Superior immunogenicity and effectiveness of the third compared to the second BNT162b2 vaccine dose.

As the effectiveness of a two-dose messenger RNA (mRNA) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine regimen decreases with time, a third dose has been recommended. Here, we assessed immunogenicity, vaccine effectiveness and safety of the third BNT162b2 vaccine dose in a prospective cohort study of 12,413 healthcare workers (HCWs). Anti-RBD immunoglobulin G (IgG) levels were increased 1.7-fold after a third dose compared with following the second dose. Increased avidity from 61.1% (95% confidence interval (CI), 56.1-66.7) to 96.3% (95% CI, 94.2-98.5) resulted in a 6.1-fold increase in neutralization titer. Peri-infection humoral markers of 13 third-dose Delta variant of concern (VOC) breakthrough cases were lower compared with 52 matched controls. Vaccine effectiveness of the third dose relative to two doses was 85.6% (95% CI, 79.2-90.1). No serious adverse effects were reported. These results suggest that the third dose is superior to the second dose in both quantity and quality of IgG antibodies and safely boosts protection from infection.

SARS-CoV-2 IgG Levels as Predictors of XBB Variant Neutralization, Israel, 2022- and 2023.

Although a vaccine against SARS-CoV-2 Omicron-XBB.1.5 variant is available worldwide and recent infection is protective, the lack of recorded infection data highlights the need to assess variant-specific antibody neutralization levels. We analyzed IgG levels against receptor-binding domain-specific SARS-CoV-2 ancestral strain as a correlate for high neutralizing titers against XBB variants.

Waning Immune Humoral Response to BNT162b2 Covid-19 Vaccine over 6 Months.

BACKGROUND: Despite high vaccine coverage and effectiveness, the incidence of symptomatic infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been increasing in Israel. Whether the increasing incidence of infection is due to waning immunity after the receipt of two doses of the BNT162b2 vaccine is unclear. METHODS: We conducted a 6-month longitudinal prospective study involving vaccinated health care workers who were tested monthly for the presence of anti-spike IgG and neutralizing antibodies. Linear mixed models were used to assess the dynamics of antibody levels and to determine predictors of antibody levels at 6 months. RESULTS: The study included 4868 participants, with 3808 being included in the linear mixed-model analyses. The level of IgG antibodies decreased at a consistent rate, whereas the neutralizing antibody level decreased rapidly for the first 3 months with a relatively slow decrease thereafter. Although IgG antibody levels were highly correlated with neutralizing antibody titers (Spearman's rank correlation between 0.68 and 0.75), the regression relationship between the IgG and neutralizing antibody levels depended on the time since receipt of the second vaccine dose. Six months after receipt of the second dose, neutralizing antibody titers were substantially lower among men than among women (ratio of means, 0.64; 95% confidence interval [CI], 0.55 to 0.75), lower among persons 65 years of age or older than among those 18 to less than 45 years of age (ratio of means, 0.58; 95% CI, 0.48 to 0.70), and lower among participants with immunosuppression than among those without immunosuppression (ratio of means, 0.30; 95% CI, 0.20 to 0.46). CONCLUSIONS: Six months after receipt of the second dose of the BNT162b2 vaccine, humoral response was substantially decreased, especially among men, among persons 65 years of age or older, and among persons with immunosuppression.

The Association Between Prebooster Vaccination Antibody Levels and the Risk of Severe Acute Respiratory Syndrome Coronavirus 2 Infection.

The correlation between anti-severe acute respiratory syndrome coronavirus 2 antibody levels and infection was reported. Here, we estimated the role of pre-fourth dose levels using data from 1098 healthcare workers. The risk of infection was reduced by 46% (95% confidence interval, 29%-59%) for each 10-fold increase in prebooster levels. Prebooster antibody levels could be used to optimally time boosters.

