In the updated version, the last section, "Who will benefit most from a bivalent booster?" was heavily edited due to the emergence of new information.
On September 1, 2022, the CDC’s Advisory Committee on Immunization Practices (ACIP) voted 13-1 in favor of a recommendation for a booster dose with the new two-strain (bivalent) vaccine containing mRNA sequences coding for both the original spike protein and the omicron BA.4/5 spike protein. The CDC recommends that everyone over 12 years of age should get a new bivalent booster to expand protection against the omicron strains currently circulating. The new Pfizer bivalent booster is authorized for those aged 12 years and older, while the Moderna bivalent booster is authorized for those 18 and older.
The ACIP meeting on September 1, 2022 was recorded and is available on the agency’s YouTube channel, offering the public an opportunity to view the scientific data and listen to clinical experts discuss this recommendation. The question and comment period elucidates the variety of expert opinions regarding whether the current data is sufficient to support a broad recommendation, which age groups stand to benefit most, and those for whom there is more uncertainty about the incremental risks and benefits of receiving this updated booster.
When should I get the booster?
Although CDC Director Rochelle Walensky, M.D., said in the agency’s press release that “...there is no bad time to get your COVID-19 booster,” the FDA’s authorization stipulates it must be at least 2 months since the last mRNA dose. This 2-month interval differs from the prior recommendation—5 months following the last dose—and is intended to allow as many people as possible to get updated protection before an anticipated SARS-CoV-2 surge this fall.
This shorter interval prompted discussion about how to communicate the timing of an omicron booster to the public. For younger males, data presented at a previous ACIP meeting suggested that a longer interval between the primary series doses reduced the risk of myopericarditis, an adverse event linked to mRNA vaccination. Other research presented in the same meeting suggested that a longer interval also provided a higher quality boost in antibodies.
Thus, with respect to the timing of a bivalent booster, ACIP member Grace Lee, MD, MPH stated her position: “I feel strongly about reducing and mitigating any potential risk if at all possible, so my personal preference is to anchor on 3 months as the minimum interval from either prior infection or vaccine dose as my recommendation.”
Individuals at an elevated high risk of complications to COVID-19, such as those over age 50, those with chronic health conditions or immune compromise should speak with their physician about the optimal timing for vaccination and other options, such as the monoclonal antibody Evusheld.
Should we be worried that there is no human data on the BA.4/5 booster?
There has been much discussion on social media about the data for the bivalent booster being gathered on 8 mice. While this may sound concerning, using animal models—whether mice or non-human primates—is part of the drug and vaccine development pathway. In addition to the mouse model data used in the bivalent vaccine development, both vaccine manufacturers have tested BA.1-containing boosters in humans, anticipating that omicron would continue to dominate.
When the data showed that the variants had shifted again over the summer to BA.4/5, the FDA asked the manufacturers to shift to a BA.4/5-containing bivalent booster instead of BA.1, which is no longer the dominant variant. To get ready for the fall and winter season, the manufacturers conducted pre-clinical testing in mice with BA.4/5 and also began enrolling human participants in clinical trials.
Although some ACIP members were concerned that there is no safety data in humans, other workgroup members expressed the opinion that every year the influenza vaccine is developed in a similar fashion. The flu vaccine is updated each year using immunobridging—a process by which the new formulation is tested to see if it induces a strong enough antibody response against the prevailing influenza strains.
How well do animal models correlate with what happens in humans?
The mouse cell also expresses the ACE2 receptor, which is one way that the SARS-CoV-2 virus enters the human cell. Researchers at Pfizer and Moderna stated during the ACIP meeting that studies in non-human primates and mice do correlate well with the immune response in humans. Perhaps a larger concern is the lack of human safety data in the younger population, views expressed by several members of the ACIP, including Drs. Sarah Long and Pablo Sanchez.
