New England Journal of Medicine

BackgroundCold chain requirements limit vaccine accessibility and deployment. SPVX02 (Stablepharma Ltd), is a lyophilised, fridge-free version of Tetadif (BB-NCIPD EAD) tetanus-diphtheria vaccine, stable for at least 18 months at temperatures up to 30{degrees}C. MethodsA multicentre, first-in-human phase 1, blinded, randomised clinical trial to evaluate the safety and tolerability of SPVX02 compared to existing approved tetanus-diphtheria (Td) vaccines was conducted. Healthy adults aged 18-55 (BMI <=32 kg/m2) who had received Td vaccination >=10 years previously were randomly assigned (1:1:1) to receive SPVX02, Tetadif, or diTeBooster (AJ Vaccines A/S). Participants and all investigatory staff were blinded to treatment allocation. Primary outcomes were incidence of adverse events during the trial period including incidence of adverse events reported in participant diaries for 7 days post-dose. Secondary outcomes were day 28 seroprotection rates. Analyses were descriptive. The trial is registered with ISRCTN (98920861). FindingsBetween April 1st and September 22nd, 2025, 120 healthy volunteers were screened and sixty participants enrolled at two of three sites. The demographic characteristics of participants were equivalent between groups. No serious adverse reactions, suspected unexpected adverse reactions, or serious adverse events occurred. Fifty-four participants experienced mild or moderate adverse events (AEs); none were severe (grade 3 or higher) AEs. Reactogenicity and tolerability profiles were similar across all groups. All participants had anti-tetanus toxoid (TT) levels >=1{middle dot}0 IU/ml at Day 28. All participants in both the SPVX02 and Tetadif groups and 19 (95%) in the diTeBooster group had anti-diphtheria (DT) toxoid levels >=0{middle dot}1 IU/ml at Day 28. InterpretationSPVX02 is safe, well tolerated, with TT and DT immunogenicity similar to approved Td vaccines. This trial provides first-in-human evidence that StablevaX (Stablepharma, UK) technology can safely reformulate an aluminium-adjuvanted vaccine stable up to 30{degrees}C for 18 months. FundingFunded by Innovate UK Smart Grant project #10083165 and Stablepharma Ltd. Research In ContextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed for randomised controlled trials with thermostable vaccines between database inception and June 2024 using the terms ("temperature stable") OR ("thermostable") AND ("vaccin*") OR ("thermostable vaccine") with no language restrictions. We identified 33 publications which described various in vitro and in vivo studies that have been performed by researchers as part of their efforts to develop thermostable vaccines. We also identified 2 publications which described randomised, controlled clinical trials that were conducted with thermostable vaccines; (1) a phase 2 clinical trial with ROTASIL, an oral rotavirus vaccine (Isanaka et al, NEJM, 2017) which is now licenced and distributed as a refrigerated product that must be stored but must be stored at 2-8{degrees}C; and (2) a phase 1 clinical trial with a current unapproved TB vaccine candidate, ID93+GLE-SE (Sagawa et al, Nature Comms, 2023) where there is no current public information regarding vaccine tolerance to freezing. Added value of this studyThis first in human study demonstrates that the reformulated thermostable aluminium hydroxide adjuvanted tetanus-diphtheria vaccine, SPVX02, is safe, well tolerated, and can boost immune responses to tetanus and diphtheria to similar levels as approved comparator vaccines. This vaccine can be stored and distributed at room temperature and is not affected by freezing. A larger Phase 2/3 trial is now planned to confirm these findings prior to consideration for market authorisation. Implications of all the available evidenceThe evidence presented here demonstrates that StablevaX technology can be successfully utilised to reformulate a vaccine to be thermostable at room temperature for an extended period of time, without compromising reactogenicity or immunogenicity. While we present data pertaining to a single vaccine, the reformulation and lyophilisation technology underpinning SPVX02 can be applied to many liquid vaccines and biological products. The WHO Immunization Agenda 2030 sets out the global strategy to improve vaccine access in resource-limited settings, prevent vaccine wastage and to reduce the logistical, financial and environmental impact of cold chain requirements. If proven successful across a broader range of vaccine products this technology has potential to significantly benefit global health.

