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Primary vaccination with mRNA-1273 (100-µg) was safe and efficacious at preventing coronavirus disease 2019 (COVID-19) in the previously reported, blinded Part A of the phase 3 Coronavirus Efficacy (COVE; NCT04470427) trial in adults (≥18 years) across 99 U.S. sites. The open-label (Parts B and C) primary objectives were evaluation of long-term safety and effectiveness of primary vaccination plus a 50-µg booster dose; immunogenicity was a secondary objective. Of 29,035 open-label participants, 19,609 received boosters (mRNA-1273 [n = 9647]; placebo-mRNA-1273 [n = 9952]; placebo [n = 10] groups). Booster safety was consistent with that reported for primary vaccination. Incidences of COVID-19 and severe COVID-19 were higher during the Omicron BA.1 than Delta variant waves and boosting versus non-boosting was associated with a significant, 47.0% (95% CI : 39.0-53.9%) reduction of Omicron BA.1 incidence (24.6 [23.4 - 25.8] vs 46.4 [40.6 - 52.7]/1000 person-months). In an exploratory Cox regression model adjusted for time-varying covariates, a longer median interval between primary vaccination and boosting (mRNA-1273 [13 months] vs placebo-mRNA-1273 [8 months]) was associated with significantly lower, COVID-19 risk (24.0% [16.0% - 32.0%]) during Omicron BA.1 predominance. Boosting elicited greater immune responses against SARS-CoV-2 than primary vaccination, irrespective of prior SARS-CoV-2 infection. Primary vaccination and boosting with mRNA-1273 demonstrated acceptable safety, effectiveness and immunogenicity against COVID-19, including emergent variants., (© 2024. The Author(s).)

Purpose of Review: The successes of the coronavirus disease 2019 (COVID-19) mRNA vaccines have accelerated the development of mRNA vaccines against other respiratory pathogens. The aim of this review is to highlight COVID-19 mRNA vaccine advances and provide an update on the progress of mRNA vaccine development against other respiratory pathogens., Recent Findings: The COVID-19 mRNA vaccines demonstrated effectiveness in preventing severe COVID-19 and death. H7N9 and H10N8 avian influenza mRNA vaccines have demonstrated safety and immunogenicity in phase 1 clinical trials. Numerous seasonal influenza mRNA vaccines are in phase 1-3 clinical trials. Respiratory syncytial virus (RSV) mRNA vaccines have progressed to phase 2-3 clinical trials in adults and a phase 1 clinical trial in children. A combined human metapneumovirus and parainfluenza-3 mRNA vaccines was found to be well tolerated and immunogenic in a phase 1 trial among adults and trials are being conducted among children. Clinical trials of mRNA vaccines combining antigens from multiple respiratory viruses are underway., Summary: The development of mRNA vaccines against respiratory viruses has progressed rapidly in recent years. Promising vaccine candidates are moving through the clinical development pathway to test their efficacy in preventing disease against respiratory viral pathogens., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Vaccine protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection wanes over time, requiring updated boosters. In a phase 2, open-label, randomized clinical trial with sequentially enrolled stages at 22 US sites, we assessed safety and immunogenicity of a second boost with monovalent or bivalent variant vaccines from mRNA and protein-based platforms targeting wild-type, Beta, Delta and Omicron BA.1 spike antigens. The primary outcome was pseudovirus neutralization titers at 50% inhibitory dilution (ID 50 titers) with 95% confidence intervals against different SARS-CoV-2 strains. The secondary outcome assessed safety by solicited local and systemic adverse events (AEs), unsolicited AEs, serious AEs and AEs of special interest. Boosting with prototype/wild-type vaccines produced numerically lower ID 50 titers than any variant-containing vaccine against all variants. Conversely, boosting with a variant vaccine excluding prototype was not associated with decreased neutralization against D614G. Omicron BA.1 or Beta monovalent vaccines were nearly equivalent to Omicron BA.1 + prototype or Beta + prototype bivalent vaccines for neutralization of Beta, Omicron BA.1 and Omicron BA.4/5, although they were lower for contemporaneous Omicron subvariants. Safety was similar across arms and stages and comparable to previous reports. Our study shows that updated vaccines targeting Beta or Omicron BA.1 provide broadly crossprotective neutralizing antibody responses against diverse SARS-CoV-2 variants without sacrificing immunity to the ancestral strain. ClinicalTrials.gov registration: NCT05289037 ., (© 2023. The Author(s).)

