#WHO emergency #guidance on use of licensed #Ebola {Zaire} #vaccine during #Bundibugyo virus disease #outbreaks - Interim guidance 31 August 2026 (Summary)

 

Context

    Ervebo® is currently the only licensed Ebola vaccine available. Ervebo®  (rVSV-EBOV-GP) is a live, recombinant vesicular stomatitis virus (rVSV)-based vaccine licensed that was prequalified by the World Health Organization (WHO) in 2019 for the prevention of Ebola virus disease caused by Ebola virus (EBOV, species Orthoebolavirus zairense, previously known as Zaire ebolavirus) in individuals aged one year or older. It is not licensed for use against Bundibugyo virus (BDBV) and therefore the use of Ervebo® against BDBV constitutes off-label use{1} BDBV and EBOV cause Ebola disease that is  clinically similar but are genetically and antigenically distinct virus species. Their  glycoproteins share approximately only 60–65% amino acid sequence  identity, a distinction that is particularly relevant for vaccination because currently  available Ebola vaccines, including Ervebo®, target the viral  glycoprotein.

    Consequently, although Ervebo® is highly effective against EBOV, the  extent to which Ervebo®-induced immunity provides clinically meaningful  protection against BDBV remains unknown. (1)

    On 19 August 2026 (2), the Strategic Advisory Group of Experts on Immunization (SAGE) reviewed and deliberated on the additional evidence that  had become available following the publication of the WHO emergency guidance  on the use of licensed Ebola virus vaccine during Bundibugyo virus disease  outbreaks, 28 May 2026. (3)

    The BDBV outbreak in the Democratic Republic of the Congo has spread  substantially, with continued transmission and high mortality, creating an urgent  need to strengthen outbreak response and reduce preventable deaths. (4) The  severity of the disease and evolving epidemiological situation increases the  imperative to consider all potentially beneficial interventions, while at the same  time carefully weighing the unknown efficacy of Ervebo® against BDBV, and resultant risks.

    A ring vaccination randomized controlled trial (henceforth referred to as  ring RCT) of Ervebo® and BDBV-specific vaccine candidates is planned to be  conducted in the Democratic Republic of the Congo as a matter of urgency. (5) If  well designed and rigorously implemented, the trial would provide the critical  evidence currently lacking on the efficacy of Ervebo® against BDBV.

Assessment of additional evidence on Ervebo® performance against BDBV since May 2026

    Findings from an increased, albeit still limited, number of studies  conducted to date in nonhuman primates and ferrets suggest some  protection by Ervebo® against BDBV-related mortality, while showing little or no  protection against viraemia and clinical disease (...).

    In the absence of an established correlate or surrogate of  protection  against BDBV, the extent to which findings from animal challenge  models (disease and laboratory-based immunological studies) can predict  protection in humans remains unknown. 

    Available human immunogenicity data regarding potential cross-protection  conferred by Ervebo® against BDBV showed that Ervebo® induces cross-reactive BDBV glycoproteinbinding antibodies which are at levels  approximately 5-fold lower than against EBOV, and that cross-neutralization of  BDBV pseudoviruses with neutralizing titres are approximately 3.5–4-fold lower  than against EBOV (...).

    No Ervebo® vaccine efficacy data against BDBV in humans have been  generated yet. 

    There are a small number of anecdotal reports of previously vaccinated  health care workers who subsequently developed BDBV disease and survived.  However, no conclusions regarding vaccine efficacy or effectiveness can be drawn  from these observations because of the very small sample size, the absence of an  appropriate comparator group, the potential for substantial bias, non-systematic  data collection, and the resulting considerable statistical uncertainty.

    Overall, the limited data and anecdotal reports are suggestive of some  protection against BDBV-related mortality and are consistent in trending towards  some as yet unquantified benefit.

    In conclusion, the available data remain insufficient to determine whether Ervebo® provides any clinically meaningful protection against  BDBV in humans or to reliably estimate the magnitude of such protection,  including protection against infection, disease, severe disease or death.

Benefit–risk considerations regarding off-label use of Ervebo® in the context of unknown efficacy against BDBV

    There is currently clinical equipoise regarding the efficacy of Ervebo®  against    BDBV. 

    Vaccine efficacy in humans remains to be established and could range  from high efficacy, with substantial clinical and public health benefit, through  moderate or partial efficacy, to limited or negligible efficacy, with little or no  meaningful protection. The lower limit of the range of potential effects may even  include harm. The potential ratio of benefits and risks of broader use therefore  differ considerably depending on where within this range the true efficacy ultimately lies.

