Background An unmet need exists for effective antivirals to treat patients hospitalized with influenza. The results of 2 phase 3 studies that evaluated the efficacy and safety of pimodivir in combination with investigator-chosen standard of care (SoC) treatment are presented.Methods Hospitalized patients (hospital study; NCT03376321) and high-risk outpatients (outpatient study; NCT03381196) with laboratory-confirmed influenza A infection were randomized 1:1 to 600 mg pimodivir twice daily + SoC or placebo twice daily + SoC for 5 days. For most patients, SoC included oseltamivir. Primary end points were Hospital Recovery Scale (HRS) at day 6 (hospital study) and median time to resolution (TTR) of influenza-related symptoms (outpatient study).Results Pimodivir + SoC (oseltamivir) treatment showed no clinical benefit over placebo + SoC on HRS at day 6 (common odds ratio, 0.943; 95% confidence interval [CI], .609-1.462; P = .397; hospital study). A shorter median TTR of 7 symptoms was estimated with pimodivir + SoC versus placebo (92.6 hours; 95% CI, 77.6-104.2 vs 105.1 hours; 95% CI, 92.7-128.6; P = .0216; outpatient study).Conclusions Pimodivir + SoC showed no additional clinical benefit versus SoC treatment alone in hospitalized patients. Pimodivir + SoC demonstrated shorter TTR of influenza symptoms versus placebo + SoC in high-risk outpatients.Clinical Trial Registration NCT03376321 and NCT03381196. Results from 2 phase 3 studies, 1 hospital based and 1 outpatient based, demonstrated that pimodivir with standard-of-care treatment offered no additional clinical benefit for hospitalized influenza patients but did shorten the time to resolution of symptoms versus placebo in high-risk outpatients.

BACKGROUND:Despite the availability of effective vaccines against COVID-19, booster vaccinations are needed to maintain vaccine-induced protection against variant strains and breakthrough infections. This study aimed to investigate the efficacy, safety, and immunogenicity of the Ad26.COV2.S vaccine (Janssen) as primary vaccination plus a booster dose. METHODS:ENSEMBLE2 is a randomised, double-blind, placebo-controlled, phase 3 trial including crossover vaccination after emergency authorisation of COVID-19 vaccines. Adults aged at least 18 years without previous COVID-19 vaccination at public and private medical practices and hospitals in Belgium, Brazil, Colombia, France, Germany, the Philippines, South Africa, Spain, the UK, and the USA were randomly assigned 1:1 via a computer algorithm to receive intramuscularly administered Ad26.COV2.S as a primary dose plus a booster dose at 2 months or two placebo injections 2 months apart. The primary endpoint was vaccine efficacy against the first occurrence of molecularly confirmed moderate to severe-critical COVID-19 with onset at least 14 days after booster vaccination, which was assessed in participants who received two doses of vaccine or placebo, were negative for SARS-CoV-2 by PCR at baseline and on serology at baseline and day 71, had no major protocol deviations, and were at risk of COVID-19 (ie, had no PCR-positive result or discontinued the study before day 71). Safety was assessed in all participants; reactogenicity, in terms of solicited local and systemic adverse events, was assessed as a secondary endpoint in a safety subset (approximately 6000 randomly selected participants). The trial is registered with ClinicalTrials.gov, NCT04614948, and is ongoing. FINDINGS:Enrolment began on Nov 16, 2020, and the primary analysis data cutoff was June 25, 2021. From 34 571 participants screened, the double-blind phase enrolled 31 300 participants, 14 492 of whom received two doses (7484 in the Ad26.COV2.S group and 7008 in the placebo group) and 11 639 of whom were eligible for inclusion in the assessment of the primary endpoint (6024 in the Ad26.COV2.S group and 5615 in the placebo group). The median (IQR) follow-up post-booster vaccination was 36·0 (15·0-62·0) days. Vaccine efficacy was 75·2% (adjusted 95% CI 54·6-87·3) against moderate to severe-critical COVID-19 (14 cases in the Ad26.COV2.S group and 52 cases in the placebo group). Most cases were due to the variants alpha (B.1.1.7) and mu (B.1.621); endpoints for the primary analysis accrued from Nov 16, 2020, to June 25, 2021, before the global dominance of delta (B.1.617.2) or omicron (B.1.1.529). The booster vaccine exhibited an acceptable safety profile. The overall frequencies of solicited local and systemic adverse events (evaluated in the safety subset, n=6067) were higher among vaccine recipients than placebo recipients after the primary and booster doses. The frequency of solicited adverse events in the Ad26.COV2.S group were similar following the primary and booster vaccinations (local adverse events, 1676 [55·6%] of 3015 vs 896 [57·5%] of 1559, respectively; systemic adverse events, 1764 [58·5%] of 3015 vs 821 [52·7%] of 1559, respectively). Solicited adverse events were transient and mostly grade 1-2 in severity. INTERPRETATION:A homologous Ad26.COV2.S booster administered 2 months after primary single-dose vaccination in adults had an acceptable safety profile and was efficacious against moderate to severe-critical COVID-19. Studies assessing efficacy against newer variants and with longer follow-up are needed. FUNDING:Janssen Research & Development.