In a randomized clinical trial, we compare early neutralizing antibody responses after boosting with bivalent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger RNA (mRNA) vaccines based on either BA.1 or BA.4/BA.5 Omicron spike protein combined with wild-type spike. Responses against SARS-CoV-2 variants exhibited the greatest reduction in titers against currently circulating Omicron subvariants for both bivalent vaccines., Competing Interests: Potential conflicts of interest. E. J. A. has received grants from Pfizer, Moderna, Janssen, GSK, Sanofi, Micron, and Regeneron through institution as well as consulting fees from Pfizer, Janssen, Moderna, and Sanofi. E. J. A. serves on safety/advisory boards for Sanofi, ACI Clinical/WCG and Kentucky Bioscience, Inc. A. R. B. has received research support from NIH-NIAID, grants from Pfizer, Cyanvac, and Merck as well as consulting fees from Janssen and GSK. L. R. B. has received grants from Wellcome Trust, Gates Foundation, NIH/Harvard Medical School through institution. Serves as member of DSMB for NIH and AMDAC for Food and Drug Administration (FDA). L. R. B. is involved in HIV and SARS-CoV-2 vaccine clinical trials conducted in collaboration with the NIH, HIV Vaccine Trials Network (HVTN), COVID Vaccine Prevention Network (CoVPN), International AIDS Vaccine Initiative (IAVI), Crucell/Janssen, Moderna, Military HIV Research Program (MHRP), the Gates Foundation, and Harvard Medical School. D. J. D. has received a contract from Leidos Biomedical research to conduct the clinical trial through institution. A. R. F. has received grants from Janssen, Pfizer, Merck, BioFire Diagnostics, and CyanVac through institution, consultant fees from Arrowhead and Icosavax, and honoraria as a speaker from Moderna and GlaxoSmithKline. A. R. F. also serves on safety/advisory boards for Novavax and received travel/meeting support from GlaxoSmithKline. S. E. F. has received funding from Leidos to Saint Louis University to conduct Protocol DMID22-0004. D. N. F. has as a contract from Centers for Disease Control and Prevention (CDC) and is the site principal investigator (PI) for clinical trials from Gilead, Regeneron, and MetroBiotech, LLC. She is the PI on 1 investigator-initiated award from Gilead and the co-PI on another investigator-initiated award from Gilead. D. N. F. served on an HBV Advisory board for Gilead in 2021 and received payment for expert testimony not related to COVID in 2022. P. A. G. has received funding for COVAIL clinical trial. P. A. G. has also received consulting fees from Janssen Vaccines. L. C. I. has received support for the present manuscript from NIH-NIAID/DMID, Moderna, Pfizer, and Sanofi. L. C. I. has also received grants from GSK, Merck, Sharpe & Dohme Corp, CDC, Novavax, AHRQ, and NIH/NLM/NIMHD as well as consulting fees from Moderna, CDC, and Pediatric Emergency Medicine Associates, LLC. L. C. I. has received honoraria as a speaker from American Academy of Pediatrics, Rockefeller University, and American Academy of Pediatrics- Georgia Chapter. L. C. I. serves on Data Safety Monitoring for NIH-Phase 2 Vaccine Trial for Monkeypox, Moderna Scientific Advisory Board- North America, and COVID-19 Task Force, Georgia. L. C. I. has a leadership role in the Pediatric Infectious Disease Society, serves as board member on the Emory University- Pediatric and Reproductive Environmental Health Scholars-Southeastern, the Center for Spatial Analytics of the Georgia Institute of Technology, and the American Academy of Pediatrics (Executive Board for Section on Infectious Diseases). L. C. I. has received travel/meeting support from the American Academy of Pediatrics and Moderna. L. A. J. has received funding from NIH for support for this study, funding from Pfizer to support a clinical trial and contract funding for research support from the CDC and the NIH, all through institution. L. A. J. also reports unpaid participation on Data Safety Monitoring Boards for NIH funded clinical trials. S. J. L. has received NIH