Characterization of Adaptive Immune Responses to SARS-CoV-2 Updated Bivalent Booster

Bivalent COVID-19 vaccines that contain two mRNAs encoding Wuhan-1 and Omicron BA.4/5 spike proteins are successful in preventing infection from the original strain and Omicron variants, but the quality of adaptive immune responses is still not well documented. This study aims at characterizing adaptive immune responses to the bivalent booster vaccination in 46 healthy participants. Plasma and PBMC were collected prior and three weeks after bivalent booster. We measured anti-N, anti-S, and RBD IgM, IgA, IgG plasma titers against original, Omicron BA.1, and BA.5 variants (pending) as well as total anti-S IgG titers and surrogate Virus Neutralization capacity against the Alpha, Delta, and BA.1 variant. With spectral flow-cytometry we identified peripheral blood B-cells specific for the RBD of the S-protein of the original and BA.1 variants. T-cell-specific responses were assessed by cytokine release assay after stimulation with SARS-CoV-2 peptides from the original, BA.1, BA.4, and BA.5 variants (pending). Finally, we performed TRB and IGH repertoire studies on sorted CD4+, CD8+, CD19+ lymphocytes, to study breadth of SARS-CoV-2 specific clonotypes (pending). 27/46 participants were analyzed;9 had SARS-CoV-2 infection (COVID+), while 18 are infection naive (COVID-). In both groups, median time since last dose of SARS-CoV-2 vaccine (3rd or 4th) was 11 months. All subjects were positive for anti-S IgG prior to bivalent booster. The COVID + group displayed anti-S IgG pre-booster levels and neutralization against BA.1 higher than the COVID- group. Significant increase post-boost of total anti-S IgG and BA.1 neutralizing activity was detected in the COVID- but not in the COVID+ group;however, no difference in neutralization activity post-boost was detected between the two groups. Furthermore, the COVIDgroup showed significant increase in the frequency of CD19+ and CD27+ switched memory B-cells specific for BA.1 RBD in post-boost compared to pre-boost samples. However, post-boost frequencies of the same B-cells were higher in the COVID+ compared to the COVID- group. These preliminary findings confirm that among individual immunized with the original COVID-19 mRNAvaccine, prior COVID infection provides increased protection against SARS-CoV-2 variants. They also demonstrate that booster immunization with the bivalent vaccine induces robust adaptive immune responses against Omicron variant.[Formula presented][Formula presented]Copyright © 2023 Elsevier Inc.

Bivalent COVID-19 vaccine antibody responses to Omicron variants suggest that responses to divergent variants would be improved with matched vaccine antigens.

We compared neutralizing antibody responses to BA.4/5, BQ.1.1, XBB, and XBB.1.5 Omicron SARS-CoV-2 variants after a bivalent or ancestral COVID-19 mRNA booster vaccine or post-vaccination infection. We found that the bivalent booster elicited moderately high antibody titers against BA.4/5 that were approximately two-fold higher against all Omicron variants than titers elicited by the monovalent booster. The bivalent booster elicited low but similar titers against both XBB and XBB.1.5 variants. These findings inform risk assessments for future COVID-19 vaccine recommendations and suggest that updated COVID-19 vaccines containing matched vaccine antigens to circulating divergent variants may be needed.

Effectiveness of the Coronavirus Disease 2019 Bivalent Vaccine.

Background: The purpose of this study was to evaluate whether a bivalent coronavirus disease 2019 (COVID-19) vaccine protects against COVID-19. Methods: The study included employees of Cleveland Clinic in employment when the bivalent COVID-19 vaccine first became available. Cumulative incidence of COVID-19 over the following 26 weeks was examined. Protection provided by vaccination (analyzed as a time-dependent covariate) was evaluated using Cox proportional hazards regression, with change in dominant circulating lineages over time accounted for by time-dependent coefficients. The analysis was adjusted for the pandemic phase when the last prior COVID-19 episode occurred and the number of prior vaccine doses. Results: Among 51 017 employees, COVID-19 occurred in 4424 (8.7%) during the study. In multivariable analysis, the bivalent-vaccinated state was associated with lower risk of COVID-19 during the BA.4/5-dominant (hazard ratio, 0.71 [95% confidence interval, .63-79]) and the BQ-dominant (0.80 [.69-.94]) phases, but decreased risk was not found during the XBB-dominant phase (0.96 [.82-.1.12]). The estimated vaccine effectiveness was 29% (95% confidence interval, 21%-37%), 20% (6%-31%), and 4% (-12% to 18%), during the BA.4/5-, BQ-, and XBB-dominant phases, respectively. The risk of COVID-19 also increased with time since the most recent prior COVID-19 episode and with the number of vaccine doses previously received. Conclusions: The bivalent COVID-19 vaccine given to working-aged adults afforded modest protection overall against COVID-19 while the BA.4/5 lineages were the dominant circulating strains, afforded less protection when the BQ lineages were dominant, and effectiveness was not demonstrated when the XBB lineages were dominant.

