By Marie Rosenthal, MS
Updated Sept. 2.
In two votes, one for the Moderna and the other for the Pfizer-BioNTech bivalent boosters, the CDC’s Advisory Committee on Immunization Practices (ACIP) voted overwhelmingly—if somewhat reluctantly—to recommend the use of the bivalent COVID-19 messenger RNA (mRNA) boosters to replace the monovalent boosters. The FDA had granted a new emergency use authorization (EUA) for both on Aug. 31.
On Sept. 1, the committee voted 13 to 1 to recommend the bivalent COVID-19 vaccine made by Moderna for people 18 years of age and older, and the Pfizer bivalent COVID-19 vaccine for those 12 years and older. CDC Director Rochelle P. Walensky, MD, MPH, endorsed the ACIP’s recommendations later that evening. The boosters should be given at least two months after the receiving the last vaccination, either a primary series or booster. This recommendation simplifies the COVID-19 vaccination schedule, several members said.
ACIP Considerations
Pablo J. Sanchez, MD, a professor of pediatrics at The Ohio State University-Nationwide Children’s Hospital, in Columbus, was the lone dissenting voice after a very long discussion, during which several members expressed concerns about the lack of clinical data to support the recommendation, especially for younger people, as well as other issues.
Helen Keipp Talbot, MD, even asked Chair Grace Lee, MD, to come back to her after everyone else voted during the first vote for the Moderna vaccine, because she wanted those extra minutes to consider. In the end, she voted yes for both vaccines. Dr. Talbot is an assistant professor of medicine, Division of Infectious Diseases at Vanderbilt University Medical Center, in Nashville, Tenn.
Dr. Sanchez called the recommendation premature and said more data were needed, but added that he would likely receive the vaccine for himself.
“I voted no because I really feel that we need the human data, and to me that’s really important—it's a new vaccine, it's a new platform. There's a lot of vaccine hesitancy already,” he explained after his vote.
Dr. Sanchez added that when all the data are available, he does think the vaccines will have similar safety profiles as the monovalent vaccines. “I personally, I'm in the age group where I'm at high risk and I'm almost sure that I will receive it,” he admitted. “I just feel … that this was a bit premature and I wish that we had seen that data. Having said that, I am comfortable that the vaccine will likely be safe like the others.”
Many said they agreed with him but felt there was an urgency in getting these vaccines out before the fall, and that these recommendations simplified the booster recommendations, which they hoped would increase uptake by the public.
Matthew F. Daley, the chair of the ACIP COVID-19 Work Group, called the lack of clinical data about bivalent BA.4 and BA.5 “one of the most important and fundamental considerations” for the ACIP to discuss, and he admitted that he struggled with the lack of data. If there was not a pandemic, then he would have been more inclined to wait for more data, he said.
However, waiting for clinical data meant “we would need to wait until November or December to start a vaccination campaign. And then, based on the modeling that we saw, there would be a cost to that, and that cost might be somewhere in the range of 9,700 deaths and 137,000 hospitalizations potentially averted,” Dr. Daily said, adding that he was reassured by the FDA’s review.
He called the bivalent vaccines “An important tool to prevent additional disease.”
Sarah S. Long, MD, a professor of pediatrics at Drexel University College of Medicine, in Philadelphia, said that she could see both points of view, but was leaning on the side of Dr. Daily because she did not expect the vaccine would be clinically inferior to the monovalent vaccine and because of its potential to decrease hospitalizations and death.
Dr. Long reminded the ACIP that every year they made recommendations for the new components of an annual influenza vaccine without seeing clinical data about the components. The influenza recommendation is made based on extrapolated data about what is believed the next season will be. “We don't usually have too much clinical information for efficacy when we are thinking about changing influenza vaccines when it is the same scaffolding, part of the same roof. We're just putting in, you know, some dormers and windows.”
COVID-19 Update
The updated boosters contain two mRNA components of the SARS-CoV-2 virus in the hope that they will provide better protection against the circulating omicron variants. Statistical modeling is predicting yet another wave from the latest omicron strain in the fall, and that wave is likely to increase hospitalizations and deaths, especially among unvaccinated people.
To date, COVID-19 vaccines are estimated to have prevented 13.7 million to 15.9 million deaths, which is a reduction of 63% in total deaths, according to Dr. Daley, who is the senior investigator at the Institute for Health Research, Kaiser Permanente Colorado, in Aurora.
Right now, the United States has seen five omicron sublineages, and although they have increased transmissibility and capability to evade the immune system, they cause milder disease for most people. However, vaccine effectiveness with the monovalent vaccine and monoclonal antibody treatments has been reduced, according to Heather Scobie, PhD, MPH, an epidemiologist at the CDC.
As of Aug. 30, there were more than 94 million cases of COVID-19 reported, and omicron caused more cases than the alpha and delta strains combined. In the beginning, there was a large increase in hospitalizations due to omicron, but that has been decreasing. However, hospitalization rates among older adults, those 65 and older, have increased relative to other age groups, but are still much lower than at the beginning of the omicron wave, Dr. Scobie explained.
As of Aug. 27, more than 1 million people have died in the United States from COVID-19. Again, there was an increase in deaths—more than from the delta wave—from omicron, but those deaths continue to decline now. However, like hospitalizations, there is a small increase in deaths among people 75 and older relative to other age groups, according to Dr. Scobie. Similarly, the increase is still much smaller than earlier in the year.
They attribute some of these declines to vaccination. In June 2022, those 50 years and older with two or more boosters had a 14 times lower risk for dying from COVID-19 compared with unvaccinated people, and a three times lower risk for dying from COVID-19 than people with only one booster, according to Dr. Scobie.
In addition, unvaccinated people are at higher risk for severe disease compared with vaccinated people, Dr. Scobie added.
