Safety and Immunogenicity of an Omicron BA.4/BA.5 Bivalent Vaccine against Covid-19

BackgroundInformation on the safety and immunogenicity of the omicron BA.4/BA.5-containing bivalent booster mRNA-1273.222 are needed. MethodsIn this ongoing, phase 2/3 trial, 50-g mRNA-1273.222 (25-g each ancestral Wuhan-Hu-1 and omicron BA.4/BA.5 spike mRNAs) is compared to 50-g mRNA-1273, administered as second boosters in adults who previously received a 2-injection (100-g) primary series and first booster (50-g) dose of mRNA-1273. The primary objectives were safety and immunogenicity 28 days post-boost. ResultsParticipants received 50-g of mRNA-1273 (n=376) or mRNA-1273.222 (n=511) as second booster doses. Omicron BA.4/BA.5 and ancestral SARS-CoV-2 D614G neutralizing antibody geometric mean titers (GMTs [95% confidence interval]) after mRNA-1273.222 (2324.6 [1921.2-2812.7] and 7322.4 [6386.2-8395.7]) were significantly higher than mRNA-1273 (488.5 [427.4-558.4] and 5651.4 (5055.7-6317.3) respectively, at day 29 post-boost in participants with no prior SARS-CoV-2-infection. A randomly selected subgroup (N=60) of participants in the mRNA-1273.222 group also exhibited cross-neutralization against the emerging omicron variants BQ.1.1 and XBB.1. No new safety concerns were identified with mRNA-1273.222. Vaccine effectiveness was not assessed in this study; in an exploratory analysis 1.6% (8/511) of mRNA-1273.222 recipients had Covid-19 post-boost. ConclusionThe bivalent omicron BA.4/BA.5-containing vaccine mRNA-1273.222 elicited superior neutralizing antibody responses against BA.4/BA.5 compared to mRNA-1273, with no safety concerns identified. (Supported by Moderna; ClinicalTrials.gov Identifier: NCT04927065)

A Bivalent Omicron-containing Booster Vaccine Against Covid-19

BackgroundUpdated vaccination strategies against acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern are needed. Interim results of the safety and immunogenicity of the bivalent omicron-containing mRNA-1273.214 booster candidate are presented. MethodsIn this ongoing, phase 2/3 trial, the 50-g bivalent vaccine mRNA-1273.214 (25-g each ancestral Wuhan-Hu-1 and omicron B.1.1.529 spike SARS-CoV-2 mRNAs) was compared to the authorized 50-g mRNA-1273 booster in adults who previously received 2-dose primary series of 100-g mRNA-1273 and a first booster dose of 50-g mRNA-1273 at least 3 months prior. Primary objectives were safety and reactogenicity, and immunogenicity of 50-g mRNA-1273.214 compared with 50-g mRNA-1273. Immunogenicity data 28 days after the booster dose are presented. ResultsFour hundred thirty-seven and 377 participants received 50-g of mRNA-1273.214, or mRNA-1273, respectively. Median time between first and second booster doses of mRNA-1273.214 and mRNA-1273 were similar (136 and 134 days, respectively). In participants with no prior SARS-CoV-2 infection, observed omicron neutralizing antibody geometric mean titers (GMTs [95% confidence interval]) after the mRNA-1273.214 and mRNA-1273 booster doses, were 2372.4 (2070.6-2718.2) and 1473.5 (1270.8-1708.4) respectively and the model-based GMT ratio (97.5% confidence interval) was 1.75 (1.49-2.04). All pre-specified non-inferiority (ancestral SARS-CoV-2 with D614G mutation [D614G] GMT ratio; ancestral SARS-CoV-2 [D614G] and omicron seroresponse rates difference) and superiority primary objectives (omicron GMT ratio) for mRNA-1273.214 compared to mRNA-1273 were met. Additionally, mRNA-1273.214 50-g induced a potent neutralizing antibody response against omicron subvariants BA.4/BA.5 and higher binding antibody responses against alpha, beta, gamma, delta and omicron variants. Safety and reactogenicity profiles were similar and well-tolerated for both vaccines groups. ConclusionThe bivalent vaccine mRNA-1273.214 50-g was well-tolerated and elicited a superior neutralizing antibody response against omicron, compared to mRNA-1273 50-g, and a non-inferior neutralizing antibody response against the ancestral SARS-CoV-2 (D614G), 28 days after immunization, creating a new tool as we respond to emerging SARS-CoV-2 variants.