    If efficacy is high or clinically meaningful, broader use while the ring RCT  is underway could potentially reduce severe disease and deaths and, if the vaccine  also protects against infection and transmission, contribute to outbreak  control. In a context where other medical countermeasures remain limited, earlier  access could provide populations at high risk with a vaccine that has a  well-characterized safety profile, while BDBV-specific vaccines remain under  evaluation and are not yet available for use. Use within appropriately designed  research frameworks could also generate complementary real-world effectiveness  data. In addition, vaccinated individuals would be expected to benefit from  protection against Ebola virus disease should they subsequently be exposed during a future EBOV outbreak.

    Conversely, if efficacy is low, negligible or absent, the balance of benefits  and risks would be substantially less favourable. Considerable financial, logistic  and human resources would be diverted to an intervention providing little or no  clinical or public health benefit. These resources could otherwise support  outbreak-control measures of established effectiveness, including surveillance,  contact tracing, timely testing and case detection, isolation, infection prevention  and control, and safe and dignified burials. These resources could also have been better invested in the development of BDBV-specific vaccines.

    A scenario in which Ervebo® provides meaningful protection against  severe disease or death, but limited or no protection against infection, viraemia or  onward transmission, would require careful consideration. Protection against  severe disease or death would constitute an important individual and public health  benefit, even in the absence of substantial effects on infection or  transmission. However, vaccination could then reduce morbidity and mortality without necessarily interrupting transmission. If this efficacy profile is  not clearly understood and communicated, vaccination could lead to false  reassurance among vaccinated individuals, communities and responders,  potentially reducing adherence to established outbreak-control measures. Such  behavioural changes could offset some of the benefits of vaccination and, if  infection and onward transmission are not sufficiently reduced, could contribute to continued transmission and potentially prolong or exacerbate the outbreak.

    If efficacy proves limited or negligible, substantial numbers of  breakthrough cases or deaths could also undermine public trust in the outbreak  response and confidence in Ebola vaccines, vaccination programmes generally,  and the health sector more broadly. Once broader vaccination has commenced, a  subsequent decision to restrict or discontinue Ervebo® use, if the evidence shows  limited efficacy, could itself create important communication and trust challenges.

    There are also important evidence-generation trade-offs. The use of  Ervebo® outside rigorous research protocols could interfere with the feasibility,  recruitment, implementation and scientific integrity of studies, particularly the ring  RCT, designed to establish vaccine efficacy for Ervebo® and BDBV-specific  vaccine candidates (which are expected to have the potential for better  performance against BDBV). This could delay the generation of the robust evidence needed to guide policy. Observational Ervebo® effectiveness  studies could provide useful complementary information but are inherently more  susceptible to bias and confounding than RCTs and may therefore be more difficult  to interpret or insufficiently robust to resolve the central question of  efficacy. Vaccine effectiveness (VE) studies of vaccines with modest efficacy are  particularly prone to these limitations. Hence the value of any observational study  depends partly on the extent to which its design can ensure that uptake of the  intervention is as close to random as possible and that outcome data are collected  systematically from all participants allowing comparable analysis, thereby reducing selection and information biases. Conversely, if the ring RCT  demonstrates clinically meaningful efficacy of Ervebo® and/or BDBV-specific  vaccine candidates, such a trial would provide a strong basis for rapidly updating  policy and expanding vaccine(s) use to benefit the wider population.

    Extensive reliance on Ervebo® could potentially affect community willingness to participate in future studies or receive BDBV-specific vaccines,  which become especially important if the efficacy of Ervebo® against BDBV is insufficient.

    Finally, widespread deployment would have implications for global vaccine security. Largescale use of available Ervebo® doses against BDBV could  temporarily deplete the International Coordinating Group on Vaccine  Provision stockpile and potentially compromise timely access to vaccine for  response to a future outbreak caused by EBOV, against which Ervebo® has demonstrated efficacy and is licensed.

    Taken together, the uncertainties described above reinforce the importance of obtaining robust efficacy data as rapidly as possible while  carefully weighing the potential benefit of any broader use against its potential negative consequences.

(...)

{1} Use of a vaccine for an unapproved indication (not described in the approved  labelling) or in an unapproved age group, dosage, or route of administration. 

(...)

© World Health Organization 2026. Some rights reserved. This work is available under the CC BY-NC-SA 3.0 IGO licence.

