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.

Initial Analysis of Viral Dynamics and Circulating Viral Variants During the mRNA-1273 Phase 3 COVE Trial

This analysis assessed the impact of mRNA-1273 vaccination on the viral dynamics of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in the ongoing Coronavirus Efficacy (COVE) trial. mRNA-1273 vaccination significantly reduced SARS-CoV-2 viral copy number (95% confidence interval [CI]) by 100-fold on the day of diagnosis (4.1 [3.4-4.8] versus placebo (6.2 [6.0-6.4] log10 copies/ml). Median times to undetectable viral copies were 4 days for mRNA-1273 and 7 for placebo. Vaccination also reduced the burden of disease and infection scores. Vaccine efficacies (95% CI) during the trial against SARS-CoV-2 variants circulating in the US were 82.4% (40.4%-94.8%) for Epsilon and Gamma, and 81.2% (36.1%-94.5%) for the Epsilon variants. The detection of other respiratory viruses during the trial was similar between groups. In those who became SARS-CoV-2 infected, the reduction of viral load after mRNA-1273 vaccination is potentially correlated to the risk of transmission, which has not been assessed in this study.

Covid-19 in the Phase 3 Trial of mRNA-1273 During the Delta-variant Surge

BackgroundFollowing emergency use authorization in December 2020, the Coronavirus Efficacy (COVE) trial was amended to an open-label phase, where participants were unblinded and those randomized to placebo were offered vaccination. Emergence of the delta variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been associated with increased incidences of coronavirus disease 2019 (Covid-19) among unvaccinated and vaccinated persons. This exploratory analysis evaluated the incidence and genetic sequences of Covid-19 cases in the ongoing COVE trial during the open-label phase, with a focus on July-August 2021, when delta-variants surged in the US. MethodsCovid-19 cases were identified in participants initially randomized to mRNA-1273 (vaccinated from July-December 2020) and those initially randomized to the placebo (vaccinated December 2020-April 2021) who received at least one dose and were SARS-CoV-2-negative at baseline in the modified-intent-to-treat population were analyzed. Included were Covid-19 cases occurring after 26-Mar-2021 with positive RT-PCR results in nasopharyngeal samples (central lab test) and reported Covid-19 symptoms. Genetic sequencing of Covid-19 cases was also performed. ResultsThere were 14,746 participants in the earlier mRNA-1273 (mRNA-1273e) group and 11,431 in the later placebo-mRNA1273 (mRNA-1273p) group. Covid-19 cases increased from the start of the open-label phase to July-August 2021. During July and August, 162 Covid-19 cases occurred in the mRNA-1273e group and 88 in the mRNA-1273p group. Of the cases sequenced, 144/149 [97%]) in the mRNA-1273 and 86/88 (99%) in the mRNA-1273p groups were attributed to delta. The incidence rate of Covid-19 was lower for the mRNA-1273p (49.0/1000 person-years) versus mRNA-1273e (77.1/1000 person-years) group [36.4% (95% CI 17.1%-51.5%) reduction]. There were fewer severe Covid-19 cases in the mRNA-1273p (6; 6.2/1000 person-years) than mRNA-1273e (13; 3.3/1000 person-years) [46.0% (95% CI -52.4%-83.2%) reduction]. Three Covid-19 related hospitalizations occurred with two resulting deaths in the mRNA-1273e group. ConclusionIncidence rates of Covid-19 and severe Covid-19 were lower during the months when delta was the dominant variant (July/August 2021) among COVE participants vaccinated more recently. Analysis of COVID-19 cases from the open-label phase of the COVE study is ongoing.

Durability of mRNA-1273-induced antibodies against SARS-CoV-2 variants

SARS-CoV-2 mutations may diminish vaccine-induced protective immune responses, and the durability of such responses has not been previously reported. Here, we present a comprehensive assessment of the impact of variants B.1.1.7, B.1.351, P.1, B.1.429, and B.1.526 on binding, neutralizing, and ACE2-blocking antibodies elicited by the vaccine mRNA-1273 over seven months. Cross-reactive neutralizing responses were rare after a single dose of mRNA-1273. At the peak of response to the second dose, all subjects had robust responses to all variants. Binding and functional antibodies against variants persisted in most subjects, albeit at low levels, for 6 months after the primary series of mRNA-1273. Across all assays, B.1.351 had the greatest impact on antibody recognition, and B.1.1.7 the least. These data complement ongoing studies of clinical protection to inform the potential need for additional boost vaccinations. One-Sentence SummaryMost mRNA-1273 vaccinated individuals maintained binding and functional antibodies against SARS-CoV-2 variants for 6 months.

Preliminary Analysis of Safety and Immunogenicity of a SARS-CoV-2 Variant Vaccine Booster

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of a global pandemic of coronavirus disease 2019 (COVID-19) that has led to more than 3 million deaths worldwide. Safe and effective vaccines are now available, including the mRNA-1273 prototype vaccine, which encodes for the Wuhan SARS-CoV-2 spike (S) protein stabilized in the prefusion conformation by 2 proline substitutions. This vaccine showed 94% efficacy in prevention of symptomatic COVID-19 disease in a phase 3 clinical study. Recently, SARS-CoV-2 variants have emerged, some of which have shown decreased susceptibility to neutralization by vaccine-induced antibody, most notably the B.1.351 variant, although the overall impact on vaccine efficacy remains to be determined. In addition, recent evidence of waning antibody levels after infection or vaccination point to the need for periodic boosting of immunity. Here we present the preliminary evaluation of a clinical study on the use of the prototype mRNA-1273 or modified COVID-19 mRNA vaccines, designed to target emerging SARS-CoV-2 variants as booster vaccines in participants previously vaccinated approximately 6 months earlier with two doses of the prototype vaccine, mRNA-1273. The modified vaccines include a monovalent mRNA-1273.351 encoding for the S protein found in the B.1.351 variant and multivalent mRNA-1273.211 comprising a 1:1 mix of mRNA-1273 and mRNA-1273.351. As single 50 {micro}g booster vaccinations, both mRNA-1273 and mRNA-1273.351 had acceptable safety profiles and were immunogenic. Antibody neutralization titers against B.1.351 and P.1 variants measured by SARS-CoV-2 pseudovirus neutralization (PsVN) assays before the booster vaccinations, approximately 6 to 8 months after the primary series, were low or below the assay limit of quantification, although geometric mean titers versus the wild-type strain remained above levels likely to be protective. Two weeks after the booster vaccinations, titers against the wild-type original strain, B.1.351, and P.1 variants increased to levels similar to or higher than peak titers after the primary series vaccinations. Although both mRNA-1273 and mRNA-1273.351 boosted neutralization of the wild-type original strain, and B.1.351 and P.1 variants, mRNA-1273.351 appeared to be more effective at increasing neutralization of the B.1.351 virus versus a boost with mRNA-1273. The vaccine trial is ongoing and boosting of clinical trial participants with the multivalent mRNA-1273.211 is currently being evaluated.