Virus World

Bivalent COVID-19 mRNA vaccines expressing both the ancestral D614G and Omicron BA.5 spike proteins were introduced in August 2022 with the goal of broadening immunity to emerging SARS-CoV-2 Omicron subvariants. Subsequent studies on bivalent boosters found neutralizing antibody responses similar to boosters with the original monovalent vaccine, likely the result of immunological imprinting. Guidelines allow for administration of a second bivalent booster in high-risk groups, but it remains unknown whether this would broaden antibody responses.

To address this question, we assessed longitudinal serum SARS-CoV-2-neutralizing titers in 18 elderly immunocompetent individuals (mean age 69) following a fourth monovalent booster and two BA.5 bivalent booster vaccines using pseudovirus neutralization assays against D614G, Omicron BA.5, and Omicron XBB.1.5. There was a small but significant increase in peak neutralizing antibody responses against Omicron BA.5 and XBB.1.5 following the first bivalent booster, but no significant increase in peak titers following the second bivalent booster. Omicron-specific neutralizing titers remained low after both doses of the BA.5 bivalent booster. Our results suggest that a second dose of the BA.5 bivalent booster is not sufficient to broaden antibody responses and to overcome immunological imprinting. A monovalent vaccine targeting only the spike of the recently dominant SARS-CoV-2 may mitigate the back boosting associated with the original antigenic sin.

Preprint at bioRxiv (August 14, 2023):

 https://doi.org/10.1101/2023.08.13.553148 

In the light of emerging SARS-CoV-2 variants of concern (VOC), bivalent COVID-19 vaccines combining the wild-type spike mRNA with an Omicron VOC BA.1 or BA.4-5 spike mRNA became available. This non-randomized controlled study examined adverse reactions, PRN (pro re nata) medication intake and inability to work after a fourth COVID-19 vaccination among 76 healthcare workers. As fourth dose either the original, monovalent BNT162b2mRNA (48.7%) or the bivalent BNT162b2mRNA original/Omicron BA.4-5 vaccine (51.3%) was administered. The rate of adverse reactions for the second booster dose was significantly higher among participants receiving the bivalent 84.6% (95% CI 70.3%-92.8%; 33/39) compared to the monovalent 51.4% (95% CI 35.9-66.6%; 19/37) vaccine (p=0.0028). Also, there was a trend towards an increased rate of inability to work and intake of PRN medication following bivalent vaccination. In view of preprints reporting inconclusive results in neutralizing antibody levels between the compared vaccines, our results and further studies on safety and reactogenicity of bivalent COVID-19 booster vaccines are highly important to aid clinical decision making in the choice between bivalent and monovalent vaccinations.

Preprint available in medRxiv (Nov.8, 2022):

https://doi.org/10.1101/2022.11.07.22281982 

The newly emerged SARS-CoV-2 Omicron BQ.1.1, XBB.1, and other sublineages have accumulated additional spike mutations that may affect vaccine effectiveness. Here we report neutralizing activities of three human serum panels collected from individuals 1-3 months after dose 4 of parental mRNA vaccine (post-dose-4), 1 month after a BA.5-bivalent-booster (BA.5-bivalent-booster), or 1 month after a BA.5-bivalent-booster with previous SARS-CoV-2 infection (BA.5-bivalent-booster-infection). Post-dose-4 sera neutralized USA-WA1/2020, BA.5, BF.7, BA.4.6, BA.2.75.2, BQ.1.1, and XBB.1 SARS-CoV-2 with geometric mean titers (GMTs) of 1533, 95, 69, 62, 26, 22, and 15, respectively; BA.5-bivalent-booster sera improved the GMTs to 3620, 298, 305, 183, 98, 73, and 35; BA.5-bivalent-booster-infection sera further increased the GMTs to 5776, 1558,1223, 744, 367, 267, and 103. Thus, although BA.5-bivalent-booster elicits better neutralization than parental vaccine, it does not produce robust neutralization against the newly emerged Omicron BA.2.75.2, BQ.1.1, and XBB.1. Previous infection enhances the magnitude and breadth of BA.5-bivalent-booster-elicited neutralization.

Preprint in bioRxiv (Nov. 02, 2022):

https://doi.org/10.1101/2022.10.31.514580 

The emergence of the highly divergent SARS-CoV-2 Omicron variant has jeopardized the efficacy of vaccines based on the ancestral spike. The bivalent COVID-19 mRNA booster vaccine within the United States is comprised of the ancestral and the Omicron BA.5 spike. Since its approval and distribution, additional Omicron subvariants have been identified with key mutations within the spike protein receptor binding domain that are predicted to escape vaccine sera. Of particular concern is the R346T mutation which has arisen in multiple subvariants, including BA.2.75.2 and BQ.1.1.