Association between Thrombin Generation and Clinical Characteristics in COVID-19 Patients.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) disease is associated with coagulopathy and an increased risk of thrombosis. An association between thrombin generation (TG) capacity, disease severity, and outcomes has not been well described. METHODS: We assessed the correlation of TG with sequential organ failure assessment (SOFA) and sepsis-induced coagulopathy (SIC) scores and clinical outcomes by analysis of plasma samples obtained from hospitalized COVID-19 patients. RESULTS: 32 patients (68.8% male), whose median age was 69 years, were assessed, of whom only 3 patients did not receive anticoagulant therapy. D-dimers were uniformly increased. During hospitalization, 2 patients suffered thrombosis, 3 experienced bleeding, and 12 died. TG parameters from anticoagulated COVID-19 patients did not significantly differ from the values obtained from non-anticoagulated healthy controls. Patients who received higher than prophylactic doses of anticoagulant therapy had increased lag time (p = 0.003), lower endogenous thrombin potential (ETP) (p = 0.037), and a reduced peak height (p = 0.006). ETP correlated with the SIC score (p = 0.038). None of the TG parameters correlated with the SOFA score or were associated with mortality. CONCLUSION: TG was not associated with disease severity among patients hospitalized with COVID-19. However, a correlation between ETP and the SIC score was noted and deserves attention.

Early Immunogenicity and Safety of the Third Dose of BNT162b2 Messenger RNA Coronavirus Disease 2019 Vaccine Among Adults Older Than 60 Years: Real-World Experience.

BACKGROUND: Despite high vaccine coverage, an increase in breakthrough coronavirus disease 2019 (COVID-19) infections, prompted administration of a third BNT162b2 dose to people aged >60 years in Israel since July 2021. Here, we report real-world immunogenicity following third dose. METHODS: Overall, 208 healthcare workers aged >60 years were included. Paired pre- and post-second and/or third dose immunoglobulin G (IgG) and neutralizing antibody titers were compared. A subpopulation of low responders to the second dose was also tested for T-cell activation. For 25 paired serum samples, we tested neutralization of wild-type vs neutralization of Delta and Lambda variants, pre- and post-third dose. Active surveillance of vaccine adverse events was conducted through surveys. RESULTS: A pronounced immune response was observed following the third dose, including a 33-fold and 51-fold increase in IgG and neutralizing antibody, respectively. The neutralizing antibody levels post-third dose were 9.34 times higher than post-second dose (geometric mean titer, 2598 [95% confidence interval {CI}, 2085-3237] vs 207 [95% CI, 126-339]). Nine previously low responders had a significant antibody increase post-third dose, and 7 of 9 showed increase in T-cell activation. Additionally, sera obtained post-third dose highly and comparably neutralized the wild-type and Delta and Lambda variants. Of 1056 responders to the adverse-event survey, none had serious events. CONCLUSIONS: We demonstrate a rapid and broad immune response to the third BNT162b2 dose in individuals >60 years of age.

Comparing immunogenicity and efficacy of two different mRNA-based COVID-19 vaccines as a fourth dose; six-month follow-up, Israel, 27 December 2021 to 24 July 2022.

We assess the immunogenicity and efficacy of Spikevax and Comirnaty as fourth dose COVID-19 vaccines. Six months post-fourth-dose, IgG levels were higher than pre-fourth dose at 1.58-fold (95% CI: 1.27-1.97) in Spikevax and 1.16-fold (95% CI: 0.98-1.37) in Comirnaty vaccinees. Nearly 60% (159/274) of vaccinees contracted SARS-CoV-2. Infection hazard ratios (HRs) for Spikevax (0.82; 95% CI: 0.62-1.09) and Comirnaty (0.86; 95% CI: 0.65-1.13) vaccinees were similar, as were substantial-disease HRs, i.e. 0.28 (95% CI: 0.13-0.62) and 0.51 (95% CI: 0.27-0.96), respectively.

Potential Antigenic Cross-reactivity Between Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and Dengue Viruses.

BACKGROUND: Coronavirus disease 2019 (COVID-19) and dengue fever are difficult to distinguish given shared clinical and laboratory features. Failing to consider COVID-19 due to false-positive dengue serology can have serious implications. We aimed to assess this possible cross-reactivity. METHODS: We analyzed clinical data and serum samples from 55 individuals with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. To assess dengue serology status, we used dengue-specific antibodies by means of lateral-flow rapid test, as well as enzyme-linked immunosorbent assay (ELISA). Additionally, we tested SARS-CoV-2 serology status in patients with dengue and performed in-silico protein structural analysis to identify epitope similarities. RESULTS: Using the dengue lateral-flow rapid test we detected 12 positive cases out of the 55 (21.8%) COVID-19 patients versus zero positive cases in a control group of 70 healthy individuals (P = 2.5E-5). This includes 9 cases of positive immunoglobulin M (IgM), 2 cases of positive immunoglobulin G (IgG), and 1 case of positive IgM as well as IgG antibodies. ELISA testing for dengue was positive in 2 additional subjects using envelope protein directed antibodies. Out of 95 samples obtained from patients diagnosed with dengue before September 2019, SARS-CoV-2 serology targeting the S protein was positive/equivocal in 21 (22%) (16 IgA, 5 IgG) versus 4 positives/equivocal in 102 controls (4%) (P = 1.6E-4). Subsequent in-silico analysis revealed possible similarities between SARS-CoV-2 epitopes in the HR2 domain of the spike protein and the dengue envelope protein. CONCLUSIONS: Our findings support possible cross-reactivity between dengue virus and SARS-CoV-2, which can lead to false-positive dengue serology among COVID-19 patients and vice versa. This can have serious consequences for both patient care and public health.

