FDA Streamlining COVID-19 Shot to a Single Formula
Plan calls for adding key variants annually
Conceding the various vaccine doses and multiple boosters have caused considerable confusion, and some degree of pandemic apathy, the FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) unanimously voted to simplify and “harmonize” the process by switching to a single vaccine formula to be administered annually for most people.1
“Speaking with colleagues, friends, family, questions I’m answering from the community — there’s so much confusion about these different formulations,” said committee member Archana Chatterjee, MD, PhD, dean of the Chicago Medical School at Rosalind Franklin University of Medicine and Science. “I concur with my colleagues that there definitely remains a need for these vaccines and for us to do our best to get them into arms. Having vaccines is not sufficient.”1
The 21 VRBPAC members voted “yes” to this question: “Does the committee recommend harmonizing the vaccine strain composition of primary series and booster doses in the U.S. to a single composition, e.g., the composition for all vaccines administered currently would be a bivalent vaccine (original plus omicron BA.4/BA.5)?”
At the Jan. 26 meeting, they outlined a new seasonal framework — roughly akin to influenza vaccine creation — to meet in the spring, determine the circulating SARS-CoV-2 strains of concern, and develop shots to administer in the fall.
“I think anything that results in better communication to get more of the unvaccinated vaccinated would be extremely valuable,” said board member Henry Bernstein, DO, MHCM, FAAP, of Cohen Children’s Medical Center in New Hyde Park, NY. “I still have some questions. But I think this is the right direction.”
VRBPAC member Ofer Levy, MD, PhD, director of the precision vaccines program at Boston Children’s Hospital, went even further in seizing the significance of the moment.
“As we have turned the corner from a pandemic phase to an endemic phase, today’s vote marks a big practical win for the American people,” Levy said. “This is going to really simplify things and benefit public health.
The new approach was roundly praised and drew a unanimous vote, but there are devils in virtually every detail as the process moves forward.
“I think this is definitely the way to go — as soon as we can figure out how to do it,” said Mark Sawyer, MD, board member and pediatric professor at the University of California, San Diego.
Mandated for HCWs?
The new vaccine strategy will begin with a VRBPAC meeting for SARS-CoV-2 strain selection expected to occur in May. It was not determined whether the original strain of COVID-19 would be included if the final product is a bivalent vaccine. The dose amounts and timing could differ from the public and risk groups like the very young, elderly, and immune-compromised.
Another unresolved matter is whether healthcare workers will be required to take this annual COVID-19 shot under the edict issued by CMS. While some healthcare facilities are requiring the current bivalent vaccine containing an omicron component, they technically are not mandated under the CMS rule for COVID-19 vaccinations. CMS defines “fully vaccinated” for healthcare staff as those who are at least two weeks out from their primary vaccination series for COVID-19. This means staff who have received a single-dose vaccine, or all required doses of a multidose vaccine for COVID-19 are CMS-compliant two weeks later. No boosters are required, nor was that word used to describe the newly planned vaccines at the VRBPAC meeting. This is likely because “booster fatigue” has become a common term with negative connotations for vaccine uptake.
“I think this is a very good decision to move forward with this from a programmatic and implementation perspective,” said Amanda Cohn, MD, chief medical officer for the CDC Vaccine Task Force. “The most concerning data point that I saw this whole day was the extremely low vaccination coverage in [children] 6 months to 2 years of age, and 2 years to 4 years of age. We have to do much, much better. We really just have to focus on getting those kids vaccinated.”
Last June, VRBPAC approved a bivalent vaccine, then launched a fall immunization effort. It is not too farfetched an analogy that this effort — with its hours of conversations about the data-less abyss that must somehow inform their efforts — blew up on the launchpad. A staggering 84.5% of those indicated for the vaccine had not received it as this report was filed.2
VRBPAC took a shot in the dark and missed. It was the meager uptake, not necessarily the content of the vaccine, that spelled failure. The added omicron subvariants B.4 and B.5 were slowly vanishing nationally as the vaccine became available, but as hoped, the formula remained efficacious against their viral descendants.
