Despite Pfizer and BioNTech suggesting the need for a COVID-19 booster within 12 months from initial Comirnaty (BNT162b2) vaccination, experts said it was unlikely a third dose would be needed that soon. The high protection rate reported at six months and robust immunogenicity levels reported despite variants of concern (VOCs) are among the reasons for their optimism.
Both companies are assessing two booster strategies: repeat vaccination with Comirnaty or with BNT162b2SA, a version of Comirnaty specific for the VOC B.1.351, first reported in South Africa. Comirnaty as a third dose should offer enough of an immunogenicity boost to protect against the original variant, experts noted. In fact, it could even supersede Comirnaty’s two-dose immunogenicity data, which would make room for any negative impact of VOCs such as B.1.351, they said.
However, experts argued that using BNT162b2SA as a booster in the wider population may be a better long-term protection investment. It would allow vaccine receivers to have a broader immunogenicity profile and perhaps heightened protection against a variety of variants, they added.
Experts also noted the exploratory nature of the 144-participant booster study. Comirnaty’s Phase I/II/III trial was amended to investigate a third dose when given approximately 6–12 months after the authorised two-dose regimen. On 28 April, this news service reported COVID-19 vaccine manufacturers such as Pfizer/BioNTech are likely to launch renegotiated vaccine prices that would include booster shots as soon as the fall.
In media interviews, Pfizer CEO Albert Bourla and BioNTech CEO Ugur Sahin have touted the possible need for a third shot within 12 months after initial vaccination. In response to a request for comment from this news service, a Pfizer spokesperson reiterated that it monitors trial participants for up to two years to study immunity with Comirnaty, with the booster investigation looking into safety and the two-dose regimen’s potential need for a booster. Pfizer’s market cap is $215.37bn, while BioNTech’s is $46.07bn.
Six-month data, preclinical research supportive of durable vaccine efficacy
Comirnaty’s six-month data is a testament to the vaccine’s durability, which is likely to be maintained up to at least 12 months following the initial two-dose regimen, said Phase III Comirnaty investigator Dr Stephen Thomas, chief, Infectious Disease Division, Upstate Medical University, Syracuse, New York. The six-month data from the Phase III portion of the Phase I/II/III trial showed a 3.7-point drop to 91.3% efficacy against symptomatic disease based on 850 confirmed infections in the placebo arm and 77 in the Comirnaty arm, according to a 1 April media release.
In general, a vaccine that triggers a durable response for the first six months typically has longer-term durability, Thomas added. And so, despite mRNA vaccines being a new technology, it is unlikely that Comirnaty’s efficacy will drop below 50% protection in the next six months, he noted. Regulatory agencies’ passing grade for Emergency Use Authorizations (EUAs) is 50%.
Even in the face of VOCs, a booster is unlikely needed within 12 months of initial vaccination, noted Dr Daniel Griffin, chief, Division of Infectious Disease, ProHealth Healthcare, New York. With the vaccine having such high protection against symptomatic disease, reduced efficacy against VOCs would still be considered protective enough, Thomas added.
There is also data showing that the two-dose regimen is efficacious enough against VOCs, Griffin added. The Phase III’s 800-volunteer South Africa cohort reported nine infections, all in the placebo group, and six were of the B.1.351 lineage.
In addition, Comirnaty’s immunogenicity remains robust when tested against VOCs, added Andrew Ward, PhD, professor, Department of Integrative Structural and Computational Biology, Scripps Research, La Jolla, California. While preclinical data (Liu Y, et al. N Engl J Med 2021; 384:1466-1468) shows B.1.351 diminishes immunogenicity, it does not drop significantly enough to question the vaccine’s protection potential, he said.
The results underscore the fact that the original virus and VOCs may have limited differences, Ward explained. The main cause for the mutations is to make the virus more transmissible, not necessarily to cause more severe disease, added Dr Alan Barrett, director, Sealy Institute for Vaccine Sciences, University of Texas Medical Branch, Galveston. SARS-CoV-2 goes through convergent evolution, which means the same sites have mutated even if they mutated independently of each other, he noted.
The six-month data announcement did not include updated immunogenicity results, but Geert Leroux-Roels, professor emeritus, Faculty of Medicine & Health Science, Ghent University, Belgium, noted even decreased immunogenicity levels could be high enough for protection to be maintained. In hepatitis B virus (HBV) vaccine development, immunogenicity levels drop but eventually plateau to provide durable protection, he added. HBV vaccines may be a better guide than influenza vaccines on how COVID-19 vaccines are likely to perform, as people do not have pre-existing immunogenicity due to natural infections, he said. While HBV vaccines can provide sustained antibody levels for at least 10 years, based on a literature search, they do not have to contend with VOCs.
Nevertheless, Thomas noted that the booster trial design is still exploratory in nature. For instance, the booster study does not differentiate timelines as to when the volunteer receives the booster, and volunteers are enrolled irrespective of their baseline antibody titer. But Leroux-Roels explained this is reflective of the real world, where people who may have the same time duration since being fully vaccinated but might have different immunogenicity levels.
Furthermore, the arms investigating BNT162b2SA only recruit participants ages 18–55 years, while disease burden is more significant in older people, Thomas added. Volunteers older than 55 are recruited in arms studying Comirnaty as a booster.
In addition, there could be vaccine design differences between doses, which underscores the exploratory nature of the trial, Barrett noted. The booster trial focuses recruitment on Phase I participants, who may have received a different version of the authorised 30µg Comirnaty dose, he explained.
Comirnaty adequate as third dose but new version would allow immunogenic diversity
The Phase I/II/III trial was amended to investigate noninferiority between two-dose Comirnaty and two booster strategies—a third Comirnaty dose or a BNT162b2SA shot—based on neutralising antibody titers after one week and one month. It is appropriate to investigate if a third dose of the original vaccine can return immunogenicity levels back to the same level as after the second dose, Ward said. Since correlates of protection are still unknown, maintaining immunogenicity through time is a rational measure, Thomas added.
In fact, a third Comirnaty dose has the potential to supersede the immunogenicity data gathered seven days after the second dose, Ward noted. The host would already have an established immunogenic memory, which the third jab would bolster, Griffin explained. In addition, if immunogenicity is increased by the third shot, there could be a higher antibody titer plateau moving forward, he added. And, because the third dose is expected to increase immunogenicity levels, it will potentially counteract the negative immunogenicity impact of VOCs, Ward said.
While Comirnaty as a booster may be efficacious enough, it may be best to use BNT162b2SA as the third dose once a booster is needed, Leroux-Roels said. BNT162b2SA is based on the spike of B.1.351. Introducing the variant of concern spike to the host would help drive evolution of the antibodies produced, Ward agreed. While the key mutations are in the receptor binding domain (RBD), there are also mutations in the rest of the spike protein, and so BNT162b2SA would lead to a broader immune response, Griffin added.
Some BNT162b2SA-vaccinated participants will also receive a second dose of the modified vaccine to investigate if it would be needed to reach noninferior immunogenicity. But a fourth dose is redundant, as the third dose of the next-generation vaccine will likely be enough, Ward said.
Administering the spike of the most advanced variant may mean that the person would also be protected against other variants that surfaced earlier in SARS-CoV-2’s evolution cycle, Ward and Barret said. The two-dose BNT162b2SA will be investigated in vaccine-naïve volunteers. These participants would also be protected against the original and preceding variants, Ward noted.
Reynald Castaneda is an Associate Editor for Clinical Trials Arena parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.