Low FXIII activity levels in intensive care unit hospitalized COVID-19 patients.

BACKGROUND: COVID-19 infection is associated with a hypercoagulable state. Severe COVID-19 patients present with high plasma fibrinogen levels, continuous deposition of fibrin and the presence of microthrombi in their lungs, accompanied by significant fibrinolysis, resulting in high D-dimer levels. Due to the role of FXIII in fibrin crosslinking and clot stabilization, we analyzed its activity levels and dynamics in COVID-19 patients hospitalized in the intensive care unit (ICU). METHODS: FXIII levels were measured in thirty four COVID-19 patients hospitalized in the ICU and in fourteen non-severe COVID-19 patients. FVIII levels were measured for comparison. Laboratory data and clinical variables were recorded. RESULTS: The average FXIII activity level in 34 ICU hospitalized COVID-19 patients was 69.9±33 %, significantly lower compared to an average of 120±20.9 % FXIII activity in 14 non-severe COVID-19 patients. FXIII activity levels were below the low normal value (< 79 % FXIII activity) in 74 % of the ICU hospitalized COVID-19 patients. In contrast, high FVIII activity was measured among all severe COVID-19 patients. Consecutive measurements, performed in fourteen ICU hospitalized COVID-19 patients, pointed to a significant decrease in FXIII activity from the average of 85.7±28.2 %, (which is in the normal range), to an average of 68.0±20.4 %, below the low normal range, within 6.4±3.4 days of ICU hospitalization. Liver functions did not differentiate between patients with low and normal FXIII activity. No inhibitor to FXIII activity was found in the plasma of severe COVID-19 patients. Levels of FXIII-A antigen correlated with FXIII activity, and were low in severe COVID-19 patients. CONCLUSIONS: Low FXIII activity levels were found in COVID-19 patients hospitalized in the ICU, with gradual decline during their hospitalization. A mechanism of consumption may account for the low FXIII activity in these patients.

Intranasal telmisartan ameliorates brain pathology in five familial Alzheimer's disease mice.

The renin-angiotensin system (RAS) is a major circulative system engaged in homeostasis modulation. Angiotensin II (Ang II) serves as its main effector hormone upon binding to its primary receptor, Ang II receptor type 1 (AT1R). It is well established that an intrinsic independent brain RAS exists. Abnormal AT1R activation both in the periphery and in the brain probably contributes to the development of Alzheimer's disease (AD) pathology that is characterized, among others, by brain inflammation. Moreover, treatment with drugs that block AT1R (AT1R blockers, ARBs) ameliorates most of the clinical risk factors leading to AD. Previously we showed that short period of intranasal treatment with telmisartan (a brain penetrating ARB) reduced brain inflammation and ameliorated amyloid burden (a component of Alzheimer's plaques) in AD transgenic mouse model. In the present study, we aimed to examine the long-term effect of intranasally administrated telmisartan on brain inflammation features including microglial activation, astrogliosis, neuronal loss and hippocampus-dependent cognition in five-familial AD mouse model (5XFAD). Five month of intranasal treatment with telmisartan significantly reduced amyloid burden in the cortex and hippocampus of 5XFAD mice as compared with the vehicle-treated 5XFAD group. Similar effects were also observed for CD11b staining, which is a marker for microglial accumulation. Telmisartan also significantly reduced astrogliosis and neuronal loss in the cortex of 5XFAD mice compared with the vehicle-treated group. Improved spatial acquisition of the 5XFAD mice following long-term intranasal administration of telmisartan was also observed. Taken together, our data suggest a significant role for AT1R blockage in mediating neuronal loss and cognitive behavior, possibly through regulation of amyloid burden and glial inflammation.