BackgroundWidespread immunity from vaccination and infection has reduced COVID-19 morbidity and mortality, but this immunity varies across the population. Understanding how repeated antigenic exposures influence antibody responses helps to inform future vaccination strategies. MethodsSerum samples collected one and six months after XBB.1.5 vaccination from 25 generally healthy healthcare workers with varying exposure histories were assessed for neutralizing activity against a range of variants, from pre-Omicron variants to latest Omicron JN.1 sublineage variants and divergent BA.3.2 variants, using lentiviral pseudoviruses. Participants were stratified by vaccination and infection history. ResultsXBB.1.5 vaccination elicited broad neutralizing responses, with strong boosting against previously encountered antigens relative to vaccine-matched XBB.1.5 and newer variants. Geometric mean neutralization titers were generally comparable across exposure groups, indicating limited influence of prior Omicron infection or bivalent vaccination, though intra-group heterogeneity was observed. At six months, overall titers declined by 36-62%. Titers remained highest against the pre-Omicron and lowest against JN.1 sublineage variants. N-terminal glycosylation (DelS31, T22N) modestly affected neutralization. ConclusionsXBB.1.5 vaccination elicited broad neutralizing antibody responses against previously encountered and vaccine-matched antigens regardless of exposure history, but titers waned after six months. This waning, compounded by continued emergence of immune-evasive variants and heterogenous population immunity, underscores the need for continually monitoring neutralizing antibody durability and breadth to guide evidence-based COVID-19 vaccine formulation updates.

BackgroundThe SARS-CoV-2 LP.8.1 subvariant was incorporated into the 2025-2026 U.S. COVID-19 vaccines (mRNA-1273.251 and mRNA-1283.251). We evaluated immunogenicity and safety of these vaccines against vaccine-matched and emerging variants in individuals aged [&ge;]65 and those aged 12-64 years at high-risk of severe COVID-19. MethodsData were generated from: (1) two independent, ongoing, phase 3b/4, open-label, single-arm studies in which participants received a single dose of 50-{micro}g mRNA-1273.251 (n=103; median age, 64.0 years) or 10-{micro}g mRNA-1283.251 (n=172, median age, 59.0 years) and followed through Day 29 post-vaccination; neutralizing antibodies (nAb) were measured at baseline (Day 1) and Day 29 using a pseudovirus neutralization assay against the vaccine-matched LP.8.1 variant; (2) Day 29 immunogenicity against circulating variants (BA.3.2.2, XFG, and NB.1.8.1) was assessed in a randomly selected subset; and (3) immune-escape potential was estimated using predictive modeling. Unsolicited adverse events (AEs), including serious AEs, leading to study withdrawal, and those of special interest, were monitored. ResultsBoth vaccines elicited robust nAbs at Day 29 against LP.8.1 (geometric mean fold-rise from baseline: 12-64 years, mRNA-1273.251, 26.3; mRNA-1283.251, 53.0; [&ge;]65 years, mRNA-1273.251, 15.4; mRNA-1283.251, 36.7) and circulating variants. Model-based estimates with mRNA-1273.251 were consistent with clinical data and indicated the highest responses against LP.8.1 and lower responses against BA.3.2.2. No vaccine-related AEs were reported in either study. ConclusionsmRNA-1273.251 and mRNA-1283.251 were well tolerated through Day 29 and elicited robust nAbs against vaccine-matched and circulating variants. In predictive models, BA.3.2.2 had the highest relative risk of immune escape following mRNA-1273.251 vaccination. SUMMARYLP.8.1-containing mRNA-1273.251 and mRNA-1283.251 vaccines given as a single dose were well tolerated and induced robust Day 29 neutralizing antibodies against LP.8.1 and circulating variants.