Using a live virus neutralization assay, we evaluated serum samples from individuals who had received either one or two monovalent boosters or the bivalent booster to determine neutralizing activity against wild-type (WA1/2020) virus and Omicron subvariants BA.1, BA.5, BA.2.75.2, and BQ.1.1. In the one monovalent booster cohort, relative to WA1/2020, we observed a reduction in neutralization titers of 9-15-fold against BA.1 and BA.5 and 28-39-fold against BA.2.75.2 and BQ.1.1. In the BA.5-containing bivalent booster cohort, the neutralizing activity improved against all the Omicron subvariants. Relative to WA1/2020, we observed a reduction in neutralization titers of 3.7- and 4-fold against BA.1 and BA.5, respectively, and 11.5- and 21-fold against BA.2.75.2 and BQ.1.1, respectively. These data suggest that the bivalent mRNA booster vaccine broadens humoral immunity against the Omicron subvariants.

Preprint in bioRxiv (Nov. 1, 2022):

 https://doi.org/10.1101/2022.10.31.514636 

On September 1, 2022, the Moderna and Pfizer–BioNTech bivalent vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) containing equal amounts of spike messenger RNA from the ancestral and omicron BA.4–BA.5 subvariants replaced their monovalent counterparts as booster doses for persons who are 12 years of age or older in the United States. We previously reported surveillance data from North Carolina on the effectiveness of these two bivalent boosters against coronavirus disease 2019 (Covid-19) during the first 3 months after deployment (September 1 to December 8, 2022); the BA.4–BA.5 subvariants were predominant during the first 2.5 months of this period.1 Here, we present two additional months of data that were obtained during a period when the omicron BQ.1–BQ.1.1 and XBB–XBB.1.5 subvariants had become predominant to show the durability of protection conferred by these two bivalent boosters against a wider range of clinical outcomes than were included in our previous report. The data sources and study design have been described previously,1-3 and updated information is provided in the Methods section of the Supplementary Appendix, available with the full text of this letter at NEJM.org. The current study used data regarding booster doses and clinical outcomes from September 1, 2022, to February 10, 2023, for all North Carolina residents who were 12 years of age or older. During this period, a total of 6,306,311 residents were eligible to receive bivalent boosters; of these residents, 1,279,802 received the injections. A total of 19,462 of the 154,581 SARS-CoV-2 infections, 253 of the 2208 Covid-19–related hospitalizations, and 79 of the 867 Covid-19–related deaths occurred after receipt of the bivalent booster (Table S1 in the Supplementary Appendix).

We considered four outcome measures: infection, severe infection resulting in hospitalization, severe infection resulting in hospitalization or death, and severe infection resulting in death. We fit the Cox regression model with a time-varying hazard ratio for severe infection and fit the proportional-rates model with a time-varying rate ratio for recurrent infection for each additional booster dose that was received (i.e., first booster vs. primary vaccination, second booster vs. first booster, or third booster vs. second booster); all measures were adjusted for the baseline characteristics shown in Table S1. We estimated the booster effectiveness on a particular day as 1 minus the hazard ratio or rate ratio on that day multiplied by 100%. 

Effectiveness against severe infection resulting in hospitalization was slightly lower, and effectiveness against infection was much lower. The effectiveness against severe infection resulting in death was the highest despite uncertainty because of the small number of events. We also analyzed the data separately for participants who received bivalent boosters before November 1, 2022 (when the BA.4–BA.5 subvariants were predominant) and after November 1, 2022 (when the BQ.1–BQ.1.1 subvariants were more prevalent and then were gradually replaced by the XBB–XBB.1.5 subvariants). The results are shown in the right column of Figure 1 and in Tables S3 and S4. The effectiveness was broadly similar between the two booster cohorts. Finally, we performed subgroup analyses according to the participant’s age and previous infection status and according to the manufacturers of the bivalent vaccine and the previous vaccine. Effectiveness against infection was higher for the Moderna bivalent vaccine than for the Pfizer–BioNTech bivalent vaccine and higher among previously infected participants than among those with no previous infection (Fig. S1).

The two types of bivalent boosters were associated with an additional reduction in the incidence of omicron infection among participants who had previously been vaccinated or boosted. Although the two bivalent vaccines were designed to target the BA.4–BA.5 subvariants, they were also associated with a lower risk of infection or severe infection with the BQ.1–BQ.1.1 and XBB–XBB.1.5 subvariants. The effectiveness was higher against hospitalization and death than against infection and waned gradually from its peak over time.

