A Shot in the Dark: FDA Adding Omicron to New Fall Vaccine
A new bivalent booster expected to be available in October
August 1, 2022
By Gary Evans, Medical Writer
With the Omicron BA.5 subvariant the dominant strain of COVID-19 in the United States as this report was filed, vaccine experts have decided to add some component of the rapidly mutating virus to a new bivalent booster that will be rolled out this fall.
As recently discussed by the Food and Drug Administration (FDA)’s vaccine advisory committee, the original vaccine against the Wuhan strain will be combined with the newest subvariants or some other component of Omicron.
With the vote 19-2 at a June 28, 2022, meeting, the FDA Vaccines and Related Biological Products Advisory Committee (VRBPAC) approved the “the inclusion of a SARS-CoV-2 Omicron component for COVID-19 booster vaccines in the United States.”
“We move forward into uncharted territory,” said VRBPAC Chairman Arnold Monto, MD. “Unfortunately, looking into the past doesn’t help us a great deal to look in the future. This virus has baffled a lot of us and made predictions almost irrelevant.”
As of July 3, 2022 — the most recent data available as this report was filed — the BA.5 subvariant of Omicron comprised 65% of cases in the United States. Meanwhile, BA.2.12.1 followed at 17% and BA.4 was causing 16% of cases.1
The general feeling among the panel was that something must be done, as accumulating evidence indicates these Omicron variants will cause breakthrough infections that can be mild or could progress unpredictably in some people. Indeed, a recently published report found that the Omicron subvariants BA.4 and BA.5 reduced neutralizing antibody titers three-fold in vaccinated subjects compared to BA.1, the original Omicron variant that emerged out of South Africa in November 2021.2
Why is the Omicron variant producing so many sub-lineages? We asked a leading researcher, who is not a member of VRBPAC: Pei-Yong Shi, PhD, a molecular biologist at the University of Texas Medical Branch in Galveston.
“The reason the later sub-lineages became dominant is because they are more fit — they can spread and replicate faster,” he says.
Endorsing the VRBPAC decision to add an Omicron component, Shi recommends strong consideration of adding BA.4 or BA.5.
“Of course, no one can predict what we will see in the late fall or winter,” he tells Hospital Infection Control & Prevention. “If Omicron continues, we are most likely to see BA.4 and BA.5 descendants.”
Making the case to anyone who has not been fully immunized with the current vaccines, Shi emphasizes that T cells and other aspects of the immune response still will prove protective, even if diminished antibodies cannot ward off initial infection by the Omicron subvariants.
“T cells are not dramatically affected by mutations,” he says.
Some VRBPAC members questioned whether there were enough data to make any changes, particularly since the existing vaccines continue to be largely effective against serious illness and death. One of the dissenting “no” votes was by Paul Offit, MD, an internationally recognized expert in virology and immunology.
“I don’t think it is fair to ask people to take a risk, with any vaccine that we get, if we don’t feel comfortable with the level of protection that we are likely to get by including Omicron,” said Offit, director of the Vaccine Education Center at the Children’s Hospital of Philadelphia.
The other dissenting vote was cast by Hank Bernstein, DO, a pediatric professor at the Zucker School of Medicine in New Hyde Park, NY.
“The strain change requirements should be data-driven,” he said, reminding the panel of its normal requirements for vaccine changes. “The data that has been presented today seems quite limited, especially for BA.4 and BA.5.”
The second VRBPAC requirement is that the current vaccines are not effective against severe disease, but the original Wuhan strain vaccine has proven resilient in reducing hospitalizations and deaths.
“The evidence [should be] compelling that a new vaccine with a strain change would improve effectiveness,” Bernstein said. “I don’t think we really have the data to be able to say that. We looked at immune response, but we really don’t have data on vaccine effectiveness.”
In addition, most of the data the committee has seen are on bivalent vaccines combined with the BA.1 variant, which no longer is in circulation, said VRBPAC member Adam Berger, PhD, director of clinical and healthcare research policy at the National Institutes of Health. Adding BA.4 or BA.5 would mean moving forward with only “preclinical data,” he said.
“I’m not sure I’m comfortable with making that leap without having some type of clinical efficacy, not just immunogenicity studies,” Berger said. “I think we really do need some clinical data.”
These points certainly have validity, but the problem the committee kept circling back to is that they likely will be darned if they do and darned if they don’t.
“This is truly a challenge and it is science at its hardest,” said Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research. “If we make a decision to wait until the evidence is irrefutable that we need to change, at that point this variant may have passed on and we’ll have something else here.”
The available data from the vaccine manufacturers show that they have generated immune responses, and the original vaccines are showing some signs of eroded protection, he argued.
“The current vaccines are no longer quite as protective against severe disease, particularly in older individuals, but probably also tailing off in younger individuals,” Marx noted.
The prevailing point seemed to be that targeting the most current strain possible at the time the vaccine must be produced will at least bring human immunity that much closer to whatever descends from it. The timeline is tight, since logistically it will take several weeks and maybe months to distribute the vaccine widely even if the manufacturers already are developing and testing candidates.
“I [understand] BA.4 and BA.5 may not be circulating later this fall, but by moving [now] we may at least bring the immune system closer to being able to respond to what’s circulating,” Marks said. “None of us has a crystal ball. We are trying to use every last ounce of what we can from predictive modeling and from the data that we have that’s emerging to try to get ahead of a virus that has been very crafty.”
Pandemic Fatigue; Winter Is Coming
The vulnerability of the U.S. population could be great this fall and winter, since many people remain unvaccinated. Many of the vaccinated have not been boosted, and even the fully compliant face waning immunity.