Background: Induction of HIV envelope (Env)-specific broadly neutralizing antibodies (bnAbs) is considered a key objective for HIV-1 vaccine development. One approach is to vaccinate with HIV Env immunogens that initially target the naive B cell receptors of a bnAb type and boost with a series of HIV Env variants. We chose a priming immunogen, the CH505 transmitted/founder Env with high affinity for the naive B cell receptor of the prototype CD4 binding site (bs) bnAb lineage, CH103, as a candidate priming immunogen to induce the initial critical step in CD4bs bnAb development. Methods: HVTN 300 is a first-in-human, open-label Phase 1 study evaluating the safety and immunogenicity of a CH505 TF chimeric (ch) Trimer adjuvanted with 3M-052-AF (a TLR7/8 agonist) + Alum. The immunogen is a recombinant, stabilized chimeric Env trimer protein with the N-terminal sequence of CH505 TF gp120 Env transplanted into the BG505 SOSIP sequence. Participants received the adjuvanted protein administered in both deltoid muscles at months 0, 2, 4, 8, and 12. Results: Adults (n=18) aged 18 to 55 were screened at a single site in Boston, USA, and 13 were enrolled. Local and systemic reactogenicity was typically mild to moderate. One participant had severe pain/tenderness, and five participants reported transient severe systemic symptoms at least once. Five participants chose to stop further vaccination due to reactogenicity. No vaccine-related SAEs occurred. Vaccine-specific B-cell response rates reached 100% two weeks post third and fifth vaccinations. Antibody blocking experiments with monoclonal antibodies demonstrated that most participants had antibodies directed to the CD4bs. Four out of 11 participants had serum neutralization signatures for CD4bs bnAb precursors. Conclusions: No safety concerns were identified. The adjuvanted CH505 TF chTrimer elicited serum antibodies capable of CD4bs-mediated neutralization against strains designed to detect early precursors of the CD4bs B-cell lineages. Trial Registration: NCT04915768 Disclosure: Presented in part at HIVR4P 2024, Lima, Peru, October 6-10, 2024

BackgroundThe Toto Bora trial tested whether a course of azithromycin reduced rates of re-hospitalization or death in the 6 months following hospitalization among Kenyan children. We hypothesized that azithromycin would reduce enteric bacteria and increase carriage of macrolide resistance in the subsequent 3 months. MethodsKenyan children (1-59 months) hospitalized and subsequently discharged for non-traumatic conditions provided fecal samples before and 3 months after randomization to a 5-day course of azithromycin or placebo. Quantitative PCR identified enteropathogens and AMR-conferring genes in fecal samples. Generalized estimating equations assessed the impact of the randomization arm on pathogen and resistance gene detection, accounting for baseline presence and site. ResultsAmong 1,393 baseline stools, 12.4% had at least one bacterial enteropathogen, 94.7% had at least one macrolide-resistance gene, and 92.6% had at least one beta-lactamase-resistance gene identified. At month 3, children randomized to azithromycin had a 6.1% higher likelihood of carrying a macrolide resistance gene compared to placebo (adjusted prevalence ratio [aPR], 1.06; 95% CI, 1.04-1.08; P<0.001). Specifically, azithromycin randomization was associated with a higher relative prevalence of erm(B) (aPR, 1.09 [95% CI, 1.04-1.15]; P=0.001), erm(C) (aPR, 1.23 [95% CI, 1.14-1.31]; P<0.001), msr(A) (aPR, 1.14 [95% CI, 1.04-1.25]; P=0.007), and msr(D) (aPR, 1.07 [95% CI, 1.03-1.11]; P=0.001). There was no difference in overall bacterial pathogen prevalence (18.9% vs 17.3%) between randomization arms, but a slightly lower proportion of children had Shigella after randomization in the azithromycin arm (3% vs. 5%, aPR, 0.79 [95% CI, 0.62, 1.01]; P=0.063). InterpretationAzithromycin at hospital discharge was associated with higher carriage of macrolide-resistance-conferring genes in the post-discharge period compared with placebo, without significant declines in enteric pathogen carriage other than modest changes to Shigella. The potential benefits and risks of empiric azithromycin need to be considered, as children are increasingly exposed to this broad-spectrum antibiotic.

Background: The U.S. 2024-2025 influenza season was characterized by sustained elevated activity from November 2024 to April 2025, with circulation of both influenza A(H1N1)pdm09 and A(H3N2), the latter of which included some antigenically drifted viruses. Methods: From October 1, 2024, to April 30, 2025, a multistate respiratory virus surveillance network enrolled adults hospitalized with acute respiratory illness in 26 U.S. medical centers. Influenza vaccine effectiveness (VE) against influenza-associated hospitalization and severe in-hospital outcomes was estimated using a test-negative study. The odds of influenza vaccination among influenza-positive case patients and influenza-negative control patients were compared using multivariable logistic regression; VE was calculated as (1-adjusted odds ratio for vaccination) x 100, expressed as a percent. Results: The 2024-2025 seasonal influenza vaccine was effective against influenza-associated hospitalization (VE: 40% [95% confidence interval (CI): 32%-47%]), consistent across age group and influenza A subtypes. Influenza vaccination also reduced the overall risk of all severe in-hospital outcomes evaluated, including standard oxygen therapy (VE: 41% [95% CI: 31%-50%]), non-invasive advanced respiratory support (VE: 38% [95% CI: 19%-52%]), invasive organ support (VE: 58% [95% CI: 44%-69%]), ICU admission (VE: 58% [95% CI: 47%-67%]), and death (VE: 52% [95% CI: 18%-71%]) with effectiveness varying by influenza A subtype and age. Conclusions: Influenza vaccination reduced the risk of influenza-related hospitalization and severe in-hospital outcomes in adults during the severe 2024-2025 influenza season compared to those not vaccinated.

