Efficacy of the mRNA-1273 SARS-CoV-2 Vaccine at Completion of Blinded Phase.

BACKGROUND: At interim analysis in a phase 3, observer-blinded, placebo-controlled clinical trial, the mRNA-1273 vaccine showed 94.1% efficacy in preventing coronavirus disease 2019 (Covid-19). After emergency use of the vaccine was authorized, the protocol was amended to include an open-label phase. Final analyses of efficacy and safety data from the blinded phase of the trial are reported. METHODS: We enrolled volunteers who were at high risk for Covid-19 or its complications; participants were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 µg) or placebo, 28 days apart, at 99 centers across the United States. The primary end point was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The data cutoff date was March 26, 2021. RESULTS: The trial enrolled 30,415 participants; 15,209 were assigned to receive the mRNA-1273 vaccine, and 15,206 to receive placebo. More than 96% of participants received both injections, 2.3% had evidence of SARS-CoV-2 infection at baseline, and the median follow-up was 5.3 months in the blinded phase. Vaccine efficacy in preventing Covid-19 illness was 93.2% (95% confidence interval [CI], 91.0 to 94.8), with 55 confirmed cases in the mRNA-1273 group (9.6 per 1000 person-years; 95% CI, 7.2 to 12.5) and 744 in the placebo group (136.6 per 1000 person-years; 95% CI, 127.0 to 146.8). The efficacy in preventing severe disease was 98.2% (95% CI, 92.8 to 99.6), with 2 cases in the mRNA-1273 group and 106 in the placebo group, and the efficacy in preventing asymptomatic infection starting 14 days after the second injection was 63.0% (95% CI, 56.6 to 68.5), with 214 cases in the mRNA-1273 group and 498 in the placebo group. Vaccine efficacy was consistent across ethnic and racial groups, age groups, and participants with coexisting conditions. No safety concerns were identified. CONCLUSIONS: The mRNA-1273 vaccine continued to be efficacious in preventing Covid-19 illness and severe disease at more than 5 months, with an acceptable safety profile, and protection against asymptomatic infection was observed. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; COVE ClinicalTrials.gov number, NCT04470427.).

High-dose rifapentine with moxifloxacin for pulmonary tuberculosis.

BACKGROUND: Tuberculosis regimens that are shorter and simpler than the current 6-month daily regimen are needed. METHODS: We randomly assigned patients with newly diagnosed, smear-positive, drug-sensitive tuberculosis to one of three regimens: a control regimen that included 2 months of ethambutol, isoniazid, rifampicin, and pyrazinamide administered daily followed by 4 months of daily isoniazid and rifampicin; a 4-month regimen in which the isoniazid in the control regimen was replaced by moxifloxacin administered daily for 2 months followed by moxifloxacin and 900 mg of rifapentine administered twice weekly for 2 months; or a 6-month regimen in which isoniazid was replaced by daily moxifloxacin for 2 months followed by one weekly dose of both moxifloxacin and 1200 mg of rifapentine for 4 months. Sputum specimens were examined on microscopy and after culture at regular intervals. The primary end point was a composite treatment failure and relapse, with noninferiority based on a margin of 6 percentage points and 90% confidence intervals. RESULTS: We enrolled a total of 827 patients from South Africa, Zimbabwe, Botswana, and Zambia; 28% of patients were coinfected with the human immunodefiency virus. In the per-protocol analysis, the proportion of patients with an unfavorable response was 4.9% in the control group, 3.2% in the 6-month group (adjusted difference from control, -1.8 percentage points; 90% confidence interval [CI], -6.1 to 2.4), and 18.2% in the 4-month group (adjusted difference from control, 13.6 percentage points; 90% CI, 8.1 to 19.1). In the modified intention-to-treat analysis these proportions were 14.4% in the control group, 13.7% in the 6-month group (adjusted difference from control, 0.4 percentage points; 90% CI, -4.7 to 5.6), and 26.9% in the 4-month group (adjusted difference from control, 13.1 percentage points; 90% CI, 6.8 to 19.4). CONCLUSIONS: The 6-month regimen that included weekly administration of high-dose rifapentine and moxifloxacin was as effective as the control regimen. The 4-month regimen was not noninferior to the control regimen. (Funded by the European and Developing Countries Clinical Trials Partnership and the Wellcome Trust; RIFAQUIN Current Controlled Trials number, ISRCTN44153044.).

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

BACKGROUND: Following 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. METHODS: Covid-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. RESULTS: There 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. CONCLUSION: Incidence 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.

Dissecting the immune response to MF59-adjuvanted and nonadjuvanted seasonal influenza vaccines in children less than three years of age.

INTRODUCTION: Annual seasonal influenza epidemics are particularly dangerous for the very young, the elderly and chronically ill individuals, in whom infection can cause severe morbidity, hospitalization and death. Existing, nonadjuvanted influenza vaccines exhibit a suboptimal immunogenicity and efficacy in immunologically naive subjects such as young children. METHODS: This phase II, randomized clinical trial was conducted to evaluate the antibody and cell-mediated responses to a trivalent influenza vaccine administered without adjuvant (TIV) or adjuvanted with MF59 (ATIV) in previously nonvaccinated children less than 3 years of age. RESULTS: The MF59-adjuvanted vaccine was well tolerated, and induced higher titers of hemagglutination inhibition antibodies able to recognize strains different from the one used in the vaccine (heterovariant) than TIV. The presence of the adjuvant MF59 induced a larger expansion of vaccine-specific CD4 T cells. Interestingly, the adjuvant MF59 did not modify the cytokine profile of the elicited T cells, characterized by the production of IL-2 and TNF-α, and did not bias the response toward either Th1 or Th2. The advantage of ATIV over TIV was more pronounced for the virus strains that had not circulated in the years that preceded this study and for the heterovariant strains. CONCLUSION: These data highlight the relevant role played by the oil-in-water adjuvant MF59 in enhancing the immunogenicity of inactivated influenza vaccines in immunologically naive individuals.