COVID-19 Vaccines: Declining Antibody Levels, Breakthrough Infections Could Spur Booster Recommendations

COVID-19 Vaccines: Declining Antibody Levels, Breakthrough Infections Could Spur Booster Recommendations

Source : 'The Pink Sheet'

Significant declines in antibody levels or concerning numbers of breakthrough infections in vaccinated individuals should spur consideration for booster doses of currently authorized COVID-19 vaccines, members of the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices said.

At a 23 June meeting, ACIP was asked what data would be needed to move forward with booster recommendations, and whether the risk of disease is enough to warrant a recommendation for boosters before additional data may be available.

The meeting marked the first of what is likely to be several ACIP discussions around the issue of COVID-19 vaccine booster doses. With three vaccines authorized for emergency use in the US, 63% of the population ages 12 years and older has received at least one dose and 53% are considered fully vaccinated, according to CDC data.

ACIP ultimately will decide whether booster doses are needed for individuals previously vaccinated with a primary series. The committee also will have to consider several related questions, including:



Whether boosters are needed for all persons or only in specific populations;


The optimal timing of boosters after the primary series; and


Whether boosters can be “mixed and matched” in a heterologous fashion with other COVID-19 vaccines, or whether they need to be matched to the vaccine used in the primary series.

Policy-making on booster doses will be coordinated with the FDA for possible amendments to the emergency use authorizations, while ACIP will make recommendations on use. Both will require data on safety, immunogenicity and public health need, said the CDC’s Sara Oliver, who serves as co-lead of the ACIP COVID-19 vaccines working group.

However, the issue of immunogenicity and antibody response is complicated by the lack of an established correlate of protection, although work in that area is ongoing, Oliver said.

Studies also are ongoing on postauthorization vaccine effectiveness as well as use of a booster vaccine that is different from the primary series.

Doran Fink, deputy director-clinical at the FDA’s Division of Vaccines and Related Products Applications, described the type of safety database the agency would want before authorizing a booster dose.


When the agency has previously considered addition of a booster dose for a vaccine approved for use as a primary series, it has looked at the safety profile of primary series in clinical trials and postmarketing, well as the safety profile of booster dose as studied in clinical trials, Fink said. The clinical trial safety database supporting approval of a booster dose typically is much smaller than the safety database expected for initial approval of the primary series because of the ability to  leverage postmarketing experience with the primary series.

“Unless there is a reason to suspect or be concerned about a specific safety concern with an additional dose, then what we would typically look for is to characterize reactogenicity to the booster dose, and evaluation for much less common adverse reactions would really be outside the realm of what’s feasible,” Fink said.

In the case of COVID-19 vaccine booster doses, the reactogenicity profile probably could be characterized with “several hundred or slightly more” booster dose recipients in a clinical trial, Fink said. “If there are specific safety concerns that could feasibly be evaluated with a somewhat larger safety database, we would take that under consideration as well.”

The ACIP COVID-19 vaccines working group concluded that data to support recommendations for booster doses currently are not available, Oliver said. The group also suggested that a recommendation for booster doses would only occur after:



Evidence of declining protection against illness, such as declines in vaccine effectiveness and not just antibody response; or


An escape variant of concern substantially impacts vaccine protection.


In addition, global vaccine availability should be considered in any discussions about recommending booster doses, the group said.

In asking whether risk of disease is enough to warrant a recommendation for boosters before additional data are available, ACIP executive secretary Amanda Cohn, senior advisor for vaccines at the National Center for Immunization and Respiratory Diseases, said the CDC is trying to gauge committee members’ “tolerance for waiting to see disease cases rise and the epidemiology shift, which would then automatically mean that there may be additional cases that that were preventable with the boosters.”

“What is … this timing and comfort level that ACIP members may have with how much data there needs to be to move forward with a booster, knowing that the more data that we wait for that potentially more preventable cases could occur?” Cohn asked.

Sharon Frey, clinical director of the Center for Vaccine Development at Saint Louis University, said she agreed with the working group’s view that there are no data for booster recommendations at this time. However, she would consider an exception for severely immunocompromised individuals who are not able to mount a strong response to a primary vaccination series.