“In November 2022, adults ages 18 years and older, who received a bivalent booster, had sixteenfold lower risk of hospitalization for COVID-19 compared to unvaccinated people. [They had a] threefold lower risk of hospitalization compared to those vaccinated without a bivalent booster,” said Heather Scobie, PhD, MPH, of the CDC Coronavirus and Other Respiratory Viruses Division.
As of Jan. 28, 2022, CDC genomic surveillance showed XBB.1.5 was riding high at 61% of SARS-CoV-2, followed by BQ.1.1 at 22% and BQ.1 at 9%.3 What is the trend of increase? As of Jan. 14, the XBB.1.5 represented 43% of genomic isolates, according to the CDC.
If will be interesting to see how vaccines fare against XBB.1.5 in ongoing studies. An antigen against it can be expected in the next vaccine unless it is overtaken by faster, fitter subvariants before the FDA holds its variant selection meeting in May.
“We haven’t had a clear kind of winner in terms of selective advantage for a while,” Scobie said. “But it’s seeming like with XBB.1.5, we are at that place now.”
The predominance of the recombinant omicron subvariant XBB.1.5 has raised considerable concern in some scientists. Among them is Eric Topol, MD, director and founder of the Scripps Research Translational Institute in La Jolla, CA.
“The XBB strain is the first fast-spreading recombinant variant — meaning it is a fusion of two omicron lineages,” Topol wrote in a commentary.4 “Its original version led to a wave of infections in Singapore. Then, it added two critical mutations to become XBB.1.5, which was first detected in New York.”
The mutated virus has a high level of immune escapability and enhanced ability to attach itself to cellular receptors. While there is no indication XBB.1.5 is more virulent, its rapid spread means more people will be infected — including those in high-risk groups.
Still, the upstart subvariant is facing a strong headwind of existing immunity, despite the lack of uptake on the bivalent booster. “The vast majority of the U.S. population has either been exposed to infection, vaccinated, or both,” Scobie said. “I think in general, we’re seeing the vaccines protect pretty well for up to three months against infection, and much longer for severe disease.”
To this, a VRBPAC member asked a counterintuitive, and possibly moot, question.
“Do we really want to stop asymptomatic infection with SARS-CoV-2?” asked Cody Meissner, MD, chief of pediatric infectious diseases at Tufts Children’s Hospital in Boston. “First of all, I don’t think that’s a reasonable objective — at least with the current generation of mRNA vaccines. You can certainly make the argument that an asymptomatic infection is desirable because it will stimulate both cellular and humoral immunity. It will kind of act like its own boost. We certainly want to stop the virus from circulating, but that’s probably not going to be possible.”
Given the level of vaccine breakthrough infections with the delta and omicron variants, Meissner could be right. The real test will be next winter, with a “triple-demic” continuing in some parts of the country.
“We see the potential advantages for the winter seasonality with a fall [vaccine] campaign,” said Peter Marks, MD, PhD, director of the FDA Center for Biologics Evaluation and Research. “Because when do we have to worry about overwhelming hospitals? It will be when we have influenza, RSV, and potentially COVID at the same time.”
Paul Offit, MD, director of the Vaccine Education Center at Children’s Hospital of Philadelphia, voted against the bivalent booster last year, in part because he saw no evidence it was better than the vaccine at that time. He was firmly on board at the most recent meeting, arguing for staying close to the emerging variants.
“I certainly support this,” Offit said. “I think it’s important to get closer to the strains that are circulating for certain groups. Right now, BA.4 is gone, BA.5 probably represents less than 5%. I think our goal to is keep people out of the hospital and not let hospitals be overwhelmed. Certain things are clear — this virus is going to be with us for years, if not decades, and there will always be vulnerable groups who will be hospitalized and killed by this virus.”