grants through institution. A. F. L. has received grants from Merck, Gilead, and ViiV through institution as well as consulting fees from Vir Biotechnology. A. F. L. has also received travel support from Merck to attend a required investigator meeting, testing kits and supplies to support research study from Hologic, and medication donated by Mayne Pharma to support research study. M. M. has received funding from Division of Microbiology and Infectious Diseases for contract number 75N93021C00012. D. C. M. has received funding from NIH/75N93019C00050-21A: CIVICS A- Option 21A-DMID Trials of COVID-19 Vaccines. J. M. has received funding from Division of Microbiology and Infectious Diseases, contract number 75N93021C00012. A. N. has received support from NIH-NIAID, CEIRR (Centers of Excellence for Influenza Research and Response) and Gates Cambridge Trust as well as grants from NIH-NIAID R01. R. M. N. has received grants from Moderna and Janssen and travel/meeting support from Moderna. C. M. P. has received funding from NIAID UM1AI148684. R. M. P. has received funding from NIH DMID COVAIL as well as grants from Janssen, Moderna, and NIH through institution. N. G. R. has received research grants from Pfizer, Merck, Sanofi, Quidel, and Lilly through institution, consulting fees from Krog, honoraria as speaker for Virology education, and travel support from Sanofi. N. G. R. serves on safety committees for ICON and EMMES and is a member of the Moderna Advisory board. D. J. S. has received support from NIH-NIAID CEIRR, grants from NIH-NIAID R01, and travel support from NIH-NIAID CEIRR for NIH-related meetings. K. T. has received funding from Division of Microbiology and Infectious Diseases contract number 75N93021C00012. E. B. W. has received funding from Leidos Biomedical Research agreement number. 22CTA-DM0009 as well as grants from Pfizer, Moderna, Sequiris, Clinetic, and Najit Technologies, with payments made to institution. E. B. W. has also received honoraria as a speaker from College of Diplomates of the American Board of Pediatric Dentistry, consulting fees from Iliad Biotechnologies, and travel/meeting support from the American Academy of Pediatrics. E. B. W. serves as member of Vaxcyte Scientific Advisory board. P. L. W. has received subcontract funding from NIH for this study as well as NIH grant funding and contract funding from Pfizer through University of Iowa. P. L. W. has also received consulting fees from Pfizer and serves on safety/advisory board for Emmes Corporation. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background Although the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are highly efficacious at preventing severe disease in the general population, current data are lacking regarding vaccine efficacy (VE) for individuals with mild immunocompromising conditions. Methods A post hoc, cross-protocol analysis of participant-level data from the blinded phase of four randomized, placebo-controlled, coronavirus disease 2019 (COVID-19) vaccine phase 3 trials (Moderna, AstraZeneca, Janssen, and Novavax) was performed. We defined a "tempered immune system" (TIS) variable via a consensus panel based on medical history and medications to determine VE against symptomatic and severe COVID-19 cases in TIS participants versus non-TIS individuals starting at 14 days after completion of the primary series through the blinded phase for each of the 4 trials. An analysis of participants living with well-controlled human immunodeficiency virus was conducted using the same methods. Results A total of 3852/30 351 (12.7%) Moderna participants, 3088/29 868 (10.3%) Novavax participants, 3549/32 380 (11.0%) AstraZeneca participants, and 5047/43 788 (11.5%) Janssen participants were identified as having a TIS. Most TIS conditions (73.9%) were due to metabolism and nutritional disorders. Vaccination (vs placebo) significantly reduced the likelihood of symptomatic and severe COVID-19 for all participants for each trial. VE was not significantly different for TIS participants versus non-TIS for either symptomatic or severe COVID-19 for each trial, nor was VE significantly different in the symptomatic endpoint for participants with human immunodeficiency virus. Conclusions For individuals with mildly immunocompromising conditions, there is no evidence of differences in VE against symptomatic or severe COVID-19 compared with those with non-TIS in the 4 COVID-19 vaccine randomized controlled efficacy trials. [ABSTRACT FROM AUTHOR]