Data Considered by the FDA
The 50-mcg booster dose of Moderna mRNA-1273.222 includes 25 mcg encoding for the original strain of the SARS-CoV-2 virus and 25 mcg of mRNA encoding for the spike protein of the BA.4/BA.5 omicron variant. The 30-mcg booster dose of the Pfizer-BioNTech bivalent booster includes 15 mcg of the original strain and 15 mcg of the omicron BA.4/BA.5 subvariants. Apart from the addition of the mRNA sequence of the omicron BA.4/BA.5 spike protein, all other components of the vaccine remain unchanged, Pfizer explained in a release about its vaccine.
Among the evidence evaluated by the FDA was human clinical data, as well as animal and other studies.
For the efficacy of the Moderna bivalent vaccine, the FDA analyzed immune response data among approximately 600 individuals 18 years of age and older, who had previously received a two-dose primary series and one booster dose of its monovalent vaccine. These participants received a second booster dose of either the monovalent Moderna COVID-19 vaccine or Moderna’s investigational bivalent COVID-19 vaccine, which contains the original and omicron BA.1 strains, at least three months after the first booster dose. After 28 days, the immune response against BA.1 of the participants who received the bivalent vaccine was better than the immune response of those who had received the monovalent vaccine.
Safety was supported by safety data from a clinical study that evaluated a booster dose of Moderna’s investigational bivalent COVID-19 vaccine (original and omicron BA.1 strains), safety data from clinical trials that evaluated primary and booster vaccination with the monovalent vaccine, and postmarketing safety data with the monovalent vaccine.
The clinical study that evaluated the safety of a booster dose of the bivalent vaccine containing the original and omicron BA.1 strains involved approximately 800 participants 18 years of age and older, who had previously received a two-dose primary series and one booster dose of Moderna’s monovalent vaccine, and then at least three months later received a second booster dose with either the monovalent or investigational bivalent vaccine.
Among the study participants who received the bivalent vaccine, the most commonly reported side effects included pain, redness and swelling at the injection site, fatigue, headache, muscle pain, joint pain, chills, swelling of the lymph nodes in the same arm of the injection, nausea/vomiting and fever.
To evaluate the Pfizer-BioNtech bivalent vaccine, the FDA analyzed immune response data among approximately 600 adults older than 55 years, who had previously received a two-dose primary series and one booster dose with its monovalent vaccine. These participants received a second booster dose of either the monovalent or investigational bivalent COVID-19 vaccine, again containing the original and omicron BA.1 strains, which occurred 4.7 to 13.1 months after the first booster dose. After one month, the immune response against BA.1 of the participants who received the bivalent vaccine was better than the immune response of those who had received the monovalent vaccine.
Safety data again were evaluated for the investigational bivalent vaccine in about 600 participants 55 years and older, who had previously received a two-dose primary series and one booster dose of the monovalent vaccine, and then 4.7 to 13.1 months later received a second booster dose of either the monovalent or investigational bivalent vaccine. Among the participants who received the bivalent vaccine, the most commonly reported side effects included pain, redness and swelling at the injection site, fatigue, headache, muscle pain, chills, joint pain and fever.
The ACIP panel was concerned that the clinical trials were of the omicron variants that were circulating earlier—variants that are no longer circulating—and that in the case of the Pfizer vaccine, were done in older adults.
This point was particularly concerning because the serious adverse event of myocarditis/pericarditis, although rare, is occurring primarily in a much younger population—adolescent and young adult males.
“FDA in its authorization considered a totality of evidence that consisted primarily of an extrapolation approach based on data from clinical trials, with similar bivalent vaccine formulations, consisting of original and omicron BA1 sublineage components, as well as extensive experience with the use of the original monovalent vaccine with both primary series and booster doses. All of these data represent data collected with human experience,” Doran Fink, MD, the acting deputy director of the Office of Vaccines Research and Review, Center for Biologics Evaluation and Research at FDA, told the ACIP members.
“Additionally, FDA considered supportive data from some animal studies that provided additional reassurance about our extrapolation approach,” he added.
However, Dr. Long was concerned about younger people who might be at risk for myocarditis and asked whether the Work Group considered recommending this booster only in older adults. Dr. Daily said they had discussed it, but still came to the consensus that it should be given to people of all ages, “although there were voices who expressed your sentiment, too.”
One reason is that the vaccine-associated risk for myocarditis is so low, he added.
In the end, most of the committee members decided to go with the Work Group recommendations.
“The updated COVID-19 boosters are formulated to better protect against the most recently circulating COVID-19 variant. They can help restore protection that has waned since previous vaccination and were designed to provide broader protection against newer variants. This recommendation followed a comprehensive scientific evaluation and robust scientific discussion. If you are eligible, there is no bad time to get your COVID-19 booster, and I strongly encourage you to receive it,” Dr. Walensky said in a statement.
Several associations also released statements supporting the recommendations.
“COVID-19 is not over, said Daniel P. McQuillen, MD, FIDSA, the president of the Infectious Diseases Society of America. “Nearly 400 people die from COVID every day, and almost 5,000 people are currently hospitalized with COVID. Vaccines are the best way to prevent serious infection, hospitalization and death. Infectious diseases experts urge everyone who is eligible to get boosters.”
Sandra-Adamson Fryhofer, MD, the board chair of the American Medical Association, and its liaison member at the ACIP also endorsed the recommendations.
“With COVID-19 infections continuing to impact the U.S. population and an increase in infections expected this fall and winter, data show that the updated bivalent vaccines will increase immune response and help provide protection against severe COVID-19 outcomes including hospitalization and death,” she said, adding that broad uptake of the bivalent booster could prevent 100,000 hospitalizations and provide an additional layer of protection against omicron.
Moderna said it would seek full approval from the FDA.