BackgroundInfluenza A(H1N1)pdm09 and A(H3N2) viruses predominated during the 2024-25 U.S. influenza season. We estimated influenza vaccine effectiveness (VE) in the United States against mild-to-moderate outpatient influenza illness by influenza type and subtype in the 2024-25 season. MethodsWe enrolled outpatients aged [&ge;]8 months with acute respiratory illness symptoms including cough in 7 states. Upper respiratory specimens were tested for influenza type/subtype by reverse-transcriptase polymerase chain reaction (RT-PCR). Influenza VE was estimated with a test-negative design comparing odds of testing positive for influenza among vaccinated versus unvaccinated participants controlling for age, study site, underlying health status, and month of illness onset. We also estimated VE of current season vaccination among adults stratified by prior season vaccination status. ResultsAmong 6,793 enrolled patients, 2,016 (30%) tested positive for influenza including 961 A(H3N2), 770 A(H1N1)pdm09, and 183 B/Victoria. Overall vaccine effectiveness against any influenza illness was 33% (95% Confidence Interval [CI]: 24 to 41): 27% (95% CI: 14 to 39) against influenza A(H3N2), 37% (95% CI: 24 to 48) against A(H1N1)pdm09, and 40% (95% CI: 12 to 59) against B/Victoria. VE did not differ based on whether or not participants had received influenza vaccine the previous season. ConclusionsInfluenza vaccination during the 2024-25 season protected against circulating influenza viruses, reducing the risk of outpatient medically attended influenza overall by approximately one-third among people who were vaccinated. Key PointsInfluenza vaccine reduced the risk of outpatient acute respiratory illness due to laboratory-confirmed influenza during the 2024-25 season by a third.

BackgroundCoxsackie B viruses cause acute infections and have been linked to chronic diseases like cardiomyopathies, type 1 diabetes, and celiac disease. Despite their clinical significance, no vaccines exist for coxsackie B virus types. PRV-101, a new candidate vaccine covering five coxsackie B virus types, showed good immunogenicity and tolerability in a phase 1 trial (PROVENT). MethodsWe conducted an extended follow-up of the PROVENT trial to assess the long-term immune response and safety of PRV-101. A total of 26 participants from the original cohort (n=32) were enrolled for additional testing approximately two years post-immunization (11 high-dose, 10 low-dose, and 5 placebo). Coxsackie B virus -specific antibody responses were measured and compared to earlier time points. ResultsPRV-101 was safe with no late adverse effects or emergence of autoantibodies linked to type 1 diabetes or celiac disease. Neutralizing virus antibodies remained elevated, with a clear dose-dependent response. In the high-dose group, antibodies against all coxsackie B virus types reached presumably protective levels, except for coxsackie B virus 2, where two participants turned seronegative. ELISA tests confirmed elevated antibody levels against coxsackie B virus proteins. DiscussionThese results suggest that PRV-101 induces durable antibody responses lasting at least two years. The findings support the continued development of PRV-101 for preventing both acute coxsackie B virus infections and chronic diseases like type 1 diabetes and celiac disease.