Suggested citation. WHO emergency guidance on the use of licensed Ebola vaccine during Bundibugyo virus disease outbreaks, 31 August 2026. Geneva:  World Health Organization; 2026. https://doi.org/10.2471/B09884

Source: 

Link: https://doi.org/10.2471/B09884

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#Nirmatrelvir–ritonavir targeting viral #persistence in post-COVID-19 condition (long #COVID) in the #USA (RECOVER-VITAL): a randomised, double-blind, placebo-controlled, phase 2 trial

 

Summary

Background

Post-acute sequelae of SARS-CoV-2 infection, more commonly known as long COVID, has emerged as a major health problem. The pathogenesis of long COVID is unknown, but among the leading hypotheses is viral persistence. We aimed to investigate whether the use of the SARS-CoV-2 antiviral nirmatrelvir–ritonavir improved long COVID symptoms.

Methods

We conducted a double-blind, placebo-controlled, randomised trial involving adults who had developed persistent symptoms (≥12 weeks) associated with three major symptom phenotypes (cognitive, autonomic, or exercise) after acute SARS-CoV-2 infection at 69 US sites. Participants were eligible if they were 18 years or older and had a previous suspected, probable, or confirmed SARS-CoV-2 infection, as defined by the Pan American Health Organization. Eligible participants were also required to have either at least two moderate symptoms from the same phenotype or one severe phenotype-associated symptom, as identified with the Cluster Targeted COVID-19 Symptom Questions. Participants were randomly allocated in a double-blind manner in a 1:1:1 ratio using permuted blocks of size 30 to receive either 15 days of active intervention followed by 10 days of placebo (300 mg nirmatrelvir–100 mg ritonavir twice daily, then 100 mg ritonavir–placebo); 25 days of active intervention (300 mg nirmatrelvir–100 mg ritonavir twice daily); or 25 days of placebo–ritonavir (100 mg ritonavir–placebo). A clinically significant change in patient-reported outcomes at day 90 comprised the primary endpoint: Patient-Reported Outcomes Measurement Information System Cognitive Function Short Form 8a, Orthostatic Hypotension Questionnaire question 1, and a modified version of the DePaul Symptom Questionnaire Post-Exertional Malaise short form. Secondary outcomes were phenotype-specific performance measures. The study was registered at ClinicalTrials.gov (NCT05595369) and is complete.

Findings

Between July 27, 2023, and Sept 6, 2024, 1207 individuals were screened. Of these, 964 were randomly allocated and 959 participants, excluding four participants who were later found ineligible and one who did not initiate treatment, were enrolled in the three phenotypes: 332 to cognitive, 334 to autonomic, and 332 to exercise. In the 959 participants in the mITT population, 643 (67%) self-reported as female, 314 (33%) were male, and two participants had a sex of unknown or undifferentiated; 750 (78%) were White; and 108 (11%) were Hispanic, Latino, or Spanish. The median age was 49 years (IQR 38–59). No statistically significant benefits were observed for any phenotype for primary endpoints. For the cognitive phenotype, adjusted differences compared to placebo were 3·2% (95% CI –10·4 to 16·8, p=0·65) for the 25-day regimen and –2·2% (–15·5 to 11·1, p=0·74) for the 15-day regimen. For the autonomic phenotype, adjusted differences were –6·4% (–18·5 to 5·7, p=0·30) for the 25-day regimen compared to placebo and –0·1% (–12·5 to 12·3, p=0·99) for the 15-day regimen compared to placebo. For exercise, adjusted differences were –7·8% (–19·5 to 3·8, p=0·19) for the 25-day regimen compared to placebo and 0·9% (–11·4 to 13·2, p=0·88) for the 15-day regimen compared to placebo. There were no differences in secondary endpoints, and no safety signals were observed; there were no deaths, and 52 serious adverse events occurred in 42 (4%) of 963 participants over the course of the study.

Interpretation

Nirmatrelvir–ritonavir for 15 days or 25 days showed no evidence of benefit in long COVID in any of the three phenotypes studied. These findings suggest additional approaches to measuring the symptom burden and treating Long COVID are needed.

Funding

National Institutes of Health.

Source: 

Link: https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(26)00406-8/fulltext

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A randomised, open-label clinical study on the efficacy of #baloxavir marboxil and #oseltamivir for post-exposure #prevention of #influenza in a #hospital setting: a study protocol

 

Abstract

Introduction 

Healthcare settings are high-risk environments for the transmission of respiratory viruses. Effective strategies to prevent hospital-acquired influenza, particularly post-exposure prophylaxis for close contacts (CCs), are urgently needed. This study aims to assess the effectiveness of baloxavir marboxil (baloxavir) and oseltamivir in preventing influenza virus infection among CCs who have been exposed to confirmed influenza cases and are unable to be immediately isolated in the hospital ward.