SARS-CoV-2 bivalent mRNA vaccine with broad protection against variants of concern.

Introduction: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant has rapidly spread around the globe. With a substantial number of mutations in its Spike protein, the SARS-CoV-2 Omicron variant is prone to immune evasion and led to the reduced efficacy of approved vaccines. Thus, emerging variants have brought new challenges to the prevention of COVID-19 and updated vaccines are urgently needed to provide better protection against the Omicron variant or other highly mutated variants. Materials and methods: Here, we developed a novel bivalent mRNA vaccine, RBMRNA-405, comprising a 1:1 mix of mRNAs encoding both Delta-derived and Omicron-derived Spike proteins. We evaluated the immunogenicity of RBMRNA-405 in BALB/c mice and compared the antibody response and prophylactic efficacy induced by monovalent Delta or Omicron-specific vaccine with the bivalent RBMRNA-405 vaccine in the SARSCoV-2 variant challenge. Results: Results showed that the RBMRNA-405 vaccine could generate broader neutralizing antibody responses against both Wuhan-Hu-1 and other SARS-CoV-2 variants, including Delta, Omicron, Alpha, Beta, and Gamma. RBMRNA-405 efficiently blocked infectious viral replication and lung injury in both Omicron- and Delta-challenged K18-ACE2 mice. Conclusion: Our data suggest that RBMRNA-405 is a promising bivalent SARS-CoV-2 vaccine with broad-spectrum efficacy for further clinical development.

Vaccine Confidence and Uptake of the Omicron Bivalent Booster in Tennessee: Implications for Vulnerable Populations.

The COVID-19 Omicron variant and its subvariants are now the dominant variants circulating in the US. Therefore, the original COVID-19 vaccine cannot offer full protection. Instead, vaccines that target the spike proteins of the Omicron variants are warranted. Hence, the FDA recommended the development of a bivalent booster. Unfortunately, despite the safety and immunogenicity of the Omicron bivalent boosters from Pfizer and Moderna, uptake in the US has been poor. At this time, only 15.8% of individuals in the US aged five and older have received the Omicron bivalent booster (OBB). The rate is 18% for those aged 18 and older. Poor vaccine confidence and booster uptake are often fueled by misinformation and vaccine fatigue. These result in more problems associated with vaccine hesitancy, which are particular prevalent in Southern states in the US. In Tennessee, the OBB vaccination rate for eligible recipients is only 5.88% at time of writing (16 February 2023). In this review, we discuss (1) the rationale for developing the OBBs; (2) the efficacy and safety of the bivalent boosters; (3) the adverse events associated with these boosters; (4) vaccine hesitancy associated with the OBBs uptake in Tennessee; (5) implications for vulnerable populations, disparities in uptake of OBBs in Tennessee, and strategies to improve vaccine confidence and OBB uptake. In support of public health, it is essential that we continue to provide education, awareness, and vaccine access to the vulnerable and medically underserved populations in Tennessee. Receiving the OBBs is the most effective method to date of protecting the public against severe COVID disease, hospitalization, and death.

Antibody Response to the BA.5 Bivalent Vaccine Shot: a Two-Year Follow-Up Study following Initial COVID-19 mRNA Vaccination.