Background Despite the availability of effective vaccines against coronavirus disease 2019 (Covid-19), the emergence of variant strains and breakthrough infections pose a challenging new reality. Booster vaccinations are needed to maintain vaccine-induced protection. Methods ENSEMBLE2 is an ongoing, randomized, double-blind, placebo-controlled, phase 3 pivotal trial including crossover vaccination after emergency authorization of Covid-19 vaccines. Adults aged ≥18 years were randomized to receive Ad26.COV2.S or placebo as a primary dose plus a booster dose at two months. The primary endpoint was vaccine efficacy against the first occurrence of molecularly-confirmed moderate to severe–critical Covid-19 with onset ≥14 days after booster vaccination in the per-protocol population. Key efficacy, safety, and immunogenicity endpoints were also assessed. Results The double-blind phase enrolled 31,300 participants, 14,492 of whom received 2 doses and were evaluable for efficacy (per-protocol set, Ad26.COV2.S n=7484; placebo n=7008). Baseline demographics and characteristics were balanced. Vaccine efficacy was 75.2% (adjusted 95% CI, 54.6-87.3) against moderate to severe–critical Covid-19 and was similar against symptomatic infection (75.6% [55.5-99.9]). Efficacy was consistent across participants with and without comorbidities, and reached 93.7% (58.5-99.9) in the US. Vaccine efficacy against severe–critical Covid-19 was 100% (32.6-100.0; 0 vs 8 cases). The booster vaccine induced robust humoral responses and exhibited an acceptable safety profile. Conclusions A homologous Ad26.COV2.S booster administered 2 months after primary single-dose vaccination in adults led to high vaccine efficacy, including against any symptomatic infection and SARS-CoV-2 variants prevalent during the study. (Funding: Janssen Research and Development and others; ENSEMBLE2 [ClinicalTrials.gov][1] number, [NCT04614948][2].) ### Competing Interest Statement KH, AV, JS, MLG, JV, TK, GS, HS, JVH, MD, and FS are employees of Johnson & Johnson and hold Johnson & Johnson stock/stock options. CT, DL, and IVD are employees of Johnson & Johnson. JRG is an employee of Johnson & Johnson and holds Johnson & Johnson stock/stock options; he is a former employee of GSK, holds GSK stock/stock options, and has received funding grants from GSK Vaccines. CS has received funding grants for research from Janssen-Cilag, AbbVie, Apeiron, B.Braun, Cepheid, Eli Lilly, GSK, Corat Therapeutics, Gilead, MSD, Roche, and ViiV Healthcare; received consulting fees from AbbVie, Cepheid, Formycon, Gilead, GSK, Molecular partners, MSD, Swedish Orphan Biovitrium, Roche, and ViiV Healthcare; received honoraria from AbbVie, Cepheid, Formycon, Gilead, GSK, Gilead, Molecular partners, MSD, Swedish Orphan Biovitrium, Roche, and ViiV Healthcare; received travel support from AbbVie, Cepheid, Formycon, Gilead, GSK, Gilead, Molecular partners, MSD, Swedish Orphan Biovitrium, Roche, and ViiV Healthcare. SF has received research grants to his institution from Janssen/Johnson & Johnson, Pfizer, Sanofi, GSK, Merck, AstraZeneca, and Valneva (no personal fees); consulting fees from Janssen/Johnson & Johnson and GSK CureVac; fees to his institution for participation on a data safety monitoring board or advisory board from AstraZeneca, Medimmune, Sanofi, Pfizer, Seqirus, Sandoz, Merck, and Janssen/Johnson & Johnson; and was chair of two UK NICE sessions (expenses paid per NICE financial regulations). ### Clinical Trial NCT04614948 ### Funding Statement This work was supported by Janssen Vaccines & Prevention B.V. in collaboration with the Biomedical Advanced Research and Development Authority, the Department of Defense, the National Institutes of Health, and the COVID-19 Prevention Network. This project has been funded in whole or in part with federal funds from the Biomedical Advanced Research and Development Authority, part of the Office of the Assistant Secretary for Preparedness and Response at the U.S. Department of Health and Human Services (HHS), under Other Transaction Agreement HHSO100201700018C and from the National Institute of Allergy and Infectious Diseases (NIAID), NIH. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All relevant ethical guidelines have been followed, all necessary institutional review board (IRB) and/or ethics committee approvals have been obtained, all necessary patient/participant consent has been obtained, and the appropriate institutional forms archived. The COV3009 (ENSEMBLE2) study was reviewed and approved by local ethics committees and IRBs (Algemeen Ziekenhuis Sint-Jan, Brugge, Belgium; Comissao Nacional de Etica em Pesquisa, Brasilia, Brazil; Instituto Nacional de Vigilancia de Medicamentos y Alimentos (Colombia), Bogota, Colombia; Comite de Protection des Personnes Ile de France III, Paris, France; Ethik-Kommission der Fakultaet f. Medizin der Technischen Universitaet Muenchen, Muenchen, Germany; Single Joint Research Ethics Board, Manila City, Philippines; Pharma Ethics, Pretoria, South Africa; Hospital Universitario La Paz, Madrid, Spain; UK NHS Research Ethics Service, Health Research Authority, London, United Kingdom; Copernicus Group IRB, Cary, North Carolina, United States. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The data sharing policy of Janssen Pharmaceutical Companies of Johnson & Johnson is available at <https://www.janssen.com/clinical-trials/transparency>. As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access (YODA) Project site at <http://yoda.yale.edu>. <http://yoda.yale.edu> [1]: http://ClinicalTrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04614948&atom=%2Fmedrxiv%2Fearly%2F2022%2F01%2F31%2F2022.01.28.22270043.atom