Methods and analysis 

This multicentre, randomised, open-label, parallel-controlled trial involves hospitalised patients with laboratory-confirmed influenza (index patients) and their CCs. CCs will be randomised into three groups: baloxavir marboxil, oseltamivir or placebo. Baloxavir (40 mg or 80 mg for ≥80 kg) will be administered as a single dose on day 1, while oseltamivir (75 mg) will be given once a day for 5 days. CCs will be monitored for influenza-like symptoms, with respiratory samples collected for rapid antigen test or reverse-transcription PCR testing at baseline, day 5±1 and day 10±1 or earlier if symptoms develop. The primary outcome is the 5-day incidence of clinical influenza, defined as laboratory-confirmed infection with concurrent fever and at least one respiratory symptom. Secondary outcomes will include the 5-day incidence of laboratory-confirmed influenza, the 10-day incidence of clinical influenza and the percentage of CCs infected with resistance-associated treatment-emergent influenza variants.

Ethics and dissemination 

The study has been approved by the Clinical Research Ethics Committee of China-Japan Friendship Hospital (2024-KY-401). The results of the study will be submitted for publication in a peer-reviewed journal with online accessibility. The full protocol, de-identified participant data and statistical code will be openly available in a public repository within 12 months after trial completion.

Trial registration number NCT06762587. 

https://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: https://creativecommons.org/licenses/by-nc/4.0/.

Source: 

Link: https://bmjopen.bmj.com/content/16/8/e118748

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Heterologous prime-boost #vaccination against #H5 avian #influenza: Safety and immunogenicity of a MF59-adjuvanted, cell-culture derived #H5N6 vaccine

 

ABSTRACT

With increasing H5 avian influenza cases reported globally and the potential for pandemic emergence, induction of cross-reactive antibody responses may represent an important attribute of an effective vaccine. This phase 2 extension study evaluated immunogenicity and safety of MF59-adjuvanted, cell culture-derived H5N6 vaccine (aH5N6c) in adults primed with MF59-adjuvanted, cell culture-derived H5N1 vaccine (aH5N1c) and in unprimed adults. Adults previously primed with two doses of aH5N1c in the parent study V89_18 were randomized to receive two aH5N6c doses (Group 1) or one aH5N6c and one placebo (Group 2) 3 weeks apart. Unprimed adults received two aH5N6c doses (Group 3). Immunogenicity was assessed by hemagglutination inhibition (HI) and microneutralization (MN) assays against the priming (H5N1) and booster (H5N6) strains on Days 1, 8, 22, 43, and 202. Among 258 exposed participants, primed subjects (Groups 1 and 2) showed higher HI geometric mean titers against both strains than unprimed (Group 3) subjects, with MN responses similarly enhanced. Heterologous H5N1 responses were robust in primed subjects (Day 43 HI GMTs: 333–343; seroconversion rates >89%) but minimal in unprimed subjects, with responses persisting to Day 202. Solicited adverse events were mild or moderate, comparable between groups, and consistent with other MF59-adjuvanted pandemic vaccines; no vaccine-related serious adverse events occurred. Heterologous H5N6 booster vaccination in H5N1-primed adults elicited strong cross-reactive immunity against the priming strain, demonstrating long-lasting immune memory for at least 6 y and supporting heterologous prime-boost strategies for pandemic preparedness against emerging H5 outbreaks.

Source: 

Link: https://www.tandfonline.com/doi/full/10.1080/21645515.2026.2712791

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#Losartan and #prednisolone for #postCOVID syndrome and cardiac inflammation: a randomized, double-blind, placebo-controlled trial

 

Abstract

Persistent cardiac symptoms are common in post-COVID syndrome, even without structural heart disease. Evidence implicates immune dysregulation, endothelial dysfunction and low-grade cardiovascular inflammation. Yet no targeted treatment exists. Myoflame-19 is a multicenter, double-blind clinical trial of 279 participants with inflammatory cardiac involvement defined by cardiovascular magnetic resonance, randomized 1:1 to losartan plus prednisolone (n = 139) or matching placebos (n = 140) for 16 weeks. The modified intention-to-treat population comprised 124 and 122 participants. The primary endpoint, change in left ventricular (LV) ejection fraction, was neutral: between-group difference 0.74 percentage points (pp), 95%CI −0.14 to 1.62, p = 0.10, unpaired t-test; supportive baseline-adjusted ANCOVA 0.99, 95%CI 0.15-1.83, p = 0.021. Among prespecified secondary endpoints, several symptom and imaging measures showed numerical differences favoring intervention, including Average Symptom Score components (modified Canadian Chest Pain Scale −4.8 pp, 95%CI −17.3 to 7.6; NYHA class −8.1 pp, −20.6 to 4.3; Long COVID symptom burden −7.7 pp, −18.9 to 3.6), native T1 and T2 values (native T1 −2.46 ms, −8.35 to 3.42; native T2 −0.31 ms, −1.16 to 0.53), and LV end-diastolic volume ( + 1.45 ml/m², −0.09 to 3.00); however, confidence intervals included the null value and these findings should be regarded as hypothesis-generating.Treatment was safe and well-tolerated. These findings indicate a neutral treatment effect on the primary endpoint. They inform targeted immunomodulation and design of future trials in post-COVID syndrome and inflammatory cardiac involvement. Trial registration: EudraCT 2022-001682-12; NCT05619653.