“Half of Americans have not received a third dose or a booster and those who have will have waning immunity as we move into the fall months of this year,” Marks said. “At that same time, we see this rapid evolution of COVID-19 variants, and that will undoubtedly continue. And that combination of waning immunity with the potential emergence of novel variants — during a time this winter when we will move inside as a population — increases our risk of a major COVID-19 outbreak.”
On July 12, 2022 — two weeks after the FDA meeting — White House COVID-19 coordinator Ashish Jha, MD, urged Americans to get boosted so they will be eligible for the bivalent booster beginning in October. He said 105 million doses of the new vaccine should be available, and likely also will be administered in November and December. He did not comment on the exact components of the vaccine.
“In terms of what to recommend to people right now, if you are over 50 [years of age] and have not gotten a booster for 2022, getting one now protects you for the rest of the summer into the fall,” Jha said.3 “Then it does not preclude you from being able to get the bivalent vaccine.”
Some of the first vials of the original vaccines are reaching their expiration dates — meaning millions of doses may be discarded. This is a “profound waste,” writes Eric Topol, MD, founder and director of Scripps Research Translational Institute in La Jolla, CA. In a recent blog post, he recommended offering the expiring vaccines to any people under age 50 years who want additional protection.4
There are indications that some version of this strategy is being considered by the White House COVID-19 panel.
In the same piece, Topol weighed in on the dangers of the BA.5 subvariant, which, in his estimate, are considerable.
“The Omicron subvariant BA.5 is the worst version of the virus that we’ve seen,” he notes.
BA.5 takes immune escape to the next level, which enhances transmissibility well beyond that of Omicron (BA.1) and other Omicron family variants, including BA.1.1, BA.2, BA.2.12.1, and BA.4.
Although there is no clear indication the subvariants cause more severe disease, an animal study awaiting peer review concluded that “infection experiments using hamsters indicated that BA.4/5 is more pathogenic than BA.2.”5
“With the extent of BA.5’s immune evasion and the recent trends of lowered vaccine effectiveness vs. severe disease (from 95% vs. Delta with a booster to ~80% vs. Omicron BA.1 or BA.2 with a booster) it would not be at all surprising to me to see further decline of protection against hospitalizations and deaths,” Topol wrote.
Although not a member of VRBPAC, he acknowledged the conundrum that the FDA panel faces. That said, “variant chasing” is a flawed approach that will have diminishing returns, he warned: “By the time a BA.5 vaccine booster is potentially available, who knows what will be the predominant strain?”
That leads to the urgent need for new “variant-proof,” true, second-generation vaccines, which Topol argues for, along with clinician Daniel Griffin, MD, PhD, an infectious disease physician at Columbia University in New York City.
Although some argue a new messenger ribonucleic acid vaccine can be created in a matter of six weeks, Griffin cautions this is an undertaking not to underestimate.
“Rolling out a new COVID vaccine on a national basis is no trivial matter, particularly when Congress is reluctant to provide the funds,” he said. “This last part is critical. [Questions will include] are they that much better? If so, for how long — a week or a month? Are they already a day late and a dollar short?”
Speaking on his weekly COVID-19 videocast, Griffin urged Congress to keep funding vaccine research: “With cars, we didn’t stop at seatbelts.”6
Given the unknown and the unpredictable, committee discussions turned to breaking the decision down to a risk-benefit choice.
“[The] point is well taken, and I think we should be transparent about this,” Marx said. “I think what this [depends on] is the epidemiology that we see over the coming months. Right now, the critical thing is the manufacturers need to know what to put into the vaccine.”
As far as who would receive the boosters, that remains unresolved, although those age 50 years and older who have had their previous shots and boosters clearly are a priority, Marx said.
However, several committee members brought up the ethical responsibility of making the booster available to children. “There is concern about serious side effects in children, but we are unlikely to learn about those in any clinical trial,” warned VRBPAC member Mark Sawyer, MD, infectious disease specialist at Rady Children’s Hospital at UC San Diego. “Particularly for myocarditis, we are only going to know that when we roll out the vaccines and the safety systems do their review.”
Marks said the sentinel systems in place for myocarditis and other vaccine adverse events are strong and are monitoring millions of individuals.
“I think we will be able to get a pretty good sense of things,” he said.
- Centers for Disease Control and Prevention. Variant proportions. Data from July 3, 2022. https://covid.cdc.gov/covid-data-tracker/#variant-proportions
- Hachmann NP, Miller J, Collier A-R, et al. Neutralization escape by SARS-CoV-2 Omicron subvariants BA.2.12.1, BA.4, and BA.5. N Engl J Med 2022;387:86-88.
- Topol E. The BA.5 story. Ground Truths. Published June 27, 2021. https://erictopol.substack.com/p/the-ba5-story
- C-span. Bivalent COVID-19 vaccine could come in October, Jha says. Published July 12, 2022. https://www.c-span.org/video/?c5023190/bivalent-covid-19-vaccine-october-dr-jha
- Kimura I, Yamasoba D, Tamura T, et al. Virological characteristics of the novel SARS-CoV-2 Omicron variants including BA.2.12.1, BA.4 and BA.5. bioRxiv 2022; May 26. doi: https://www.biorxiv.org/content/10.1101/2022.05.26.493539v1. [Preprint].
- Racaniello V. TWiV 916: COVID-19 clinical update #122 with Dr. Daniel Griffin. YouTube. Published July 8, 2022. https://www.youtube.com/watch?v=kaJN0aTZTog&t=1117s
With the Omicron BA.5 subvariant currently the dominant strain of COVID-19 in the United States, vaccine experts have decided to add some component of the rapidly mutating virus to a new bivalent booster that will be rolled out this fall.
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