Clinicians and public health epidemiologists are loath to make bold moves with a dearth of data, but one dire projection recently swayed clearly uncomfortable members of the Centers for Disease Control and Prevention’s (CDC) Advisory Committee on Immunization Practices (ACIP).
CDC models estimate that thousands of lives could have been lost to COVID-19 if public health officials delayed approval of the new bivalent booster shots to accumulate more data on efficacy and safety.
Although many ACIP members agreed more data is needed on the Omicron BA.4 and BA.5 subvariants included in the new bivalent vaccines, the cost of delay would be measured in lives and hospitalizations, said Matthew Daley, MD, of Kaiser Permanente Colorado, a member of the ACIP work group that recommended approving the vaccines to the full committee.
“In the abstract — not in a pandemic with some 90,000 cases a day — I might think it would have been better to have clinical data for BA.4 and BA.5,” he said. “What would be the harm in waiting for clinical data? In my understanding, we would have to wait until November or December to start a vaccination campaign.
“Based on the [CDC] modeling that we saw, the cost of doing that might be in the range of 9,700 deaths and 137,000 hospitalizations.”
Although it took something of a leap of faith, both the CDC and the Food and Drug Administration (FDA) recently approved two new bivalent vaccine boosters containing the original Wuhan strain and the two Omicron subvariants.
The approved vaccines, which were being widely rolled out as this report was filed, are manufactured by the same companies who created the original messenger ribonucleic acid (mRNA) monovalent vaccines given in a two-shot initial series. The new bivalent booster by Pfizer-BioNTech is recommended for people 12 years of age and older. A similar bivalent booster by Moderna is recommended for those 18 years of age and older. With the approval of the new boosters, using the monovalent vaccines to boost immunity (the original SARS-CoV-2 vaccine as the booster) with a third or fourth shot after the two-shot series no longer is an approved practice.
Omicron BA.5 Dominates
The boosters have Omicron BA.4 and BA.5 spike protein components to generate immunity against these highly transmissible subvariants. The FDA and CDC officially approved the boosters on Sept. 1 and 2, 2022, respectively. As of Sept. 10, BA.5 comprised 87.5% of circulating subvariants, with BA.4.6 at 9.2% and BA.4 at 2.2%.1
Advisory committee members for both agencies made the decision to move ahead, although conceding the highly mutable SARS-CoV-2 virus could change again or a new variant could emerge and surpass Omicron.
The hopes expressed at ACIP that the new boosters are a transitional step toward something like an annual seasonal flu shot, were tempered by one committee member.
“While I whole heartedly embrace this idea of [annual shots] becoming more routine, I think it is important for people to understand that — while we hope we can go in that direction and we are all ready to change the way that we are dealing with this pandemic — things might change,” said ACIP member Beth Bell, MD, MPH, of the University of Washington. “We don’t know what the future is going to hold [in terms] of the virus and the pandemic. We all recognize we might not get there as quickly as we would like.”
Similar thoughts were expressed at an FDA advisory committee meeting in June when the decision to add an Omicron component to a bivalent vaccine was approved. (See Hospital Infection Control & Prevention, August 2022.) There also were concerns with the lack of data on adding BA.4 and BA.5 to a bivalent vaccine, a theme that was echoed in ACIP discussions.
Somewhat controversially, the FDA used some efficacy and safety data from mice research. At a June meeting with the agency, Pfizer showed that its BA.5 shot increased antibodies in mice 2.6-fold compared with the original vaccine.
The lack of sufficient efficacy data in humans was a recurrent theme in the ACIP meeting. Of course, safety has been a concern, but perhaps less so, given that millions of doses of the monovalent versions of mRNA vaccines have now been distributed. There are more data on a bivalent vaccine containing the original strain and the Omicron B.1 subvariant, which was the first to emerge and now no longer is circulating. That vaccine is expected to be used in Canada and Europe, but the FDA wanted to get closer to current viral iterations with the hope of prolonged immunity.
“We are extrapolating the data that we have seen for bivalent B1 vaccine to hopefully get similar data [for BA.4 and BA.5],” said ACIP member Pablo Sanchez, MD, of Ohio State. “I am concerned about that extrapolation, and ultimately I don’t want to establish a precedent of recommending a vaccine that we don’t have data on.”
In casting the only “no” vote at ACIP, Sanchez also cited the rare but real risk of post-vaccination heart inflammation and myocarditis in adolescent and young adult males.
The CDC reports that “rare cases of myocarditis or pericarditis have occurred most frequently in adolescent and young adult males, ages 16 years and older, within seven days after receiving the second dose of an mRNA COVID-19 vaccine.”2 The CDC has decided the risk-benefit question tilts toward vaccination — compared to SARS-CoV-2 infection — and that line of thinking prevailed with the new booster as well.
Although this heart inflammation is self-limited in many, some patients with post-vaccination myocarditis have been hospitalized. One study looking at a cohort of 69 of these patients found the median length of stay was four days, but all patients recovered and were discharged.3
Flu Shot Analogy
As some panel members voiced concerns, the CDC’s Melinda Wharton, MD, MPH, ACIP executive secretary, stressed the agency’s experience with this process for the annual flu vaccine.
“Every year we use influenza vaccines that are based on flu strains without clinical studies being done,” she said. “We have well-established platforms. There are changes made in the particular strains that are included, but overall, the vaccines are incredibly similar year to year. This is really analogous to that.
“We have used hundreds of millions of doses of these [monovalent mRNA] vaccines. We have a lot of familiarity with the vaccines and their performance.”
Doran Fink, MD, PhD, FDA liaison to ACIP, said the agency is comfortable moving ahead. “We have a tremendous amount of experience with the monovalent vaccine across these age groups,” she said. “There are some differences, but by and large we are seeing primary doses and booster doses trend in the same direction.”
Veronica McNally, JD, consumer representative for ACIP, said she was reassured by these CDC and FDA comments, emphasizing the surveillance systems now widely in use provide the needed safety net to go forward with the booster.
“There is a demonstrated ability to respond very quickly to any issue we need to address,” she said.
As discussions continued, ACIP Chair Grace Lee, MD, of Stanford University, called on the committee to make a decision and vote on the matter.
“I would like to have more information — it would be better to have more information,” she said. “But again, we have a decision to make for what we anticipate will be a tough winter season ahead both with flu and COVID-19. Our job is to do our best to protect public health.”
After the vote for booster approval, Lee told ACIP members she would call them back into session if something they need to address changes.
“I am going to remain optimistic, but we might not be out of the woods yet,” Lee said. “If anything changes, ACIP will meet again.”
After the meeting, the CDC issued a statement that it expects to recommend updated COVID-19 boosters for other pediatric groups, per the discussion and evaluation of the data by ACIP, in the coming weeks: “When data are available and FDA authorizes these other types of COVID-19 boosters, CDC will quickly move to help make them available in the United States.”
- Centers for Disease Control and Prevention. Variant proportions. Sept. 10, 2022. https://covid.cdc.gov/covid-data-tracker/#variant-proportions
- Centers for Disease Control and Prevention. Clinical considerations: Myocarditis and pericarditis after receipt of mRNA COVID-19 vaccines among adolescents and young adults. Last reviewed June 3, 2022. https://www.cdc.gov/vaccines/covid-19/clinical-considerations/myocarditis.html
- Matta A, Kunadharaju R, Osman M, et al. Clinical presentation and outcomes of myocarditis post mRNA vaccination: A meta-analysis and systematic review. Cureus 2021;13:e19240.