Published in NEJM (April 12, 2023):

https://doi.org/10.1056/NEJMc2302462 

Moderna said its new booster appears to be more effective against Omicron variants than its original vaccine, and that it also seems effective against a new worrisome variant, BQ1.1. New data indicate Moderna’s Covid bivalent booster may be more effective against currently circulating Omicron variants of the virus than its original vaccine, the company said Monday.  Like data released by Pfizer and BioNTech regarding their Covid vaccine, the new data involves lab measurements of antibodies and their ability to neutralize the SARS-CoV-2 virus, not data on how well the vaccines prevent cases of symptomatic illness or severe disease. Moderna said in a press release that giving its current booster led to an increase in the number of antibodies that neutralize the most common Omicron variants, BA.4 and BA.5, by 15-fold. The data have not been published in a peer-reviewed journal or released in a preprint. That meant that the geometric mean titers of BA.4/BA.5 antibodies were 5.11-fold higher for those who received the new booster compared to those who received a booster of the original Moderna Covid vaccine if those people had been previously infected with Covid. For those without previous Covid infection, those numbers were 6.29 times higher than with the original vaccine. One caveat is that with previous studies of experimental Moderna boosters that targeted new strains of the virus, it was possible to compare volunteers who received the original vaccine and the modified one at the same time.

But the new booster, which targets both the original strain of the SARS-CoV-2 virus and the Omicron sub-variants BA.4/BA.5, was authorized by the Food and Drug Administration before such a study was conducted. Jacqueline Miller, a Moderna senior vice president, said that the company did not think it was ethical to enroll a new cohort on the original Moderna booster when the recommendations from the FDA and the Centers for Disease Control and Prevention were that people should get a booster that is more targeted at the BA.4/BA.5 strains. So far, results have been mixed as to whether the BA.4/BA.5 boosters are more effective against the new strains than the original shots. Studies conducted in the laboratories of the vaccine researcher Daniel Barouch, of Beth Israel Deaconess Medical Center, and the virologist David Ho, of Columbia University, have indicated that the new shots may not be more effective than the original one. But studies conducted at the University of Texas and at Emory University have shown that the new shots may yield better antibody protection. Miller emphasized that Moderna has used consistent methods for its antibody studies, including for the earlier studies that showed the original vaccine was effective, and that those studies have been greenlit by the FDA.

Eric Topol, director and founder of the Scripps Research Translational Institute, said that he viewed the new results as positive and largely confirmatory of the Emory work. He also praised the study for its relatively large size, involving 511 previously vaccinated volunteers. “This study is encouraging and suggests that the bivalent boosters provide an added benefit compared to the prior mRNA-1273 booster,” said Mehul Suthar, lead author of the Emory analysis, in an email. “We will need to stay up to date with this bivalent booster to protect against yet another Omicron wave this fall/winter.” Moderna also said that the new booster appeared to be effective against a new worrisome variant, BQ1.1, in a preliminary study using samples from 40 of the study’s volunteers. “​​What people have been looking for is an understanding of, ‘if I got this booster what does my protection look like against BQ1.1 or some other variant,’” Miller said. “Ultimately the effectiveness data are the really important data.” She said that Moderna expects data from an ongoing observational study to help answer that question in the first quarter of next year.

Neutralizing antibodies that target the BA.4 and BA.5 subvariants were four-fold higher in people aged 55 and older who received the bivalent booster than in those who received a monovalent booster. New data from Pfizer and BioNTech on their bivalent Covid-19 vaccine suggests the updated product may be more protective against more recent Omicron subvariants than the original version of the vaccine, the companies said in a statement released Friday. The companies said the levels of neutralizing antibodies that target the BA.4 and BA.5 subvariants of the SARS-CoV-2 virus were four-fold higher in people aged 55 and older who received the bivalent booster than in similarly aged people who received a monovalent booster. The bivalent, which was given an emergency use authorization at the end of August, targets both the original version of the SARS-2 virus and the BA.4/BA.5 variants. Recently BA.5 has been the dominant strain in the United States, but an alphabet soup of newer subvariants — BA.4.6, BQ.1.1 among them — is starting to crowd it out. The new data from the companies only looks at what getting the the booster did to antibody levels in recipients. The trial did not test whether people who received the updated boosters were less likely to contract Covid than people who received one of the older boosters.