Source: 

Link: https://www.nature.com/articles/s41467-026-75991-w

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#Baloxavir, #favipiravir, or #oseltamivir in patients with non-severe symptomatic seasonal #influenza (AD ASTRA): a phase 2, open-label, adaptive, RCT

 

Summary

Background

The oral antiviral therapies baloxavir marboxil (hereafter baloxavir), favipiravir, and oseltamivir have not been simultaneously compared for the treatment of seasonal influenza. We aimed to determine their relative efficacies in accelerating viral clearance in patients with symptomatic influenza virus infection at low risk of progression to severe disease.

Methods

We conducted a phase 2, open-label, randomised, controlled, adaptive platform trial in patients aged 18–60 years in Thailand, Laos, Nepal, and Brazil, recruited in four hospital outpatient or primary care departments with acute influenza (≤ 4 days of symptoms) and a low risk of progression to severe disease. Patients were randomly assigned 1:1:1:1:1 using a centralised online app to receive baloxavir (single oral dose of 40 mg if bodyweight <80 kg or 80 mg if bodyweight ≥80 kg), favipiravir (oral loading dose of 1800 mg, followed by 1800 mg 12 h later, and then 800 mg twice daily for 4 days), oseltamivir (oral dose 75 mg twice daily for 5 days), no study drug, or another ongoing intervention (reported separately). Randomisation was stratified by site and used block sizes of 15. The primary endpoint was the rate of oropharyngeal influenza viral RNA clearance, estimated under a Bayesian hierarchical linear model fitted to the daily log10 oropharyngeal viral densities from day 0 to day 5. Analyses were conducted in the modified intention-to-treat population (mITT), defined as patients with PCR-confirmed influenza with more than 250 viral RNA copies per mL at randomisation. Intervention groups were assessed for superiority over the no study drug group (posterior probability >0·9 that the relative increase in viral clearance was ≥20%); if superiority was met, intervention groups were assessed for non-inferiority relative to baloxavir (posterior probability >0·9 that the relative reduction in viral clearance was ≤10%). Secondary outcomes included time to resolution of fever and time to resolution of all symptoms. The trial is registered with ClinicalTrials.gov (NCT05648448) and is ongoing.

Findings

Between Feb 22, 2023, and Dec 12, 2025, 944 patients with influenza virus infection were randomly assigned to baloxavir (n=199; mITT 163 [82%]), favipiravir (n=223; mITT 196 [88%]), oseltamivir (n=200; mITT 170 [85%]), no study drug (n=228; mITT 200 [88%]) or other interventions (n=94). 120 patients were excluded based on baseline viral density (≤250 copies per mL), and one participant withdrew before collection of quantitative PCR results on day 0. 457 (63%) patients in the mITT population were female and 272 (37%) were male. Compared with no study drug, viral clearance rates were accelerated by 86% (95% credible interval [CrI] 60–117) with baloxavir, 66% (45–94) with favipiravir, and 49% (28–74) with oseltamivir. For all interventions, the posterior probability that the relative increase in viral clearance was 20% or more was 1·0. Compared with baloxavir, oseltamivir was inferior (20% slower clearance, 95% CrI 6 to 32; posterior probability 0·93 that the relative reduction in viral clearance was <10%); non-inferiority could not be shown for favipiravir (10% slower clearance, 95% CrI –4 to 22; posterior probability 0·55 that the relative reduction in viral clearance was <10%). Median time to fever resolution was accelerated with all three antivirals compared with no study drug (absolute differences ranging from 0·5 days to 0·9 days), whereas time to resolution of all symptoms was not significantly different between groups. 31 adverse events of grade 3 or above occurred, five of which were considered severe (one in the favipiravir group, one in the oseltamivir group, and three in the no study drug group).

Interpretation

Oral baloxavir, favipiravir, and oseltamivir accelerated influenza viral clearance rates in adults with early non-severe seasonal influenza at low risk of progression to severe disease. Baloxavir had the greatest in-vivo antiviral efficacy, followed by favipiravir and oseltamivir. These antivirals shortened fever duration but showed no clear effects on time to complete symptom resolution. This pharmacometric approach can inform prioritisation of antiviral agents for further study and potential inclusion in pandemic stockpiles.