Although many studies have been conducted on the increase in spike antibody levels after vaccination, there is insufficient prospective and longitudinal information on the BA.5-adapted bivalent vaccine up to the fifth vaccination. In this study, we conducted a follow-up study of spike antibody levels and infection history in 46 health care workers who received up to 5 vaccinations. Monovalent vaccines were administered for the first to fourth vaccinations, and a bivalent vaccine was administered for the fifth vaccination. 11 serum samples were collected from each participant, and antibody levels were measured in a total of 506 serum samples. During the observation period, 43 of the 46 health care workers had no infection history, and 3 had a history of infection. Spike antibody levels peaked at 1 week after the second booster vaccination and gradually declined until the 27th week after the second vaccination. After 2 weeks following the fifth BA.5-adapted bivalent vaccine, the spike antibody levels significantly increased (median: 23,756 [IQR: 16,450 to 37,326]), compared to those measured before vaccination (median: 9,354 [IQR: 5,904 to 15,784]) (paired Wilcoxon signed-rank test, P = 5.7 × 10-14). These changes in antibody kinetics were observed regardless of age or sex. These results suggest that booster vaccination increased the spike antibody levels. Regular vaccination is effective in maintaining long-term antibody levels. IMPORTANCE A COVID-19 bivalent mRNA vaccine was developed and administered to health care workers. The COVID-19 mRNA vaccine induces a robust antibody response. However, little is known about the antibody response to vaccines in serially collected blood samples from the same individuals. Here, we provide two-year follow-up data on the humoral immune response to COVID-19 mRNA vaccines in health care workers who received up to five vaccinations, including the BA.5-adapted bivalent vaccine. The results suggest that regular vaccination is effective in maintaining long-term antibody levels and have implications for vaccine efficacy and booster dose strategies in health care settings.

Potent Omicron-neutralizing antibodies isolated from a patient vaccinated 6 months before Omicron emergence.

Therapeutic antibodies are an important tool in the arsenal against coronavirus infection. However, most antibodies developed early in the pandemic have lost most or all efficacy against newly emergent strains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), particularly those of the Omicron lineage. Here, we report the identification of a panel of vaccinee-derived antibodies that have broad-spectrum neutralization activity. Structural and biochemical characterization of the three broadest-spectrum antibodies reveal complementary footprints and differing requirements for avidity to overcome variant-associated mutations in their binding footprints. In the K18 mouse model of infection, these three antibodies exhibit protective efficacy against BA.1 and BA.2 infection. This study highlights the resilience and vulnerabilities of SARS-CoV-2 antibodies and provides road maps for further development of broad-spectrum therapeutics.

Fifth bivalent omicron BA.4/BA.5 vaccination neutralization of SARS-CoV-2 in heart transplant recipients.

In 2022, the antigenically divergent SARS-CoV-2 omicron variants (BA.1, BA.2, BA.4, BA.5) outcompeted previous variants and continued to cause substantial numbers of illnesses and deaths. We evaluated the safety and immunogenicity of the bivalent original/omicron BA.4/BA.5 Pfizer/BioNTech vaccine administered as a fifth dose to heart transplant recipients (HTxRs). We compared neutralization (using live virus assays) of SARS-CoV-2-infected cells in serum samples from HTxRs who had previously received 4 doses of the monovalent BNT162b2 vaccine with samples from HTxRs with breakthrough infection after 4 monovalent BNT162b2 doses. The fifth vaccination induced high neutralization efficiency against the wild-type virus and omicron BA.1, BA.2, BA.4, and BA.5 variants, with significantly higher neutralization efficiency being induced in HTxRs with breakthrough infection than in those without. Neutralizing titers in those with breakthrough infection were sustained above the level induced by the fifth dose in the uninfected. We conclude that the fifth bivalent vaccine is immunogenic, including to variants, with higher vaccine immunogenicity conferred by breakthrough infection. Nevertheless, the clinical protection conferred by the fifth dose is yet to be determined. The sustained neutralization responses in those with breakthrough infection support the notion of delaying booster in those with natural breakthrough infection.

Effect of monovalent and bivalent live attenuated vaccines against QX-like IBV infection in young chickens.