Differential effect of intranasally administrated kinin B1 and B2 receptor antagonists in Alzheimer's disease mice.

An Increasing body of evidence supports a critical role of brain inflammation in the pathogenesis of Alzheimer's disease. A principal aspect of the brain immune response to inflammation is the activation of microglia. It has been shown that the kinin system is activated during brain inflammation and previously we demonstrated that bradykinin B1 receptor agonist reduced microglial activation in vitro. The aim of the present study was to investigate the effects of bradykinin B1 or B2 receptor antagonists on microglial release of pro-inflammatory factors in BV2 microglia. In vivo, we focused on the effects of intranasally given kinin antagonists on amyloid burden and microglia/macrophage marker expression in brains of 5X familial Alzheimer's disease mice. The present data show that pharmacological antagonism of B1 receptor (R-715) but not B2 receptor (HOE-140) markedly increased nitric oxide and tumor necrosis factor alpha release from BV2 microglial cells. We also showed that intranasal treatment with R-715 but not HOE-140 of Alzheimer's mice enhanced amyloid beta burden and microglia/macrophages activation. Taken together, our data reveal a possible role for the bradykinin B1 receptor in neuroinflammation and in the control of Abeta accumulation in transgenic mice, possibly through regulation of glial cell responses.

Humoral response superiority of the monovalent XBB.1.5 over the bivalent BA.1 and BA.5 mRNA COVID-19 vaccines.

JN.1, the dominating SARS-CoV-2 variant, is antigenically distinct from ancestral BA.1, BA.5 and XBB.1.5 variants, raising concern about effectiveness of updated COVID-19 vaccines. Here, we compared the neutralizing antibody response against JN.1, 1-month after receipt of the three available Moderna mRNA vaccines. Sera obtained from 37, 30 and 30 XBB.1.5, BA.1 and BA.4-5 -vaccine recipients, respectively, were tested for anti-RBD IgG and for JN-1 specific neutralizing antibody levels. Geometric mean fold rise (GMFR) in JN.1 specific neutralizing titers was 27 (95 % CI: 17-43.1), 10.1 (95 % CI: 6.48-15.7) and 8.77 (95 % CI: 5.69-13.5) following XBB.1.5, BA.1 and BA.4-5 vaccines, respectively, translating into a 64 % lower adjusted response (geometric mean ratio [GMR] = 0.36, 95 % CI: 0.21-0.6) in the BA.1 arm, and a 75 % lower response (GMR = 0.25, 95 % CI: 0.15-0.43) in the BA.4-5 arm. This suggests that XBB.1.5 vaccination will most likely, result in improved effectiveness against JN.1 compared with other COVID-19 vaccines.

Immunogenicity and Reactogenicity of Coadministration of COVID-19 and Influenza Vaccines.

Importance: COVID-19 and seasonal influenza vaccines were previously given separately, although their coadministration is warranted for vaccination adherence. Limited data on their coadministration have been published. Objective: To compare the reactogenicity and immunogenicity of COVID-19 and influenza vaccinations administered together with those of COVID-19 vaccination alone. Design, Setting, and Participants: This prospective cohort study included health care workers at a large tertiary medical center in Israel who received the Influvac Tetra (Abbott) influenza vaccine (2022/2023), the Omicron BA.4/BA.5-adapted bivalent (Pfizer/BioNTech) vaccine, or both. Vaccination began in September 2022, and data were collected until January 2023. Vaccines were offered to all employees and were coadministered or given separately. Adverse reaction questionnaires were sent, and serologic samples were also collected. Exposures: Receiving COVID-19 vaccine, influenza vaccine, or both. Main Outcomes and Measures: The main outcomes for the reactogenicity analysis were symptoms following vaccine receipt, assessed by a digital questionnaire: any local symptoms; fever; weakness or fatigue; any systemic symptoms; and their duration. The immunogenicity analysis' outcome was postvaccination anti-spike IgG titer. Results: This study included 2 cohorts for 2 separate analyses. The reactogenicity analysis included 588 participants (of 649 questionnaire responders): 85 in the COVID-19 vaccine-alone group (median [IQR] age, 71 [58-74] years; 56 [66%] female); 357 in the influenza vaccine-alone group (median [IQR] age, 55 [40-65] years; 282 [79%] female); and 146 in the coadministration group (median [IQR] age, 61 [50-71] years; 81 [55%] female). The immunogenicity analysis included 151 participants: 74 participants in the COVID-19 vaccine group (median [IQR] age, 67 [56-73] years; 45 [61%] female) and 77 participants in the coadministration group (median [IQR] age, 60 [49-73] years; 42 [55%] female). Compared with COVID-19 vaccination alone, the risk of systemic symptoms was similar in the coadministration group (odds ratio, 0.82; 95% CI, 0.43-1.56). Geometric mean titers in the coadministration group were estimated to be 0.84 (95% CI, 0.69-1.04) times lower than in the COVID-19 vaccine-alone group. Conclusions and Relevance: In this cohort study of health care workers who received a COVID-19 vaccine, an influenza vaccine, or both, coadministration was not associated with substantially inferior immune response or to more frequent adverse events compared with COVID-19 vaccine administration alone, supporting the coadministration of these vaccines.