Funding

Wellcome Trust.

Source: 

Link: https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(26)00255-0/fulltext

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Immunogenicity and safety of AS03-adjuvanted A/Astrakhan/3212/2020 #H5N8 -like #influenza #vaccine in adults: Phase 1/2, observer-blinded, randomized trial

 

ABSTRACT

Influenza pandemics arise from novel influenza A viruses. Recent emergence of a new clade (2.3.4.4.b) of the highly pathogenic H5N1 in animals and humans highlighted its pandemic potential. We evaluated the immunogenicity and safety of GSK’s AS03-adjuvanted H5N8 vaccine in adults. In this phase 1/2, observer-blinded, age-stratified, randomized trial, healthy US adults (age, ≥18 y) received two intramuscular doses of hemagglutinin antigen (3.75 or 7.50 μg) with AS03A or AS03B, administered 21 d apart. Immunogenicity – seroprotection rates (SPRs), seropositivity, geometric mean titers (GMTs), geometric mean fold rise (GMFR), and seroconversion rates (SCRs) – was evaluated on day 43 using hemagglutination inhibition (HI) and microneutralization (MN) assays. Safety was monitored throughout the study. Of 520 enrolled participants, 518 were vaccinated. On day 43, the US Food and Drug Administration’s (FDA) Center for Biologics Evaluation and Research criteria for influenza vaccines were met. HI SPRs, seropositivity rates, SCRs, GMTs, and GMFR appeared to be higher in the AS03A vs AS03B group. Immune responses were generally higher in younger (aged 18–64 y) vs older (aged ≥65 y) adults. Immune responses were also detected in MN assays, with a correlation between HI and MN responses on day 43 across age groups and vaccine formulations. Safety was acceptable, with no increase in adverse events post-dose 2. Reactogenicity appeared more common in younger adults. The antigen-sparing potential of AS03 was demonstrated, with an acceptable safety profile. The benefit/risk profile was favorable for all formulations tested, including 3.75 µg AS03A (licensed in the US).

ClinicalTrials.gov registration: NCT05975840.

Source: 

Link: https://www.tandfonline.com/doi/full/10.1080/21645515.2026.2649314

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#Ensitrelvir for #Covid19 Postexposure #Prophylaxis in #Household Contacts

 

Abstract

Background

Ensitrelvir, an oral inhibitor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3C-like protease, is approved in Japan for the treatment of mild-to-moderate coronavirus disease 2019 (Covid-19). Previously, no antiviral agents were approved for postexposure prophylaxis in household contacts of patients with Covid-19.

Methods

In this double-blind, randomized, placebo-controlled trial, we randomly assigned persons who were SARS-CoV-2–negative on local diagnostic testing but were household contacts of a patient with Covid-19 (the index patient) to receive either ensitrelvir (375 mg on day 1 and 125 mg daily on days 2 through 5) or placebo within 72 hours after symptom onset in the index patient. The primary end point was Covid-19 (defined by a central laboratory–confirmed positive reverse-transcriptase–polymerase-chain-reaction assay and the presence of ≥1 of 14 prespecified Covid-19 symptoms lasting ≥48 hours) by day 10 in a household contact in the modified intention-to-treat population (all the participants who underwent randomization, had a central laboratory–confirmed negative RT-PCR test for SARS-CoV-2 at baseline, and received at least one dose of the trial drug or placebo).

Results

The modified intention-to-treat population included 1030 participants in the ensitrelvir group and 1011 in the placebo group. The mean age of the participants was 42.4 years; 71.1% had undergone randomization within 48 hours after symptom onset in the index patient, and 37.0% had at least one risk factor for severe Covid-19. The incidence of Covid-19 was lower in the ensitrelvir group than in the placebo group (2.9% vs. 9.0%; risk ratio, 0.33; 95% confidence interval [CI], 0.22 to 0.49; P<0.001). The incidence of adverse events during the trial was similar in the two groups (15.1% in the ensitrelvir group and 15.5% in the placebo group), as was the incidence of serious adverse events (0.2% in each group). No Covid-19–related hospitalizations or deaths were reported.

Conclusions

Ensitrelvir administered to household contacts of a patient with Covid-19 within 72 hours after symptom onset in the index patient was effective in preventing Covid-19 in the contacts. (Funded by Shionogi; SCORPIO-PEP Japan Registry for Clinical Trials number, jRCT2031230124; ClinicalTrials.gov number, NCT05897541.)

