In a recent study posted to the medRxiv* preprint server, a team of researchers evaluated the immunogenicity and safety of the coronavirus disease 2019 (COVID-19) bivalent messenger ribonucleic acid (mRNA) vaccine mRNA-1273.222 and tested the neutralizing ability of the two bivalent vaccines — mRNA-1273.222 and mRNA-1273.214 — against the newly emergent Omicron subvariants.
Study: Safety and Immunogenicity of Omicron BA.4/BA.5 Bivalent Vaccine Against Covid-19. Image Credit: Wachiwit/Shutterstock
*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
Background
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron subvariants with novel mutations in their spike protein region have shown the ability to evade the neutralizing antibodies elicited by the earlier COVID-19 vaccines, including the monovalent mRNA-1273 vaccine.
Although booster doses have increased the protection against SARS-CoV-2 infections during the Omicron wave, increasing immune evasion by the Omicron subvariants has highlighted the need for variant-specific booster vaccines.
Clinical trials have shown that the mRNA-1273.214 bivalent vaccine containing Omicron BA.1 does not cause adverse reactions and elicits a stronger neutralizing antibody response against Omicron BA.1. The vaccine was also seen to be cross-reactive against Omicron subvariants BA.2.75 and BA.4/BA.5.
However, the emergence of subvariants such as BQ.1.1 and XBB.1 emphasizes the need for more effective bivalent vaccines. The mRNA-1273.222 bivalent vaccine containing Omicron BA.4/BA.5 improved protection against infection, but its safety, immunogenicity, and efficacy against newly emergent variants such as BQ.1.1 and XBB.1 need to be investigated.
About the study
In the present study, the team conducted open-label, phase two and three trials to compare the immunogenicity, reactogenicity, and safety of the bivalent mRNA-1273.222 booster vaccine with that of the widely used monovalent mRNA-1273 booster dose in adults who had received primary vaccinations and one mRNA-1273 booster shot.
The mRNA-1273 vaccine comprises a single mRNA that codes for the spike glycoprotein of the SARS-CoV-2 Wuhan-Hu-1 strain, while the bivalent vaccine contains an additional mRNA encoding the Omicron BA.4/BA.5 spike glycoprotein.
The study excluded adults who had infections in the three months leading up to the screening for these trials. Participants were intramuscularly administered a 50-µg second booster dose of mRNA-1273 between February and March 2022 or a 50-µg booster dose of mRNA-1273.222 between August 10th and 23rd, 2022.
The safety and reactogenicity evaluation assessed the solicited systemic and local reactions within a week of vaccination and unsolicited adverse reactions within four weeks of vaccine administration. The study also evaluated serious adverse reactions such as those requiring medical attention, leading to withdrawal from the study, or being of special interest during the study period.
The immunogenicity assessment objectives included calculating the seroresponse rate (SRR) difference and geometric mean titer (GMT) ratio (GMR) to determine non-inferior neutralizing antibody responses against the D614G mutation carrying ancestral SARS-CoV-2 strain and the Omicron BA.4/BA.5 subvariant, and the superior neutralizing antibody responses against Omicron BA.4/BA.5 based on GMR values four weeks after the administration of the monovalent or bivalent booster vaccine.
Additionally, neutralization assays using pseudotyped lentiviruses containing full-length spike proteins of the ancestral (D614G) strain or the Omicron subvariants BA.4/BA.5, XBB.1, and BQ.1.1 were used to determine the GMT at the half-maximal inhibitory concentration (IC50). Selected participants vaccinated with the bivalent mRNA-1273.214 vaccine were also tested for cross-neutralization against the BQ.1.1 and XBB.1 subvariants.
Results
The results reported that the neutralizing antibody titers against the ancestral D614G strain and Omicron BA.4/BA.5 subvariants were significantly higher after the administration of the bivalent mRNA-1273.222 booster dose as compared to the monovalent mRNA-1273 booster vaccine.
The GMT values for neutralizing antibody responses against Omicron BA.4/BA.5 after the administration of the mRNA-1273.222 and mRNA-1273 booster dose were 2324.6 and 488.5, respectively, while those against the ancestral D614G strain were 7322.6 and 5651.4, respectively.
The adverse reactions observed in participants who received the mRNA-1273.222 booster vaccine were similar or lower in frequency than in those who received the monovalent mRNA-1273 vaccine. The results from the present study and previous studies assessing the reactogenicity and safety of the bivalent mRNA-1273.214 vaccine cumulatively suggested that the bivalent booster vaccines have similar safety profiles to the monovalent mRNA-1273 vaccine.
Randomly selected participants from the bivalent mRNA-1273.222 vaccination group also exhibited cross-neutralizing ability against the newly emergent BQ.1.1 and XBB.1 Omicron subvariants. The bivalent vaccines mRNA-1273.222 and mRNA-1273.214 elicited 20-fold and four-fold cross-neutralizing antibody titers, respectively, against the BQ.1.1 subvariant and a 12-fold and four-fold response against the XBB.1 subvariant.
Compared to the neutralizing antibody responses against the Omicron BA.4/BA.5 subvariants, both bivalent vaccines elicited 4–5-fold and 12–15-fold lower neutralizing antibody responses against the BQ.1.1 and XBB.1 subvariants, respectively.
Conclusions
Overall, the results indicated that the bivalent mRNA-1273.222 vaccine containing mRNAs encoding the spike glycoproteins of the ancestral Wuhan-Hu-1 strain and the Omicron BA.4/BA.5 subvariants raised no safety concerns and elicited significantly higher neutralizing antibody responses against BA.4/BA.5 than the original monovalent mRNA-1273 vaccine. The mRNA-1273.222 vaccine also exhibited substantial cross-neutralization ability against the newly emergent BQ.1.1 and XBB.1 subvariants.
*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
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