Respiratory syncytial virus (RSV) causes substantial infant morbidity and mortality, particularly in low- and middle-income countries (LMICs). RSM01 is a long-acting RSV monoclonal antibody (mAb) in development for LMICs. To date, RSM01 resistant mutants have not been able to be generated in vitro. We systematically assessed the in vitro resistance barrier of RSM01 relative to licensed RSV mAbs and the susceptibility of a panel of global contemporary strains to RSM01. The emergence of mAb-resistant mutant (MARM) was assessed for RSM01, nirsevimab, and palivizumab. Triple plaque-purified RSV-A2 and RSV-B1 were serially passaged under mAb pressure to generate MARMs, which were phenotyped and genotyped. Moderate resistance was defined as > 3-fold and high resistance > 30-fold increase in IC50 compared with parental strains. The susceptibility of contemporary clinical strains from South Africa, Argentina, and the Netherlands to RSM01 was tested in a neutralisation assay. RSV-A and B lab strains developed high resistance to palivizumab and nirsevimab, while RSM01 pressure induced moderate resistance. No MARMs demonstrated a fitness advantage; one RSM01 MARM incurred fitness costs. RSM01 potently neutralized global contemporary RSV-A and B strains. In conclusion, in vitro RSM01 resistance was infrequent and moderate, suggesting a high resistance barrier in vitro. Laboratory-selected MARMs may not directly predict clinical escape, but the confirmation of the high barrier to resistance of RSM01 is encouraging and provides an alternative in the event that resistance is observed with widespread use of current licensed anti-RSV mAbs. One Sentence SummaryIn vitro RSV resistance to RSM01 is infrequent and moderate, suggesting a high barrier to resistance.

Typhoid fever remains a significant public health challenge in low- and middle-income countries. In 2018, The World Health Organization recommended a single dose typhoid conjugate vaccine (TCV) for routine immunization in endemic settings; however, evidence guiding booster doses remains limited. Homologous TCV booster doses have demonstrated immune boosting. This study assessed the immunogenicity and safety of a heterologous booster using a Vi capsular polysaccharide-CRM197 TCV (Vi-CRM) administered 5-6 years after primary vaccination with a Vi capsular polysaccharide tetanus toxoid TCV (Vi-TT) in children. Children previously enrolled in a Phase 2 trial were recruited. Participants who had received TCV at 9-11 or 15-23 months were given a Vi-CRM booster at 6-7 years of age (Booster-TCV group), and controls received their first TCV dose at the same age (1st-TCV group). Serum anti-Vi IgG concentrations were measured at baseline and 28 days post-vaccination. Solicited and unsolicited adverse events (AEs) and serious adverse events (SAEs) were recorded. Among 147 children enrolled, 87 received a second and 60 received a first TCV dose. Baseline anti-Vi IgG geometric mean titers (GMT) were higher in the Booster-TCV group (21.5 EU/mL; 95% CI: 17.2-26.8) than in the 1st-TCV group (5.5 EU/mL; 95% CI: 4.5-6.7). At day 28, GMTs rose markedly in both groups: 5140.0 EU/mL (95% CI: 4302.0-6141.3) in the Booster-TCV group and 2084.8 EU/mL (95% CI: 1724.4-2520.5) in the 1st-TCV group. Local reactions and systemic AEs were mild. No SAEs were observed. Vi-TT-induced immunity persisted for at least 5-6 years, and a heterologous booster triggered a strong immune response with universal seroconversion. These findings support heterologous prime-boost strategies to maintain protection in school-age children and inform optimization of TCV schedules in endemic regions.

Background. Recent meta-analyses of randomized controlled trials (RCTs) claimed efficacy of higher-dose fluvoxamine (2 x 100 mg/day, as opposed to 2 x 50 mg/day) in prevention of disease deterioration in adults with mild - moderate COVID-19 disease. Objectives. Investigate whether such claims are supported by the data. Methods. Systematic review and meta-analysis of RCTs evaluating higher-dose fluvoxamine in this indication. Results. Seven studies declared as RCTs were identified, one of which was severely biased (open-label, non-standardized and unreported standard of care as a control), and eventually ended as non-randomized (huge attrition). Composite endpoints of deterioration in the 6 included placebo-controlled trials contained elements susceptible to error and bias. Three trials were small (<100 patients/arm), three were larger (270 - 750 patients/arm). Deaths and need for mechanical ventilation were sporadic and observed in only one trial. Hospitalizations were also sporadic in 5/6 trials. Frequentist methods generally appropriate for random-effects analysis of low number of trials with rare outcomes (generalized linear mixed models, beta-binomial or binomial-normal) greatly underestimated heterogeneity, but still did not document benefits regarding the composite endpoints or hospitalizations. Bayesian hierarchical models revealed huge heterogeneity and indicated no benefit regarding: (i) composites of deterioration, large trials OR = 0.78 (95% CrI 0.55 - 1.21); multiplicity corrected OR = 0.87 (0.64 - 1.21); (ii) hospitalizations, small trials OR = 0.88 (0.45 - 1.72); large trials OR = 0.94 (0.52 - 1.75); all trials OR = 0.81 (0.47 - 1.43). Heterogeneity was unlikely due to clinical particulars (vaccination status, treatment duration, time horizon), and more likely due to unidentified bias. Conclusions. RCTs do not support efficacy of higher-dose fluvoxamine in prevention of disease deterioration in adults with mild - moderate COVID-19 disease.