Source: 

Link: https://www.nejm.org/doi/full/10.1056/NEJMoa2509306?query=TOC

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Efficacy and #Safety of an #mRNA Seasonal #Influenza #Vaccine in Adults

 

Abstract

Background

Seasonal influenza causes substantial illness and death in adults 50 years of age or older, even with current vaccines. An investigational messenger RNA (mRNA)–based vaccine called mRNA-1010 encodes hemagglutinin glycoproteins from World Health Organization–recommended influenza strains.

Methods

In this phase 3, double-blind, active-controlled trial, we randomly assigned adults 50 years of age or older to receive trivalent mRNA-1010 (37.5 μg, which includes 12.5 μg of each strain) or a licensed standard-dose comparator. The primary efficacy end point was relative vaccine efficacy against reverse-transcriptase–polymerase-chain-reaction (RT-PCR)–confirmed, protocol-defined influenza-like illness caused by influenza A or B, from at least 14 days after vaccination through the end of the influenza season. Hypothesis testing was conducted hierarchically to assess noninferiority (lower boundary of the 95% confidence interval [CI], >−10%), superiority (lower boundary of the 95% CI, >0%), and a higher level of superiority (lower boundary of the 95% CI, >9.1%).

Results

A total of 40,703 participants received mRNA-1010 (20,350 participants) or the standard-dose comparator (20,353 participants); the median follow-up was 181 days (range, 1 to 227). RT-PCR–confirmed, protocol-defined influenza-like illness was observed in 411 of 20,179 recipients of mRNA-1010 (2.0%) and 557 of 20,124 recipients of the standard-dose comparator (2.8%), which corresponds to a relative vaccine efficacy of 26.6% (95% CI, 16.7 to 35.4), thereby meeting the criteria for noninferiority, superiority, and higher-level superiority. Solicited adverse reactions were more frequent with mRNA-1010 than with the standard-dose comparator (injection-site pain in 65.8% vs. 29.8%, fatigue in 45.1% vs. 20.3%, headache in 37.8% vs. 18.0%, and myalgia in 35.4% vs. 11.6%); most reactions were mild to moderate and transient. Serious adverse events were reported in 2.2% of the recipients of mRNA-1010 (with three events considered by the investigator to be vaccine-related) and in 1.9% of the recipients of the standard-dose comparator (with two events considered by the investigator to be vaccine-related).

Conclusions

In this trial, mRNA-1010 was superior to standard-dose licensed vaccines for prevention of RT-PCR–confirmed, protocol-defined influenza-like illness in adults 50 years of age or older. Solicited adverse reactions were more frequent with mRNA-1010. (Funded by Blackstone Life Sciences and Moderna; Fluent ClinicalTrials.gov number, NCT06602024.)

Source: 

Link: https://www.nejm.org/doi/full/10.1056/NEJMoa2516491?query=TOC

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A Phase 1/2 Dose-Ranging Safety and Immunogenicity Study of #mRNA-Based Candidate #Pandemic #Influenza #Vaccines in Healthy Adults

 

Abstract

Background

Influenza A viruses pose a persistent pandemic threat. We report safety, reactogenicity, and immunogenicity findings for mRNA-1018 pandemic influenza vaccine candidates from a phase 1/2 study in healthy adults.

Methods

In Part A, participants were randomized to receive 1 of 4 mRNA-1018 candidates at 1 of 3 dose levels across 2 influenza A groups: (1) H5N8/H5-only or (2) H7N9/H7-only. H5N8 and H7N9 candidates were administered at 25, 50, or 100-µg and H5-only and H7-only at 12.5, 25, or 50-µg. Part B participants were randomized to receive 12.5, 25, or 50-µg H5-only-CG. Primary objectives were to evaluate the safety and reactogenicity of vaccine candidates. Secondary objectives included evaluation of humoral immunogenicity through day 205 by hemagglutination inhibition (HAI), neuraminidase inhibition, and microneutralization assays.

Results

Parts A and B comprised 1195 and 304 dosed participants, respectively. Overall, solicited local adverse reactions (ARs) within 7 days of vaccination occurred in 76.8% of participants across vaccine candidates and dose levels, most commonly injection-site pain. Solicited systemic ARs were reported in 62.8% of participants, most frequently fatigue and headache. Solicited ARs were predominantly grade 1–2 in severity, with few grade 3 and no grade 4 events. Post-vaccination immune responses, assessed absolutely, by HAI titers and dynamically, by seroconversion rates, tended to increase with vaccine dose. H5-based candidates induced stronger strain-specific HAI, but with comparable microneutralization titers, versus H7-based candidates.

