The FDA and CDC both approved the updated bivalent COVID-19 vaccines last week. The promise of the mRNA vaccine technology platform was always that we could update them quickly. We may finally have achieved an advantage over SARS-COV-2 as the updated vaccine recipe matches the current dominant circulating BA.5 strain (and slow growing BA.4.6 strain) without another more transmissible variant of concern yet on the horizon.
However, we are concerned that the CDC may again be missing the boat with its recommendations on timing for when most American adults should receive this booster. Following its Advisory Committee on Immunization Practices (ACIP) meeting on September 1, the CDC stated that adults who completed their primary vaccine series are eligible for the updated booster if it’s been at least two months since their previous vaccine. They advised those who recently had an infection to wait 3 months before getting boosted.
However, such a short interval is not optimal if we are aiming for robust fall/winter-long protection and could also be counter-productive. The CDC should recommend a 6-month interval between a previous booster or infection and the new updated vaccine for healthy adults for two primary reasons: updated immunologic studies and recognition that millions of Americans had post-vaccination infection with Omicron variants this year and thereby have strong current protection against re-infection with BA.5.
We previously called on the CDC to extend the recommended interval between primary doses of both mRNA vaccines to 8 weeks primarily on the basis of immunologic studies demonstrating a higher antibody response, amplified T cells, and enriched memory B cells with a longer time period between doses.
Recent research studies during the Omicron variant era continue to demonstrate the benefit of an extended interval between doses in terms of increasing both neutralizing antibodies and memory B cells. A booster provides antibody protection for at least 6 months according to a recent study. Another study demonstrated that antibody levels stabilized 6-9 months post-vaccination for study participants both with and without previous infection.
Memory B cells were even more robust after vaccination–demonstrating maintained reactivity against all variants including Omicron for at least 9-10 months after the primary 2-dose series; with an additional positive response to a 3rd dose booster. An additional study showed that memory B cells continue to mature for approximately 6 months, after either vaccination or infection. B cell immunity—as well as T cell immunity to COVID vaccines–provided protection against severe illness and did not lead to high levels of hospitalization as BA.5 became dominant this summer.
One of the aims of the Omicron-specific vaccines is to increase antibodies and prevent even mild infections. The antibody level plateau at the 6 month mark would thus signal an ideal time to boost with a BA.4/5-focused vaccine since a low pre-boost antibody level actually correlated with a greater fold increase post-boosting. To put it another way—high levels of circulating antibodies from short interval boosting may limit the added protection of another booster. Another recent study by the NIH showed the same concern after a recent infection, but even more drastically: giving a booster 2 months after a recent infection actually abrogates effective B cell responses.
Millions infected by Omicron
A recent study in JAMA showed that 56% of people who were infected with the Omicron variant were unaware of the infection. And the actual number of daily infections this past summer vastly exceeds the official tabulation given the scale of unreported home rapid antigen testing. In addition, millions of Americans have received their third and fourth vaccine doses in the last few months.
The benefit of this degree of population immunity can be extrapolated from a recent study out of Portugal which shows, contrary to previous concerns for BA.5 re-infection, that a previous BA.1/2 infection provides upwards of 75.3% protection against re-infection with BA.5. This was consistent with a Qatar study showing 79.7% protection against re-infection.
All of this data means that there is a high amount of active population-level immunity to COVID-19 in the U.S. that is protective against severe disease. Our booster strategy should recognize this existing immunity and seek to build upon it in a manner that prolongs the protection of this shot throughout the winter. Short-interval repeat boosting or boosting too soon after a post-vaccination infection will limit the neutralizing antibody response and stunt the expansion of memory B cells.
After considerable expert input, the CDC formally updated its guidelines in February 2022 to recommend an extended dosing interval for the primary vaccine series, but significantly lagged behind their counterparts in Canada, Europe, and India to adopt this 8-week interval. Moreover, the extension of the vaccine interval was not advertised very widely. The CDC now has an opportunity to take these immunologic principles for the updated Omicron booster and make them work better.
The Canadian National Advisory Committee on Immunization, already ahead of the curve, formally recommended this past week that the updated bivalent vaccine be offered at an interval of 6 months after previous vaccination or infection.
In a recent survey by the CDC, 72% of those polled will “definitely” or “probably” get an updated booster. The interest in an updated booster is significant because only half of eligible Americans got the first recommended booster dose and only 34% of those 50+ got a second booster. That is why it is absolutely critical that we get the recommendations on timing right for this updated Omicron booster, the first update in the mRNA vaccines since their roll-out in January 2021.
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