Since 1999, QX-like (GI-19) avian infectious bronchitis viruses have been the predominant strains in China till now. Vaccination is the most effective way to control the disease, while live attenuated vaccine is widely used. In the current research, we evaluated the effect of several monovalent and bivalent live IBV vaccines in young chickens against the QX-like (GI-19) IBV infection. The results showed that monovalent 4/91 and bivalent Ma5+LDT3 vaccines could provide efficient protection in day-old chickens that reduced morbidity and mortality, ameliorated histopathology lesions, and reduced viral loads were observed. These data suggest that vaccination through nasal route with monovalent 4/91 or bivalent Ma5+LDT3 in day-old chickens could serve a safe and effective vaccination strategy for controlling QX-like (GI-19) infectious bronchitis virus.

Neutralizing Antibody Response of the Wild-Type/Omicron BA.1 Bivalent Vaccine as the Second Booster Dose against Omicron BA.2 and BA.5.

In addition to the original monovalent vaccines available for SARS-CoV-2, bivalent vaccines covering wild-type (WT) and Omicron BA.1 are also available. However, there is a lack of real-world data on the immunogenicity of bivalent vaccines as second boosters against the dominant Omicron sublineages, including BA.2 and BA.5. Healthcare workers (n = 565) who received the first booster vaccination were followed for 2 weeks after the second booster dose of the monovalent mRNA-1273 (WT group, n = 168) and bivalent BNT162b2 (WT+BA.1 group, n = 23) vaccines. Participants with previous SARS-CoV-2 infections were excluded from the study. The anti-receptor binding domain (RBD) antibody levels after the second booster dose in the WT and WT+BA.1 group were similar (median [interquartile range], 26,262.0 [16,951.0 to 38,137.0] U/mL versus 24,840.0 [14,828.0 to 41,460.0] U/mL, respectively). Although the neutralization activities of the pooled sera were lower against BA.5 than against other variants in both groups, the activities against BA.2 and BA.5 in the WT+BA.1 group were higher than those of the WT group in both pseudotyped and live virus assays. Vaccine-related symptoms, including systemic and local symptoms, were strongly correlated with anti-RBD antibody levels and neutralizing titers. In conclusion, the second booster dose of the bivalent (WT/Omicron BA.1) vaccine induced higher neutralizing activity against BA.2 and BA.5 than that of the original monovalent vaccine. IMPORTANCE Although Omicron BA.1-containing bivalent vaccines have been authorized, real-world data validating their safety and antibody responses remain scarce. We conducted a prospective longitudinal study to assess the safety, immunogenicity, and reactogenicity of the second booster dose with the Omicron BA.1 bivalent vaccine in health care workers. Compared with the original monovalent vaccine, the bivalent (WT+BA.1) vaccine elicited higher levels of neutralizing antibodies against the Omicron BA.2 and BA.5 subvariants. The frequency of adverse events after the second booster dose was similar to that of the monovalent vaccine. BA.5-neutralizing antibodies induced by the bivalent Omicron BA.1-containing vaccine were expected to decline. A prospective longitudinal study should be performed to determine the persistence of the humoral immunity.

Protection against severe COVID-19 after second booster dose of adapted bivalent (original/Omicron BA.4-5) mRNA vaccine in persons ≥ 60 years, by time since infection, Italy, 12 September to 11 December 2022.

Effectiveness against severe COVID-19 of a second booster dose of the bivalent (original/BA.4-5) mRNA vaccine 7-90 days post-administration, relative to a first booster dose of an mRNA vaccine received ≥ 120 days earlier, was ca 60% both in persons ≥ 60 years never infected and in those infected > 6 months before. Relative effectiveness in those infected 4-6 months earlier indicated no significant additional protection (10%; 95% CI: -44 to 44). A second booster vaccination 6 months after the latest infection may be warranted.

Public health impact and economic value of booster vaccination with Pfizer-BioNTech COVID-19 vaccine, bivalent (Original and Omicron BA.4/BA.5) in the United States.