Dr. Sanchez (video time stamp 2’24”) was uncomfortable with extrapolating data from those age 55 and older who received Pfizer’s prototype BA.1 booster to the younger population known to be at increased risk for myopericarditis. “My concern is the data that we have on BA.1 is really for 18 and over for Moderna, and for Pfizer we have nothing less than 55 years of age, and yet we are making a recommendation for those age 12 and over, and that is the younger age group where myocarditis is a real side effect. We are extrapolating the data from the bivalent BA.1 to hopefully see similar data for the BA.4/5. I am just concerned about that extrapolation, and ultimately, I really don’t want to establish a precedent on a vaccine that we don’t have clinical data on.” Dr. Sanchez voted against the booster recommendation.
Do I lose any protection against the original strain?
To be approved, the bivalent vaccine had to prove better immunogenicity against omicron, and no loss in activity against the ancestral strain. Both the Pfizer and Moderna bivalent boosters met these criteria. The lipid nanoparticle contains the mRNA code for both spike proteins. When the mRNA enters the cell, ribosomes transcribe both strains—the original strain and the omicron strain—providing good cross-variant protection.
Because both strains are encoded in the mRNA, the cells build the spike protein in an open conformation which provides the immune system access to many different epitopes. This open conformation allows for the body to create antibodies not only to the ancestral strain and omicron, but also beta and delta as seen in the slide below presented at the ACIP meeting. The BA.4/5 bivalent (far right columns) compared to the prototype BA.1 (middle columns) provided a balanced response to all the omicron sublineages (BA.1, BA.2, BA2.12.1 and BA.4/5).
Who will benefit most from a bivalent booster?
In the end, the ACIP workgroup preferred a blanket booster recommendation due to concerns about complicated, risk-stratified messaging. However, this approach diverges from the strategy adopted by peer nations and ignores expert opinion. For example, instead of a universal booster recommendation, the United Kingdom is tailoring its “autumn booster” campaign according to risk by recommending it to those age 50 years and older and those in clinical risk groups.
Expert opinion also suggests a more risk-stratified approach would be appropriate at this stage. Vaccine developer Dr. Paul Offit, professor of pediatrics at Children’s Hospital of Philadelphia and member of FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC), was one of two members to vote against a booster dose for the general population in September 2021. In a recent interview regarding the bivalent booster for fall 2022, he explained why it is important to think about who benefits most from a booster and why caution is important when data is lacking in young people.
“The people who really benefited from a third dose,” he explained, “are the elderly, those with chronic lung disease, or chronic heart disease, or chronic kidney or neurological disease, because even a mild illness could land them in the hospital; and the third group [to benefit] are the immunocompromised.” There is no data yet demonstrating the additional benefit of boosting a young, healthy population. Thus, regarding the new bivalent booster, Dr. Offit elaborated that “It’s hard for me to embrace immunizing everybody — healthy young people — when we haven’t really showed that they clearly benefited from booster doses.”
It is important to remember that a respiratory virus with such a short incubation period like omicron can cause mild to moderate illness while antibodies ramp up, but the protection against severe disease is provided by memory T cells which target infected cells. These memory T cells are on constant patrol and recognize when cells are infected by a virus and ask them to self-destruct. The cellular debris is then cleaned up by the lymphatic system, causing the swollen glands we associate with illness. Because these cytotoxic T cells continue to recognize 80% of the epitopes on the variants of concern, we continue to benefit from long-lasting protection against severe disease.
The clinical trials, which are ongoing in humans, will gather additional safety and clinical data this fall. In the meantime, clinicians appreciate having an updated bivalent booster available for those most at risk because it may offer transient protection against symptomatic disease which could cause a more frail, elderly person to be hospitalized this winter.
SARS-CoV-2 is highly transmissible and has a very short incubation period.
Symptomatic illness can occur while antibodies ramp up in response to infection.
SARS-CoV-2 can cause the elderly or medically vulnerable to become very ill with COVID-19.
Boosters can help protect the most vulnerable by increasing antibody levels.
Antibodies wane quickly, thus protection against mild illness is short-lived.
Memory T and B cells provide long-lasting protection against severe disease.
Cytotoxic T cells ask infected cells to self-destruct, helping to prevent critical illness.
Boosters may protect the most vulnerable, but evidence is currently lacking on additional benefit for young, healthy people.