The coronavirus disease 2019 (COVID-19) pandemic and associated increase in family care responsibilities resulted in unsustainable personal and professional workloads for infectious diseases (ID) faculty on the front lines. This was especially true for early-stage faculty (ESF), many of whom had caregiving responsibilities. In addition, female faculty, underrepresented in medicine and science faculty and particularly ESF, experienced marked declines in research productivity, which significantly impacts career trajectories. When combined with staffing shortages due to an aging workforce and suboptimal recruitment and retention in ID, these work-life imbalances have brought the field to an inflection point. We propose actionable recommendations and call on ID leaders to act to close the gender, racial, and ethnic gaps to improve the recruitment, retention, and advancement of ESF in ID. By investing in systemic change to make the ID workforce more equitable, we can embody the shared ideals of diversity and inclusion and prepare for the next pandemic. [ABSTRACT FROM AUTHOR]

Background: The COVID-19 standard of care (SOC) evolved rapidly during 2020 and 2021, but its cumulative effect over time is unclear.Objective: To evaluate whether recovery and mortality improved as SOC evolved, using data from ACTT (Adaptive COVID-19 Treatment Trial).Design: ACTT is a series of phase 3, randomized, double-blind, placebo-controlled trials that evaluated COVID-19 therapeutics from February 2020 through May 2021. ACTT-1 compared remdesivir plus SOC to placebo plus SOC, and in ACTT-2 and ACTT-3, remdesivir plus SOC was the control group. This post hoc analysis compared recovery and mortality between these comparable sequential cohorts of patients who received remdesivir plus SOC, adjusting for baseline characteristics with propensity score weighting. The analysis was repeated for participants in ACTT-3 and ACTT-4 who received remdesivir plus dexamethasone plus SOC. Trends in SOC that could explain outcome improvements were analyzed. (ClinicalTrials.gov: NCT04280705 [ACTT-1], NCT04401579 [ACTT-2], NCT04492475 [ACTT-3], and NCT04640168 [ACTT-4]).Setting: 94 hospitals in 10 countries (86% U.S. participants).Participants: Adults hospitalized with COVID-19.Intervention: SOC.Measurements: 28-day mortality and recovery.Results: Although outcomes were better in ACTT-2 than in ACTT-1, adjusted hazard ratios (HRs) were close to 1 (HR for recovery, 1.04 [95% CI, 0.92 to 1.17]; HR for mortality, 0.90 [CI, 0.56 to 1.40]). Comparable patients were less likely to be intubated in ACTT-2 than in ACTT-1 (odds ratio, 0.75 [CI, 0.53 to 0.97]), and hydroxychloroquine use decreased. Outcomes improved from ACTT-2 to ACTT-3 (HR for recovery, 1.43 [CI, 1.24 to 1.64]; HR for mortality, 0.45 [CI, 0.21 to 0.97]). Potential explanatory factors (SOC trends, case surges, and variant trends) were similar between ACTT-2 and ACTT-3, except for increased dexamethasone use (11% to 77%). Outcomes were similar in ACTT-3 and ACTT-4. Antibiotic use decreased gradually across all stages.Limitation: Unmeasured confounding.Conclusion: Changes in patient composition explained improved outcomes from ACTT-1 to ACTT-2 but not from ACTT-2 to ACTT-3, suggesting improved SOC. These results support excluding nonconcurrent controls from analysis of platform trials in rapidly changing therapeutic areas.Primary Funding Source: National Institute of Allergy and Infectious Diseases. [ABSTRACT FROM AUTHOR]

