In a study recently posted to the bioRxiv* preprint server, researchers analyzed the antibody response induced by the new bivalent messenger ribonucleic acid (mRNA) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in individuals who have been fully vaccinated with monovalent vaccines and those who have had breakthrough infection with the SARS-CoV-2 Omicron BA.4/BA.5 variants.
Background
The evolution of the SARS-CoV-2 virus has caused the emergence of many more infectious variants than the ancestral strain. The SARS-CoV-2 Omicron variant and many of its sub-lineages have been shown to remarkably escape humoral immunity acquired from previous infection or vaccination.
Recently, the United States Food and Drug Administration (FDA) granted emergency use authorizations (EUAs) to new bivalent messenger ribonucleic acid (mRNA) vaccine formulations of the original Pfizer and Moderna vaccines. These bivalent mRNA vaccines target the spike protein of both the ancestral SARS-CoV-2 strain and the SARS-CoV-2 Omicron BA.4/BA.5 variant.
Data published on neutralizing antibody responses induced by bivalent mRNA vaccines are limited to animal and human studies using a bivalent vaccine targeting the spike protein of Omicron BA.1 and the wild type strain. Despite the extensive use of the new bivalent Omicron BA.4/BA.5 mRNA vaccines as booster shots, very little information is available on the antibody responses they induce in humans.
About the study
In the present study, the researchers collected sera from multiple cohorts, including 1) individuals who have received three or four monovalent mRNA vaccine doses, 2) individuals who have had breakthrough infection with the Omicron BA.4/BA.5 variant following monovalent mRNA vaccination, and 3) those receiving the bivalent mRNA vaccines as a fourth dose.
The team used pseudovirus neutralization assays to test the sera for neutralization against the ancestral SARS-CoV-2 virus, Omicron sub-lineages, and other related sarbecoviruses. They compared virus neutralization by sera collected from individuals vaccinated with three doses of the original monovalent vaccines and a fourth dose of the bivalent vaccine targeting BA.4/BA.5 to sera from individuals vaccinated with three or four monovalent vaccines and individuals with Omicron BA.4/BA.5 breakthrough infection post mRNA vaccination.
They tested all collected sera for neutralization against the D614G ancestral SARS-CoV-2 viral strain and the Omicron BA.1/BA.2, BA.4/BA.5, BA.4.6, BA.2.75, and BA.2.75.2 sub-lineages. They also tested the sera against many related sarbecoviruses, including GD-pangolin, SARS-CoV, and WIV1.
Individuals vaccinated with four monovalent vaccine doses were older with a mean age of 55.3 compared to those who received a bivalent vaccine booster with a mean age of 36.4. Sera were collected from all cohorts at similar time points following the booster dose – mean of 24.0 days for the monovalent group and mean of 26.4 days for the bivalent cohort).
Results
All groups exhibited the highest neutralization antibody titers (ID50) against the D614G ancestral SARS-CoV-2 strain. Boosted sera had the lowest geometric mean ID50 titers, and BA.4/BA.5 breakthrough sera had the highest ID50 titers against SARS-CoV-2 variants. No significant difference was observed in neutralization between individuals who received four monovalent vaccine doses and individuals who received a bivalent vaccine as a fourth dose for any of the tested SARS-CoV-2 variants.
Interestingly, in the case of the three related sarbecoviruses – WIV1, SARS-CoV, and GD-Pangolin – neutralizing antibody titers of individuals who received a fourth dose of a monovalent vaccine were slightly yet significantly higher than those who received the bivalent vaccine as a fourth vaccine dose.
The researchers observed that at approximately three to five weeks after the booster shot, individuals who received the bivalent mRNA vaccine as a fourth dose had neutralizing antibody titers similar to those who received a monovalent mRNA vaccine as a fourth dose against all SARS-CoV-2 variants tested in the study, including the Omicron BA.4/BA.5 sublineages.
Conclusion
Overall, at the time of the study, a bivalent mRNA vaccine administered as a fourth dose targeting the ancestral SARS-CoV-2 strain and Omicron BA.4/BA.5 did not induce greater neutralizing antibody responses compared to the monovalent vaccines. According to the authors, the above findings may indicate immunological imprinting. Further follow-up would help determine if the neutralizing antibody responses to the bivalent vaccine will decrease in time, including the antibody responses to a second bivalent vaccine booster.
*Important notice
bioRxiv 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.