OBJECTIVE: To assess the public health impact and economic value of booster vaccination with the Pfizer-BioNTech COVID-19 Vaccine, Bivalent in the United States. METHODS: A combined cohort Markov decision tree model estimated the cost-effectiveness and budget impact of booster vaccination compared to no booster vaccination in individuals aged ≥5 years. Analyses prospectively assessed three scenarios (base case, low, high) defined based upon the emergence (or not) of subvariants, using list prices. Age-stratified parameters were informed by literature. The cost-effectiveness analysis estimated cases, hospitalizations and deaths averted, Life Years (LYs) and Quality Adjusted Life Years (QALYs) gained, the incremental cost-effectiveness ratio (ICER), the net monetary benefit (NMB), and the Return on Investment (ROI). The budget impact analyses used the perspective of a hypothetical 1-million-member plan. Sensitivity analyses explored parameter uncertainty. Conservatively, indirect effects and broad societal benefits were not considered. RESULTS: The base case predicted that, compared to no booster vaccination, the Pfizer-BioNTech COVID-19 Vaccine, Bivalent could result in ∼3.7 million fewer symptomatic cases, 162 thousand fewer hospitalizations, 45 thousand fewer deaths, 373 thousand fewer discounted QALYs lost, and was cost-saving. Using a conservative value of $50,000 for 1 LY, every $1 invested yielded estimated $4.67 benefits. Unit costs, health outcomes and effectiveness had the greatest impact on results. At $50,000 per QALY gained, the booster generated a 34.2 billion NMB and probabilistic sensitivity analyses indicated a 92% chance of being cost-saving and 98% of being cost-effective. The bivalent was cost-saving or highly cost-effective in high and low scenarios. In a hypothetical 1-million-member health plan population, the vaccine was predicted to be a budget-efficient solution for payers. CONCLUSIONS: Booster vaccination with the Pfizer-BioNTech COVID-19 Vaccine, Bivalent for the US population aged ≥5 years could generate notable public health impact and be cost-saving based on the findings of our base case analyses.

Bivalent second booster dose of the COVID-19 vaccine: Eligible populations' reasons for receiving in Italy.

The Italian Ministry of Health recommended the administration of the bivalent second booster dose of the new available mRNA COVID-19 vaccine for subjects aged 60 y and over, aged 12 y and over with high frailty motivated by concomitant/preexisting conditions, and health-care workers. The purposes of this cross-sectional survey were to investigate the reasons for receiving the bivalent second booster dose of the COVID-19 vaccine and associated influencing factors among the eligible population attending two immunization centers randomly selected in the city of Naples, Italy. A total of 535 subjects participated. Only 17.5% revealed high concern about the possibility of acquiring the COVID-19 disease. Those younger, those who had at least one chronic medical condition, and those who had a higher perceived seriousness of the COVID-19 disease were more likely to be very concerned. Having a higher belief of the vaccine's safety and usefulness were significant positive predictors of the respondents' belief of the efficacy of the bivalent second booster dose. The two most common reasons reported for receiving the bivalent second booster dose included the protection for themselves and for their cohabitants. Those younger and those who had a higher perception of the vaccine's usefulness in preventing SARS-CoV-2 infection were more likely to receive the bivalent second booster dose for the protection of their cohabitants. Health-care organizations and health-care professionals can use these findings in their efforts to design educational and communication interventions to accelerate the uptake of this vaccine for reducing the frequency of this disease.

Insights for COVID-19 in 2023.

Predictions for a near end of the pandemic by the World Health Organization should be interpreted with caution. Current evidence indicates that the efficacy of a fourth dose of classical mRNA vaccines (BT162b2 or mRNA-1273) is low and short-lived in preventing SARS-CoV-2 infection in its predominant variant (Omicron). However, its efficacy is high against severe symptomatic infection, hospitalization and death. The new vaccines being introduced are bivalent and active against the Omicron variants. Potential new vaccines to be introduced in the coming year include a vaccine based on a recombinant protein that emulates the receptor binding domain of the Spike protein under development by the Spanish company Hipra, as well as vaccines for nasal or oral administration. Available information suggests that vaccines against COVID-19 can be administered in association with influenza vaccination without particular complications. New drugs against COVID-19, both antiviral and anti-inflammatory, are under investigation, but this does not seem to be the case with monoclonal antibodies. The indication to use masks in some circumstances will be maintained next year in view of the accumulation of scientific data on their efficacy. Finally, the long COVID or Post-COVID syndrome may continue to affect a very high proportion of patients who have had the disease, requiring combined diagnostic and therapeutic resources.