“I think that I would lean towards giving at least one more … a  third vaccination using the mRNA vaccines or a second Janssen,” in such individuals, Frey said.

Current data suggest a very durable response with the mRNA vaccines, unlike with influenza vaccines where antibody levels decline rapidly within six months following vaccination, Frey said.

However, “we have to watch very carefully … to see if there is starting to be a significant decline in what we do have to measure right now, which is the antibody level, and we can make a correlation with protection somewhat with that antibody level when we look at protection against some of the variants,” Frey said.

Booster dose recommendations could be triggered when antibodies decline to a certain level, Frey said, acknowledging that “we don’t know what it is” yet.

“I think the only thing we can do at this moment is if we start to see an uptick in reinfections in people, or new infections in people who have been vaccinated, that’s our clue that we need to move quickly,” Frey said.

However, Frey noted ACIP might only be able to make a recommendation for a booster dose of the originally authorized vaccines, rather than formulations targeting a specific SARS-CoV-2 variant, because the latter might still be in development. “We can’t make a recommendation for a booster against something that needs to be made de novo or is a novel variant or a novel strain or novel vaccine if we don’t have it available,” she said.

The manufacturers of vaccines currently available under EUA – Pfizer Inc./BioNTech SE, Moderna, Inc. and Janssen Biotech Inc. – already are in talks with the US government about booster dose purchases. ("US Govt Plans To Control COVID Vaccine Distribution At Least Through 2022 Already Authorized Products Have Booster Advantage" "Pink Sheet" )

Sarah Long, a professor of pediatrics at Drexel University, said breakthrough infections in vaccinated people at increased risk of COVID-19 due to age or occupation, or elderly individuals in long-term care facilities, could trigger booster recommendations.

It would be a mistake to give booster doses without some information as to whether the follow-on doses actually boost the immune system, Long said. In addition, she would want at least “a little bit of safety data, especially since we have seen the second dose of the mRNA vaccine may be causing a little trouble, so that we would have some idea that there would be benefit of the booster before we might incur unknown risk.”

The Pfizer/BioNTech and Moderna mRNA vaccines have been associated with an imbalance in reports of myocarditis and pericarditis, particularly following the second dose, among young men and older male adolescents. ("mRNA COVID-19 Vaccines To Add Warning Language On Myocarditis Risk" "Pink Sheet" )

She took a different view than Frey on the issue of immunocompromised individuals or organ transplant recipients who have not responded to vaccination with a primary series. “I would myself not want to give a third dose just because it seems like a good thing to do right now without data. I would try to get some data that it would be of benefit,” Long said.

Grace Lee, pediatrics professor at Stanford University, said it would be hard to make a booster recommendation absent solid data on correlates of protection. However, she would be more willing to recommend boosters if breakthrough cases of severe disease start to occur.

ACIP chairman Jose Romero, Arkansas’ secretary of health, took a more proactive view on the use of boosters, comparing it to annual recommendations for use of influenza vaccines aimed at heading off outbreaks.

Information about the disease burden of new variants in the US will inform whether we should begin considering use of boosters ahead of outbreaks, Romero said. “We should begin to consider using these boosters before we have evidence of disease from these variants if this continues to be an ongoing virus with periodic recirculation.”

Helen Keipp Talbot, associate professor of medicine at Vanderbilt University, said she worried that the talk of boosters would become a distraction in the US.

“Prior to going around and giving everyone boosters, we really need to improve the overall vaccination rate because that will improve the protection for those that … continue to be at risk,” Talbot said.

She also urged the committee to approach its discussions about booster recommendations with a global perspective.

“We really do need to talk about the rest of the world. It’s not something that we typically do. ACIP is the US committee on immunization practices. It is not one for the world,” Talbot said.

“But we are now a very small world thanks to air travel and other luxuries, and variants are surging, causing large numbers of deaths across the world. So it is critical to prevent further evolution of variants by providing vaccines to these countries. And it’s not only critical for a selfish reason, it is incredibly important for humane reasons.”

By Sue Sutter

  • July 05, 2021
    Booster dose recommendations could be triggered when antibodies decline to a certain level