In a recent article published in The New England Journal of Medicine, researchers reported the findings of the phase III trial evaluating the Omicron BA.1–adapted mono and bivalent BNT162b2 coronavirus disease 2019 (COVID-19) vaccine in 55-year-old adults. These individuals had already received three 30μg doses of the BNT162b2 vaccine.
First, the trial evaluated the superiority of the BA.1-adapted vaccines to BNT162b2 based on 50% neutralizing titers (NT50) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and non-inferiority based on seroresponse to Omicron BA.1. Secondarily, trial determined the non-inferiority of bivalent BA.1 to BNT162b2 based on the 50% neutralizing titers against the ancestral strain of SARS-CoV-2.
The monovalent BA.1 vaccine has Omicron BA.1 spike (S) glycoprotein sequence. On the other hand, its bivalent form contains equal amounts of S messenger ribonucleic acid (mRNA) of ancestral and BA.1 strain formulated into lipid nanoparticles.
The primary series of BNT162b2 mRNA-technology-based COVID-19 vaccine showed an efficacy of 95 to 100% in its phase II and III trials early during the pandemic. However, its protective efficacy drastically dropped against antigenically distinct Omicron subvariant, B.1.1.529. Also, BNT162b2-induced immunity waned quicker than previous variants of concern (VOCs).
In such a situation, regulatory agencies recommended engineering sequence-adapted BNT162b2 vaccine matching Omicron BA.1. While trials of sequence-adapted BNT162b2 vaccine were underway, Omicron mutated further, giving rise to new BA.4/BA.5 and BA.2.75 subvariants.
About the study
In the present study, researchers evaluated boosting strategies with Omicron BA.1–adapted BNT162b2 vaccines and the effect of varying their dosages based on 50% neutralizing titers against SARS-CoV-2.
In September 2022, Omicron BA.5 caused 88% of SARS-CoV-2 infections in the United States of America and became the dominant Omicron subvariant globally. So the researchers additionally assessed whether these BA.1 sequence-adapted BNT162b2 vaccines neutralized BA.2.75 and BA.4/BA.5 subvariants of Omicron.
To this end, they randomized 1846 participants to receive one of the following vaccine doses:
i)30/60 μg of BNT162b2,
ii)30/60 μg of monovalent BA.1,
iii)15+15 μg of BNT162b2 and monovalent BA.1, and
iv) 30+30 μg of BNT162b2 and monovalent BA.1 of bivalent BA.1.
The researchers used a recombinant SARS-CoV-2 neutralization assay to estimate 50% neutralizing titers against SARS-CoV-2 before and one month following vaccination. They reported results as geometric mean titers (GMTs) and geometric mean ratios (GMRs). Furthermore, they recorded differences in percentages of participants with a seroresponse. The team also collected data on BA.1-adapted BNT162b2 vaccine on adverse and serious adverse events occurring within one and six months of vaccination.
After a month of vaccination, Omicron BA.1-adapted bivalent and monovalent vaccines exhibited superior neutralizing activity against BA.1 than 30 μg of BNT162b2 vaccine, with NT50 GMRs of 1.56, 1.97, and 3.15, respectively. However, two doses of bivalent and 60 μg of monovalent BA.1 were non-inferior to 30 μg of the BNT162b2 vaccine. They elicited adequate seroresponse against Omicron BA.1, albeit inter-group differences ranged between 10.9 and 29.1 percentage points.
Likewise, bivalent BA.1 was non-inferior to 30 μg of BNT162b2 vaccine based on neutralizing activity against the ancestral SARS-CoV-2 strain, with NT50 GMRs of 0.99 and 1.30, respectively. Notably, neutralizing titers against BA.2.75 and BA.4/BA.5 were numerically higher with a 30μg dosage of bivalent BA.1 than a similar dose of 30μg BNT162b2.
Thankfully, 30 μg and 60 μg doses of monovalent and bivalent BA.1 were safe as the 30 μg dosage of BNT162b2. The researchers noted the most adverse events, equal to 8.5%, in the group that received 30 μg of monovalent BA.1 vaccine, followed by 60μg of bivalent-BA.1 group having adverse events in 10.4% of its members.
Omicron BA.1–adapted monovalent and bivalent BNT162b2 vaccines substantially increased the immunogenicity against Omicron BA.1 in adults ≥55 years. They also showed comparable and robust neutralization titers against the ancestral SARS-CoV-2 strain. Indeed, these sequence-adapted vaccines worked better against BA.1 than the fourth dose of the original 30 μg BNT162b2 vaccine. Furthermore, these vaccines elicited numerically higher neutralizing titers against Omicron's other new subvariants, BA.2.75 and BA.4/BA.5. The use of adaptive vaccine strategies could maximize protection against future immunity-evading SARS-CoV-2 mutants.
Additionally, trial data did not indicate any safety concerns for Omicron BA.1–adapted BNT162b2 vaccines. To conclude, the present study highlighted the significance of surveillance for new SARS-CoV-2 VOCs. It remains a crucial exercise to determine the need for a variant-adapted vaccine.
- Patricia Winokur, Juleen Gayed, David Fitz-Patrick, Stephen J. Thomas, Oyeniyi Diya, Stephen Lockhart, Xia Xu, Ying Zhang, Vishva Bangad, Howard I. Schwartz, Douglas Denham, Jose F. Cardona et al. (2023). Bivalent Omicron BA.1–Adapted BNT162b2 Booster in Adults Older than 55 Years. The New England Journal of Medicine. doi: 10.1056/NEJMoa2213082 https://www.nejm.org/doi/full/10.1056/NEJMoa2213082?query=recirc_top_ribbon_article_11