Ph-Positive B-Cell Acute Lymphoblastic Leukemia Occurring after Receipt of Bivalent SARS-CoV-2 mRNA Vaccine Booster: A Case Report.

The coronavirus disease 2019 (COVID-19) pandemic is a universal emergency public health issue. A large proportion of the world's population has had several spike antigen exposures to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and/or COVID-19 vaccinations in a relatively short-term period. Although sporadic hematopoietic adverse events after COVID-19 vaccine inoculation were reported, there is currently no sufficient evidence correlating anti-spike protein immune responses and hematopoietic adverse events of vaccinations. We reported the first case of Ph-positive B-cell acute lymphoblastic leukemia (ALL) occurring after a bivalent mRNA COVID-19 vaccine inoculation. The otherwise healthy 43-year-old female patient had a total of six spike antigen exposures in the past 1.5 years. Informative pre-vaccine tests and bone marrow study results were provided. Although the causal relationship between bivalent vaccinations and the subsequent development of Ph-positive B-cell ALL cannot be determined in the case report, we propose that anti-spike protein immune responses could be a trigger for leukemia. Clinicians must investigate the hematopoietic adverse events closely after COVID-19 vaccinations. Further pre-clinical studies to investigate the safety of bivalent mRNA COVID-19 vaccine are required.

Immune evasion of neutralizing antibodies by SARS-CoV-2 Omicron.

Since its emergence at the end of 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the infection of more than 600 million people worldwide and has significant damage to global medical, economic, and political structures. Currently, a highly mutated variant of concern, SARS-CoV-2 Omicron, has evolved into many different subvariants mainly including BA.1, BA.2, BA.3, BA.4/5, and the recently emerging BA.2.75.2, BA.2.76, BA.4.6, BA.4.7, BA.5.9, BF.7, BQ.1, BQ.1.1, XBB, XBB.1, etc. Mutations in the N-terminal domain (NTD) of the spike protein, such as A67V, G142D, and N212I, alter the antigenic structure of Omicron, while mutations in the spike receptor binding domain (RBD), such as R346K, Q493R, and N501Y, increase the affinity for angiotensin-converting enzyme 2 (ACE2). Both types of mutations greatly increase the capacity of Omicron to evade immunity from neutralizing antibodies, produced by natural infection and/or vaccination. In this review, we systematically assess the immune evasion capacity of SARS-CoV-2, with an emphasis on the neutralizing antibodies generated by different vaccination regimes. Understanding the host antibody response and the evasion strategies employed by SARS-CoV-2 variants will improve our capacity to combat newly emerging Omicron variants.

Analysis of hematologic adverse events reported to a national surveillance system following COVID-19 bivalent booster vaccination.

Hematologic complications, including vaccine-induced immune thrombotic thrombocytopenia (VITT), immune thrombocytopenia (ITP), and autoimmune hemolytic anemia (AIHA), have been associated with the original severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines. However, on August 31, 2022, new formulations of the Pfizer-BioNTech and Moderna vaccines were approved for use without clinical trial testing. Thus, any potential adverse hematologic effects with these new vaccines remain unknown. We queried the US Centers for Disease Control Vaccine Adverse Event Reporting System (VAERS), a national surveillance database, through February 3, 2023, all reported hematologic adverse events that occurred within 42 days of administration of either the Pfizer-BioNTech or Moderna Bivalent COVID-19 Booster vaccine. We included all patient ages and geographic locations and utilized 71 unique VAERS diagnostic codes pertaining to a hematologic condition as defined in the VAERS database. Fifty-five reports of hematologic events were identified (60.0% Pfizer-BioNTech, 27.3% Moderna, 7.3% Pfizer-BioNTech bivalent booster plus influenza, 5.5% Moderna bivalent booster plus influenza). The median age of patients was 66 years, and 90.9% (50/55) of reports involved a description of cytopenias or thrombosis. Notably, 3 potential cases of ITP and 1 case of VITT were identified. In one of the first safety analyses of the new SARS-CoV-2 booster vaccines, we identified few adverse hematologic events (1.05 per 1,000,000 doses), most of which could not be definitively attributed to vaccination. However, three reports of possible ITP and one report of possible VITT highlight the need for continued safety monitoring of these vaccines as their use expands and new formulations are authorized.