Humoral Immunity of Unvaccinated COVID-19 Recovered vs. Naïve BNT162b2 Vaccinated Individuals: A Prospective Longitudinal Study.

To study the differences in the immune response to SARS-CoV-2 infection compared to the response to vaccination, we characterized the humoral immune kinetics of these situations. In this prospective longitudinal study, we followed unvaccinated COVID-19-recovered individuals (n = 130) and naïve, two-dose BNT162b2-vaccinated individuals (n = 372) who were age- and BMI-matched for six months during the first pandemic year. Anti-RBD-IgG, neutralizing antibodies (NAbs), and avidity were assessed monthly. For recovered patients, data on symptoms and the severity of the disease were collected. Anti-RBD-IgG and NAbs titers at peak were higher after vaccination vs. after infection, but the decline was steeper (peak log IgG: 3.08 vs. 1.81, peak log NAbs: 5.93 vs. 5.04, slopes: -0.54 vs. -0.26). Peak anti-RBD-IgG and NAbs were higher in recovered individuals with BMI > 30 and in older individuals compared to individuals with BMI < 30, younger population. Of the recovered, 42 (36%) experienced long-COVID symptoms. Avidity was initially higher in vaccinated individuals compared with recovered individuals, though with time, it increased in recovered individuals but not among vaccinated individuals. Here, we show that while the initial antibody titers, neutralization, and avidity are lower in SARS-CoV-2-recovered individuals, they persist for a longer duration. These results suggest differential protection against COVID-19 in recovered-unvaccinated vs. naïve-vaccinated individuals.

Humoral Response to the Fourth BNT162b2 Vaccination and Link Between the Fourth Dose, Omicron Infection, and Disease Severity in Renal Transplant Recipients.

BACKGROUND: The effectiveness of the fourth BNT162b2 vaccination in reducing the rate and severity of coronavirus disease 2019 (COVID-19) caused by the Omicron variant in renal transplant recipients (RTRs) is unknown. METHODS: Interviews were conducted with 447 RTRs regarding the status and timing of the fourth vaccination, prior vaccinations, and preceding COVID-19 infection. RTRs with polymerase chain reaction-confirmed COVID-19 infection from December 1, 2021, to the end of March 2022 were considered to have been infected with the Omicron variant and were interviewed to determine their disease severity. In a subgroup of 74 RTRs, the humoral response to the fourth dose was analyzed. In 30 RTRs, microneutralization assays were performed to reveal the humoral response to wild-type, Delta, and Omicron variant isolates before and after the fourth dose. RESULTS: Of 447 RTRs, 144 (32.2%) were infected with the Omicron variant, with 71 (49.3%) of the infected RTRs having received the fourth vaccine dose. RTRs who did not receive the fourth dose before the infection had more serious illness. In a subgroup of 74 RTRs, the fourth dose elicited a positive humoral response in 94.6% (70/74), with a significant increase in geometric mean titer for receptor-binding domain immunoglobulin G and neutralizing antibodies ( P < 0.001). The humoral responses to the Omicron variant before and after the fourth dose were significantly lower than the responses to the wild-type and the Delta variants. CONCLUSIONS: Overall, the fourth BNT162b2 dose was effective in reducing the rate and severity of Omicron disease in RTRs, despite the reduced humoral response to the variant.

Factors Associated With Protection From SARS-CoV-2 Omicron Variant Infection and Disease Among Vaccinated Health Care Workers in Israel.