Conclusions

Vaccine candidates were sufficiently well-tolerated and immunogenic. Further development of mRNA pandemic influenza vaccines is warranted for pandemic preparedness.

Source: 

Link: https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciag278/8662346

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Oral #Nirmatrelvir – Ritonavir for #Covid19 in Higher-Risk #Outpatients

 

Abstract

Background

Nirmatrelvir–ritonavir has been shown to reduce progression to severe illness from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in unvaccinated high-risk outpatients. The effectiveness of nirmatrelvir–ritonavir in persons who have been vaccinated, infected naturally, or both is unclear.

Methods

In two open-label platform trials (PANORAMIC in the United Kingdom and CanTreatCOVID in Canada), we enrolled higher-risk adults (≥50 years of age or ≥18 years of age with coexisting conditions) in the community who tested positive for SARS-CoV-2 and had been unwell for 5 days or less. The participants were randomly assigned to receive usual care plus nirmatrelvir (300 mg)–ritonavir (100 mg) twice a day for 5 days or to receive usual care alone. The primary outcome was hospitalization or death from any cause within 28 days after randomization.

Results

From December 8, 2021, to September 30, 2024, a total of 3516 participants in the PANORAMIC trial and 716 participants in the CanTreatCOVID trial underwent randomization. In the PANORAMIC trial, 14 of 1698 participants (0.8%) in the nirmatrelvir–ritonavir group and 11 of 1673 participants (0.7%) in the usual-care group were hospitalized or died (adjusted odds ratio, 1.18; 95% Bayesian credible interval, 0.55 to 2.62; probability of superiority, 0.334). In the CanTreatCOVID trial, 2 of 343 participants (0.6%) in the nirmatrelvir–ritonavir group and 4 of 324 participants (1.2%) in the usual-care group were hospitalized or died (adjusted odds ratio, 0.48; 95% Bayesian credible interval, 0.08 to 2.23; probability of superiority, 0.830). In a substudy involving 634 participants, viral load was reduced by the end of treatment with nirmatrelvir–ritonavir. Serious adverse events with nirmatrelvir–ritonavir were reported in 9 participants in the PANORAMIC trial and in 4 participants in the CanTreatCOVID trial.

Conclusions

In two open-label trials, nirmatrelvir–ritonavir did not reduce the incidence of hospitalization or death among vaccinated higher-risk participants with SARS-CoV-2 infection. (Funded by the National Institute for Health and Care Research, and others; PANORAMIC ISRCTN number, 2021-005748-31; CanTreatCOVID ClinicalTrials.gov number, NCT05614349.)

Source: 

Link: https://www.nejm.org/doi/full/10.1056/NEJMoa2502457?query=TOC

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Heterologous two-dose #Ebola #vaccine regimen in #pregnant women in #Rwanda: a randomized controlled phase 3 trial

 

Abstract

Risk of death for both mother and fetus following Ebola virus infection is extremely high. In this study, healthy women in Rwanda aged ≥18 years were randomized to two-dose Ebola vaccination (Ad26.ZEBOV, MVA-BN-Filo) during pregnancy (group A) or postpartum (group B). Unvaccinated pregnant group B women served as control. This was a parallel, randomized, controlled, open-label, single-center trial to evaluate the safety (primary endpoint—outcomes of interest and serious adverse events (SAEs)) and immunogenicity (secondary endpoint) of the two-dose Ebola vaccination. Among 3,484 women screened, 2,013 were randomized, and 2,012 women and 1,945 infants born alive were descriptively analyzed. Adverse outcomes of interest occurred in women (5.2% in group A and 7.3% in group B) and infants (26.0% in group A and 25.6% in group B). The most common maternal outcome of interest was pathways to preterm birth (3.2% in group A and 3.4% in group B), and the most common infant outcome of interest was small for gestational age (14.3% in group A and 11.8% in group B). Maternal/fetal and neonatal/infant SAE frequencies were comparable between groups (9.8% in group A, 9.0% in group B and 21.9% in group A, 15.9% in group B, respectively). Anti-Ebola virus glycoprotein-specific binding antibody response (secondary endpoint) was sustained in ≥90% of women at 1 year postdose 1. In group A, binding antibodies were detected in cord blood (99%) and infant serum (95%) samples 14 weeks postbirth. The trial met all primary and secondary objectives. Ad26.ZEBOV, MVA-BN-Filo did not raise concerns regarding adverse maternal/fetal or neonatal/infant outcomes, had no unexpected safety issues, and induced binding antibody responses in women and offspring through passive transfer. ClinicalTrials.gov registration: NCT04556526.

Source: Nature Medicine, https://www.nature.com/articles/s41591-025-03932-z

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