As the FDA has had to make some key decisions in the absence of data, Offit called on the CDC to provide more detailed information on hospitalized COVID-19 patients.
“We need the CDC to tell us exactly who it is who’s getting hospitalized and dying from this virus. What are their ages? Specifically, what are their comorbidities?” Offit asked. “If they are immune-compromised, in what manner are they immune-compromised? Did they recently get a vaccine, were they treated with antivirals? That has to be provided in concert with immunological data. What are the predictors not just for antibodies but cellular immunity? Only then can we really best make the decision about who gets vaccinated with what and when.”
Alarm Tripped on Vaccine Safety
The discussion turned to vaccine safety after the CDC announced it had detected a “signal” of possible higher risk of ischemic stroke following vaccination of those older than age 65 years.
CDC’s Vaccine Safety Datalink (VSD), a near real-time surveillance system, identified a signal in the statistical criteria requiring an additional investigation into safety concerns for ischemic stroke in people older than age 65 years who received the bivalent Pfizer-BioNTech COVID-19 vaccine. This preliminary signal has not been identified with the bivalent Moderna COVID-19 vaccine.5
“There also may be other confounding factors contributing to the signal identified in the VSD that merit further investigation,” the CDC stated. “Furthermore, it is important to note that, to date, no other safety systems have shown a similar signal, and multiple subsequent analyses have not validated this signal.”
Several other surveillance systems looked for the adverse outcome but have turned up nothing thus far. According to the CDC, these include:
- The Vaccine Adverse Event Reporting System managed by CDC and FDA;
- Pfizer-BioNTech’s global safety database;
- Surveillance systems in other countries.
“Although the totality of the data currently suggests that it is very unlikely that the signal in VSD represents a true clinical risk, we believe it is important to share this information with the public, as we have in the past, when one of our safety monitoring systems detects a signal,” the CDC stated.
No change in vaccination practice is recommended. The CDC continues to recommend everyone older than 6 months of age stay up to date with COVID-19 vaccination, including those eligible to receive a bivalent vaccine.
“Our systems are designed to be sensitive to broadly capture potential safety concerns and to be able to rapidly assess those concerns,” said Tom Shimabukuro, MD, MPH, MBA, deputy director of the CDC Immunization Safety Office. “The thoroughness in which these findings are being assessed demonstrates that the safety system works. You basically saw that process in action working. I think the public and the medical community should be confident that the government has the systems in place to rapidly detect potential safety problems and assess them. We place a priority on communicating in a timely and transparent manner.”
The FDA is investigating whether the bivalent booster was administered with high-dose influenza vaccine and whether that could have triggered a drug interaction. “We will specifically address the question of concomitant influenza vaccinations by looking at individuals who received either an adjuvanted or high-dose influenza vaccine on the same day that they received their COVID-19 bivalent booster,” said Richard Forshee, PhD, deputy director of the FDA’s Office of Biostatistics.
REFERENCES
- U.S. Food and Drug Administration. Vaccines and Related Biological Products Advisory Committee January 26, 2023, meeting announcement.
- Centers for Disease Control and Prevention. Trends in number of COVID-19 vaccinations in the US. Jan. 26, 2023.
- Centers for Disease Control and Prevention. Variant proportions. Jan. 31, 2022.
- Topol E. The coronavirus is speaking. It’s saying it’s not done with us. The Washington Post. Jan. 8, 2023.
- Centers for Disease Control and Prevention. CDC & FDA identify preliminary COVID-19 vaccine safety signal for persons aged 65 years and older. Jan. 13, 2023.
Conceding the various vaccine doses and multiple boosters have caused considerable confusion, and some degree of pandemic apathy, the FDA’s Vaccines and Related Biological Products Advisory Committee unanimously voted to simplify and “harmonize” the process by switching to a single vaccine formula to be administered annually for most people.
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