Importance: A correlation between antibody levels and risk of infection has been demonstrated for the wild-type, Alpha, and Delta SARS-COV-2 variants. High rates of breakthrough infections by the Omicron variant emphasized the need to investigate whether the humoral response elicited by mRNA vaccines is also associated with reduced risk of Omicron infection and disease. Objective: To investigate whether the high antibody levels in individuals who have received at least 3 doses of an mRNA vaccine are associated with reduced risk of Omicron infection and disease. Design, Setting, and Participants: This prospective cohort study used serial real time-polymerase chain reaction (RT-PCR) and serological test data from January and May 2022 to assess the association of preinfection immunoglobin G (IgG) and neutralizing antibody titers with incidence of Omicron variant infection, incidence of symptomatic disease, and infectivity. Participants included health care workers who had received 3 or 4 doses of an mRNA COVID-19 vaccine. Data were analyzed from May to August 2022. Exposures: Levels of SARS-CoV-2 anti-receptor binding domain IgG and neutralizing antibodies. Main Outcomes and Measures: The main outcomes were incidence of Omicron infection, incidence of symptomatic disease, and infectivity. Outcomes were measured using SARS-COV-2 PCR and antigen testing and daily online surveys regarding symptomatic disease. Results: This study included 3 cohorts for 3 different analyses: 2310 participants were included in the protection from infection analysis (4689 exposure events; median [IQR] age, 50 [40-60] years; 3590 [76.6%] among female health care workers), 667 participants (median [IQR] age, 46.28 (37.44,54.8); 516 [77.4%] female) in the symptomatic disease analysis, and 532 participants (median [IQR] age, 48 [39-56] years; 403 [75.8%] female) in the infectivity analysis. Lower odds of infection were observed for each 10-fold increase in preinfection IgG (odds ratio [OR], 0.71; 95% CI, 0.56-0.90) and for each 2-fold increase in neutralizing antibody titers (OR, 0.89; 95% CI, 0.83-0.95). The odds of substantial symptomatic disease were reduced for each 10-fold increase in IgG levels (OR, 0.48; 95% CI, 0.29-0.78) and for each 2-fold increase in neutralizing antibodies levels (OR, 0.86; 95% CI, 0.76-0.96). Infectivity, assessed by mean cycle threshold value, was not significantly decreased with increasing IgG or neutralizing antibodies titers. Conclusions and Relevance: In this cohort study of vaccinated health care workers, IgG and neutralizing antibody titer levels were associated with protection against infection with the Omicron variant and against symptomatic disease.

Immunogenicity of Omicron BA.1-adapted BNT162b2 vaccines: randomized trial, 3-month follow-up.

OBJECTIVES: The capability of the SARS-CoV-2 Omicron variant to escape immunity conferred by mRNA vaccines has led to the development of Omicron-adapted vaccines. In this study, we aimed to compare the immune response with the ancestral strain and with the BA.1 Omicron variant after administration of the original vaccine and the Omicron-adapted vaccine. METHODS: This is an ongoing phase 3, double-blinded randomized controlled trial, comparing the original BNT161b2 vaccine, monovalent Omicron BA.1-adapted BNT161b2 vaccine, and bivalent combinations. Each vaccine was given at a 30 µg and 60 µg dose. Primary outcomes considered included neutralization titers of SARS-CoV-2 ancestral strain and Omicron BA.1. Exploratory endpoints included neutralization titers for Omicron BA.5, and the incidence of COVID-19 cases. RESULTS: Overall, 122 individuals (22, 19, 20, 20, 20, 20, and 21 in each arm) completed a 90-day follow-up. Three months after vaccination, adjusting for baseline levels, neutralizing antibody titers were 0.63 (95% CI: 0.3-1.32) and 0.54 (0.24-1.2) for monovalent/60 µg, 0.9 (0.42-1.92) and 2.69 (1.17-6.17) times for monovalent-Omi.BA.1/30 µg, 1.28 (0.6-2.75) and 2.79 (1.21-6.41) times for monovalent-Omi.BA.1/60 µg, 0.96 (0.46-1.97) and 2.07 (0.93-4.58) times for bivalent-Omi.BA.1/30 µg, and 0.79 (0.38-1.63) and 1.95 (0.88-4.32) times for bivalent-Omi.BA.1/60 µg when compared with BNT162b2/30 µg against the ancestral strain and BA.1 variant, respectively. DISCUSSION: BA.1-adapted mRNA vaccines lead to a stronger neutralizing antibody response against the Omicron BA.1 sub-variant.