Vaccination remains a critical mitigation tool in the ongoing coronavirus disease 2019 (Covid-19) pandemic. The 30 μg dose of the BNT162b2 messenger RNA (mRNA) vaccine (Pfizer-BioNTech vaccine) encoding the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is authorized as a primary series of two dosage for people 12 years of age or older; a phase 2-3 trial conducted early in the pandemic showed 95-100% efficacy with this primary series.
BNT162b2 has provided broad protection in previously dominant SARS-CoV-2 variants of concern, which had relatively low potential to escape vaccine-induced immunity. In contrast, efficacy against mild disease caused by the more antigenically distinct B.1.1.529 (omicron) variant has been markedly reduced. Although immune escape could be mitigated with a third or fourth vaccine dose, efficacy against the omicron BA.1 subvariant, including efficacy in preventing severe disease, declined more rapidly than that seen for previous variants of concern.
Because it was desirable to design a sequence-tailored vaccine that matched the circulating variant of interest, an approach supported by regulatory agencies, this trial sought to evaluate booster strategies with different dose levels and omicron BA-tailored BNT162b2 vaccines. 1. During the conduct of the trial and due to the high transmissibility of omicron BA.1, other omicron BA.1 mutations led to the emergence and subsequent dominance of the omicron BA.4 and BA.5 subvariants and the recently identified omicron BA subvariant that are comparatively even more antigenically distinct from previous SARS-CoV-2 variants of concern than the BA.1 subvariant. 16-18 Therefore, we also evaluated the ability of the adapted monovalent BNT162b2 and bivalent omicron BA.1 vaccines to neutralize BA.4 and BA.5, which encode the same spike sequence, 17 and BA.2.75.
Background
The emergence of immune escape variants of severe acute respiratory syndrome coronavirus 2 justifies the use of sequence-adapted vaccines to provide protection against coronavirus disease 2019.
Methods
In an ongoing phase 3 trial, adults aged 55 years and older who had previously received three 30 μg doses of the BNT162b2 vaccine were randomly assigned to receive 30 μg or 60 μg of BNT162b2, 30 μg or 60 μg of B.1.1 .529 monovalent (omicron) BNT162b2 adapted to BA.1 (BA.1 monovalent), or 30 μg (15 μg BNT162b2+15 μg BA.1 monovalent) or 60 μg (30 μg BNT162b2+30 μg BA. 1 monovalent) of BNT162b2 adapted to BA.1 (BA.1 bivalent ).
The primary objectives were to determine the superiority (with respect to 50% neutralization titer [NT 50] against BA.1) and non-inferiority (with respect to seroresponse) of vaccines adapted from BA.1 to BNT162b2 (30 μg). .
A secondary objective was to determine the non-inferiority of BA.1 bivalent to BNT162b2 (30 μg) with respect to neutralizing activity against the ancestral strain. Exploratory analyzes evaluated immune responses against omicron subvariants BA.4, BA.5, and BA.2.75.
Results
A total of 1846 participants were randomized. One month after vaccination, bivalent BA.1 (30 μg and 60 μg) and monovalent BA.1 (60 μg) showed higher neutralizing activity against BA.1 than BNT162b2 (30 μg), with geometric mean ratios NT 50 (GMR) of 1.56 (95% confidence interval [CI], 1.17 to 2.08), 1.97 (95% CI, 1.45 to 2.68), and 3. 15 (95% CI, 2.38 to 4.16), respectively.
Bivalent BA.1 (both doses) and monovalent BA.1 (60 μg) were also not inferior to BNT162b2 (30 μg) with respect to seroresponse against BA.1; differences between groups ranged from 10.9 to 29.1 percentage points.
Bivalent BA.1 (either dose) was noninferior to BNT162b2 (30 μg) with respect to neutralizing activity against the ancestral strain, with NT 50GMR of 0.99 (95% CI, 0.82 to 1.20 ) and 1.30 (95% CI, 1.07 to 1.58), respectively.
The neutralizing titers of BA.4–BA.5 and BA.2.75 were numerically higher with 30 μg of bivalent BA.1 than with 30 μg of BNT162b2.
The safety profile of either dose of monovalent or bivalent BA.1 was similar to that of BNT162b2 (30 μg).
Adverse events were more common in the 30 μg monovalent BA.1 (8.5%) and 60 μg bivalent BA.1 groups (10.4%) than in the other groups (3.6 to 6. 6%).
Conclusions The adapted monovalent or bivalent omicron BA.1 vaccine candidates had a safety profile similar to that of BNT162b2 (30 μg), induced substantial neutralizing responses against ancestral and omicron BA.1 strains, and, to a lesser extent, neutralized BA.4, BA strains. .5 and BA.2.75. |
Discussion
In the current analysis, the adapted monovalent BNT162b2 and bivalent omicron BA.1 vaccines were shown to induce higher neutralization titers than the original 30 μg dose of BNT162b2 when administered as a fourth dose . Among adults aged 55 years and older who had previously received three 30 μg doses of BNT162b2, the increase in immunogenicity against omicron BA.1 was substantially greater with omicron BA.1-adapted BNT162b2 vaccines than with the original 30 μg dose by BNT162b2.
Since the goal of adapted vaccines is to provide a greater breadth of immunity against SARS-CoV-2 variants and since the future evolutionary steps of SARS-CoV-2 are uncertain, bivalent vaccines that incorporate a descendant lineage are preferred. of omicrons and an ancestral virus.
In the current trial, the observed safety profiles of the omicron BA.1-adapted BNT162b2 vaccines did not indicate any concerns about administering a fourth dose and were consistent with the known safety profile of the original 30 μg dose of BNT162b2.
It is essential to maintain vaccination against Covid-19 to protect health, social and economic systems against possible new waves and new variants of SARS-CoV-2 of concern, while ensuring that surveillance mechanisms are in place to determine if a variant has been adapted and when vaccination is warranted. Booster doses with BNT162b2 vaccines adapted to the bivalent variant aim to provide broad protection against circulating and emerging variants. In the current trial, boosting with the adapted omicron BA.1 monovalent or bivalent candidate vaccines had a similar safety profile to that of the original 30 μg dose of BNT162b2, induced substantial neutralizing responses against ancestral strains and omicron BA.1, and neutralized strains BA.4, BA.5 and BA.2.75 to a lesser extent than strain BA.1.
(Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04955626. opens in new tab.)
