccine is approved. The American Medical Association (AMA) recently released a statement noting physicians have an ethical obligation to be immunized when a safe and effective COVID-19 vaccine is developed. The ethical opinion adopted by the AMA House of Delegates also states doctors “have an ethical responsibility to encourage patients to accept immunization when the patient can do so safely, and to take appropriate measures in their own practice to prevent the spread of infectious disease in healthcare settings.”3

“In the context of a highly transmissible disease that poses significant medical risk for vulnerable patients or colleagues, or threatens the availability of the healthcare workforce, particularly a disease that has potential to become epidemic or pandemic, and for which there is an available, safe, and effective vaccine, physicians have a responsibility to accept immunization absent a recognized medical contraindication or when a specific vaccine would pose a significant risk to the physician’s patients,” according to the policy.3

‘Plug and Play’ Vaccines

Paul Offit, MD, a member of the FDA Vaccine Advisory Committee, predicted recently at the IDWeek 2020 infectious disease conference that vaccines using the messenger RNA platform would be the first to roll out.

“The reason that the messenger RNA vaccines will be the first is because they are the easiest to construct and mass produce,” said Offit, an infectious diseases physician and director of the Vaccine Education Center at Children’s Hospital of Philadelphia. “It is not necessarily because they are going to be the last, best vaccines. It is because they are they the easiest to make. They are the so-called ‘plug and play’ vaccines. You just take the gene of interest — in this case, the gene that causes the coronavirus spike protein — and plug it into your system.”

Indeed, the spike protein, which the coronavirus uses to attack and invade cells, is the target of many other vaccines still under development with different platforms, creating the possibility that several effective vaccines eventually will be developed, said Anthony Fauci, MD, director of NIAID.

“I think it is quite conceivable that will occur,” he noted in a news interview. “The Moderna and Pfizer [vaccines] are strikingly similar, but other types of platforms are [also targeting] the spike protein of the coronavirus.”4

Both the Moderna and Pfizer vaccines are administered in two doses, with the former at four weeks apart and the latter at three weeks.

“The primary endpoint of the Phase 3 COVE study is based on the analysis of COVID-19 cases confirmed and adjudicated starting two weeks following the second dose of vaccine,” Moderna stated. “This first interim analysis was based on 95 cases, of which 90 cases of COVID-19 were observed in the placebo group vs. five cases observed in the mRNA-1273 group, resulting in a point estimate of vaccine efficacy of 94.5%.”1

For its part, Pfizer said, “the case split between vaccinated individuals and those who received the placebo indicates a vaccine efficacy rate above 90%, at 7 days after the second dose. … Analysis evaluated 94 confirmed cases of COVID-19 in trial participants … [The vaccine] BNT162b2, against SARS-CoV-2, has demonstrated evidence of efficacy against COVID-19 in participants without prior evidence of SARS-CoV-2 infection, based on the first interim efficacy analysis conducted on Nov. 8, 2020, by an external, independent [review board] from the Phase 3 clinical study.”2

“Now, we have two vaccines that are really quite effective,” Fauci said. “This is a really a strong step forward to where we want to be [in terms of] getting control of this outbreak.” Fauci projected that vaccines from both companies should be available by the end of December 2020, with larger stockpiles accessible in 2021.4

One key difference in the two vaccines is Pfizer requires subfreezing storage and handling, while the Moderna vaccine requires less demanding frozen storage.

“The storage and handling requirements of the Moderna vaccine are less stringent than those of the Pfizer vaccine,” Schaffner says. “They resemble the requirements of most routinely used vaccines. That will ease the logistical complexities of distribution and administration, permitting it to be used in local doctors’ offices, clinics, and pharmacies. This will allow us to bring the vaccine to the people rather than having to bring the people to the vaccine.”

If both vaccines are approved and made available, Pfizer’s could be deployed to facilities that have the capacity to maintain the extreme temperature levels.

“I would guess that probably the only reasonable way to do this is to establish vaccine centers for the Pfizer vaccine,” Offit said in a recent interview. “The center is just devoted to giving vaccine, [along] with hospitals, assuming [their] pharmacies would be willing to take this on. I think otherwise it would be really hard to do this, but we’ll see.”5

Both vaccines must be thoroughly analyzed and reviewed by the FDA, including a safety requirement to follow at least 50% of vaccine recipients for a median of two months. Pfizer previously began this requirement. The company filed an EUA application with the FDA on Nov. 20, 2020.

According to its industry news release, 42% of Pfizer vaccine recipients come from diverse backgrounds. No serious safety issues have been observed thus far. The protective effect is at 28 days, one week after the second dose. The vaccine can cause local and systemic reactions, Schaffner says.