Functional impairment of interferon, a natural antiviral component of the immune system, is associated with the pathogenesis and severity of COVID-19. We aimed to compare the efficacy of interferon beta-1a in combination with remdesivir compared with remdesivir alone in hospitalised patients with COVID-19. We did a double-blind, randomised, placebo-controlled trial at 63 hospitals across five countries (Japan, Mexico, Singapore, South Korea, and the USA). Eligible patients were hospitalised adults (aged ≥18 years) with SARS-CoV-2 infection, as confirmed by a positive RT-PCR test, and who met one of the following criteria suggestive of lower respiratory tract infection: the presence of radiographic infiltrates on imaging, a peripheral oxygen saturation on room air of 94% or less, or requiring supplemental oxygen. Patients were excluded if they had either an alanine aminotransferase or an aspartate aminotransferase concentration more than five times the upper limit of normal; had impaired renal function; were allergic to the study product; were pregnant or breast feeding; were already on mechanical ventilation; or were anticipating discharge from the hospital or transfer to another hospital within 72 h of enrolment. Patients were randomly assigned (1:1) to receive intravenous remdesivir as a 200 mg loading dose on day 1 followed by a 100 mg maintenance dose administered daily for up to 9 days and up to four doses of either 44 μg interferon beta-1a (interferon beta-1a group plus remdesivir group) or placebo (placebo plus remdesivir group) administered subcutaneously every other day. Randomisation was stratified by study site and disease severity at enrolment. Patients, investigators, and site staff were masked to interferon beta-1a and placebo treatment; remdesivir treatment was given to all patients without masking. The primary outcome was time to recovery, defined as the first day that a patient attained a category 1, 2, or 3 score on the eight-category ordinal scale within 28 days, assessed in the modified intention-to-treat population, defined as all randomised patients who were classified according to actual clinical severity. Safety was assessed in the as-treated population, defined as all patients who received at least one dose of the assigned treatment. This trial is registered with ClinicalTrials.gov , NCT04492475. Between Aug 5, 2020, and Nov 11, 2020, 969 patients were enrolled and randomly assigned to the interferon beta-1a plus remdesivir group (n=487) or to the placebo plus remdesivir group (n=482). The mean duration of symptoms before enrolment was 8·7 days (SD 4·4) in the interferon beta-1a plus remdesivir group and 8·5 days (SD 4·3) days in the placebo plus remdesivir group. Patients in both groups had a time to recovery of 5 days (95% CI not estimable) (rate ratio of interferon beta-1a plus remdesivir group vs placebo plus remdesivir 0·99 [95% CI 0·87–1·13]; p=0·88). The Kaplan-Meier estimate of mortality at 28 days was 5% (95% CI 3–7%) in the interferon beta-1a plus remdesivir group and 3% (2–6%) in the placebo plus remdesivir group (hazard ratio 1·33 [95% CI 0·69–2·55]; p=0·39). Patients who did not require high-flow oxygen at baseline were more likely to have at least one related adverse event in the interferon beta-1a plus remdesivir group (33 [7%] of 442 patients) than in the placebo plus remdesivir group (15 [3%] of 435). In patients who required high-flow oxygen at baseline, 24 (69%) of 35 had an adverse event and 21 (60%) had a serious adverse event in the interferon beta-1a plus remdesivir group compared with 13 (39%) of 33 who had an adverse event and eight (24%) who had a serious adverse event in the placebo plus remdesivir group. Interferon beta-1a plus remdesivir was not superior to remdesivir alone in hospitalised patients with COVID-19 pneumonia. Patients who required high-flow oxygen at baseline had worse outcomes after treatment with interferon beta-1a compared with those given placebo. The National Institute of Allergy and Infectious Diseases (USA). [ABSTRACT FROM AUTHOR]