“These data demonstrate that our BA.4/BA.5-adapted bivalent vaccine works as conceptually planned in providing stronger protection against the Omicron BA.4 and BA.5 sublineages,” Ugur Sahin, CEO and co-founder of BioNTech, said in the statement. “In the next step and as part of our science-based approach, we will continue to evaluate the cross-neutralization of the adapted vaccine against new variants and sublineages. Our aim is to provide broader immunity against Covid-19 caused by SARS-CoV-2, including Omicron and other circulating strains.” The companies also reported that one month after the trial participants got a dose of the bivalent booster, neutralizing antibodies targeting Omicron BA.4/BA.5 viruses increased 13.2-fold from pre-booster levels in adults who were older than 55 years of age; they increased 9.5-fold for adults 18 to 55 years of age. By comparison, in adults older than 55 who received a booster dose of the original vaccine, antibody titers to BA.4 and BA.5 rose 2.9-fold over the same period. Of late there have been a number of small studies that have tried to get an answer to the question of whether the updated vaccines are likely to be more protective than the original version against Omicron viruses. Three concluded that updating the vaccine did not make a difference while two suggested there was a benefit. But differences in the designs of the studies make them hard to compare to each other and to the Pfizer data. And at the end of the day, the important question is whether what was seen in terms of antibody production will translate into better protection for people who receive the bivalent vaccine, said Florian Krammer, a vaccinologist at Mount Sinai School of Medicine in Manhattan. He thought it might.

“A four-fold higher titer, that would be good,” said Krammer, who has done some paid consulting work for Pfizer. “Four-fold is usually the magical cut-off for a lot of us when we look at neutralization. Four-fold seems to mean something.” He cautioned though, that with different groups coming up with different estimates of whether the bivalent vaccine generated a significant improvement in antibody levels, “we really need to figure out what the truth is here and who is right in terms of measuring.” Eric Topol, director of the Scripps Research Translational Institute, thought the results were promising. “I think this is encouraging,” Topol told STAT. “We just need more people to get the darn booster.” Data from the Centers for Disease Control show uptake of the bivalent boosters has been slow, with only 26.3 million people having received it so far. Even in the highest risk age group, people 65 and older, uptake has been modest. To date only 23% of Americans in that age group have received a bivalent booster. 

Pfizer press release (Nov. 04, 2022) available here:

https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-announce-updated-clinical-data-omicron 

BACKGROUND

The safety and immunogenicity of the bivalent omicron-containing mRNA-1273.214 booster vaccine are not known.

METHODS

In this ongoing, phase 2–3 study, we compared the 50-μg bivalent vaccine mRNA-1273.214 (25 μg each of ancestral Wuhan-Hu-1 and omicron B.1.1.529 [BA.1] spike messenger RNAs) with the previously authorized 50-μg mRNA-1273 booster. We administered mRNA-1273.214 or mRNA-1273 as a second booster in adults who had previously received a two-dose (100-μg) primary series and first booster (50-μg) dose of mRNA-1273 (≥3 months earlier). The primary objectives were to assess the safety, reactogenicity, and immunogenicity of mRNA-1273.214 at 28 days after the booster dose.

RESULTS

Interim results are presented. Sequential groups of participants received 50 μg of mRNA-1273.214 (437 participants) or mRNA-1273 (377 participants) as a second booster dose. The median time between the first and second boosters was similar for mRNA-1273.214 (136 days) and mRNA-1273 (134 days). In participants with no previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the geometric mean titers of neutralizing antibodies against the omicron BA.1 variant were 2372.4 (95% confidence interval [CI], 2070.6 to 2718.2) after receipt of the mRNA-1273.214 booster and 1473.5 (95% CI, 1270.8 to 1708.4) after receipt of the mRNA-1273 booster. In addition, 50-μg mRNA-1273.214 and 50-μg mRNA-1273 elicited geometric mean titers of 727.4 (95% CI, 632.8 to 836.1) and 492.1 (95% CI, 431.1 to 561.9), respectively, against omicron BA.4 and BA.5 (BA.4/5), and the mRNA-1273.214 booster also elicited higher binding antibody responses against multiple other variants (alpha, beta, gamma, and delta) than the mRNA-1273 booster. Safety and reactogenicity were similar with the two booster vaccines. Vaccine effectiveness was not assessed in this study; in an exploratory analysis, SARS-CoV-2 infection occurred in 11 participants after the mRNA-1273.214 booster and in 9 participants after the mRNA-1273 booster.

CONCLUSIONS

The bivalent omicron-containing vaccine mRNA-1273.214 elicited neutralizing antibody responses against omicron that were superior to those with mRNA-1273, without evident safety concerns. (Funded by Moderna; ClinicalTrials.gov number, NCT04927065. opens in new tab.)

Published in NEJM (Sept.16, 2022):

https://doi.org/10.1056/NEJMoa2208343