“One of the things that is characteristic of this vaccine — like shingles vaccine, but worse — is that it is very reactogenic,” Schaffner says. “A lot of people get sore arms that can last a day or two. There are other people who feel rather puny for days, with aches and pains, headaches, even a degree of fever.”

Complicating matters, in terms of getting people to return for the second dose, is that the side effects are worse after the final shot. “It’s also reactogenic systemically,” he says. “Not everybody, of course, but it is a notable percentage, and we will have to alert recipients to this. Some people are going to make that calculation that 80% of people with COVID do pretty well — is it worth taking another dose?”

With healthcare workers designated a top priority, arrangements to immunize them in shifts may have to account for possible sick staff the following day.

“You don’t want to give it to all the workers in a long-term care facility and have a third of them not come in to work the next day,” Schaffner says. “That would complicate the scheduling considerably as we go forward. Even larger hospitals, given the shortage of workers we have now, will need to be careful about their scheduling.”

While Schaffner described the Pfizer side effects in the absence of company-released data, Moderna released specifics that nevertheless made direct comparisons difficult.

“The majority of adverse events were mild or moderate in severity,” Moderna stated. “Grade 3 (severe) events greater than or equal to 2% in frequency after the first dose included injection site pain (2.7%), and after the second dose included fatigue (9.7%), myalgia (8.9%), arthralgia (5.2%), headache (4.5%), pain (4.1%), and erythema/redness at the injection site (2.0%). These solicited adverse events were generally short-lived.”1

Reaching At-Risk Groups

The Moderna trial was a randomized, 1:1, placebo-controlled study testing of the mRNA-1273 vaccine at the 100-µg dose level in 30,000 participants in the U.S., ages 18 years and older. The study included more than 7,000 participants older than age 65 years. It also included 5,000 Americans younger than age 65 years with high-risk, chronic diseases, such as diabetes, severe obesity, and cardiac disease, that put them at increased risk of severe COVID-19 infection.

“These medically high-risk groups represent 42% of the total participants in the Phase 3 COVE study,” Moderna noted. “The study also included communities that have historically been underrepresented in clinical research and have been disproportionately impacted by COVID-19. The study included more than 11,000 participants from communities of color, representing 37% of the study population, which is similar to the diversity of the U.S. at large. This includes more than 6,000 participants who identify as Hispanic or Latinx, and more than 3,000 participants who identify as Black or African American.”

Of 11 severe cases of COVID-19 cases in the trial, all occurred in the placebo group and none in the vaccinated group. “The 95 COVID-19 cases included 15 older adults (ages 65+) and 20 participants identifying as being from diverse communities — including 12 Hispanic or Latinx, four Black or African Americans, three Asian Americans, and one multiracial,” Moderna stated.1

By the end of 2020, Moderna expects to produce approximately 20 million doses of mRNA-1273 to ship in the United States. The company estimates it will manufacture 500 million to 1 billion doses globally in 2021.

Pfizer and BioNTech expect to produce up to 50 million vaccine doses in 2020 and up to 1.3 billion doses in 2021. They also plan to submit data from the full Phase III trial to a scientific peer-reviewed publication.2

REFERENCES

  1. Moderna. Moderna’s COVID-19 vaccine candidate meets its primary efficacy endpoint in the first interim analysis of the phase 3 COVE study. Nov. 16, 2020. https://investors.modernatx.com/news-releases/news-release-details/modernas-covid-19-vaccine-candidate-meets-its-primary-efficacy
  2. Pfizer. Pfizer and BioNTech announce vaccine candidate against COVID-19 achieved success in first interim analysis from phase 3 study. Nov. 9, 2020. https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-announce-vaccine-candidate-against
  3. O’Reilly KB. Are physicians obliged to get vaccinated against COVID-19? American Medical Association, Nov. 16, 2020. https://www.ama-assn.org/delivering-care/public-health/are-physicians-obliged-get-vaccinated-against-covid-19
  4. Stump S. Dr. Fauci “concerned” about Trump stalling Biden transition at critical time in pandemic. Today, Nov. 16, 2020. https://www.today.com/health/dr-fauci-concerned-about-trump-stalling-biden-transition-t199179
  5. Doctor Radio Reports. Dr. Paul Offit, vaccinology expert and member of the FDA’s Vaccines Advisory Committee, weighs in on the challenges of distributing the vaccine. SiriusXM Doctor Radio, Nov. 10, 2020. https://www.siriusxm.com/clips/clip/e7adfb79-ca09-4825-b8ca-1aa0c124dea0/4ea9b6dd-e810-4788-b4f7-0c72b9b39529