Anti-nucleocapsid antibodies following SARS-CoV-2 infection in the blinded phase of the mRNA-1273 Covid-19 vaccine efficacy clinical trial

ImportanceThe performance of immunoassays for determining past SARS-CoV-2 infection, which were developed in unvaccinated individuals, has not been assessed in vaccinated individuals. ObjectiveTo evaluate anti-nucleocapsid antibody (anti-N Ab) seropositivity in mRNA-1273 vaccine efficacy trial participants after SARS-CoV-2 infection during the trials blinded phase. DesignNested analysis in a Phase 3 randomized, placebo-controlled vaccine efficacy trial. Nasopharyngeal swabs for SARS-CoV-2 PCR testing were taken from all participants on Day 1 and Day 29 (vaccination days), and during symptom-prompted illness visits. Serum samples from Days 1, 29, 57, and the Participant Decision Visit (PDV, when participants were informed of treatment assignment, median day 149) were tested for anti-N Abs. SettingMulticenter, randomized, double-blind, placebo-controlled trial at 99 sites in the US. ParticipantsTrial participants were [≥] 18 years old with no known history of SARS-CoV-2 infection and at appreciable risk of SARS-CoV-2 infection and/or high risk of severe Covid-19. Nested sub-study consists of participants with SARS-CoV-2 infection during the blinded phase of the trial. InterventionTwo mRNA-1273 (Moderna) or Placebo injections, 28 days apart. Main Outcome and MeasureDetection of serum anti-N Abs by the Elecsys (Roche) immunoassay in samples taken at the PDV from participants with SARS-CoV-2 infection during the blinded phase. The hypothesis tested was that mRNA-1273 recipients have different anti-N Ab seroconversion and/or seroreversion profiles after SARS-CoV-2 infection, compared to placebo recipients. The hypothesis was formed during data collection; all main analyses were pre-specified before being conducted. ResultsWe analyzed data from 1,789 participants (1,298 placebo recipients and 491 vaccine recipients) with SARS-CoV-2 infection during the blinded phase (through March 2021). Among participants with PCR-confirmed Covid-19 illness, seroconversion to anti-N Abs at a median follow up of 53 days post diagnosis occurred in 21/52 (40%) of the mRNA-1273 vaccine recipients vs. 605/648 (93%) of the placebo recipients (p < 0.001). Higher SARS-CoV-2 viral copies at diagnosis was associated with a higher likelihood of anti-N Ab seropositivity (odds ratio 1.90 per 1-log increase; 95% confidence interval 1.59, 2.28). Conclusions and RelevanceAs a marker of recent infection, anti-N Abs may have lower sensitivity in mRNA-1273-vaccinated persons who become infected. Vaccination status should be considered when interpreting seroprevalence and seropositivity data based solely on anti-N Ab testing Trial RegistrationClinicalTrials.gov NCT04470427 Key PointsO_ST_ABSQuestionC_ST_ABSDoes prior mRNA-1273 vaccination influence anti-nucleocapsid antibody seroconversion and/or seroreversion after SARS-CoV-2 infection? FindingsAmong participants in the mRNA-1273 vaccine efficacy trial with PCR-confirmed Covid-19, anti-nucleocapsid antibody seroconversion at the time of study unblinding (median 53 days post diagnosis and 149 days post enrollment) occurred in 40% of the mRNA-1273 vaccine recipients vs. 93% of the placebo recipients, a significant difference. Higher SARS-CoV-2 viral copy number upon diagnosis was associated with a greater chance of anti-nucleocapsid antibody seropositivity (odds ratio 1.90 per 1-log increase; 95% confidence interval 1.59, 2.28). All infections analyzed occurred prior to the circulation of delta and omicron viral variants. MeaningConclusions about the prevalence and incidence of SARS-CoV-2 infection in vaccinated persons based on anti-nucleocapsid antibody assays need to be weighed in the context of these results.

