A trio of new studies concludes that the COVID-19 bivalent (two-strain) vaccine booster offers added protection against infection with the Omicron and its major subvariants and against severe illness.
Significant protection against severe disease
In the New England Journal of Medicine (NEJM), University of North Carolina (UNC) researchers parsed data from the state's COVID-19 surveillance and vaccine-management systems from Sep 1 to Dec 8, 2022, a period in which the bivalent Pfizer/BioNTech and Moderna mRNA vaccine boosters were administered.
The team also pulled data from May 25 to Aug 31, 2022, when only monovalent (single-strain) boosters were administered to compare rates of severe infection from the Omicron BA.4.6, BA.5, BQ.1, and BQ.1.1 subvariants. Authorized on Aug 31, 2022, for Americans aged 12 and older, the bivalent booster contains the spike protein from the wild-type SARS-CoV-2 virus, BA.4, and BA.5.
Of the 6,242,259 people eligible for a booster, 5% received a monovalent dose from May 25 to Aug 31. Three percent of 1,896 boosted participants reported COVID-19 hospitalizations, and 3% of 690 died. From Sep 1 to Nov 3, 17% of 6,283,483 eligible participants received a bivalent booster, 5% of 1,093 of them reported COVID-19 hospitalizations, and 3% of 514 died.
Booster effectiveness peaked at 1 month and then waned. Vaccine effectiveness (VE) against severe infection resulting in hospitalization 15 to 99 days after receipt of one monovalent booster dose was 25.2% (95% confidence interval [CI], -0.2% to 44.2%), and the corresponding VE for a bivalent booster dose was 58.7% (95% CI, 43.7% to 69.8%).
The difference in VE against Omicron hospitalization between the bivalent and monovalent boosters was 33.5 percentage points (95% CI, 2.9 to 62.1). VE against hospitalization or death was 24.9% (95% CI, 1.4% to 42.8%) for one monovalent booster dose and 61.8% (95% CI, 48.2% to 71.8%) for a bivalent dose. The difference in VE against Omicron hospitalization or death between the bivalent and monovalent boosters was 36.9 percentage points (95% CI, 12.6 to 64.3).
Results of subanalyses restricted to participants 18 years and younger or 65 and older, COVID-naïve participants, and those who received an mRNA vaccine as their primary vaccine produced similar results. VE was similar for the Pfizer and Moderna boosters and after the first, second, and third booster doses.
"Very strong unmeasured confounders would be required in order to fully explain away the observed effectiveness of bivalent boosters," the researchers concluded.
In a UNC at Chapel Hill press release, senior author Zack Moore, MD, MPH, state epidemiologist at the North Carolina Department of Health and Human Services, said that the increased VE in the study shows why it's important for people to get the bivalent booster, even if they originally received one monovalent dose.
"The takeaway is that the updated booster offers significant protection against hospitalization or death from COVID-19," he said. "Only a small percentage of the North Carolinians have received updated boosters so far. Hopefully, the findings of our study will encourage people to take advantage of these effective vaccines."
Younger adults benefitted the most
A study by Centers for Disease Control and Prevention (CDC) researchers evaluated the bivalent vaccine's effectiveness against symptomatic Omicron XBB and XBB.1.5 subvariants from December 2022 to January 2023.
In the study, published in Morbidity and Mortality Weekly Report, the investigators analyzed data from the Increasing Community Access to Testing national pharmacy program for COVID-19 testing from adults with healthy immune systems.
Compared with no booster, bivalent dose VE against symptomatic BA.5 infection among 29,175 adults who had received two to four monovalent vaccine doses was 52%, and VE against symptomatic XBB/XBB.1.5 infection was 48%, in adults aged 18 to 49 years 2 or 3 months after receipt. VE against symptomatic BA.5 infection was 43% among participants aged 50 to 64 years and 37% among those 65 and older.
VE against symptomatic XBB/XBB.1.5 infection was 49% among participants aged 18 to 49 years, 40% among those aged 50 to 64, and 43% among those aged 65 years and older. Evidence of waning VE 2 to 3 months after receiving a bivalent dose was minimal, although the researchers said the estimates were imprecise.
VE against symptomatic XBB/XBB.1.5 infection was 49% among participants aged 18 to 49 years, 40% among those 50 to 64, and 43% among those 65 and older.
The authors said the results show the additional benefit of a bivalent booster. "As new SARS-CoV-2 variants emerge, continued vaccine effectiveness monitoring is important," they wrote. "All persons should stay up to date with recommended COVID-19 vaccines, including receiving a bivalent booster dose when they are eligible."
More effective against subvariants
Another NEJM study, this one by researchers from the University of Texas Medical Branch, Pfizer, and BioNTech, evaluated VE against the wild-type virus, BA.4.6, BA.2.75.2, BQ.1.1, and XBB.1 subvariants in adults older than 55 years. The participants had received three doses of the monovalent Pfizer vaccine and either a fourth monovalent dose of the Pfizer vaccine roughly 6.6 months after the third dose or the bivalent vaccine about 11 months after the third dose.
The team obtained serum samples from participants on the day of the fourth dose and 1 month later for a spike-protein neutralization assay.
The fourth monovalent vaccine dose triggered an increase in concentrations of neutralizing antibodies of 3.0 against the wild-type virus, 2.9 against BA.4/BA.5, 2.3 against BA.4, 2.1 against BA.2.75.2, 1.8 against BQ.1.1, and 1.5 against XBB.1, which has now become the dominant variant in the United States. The bivalent booster increased neutralizing antibody concentrations by 5.8, 13.0, 11.1, 6.7, 8.7, and 4.8, respectively.
Among COVID-naïve participants, the monovalent vaccine produced neutralizing antibody concentration increases of 4.4 against the wild-type virus, 3.0 against BA.4/BA.5, 2.5 against BA.4.6, 2.0 against BA.2.75.2, 1.5 against BQ.1.1, and 1.3 against XBB.1. The bivalent booster increased neutralizing antibody levels by 9.9, 26.4, 22.2, 8.4, 12.6, and 4.7, respectively.
Among previously infected participants, the monovalent vaccine increased neutralizing antibody concentrations by 2.0 against the wild-type virus, 2.8 against BA.4/BA.5, 2.1 against BA.4.6, 2.1 against BA.2.75.2, 2.2 against BQ.1.1, and 1.8 against XBB.1. The bivalent booster increased neutralizing antibody concentrations by 3.5, 6.7, 5.6, 5.3, 6.0, and 4.9, respectively.
Despite different intervals from doses 3 to 4, the antibody levels before the fourth dose were similar in the monovalent and the bivalent groups, regardless of previous infection status.
"After the fourth dose, higher neutralizing titers developed in participants with a history of SARS-CoV-2 infection than in those without a history of infection," the authors wrote. "For each tested omicron sublineage, the difference between the original and bivalent neutralizing geometric mean factor increase was greater in the serum samples obtained from participants without previous infection than in those obtained from participants with previous infection."
After the fourth dose, higher neutralizing titers developed in participants with a history of SARS-CoV-2 infection than in those without a history of infection.
Of all the sublineages, BA.2.75.2, BQ.1.1, and XBB.1 had the lowest vaccine-triggered neutralization, the authors said. "However, neutralizing titers after a bivalent booster were several times as high as those after the original BNT162b2 [Pfizer] vaccine. These data suggest that the bivalent vaccine is more immunogenic than the original vaccine, with greater breadth of responses against circulating omicron sublineages."