Safety and Immunogenicity of a 100 μg mRNA-1273 Vaccine Booster for Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2)

ImportanceDue to the emergence of highly transmissible SARS-CoV-2 variants, evaluation of boosters is needed. ObjectivesEvaluate safety and immunogenicity of 100-{micro}g of mRNA-1273 booster dose in adults. DesignOpen-label, Phase 2/3 study. SettingMulticenter study at 8 sites in the U.S. ParticipantsThe mRNA-1273 100-{micro}g booster was administered to adults who previously received a two dose primary series of 100-{micro}g mRNA-1273 in the phase 3 Coronavirus Efficacy (COVE) trial, at least 6 months earlier. InterventionLipid nanoparticle containing 100-{micro}g of mRNA encoding the spike glycoprotein of SARS-CoV-2 (Wuhan-HU-1). Main Outcomes and MeasuresSolicited local and systemic adverse reactions, and unsolicited adverse events were collected after vaccination. Primary immunogenicity objectives were to demonstrate non-inferiority of the neutralizing antibody (nAb) response against SARS-CoV-2 based on the geometric mean titer (GMTs) and the seroresponse rates (SRRs) (booster dose vs. primary series in a historical control group). nAbs against SARS-CoV-2 variants were also evaluated. ResultsThe 100-{micro}g booster dose had a greater incidence of local and systemic adverse reactions compared to the second dose of mRNA-1273 as well as the 50-{micro}g mRNA-1273 booster in separate studies. The geometric mean titers (GMTs; 95% CI) of SARS-CoV-2 nAbs against the ancestral SARS-CoV-2 at 28 days after the 100-{micro}g booster dose were 4039.5 (3592.7,4541.8) and 1132.0 (1046.7,1224.2) at 28 days after the second dose in the historical control group [GMT ratio=3.6 (3.1,4.2)]. SRRs (95% CI) were 100% (98.6,100) at 28 days after the booster and 98.1% (96.7,99.1) 28 days after the second dose in the historical control group [percentage difference=1.9% (0.4,3.3)]. The GMT ratio (GMR) and SRR difference for the booster as compared to the primary series met the pre-specified non-inferiority criteria. Delta-specific nAbs also increased (GMT fold-rise=233.3) after the 100-{micro}g booster of mRNA-1273. Conclusions and RelevanceThe 100-{micro}g mRNA-1273 booster induced a robust neutralizing antibody response against SARS-CoV-2, and reactogenicity was higher with the 100-{micro}g booster dose compared to the authorized booster dose level in adults (50-{micro}g). mRNA-1273 100-{micro}g booster dose can be considered when eliciting an antibody response might be challenging such as in moderately or severely immunocompromised hosts. Trial Registration: NCT04927065 Key PointsQuestion: What is the safety and immunogenicity of a booster dose of 100 {micro}g of mRNA-1273 in adults who previously received the primary series of mRNA-1273? Findings: In this open-label, Phase 2/3 study, the 100 {micro}g booster dose of mRNA-1273 had a greater incidence of local and systemic adverse reactions compared to a 50 {micro}g booster dose of mRNA- 1273 or after the second dose of mRNA-1273 during the primary series. The 100 {micro}g booster dose of mRNA-1273 induced a robust antibody response against the ancestral SARS-CoV-2 and variants. Meaning: mRNA-1273 100 {micro}g booster dose might be considered when eliciting an antibody response might be challenging, such as in moderately or severely immunocompromised hosts.

Immune Memory Response After a Booster Injection of mRNA-1273 for Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2)

Rising breakthrough infections of coronavirus-2 (SARS-CoV-2) in previously immunized individuals has raised concerns for a booster to combat suspected waning immunity and new variants. Participants immunized 6-8 months earlier with a primary series of two doses of 50 or 100 {micro}g of mRNA-1273 were administered a booster injection of 50 {micro}g of mRNA-1273. Neutralizing antibody levels against wild-type virus and the Delta variant at one month after the booster were 1.7-fold and 2.1-fold higher, respectively, than those 28 days post primary series second injection indicating an immune memory response. The reactogenicity after the booster dose was similar to that after the second dose in the primary series of two doses of mRNA-1273 (50 or 100 {micro}g) with no serious adverse events reported in the one-month follow-up period. These results demonstrate that a booster injection of mRNA-1273 in previously immunized individuals stimulated an immune response greater than the primary vaccination series.