Long COVID is a disabling chronic illness with no proven treatments. Persistence of SARS-CoV-2 has been proposed as a biological driver of the disease. We conducted a placebo-controlled, double-blind, 2:1 randomized mechanistic trial of the SARS-CoV-2-specific monoclonal antibody AER002 in 36 participants who met the World Health Organization case definition of Long COVID. After baseline characterization, participants received a single infusion and were followed for 360 days. The primary endpoint was the PROMIS-29 Physical Health Summary Score (PHSS) at 90 days; secondary and exploratory endpoints included patient-reported and objective measures of physical, cognitive, and neurologic function as well as blood-, imaging-, and tissue-based biomarkers. While AER002 was safe and well tolerated, no significant differences in physical health, quality of life, objective measures of physical function or cognition, or blood-based biomarkers were demonstrated between the treatment and control arms. In a post-hoc analysis, participants with a lower baseline SARS-CoV-2 antibody level and higher drug exposure were more likely to express a perceived treatment benefit based on the Patient Global Impression of Change scale (p<0.05 for anti-S, S1, and RBD). Although AER002 was not efficacious in this proof-of-concept study of people with broadly defined Long COVID, our findings could inform recruitment or dosing strategies employed in future trials using monoclonal antibodies to target viral persistence as a driver of Long COVID.

AO_SCPLOWBSTRACTC_SCPLOWInfluenza A subclade K viruses caused high infection rates in the 2025/2026 Northern Hemisphere season, raising concerns about antigenic drift and reduced vaccine effectiveness. We measured antibody responses in matched human pre- and post-vaccination sera against a vaccine-like as well as subclade K isolates. Pre-existing immunity to subclade K variants was noted with seasonal influenza vaccination boosting titers two-fold against subclade K and three-fold against the vaccine-like strain, indicating little antigenic drift. These data contrast ferret-based predictions of marked antigenic drift.

APC148 is a novel metallo-beta-lactamase inhibitor with broad activity against Ambler class B enzymes including NDM, VIM and IMP. It is being developed for patients with serious infections caused by multidrug-resistant Gram-negative bacteria. APC148 is combined with the broad-spectrum beta-lactam antibiotic meropenem and the serine-beta-lactamase inhibitor avibactam, which targets Ambler class A, C, and some class D (OXA-48-like) enzymes. In combination with meropenem and avibactam, APC148 demonstrated superior in vitro activity against a global, multidrug resistant collection of Enterobacterales, showing its promising activity against beta-lactamase producing pathogens. In this randomized, placebo-controlled, first-in-human study, the safety, tolerability and pharmacokinetics of APC148 were evaluated in healthy adults. Single doses ranging from 50 mg to 760 mg APC148 were administered intravenously over 3 h to 46 participants across six dose groups. APC148 was well tolerated at all dose levels. All adverse events were of mild intensity, and no serious adverse events or adverse events leading to study- or treatment discontinuation occurred. The pharmacokinetics of APC148 were dose-proportional with low plasma clearance, low to moderate volume of distribution and a mean plasma half-life of 2.6 h. APC148 is well tolerated in humans at therapeutically relevant doses and represents a promising candidate in the fight against antibiotic-resistant bacteria. (This study has been registered at ClinicalTrials.gov under registration number NCT06360640).

ImportanceRecent reports have highlighted an intense influenza activity related to the circulation of the influenza A(H3N2) subclade k variant. There is no data available on the impact of the emergence of H3N2 subclade k on the severity of the 2025-2026 epidemic or on the clinical phenotype of patients requiring admission to the intensive care unit (ICU). ObjectiveTo compare the clinical presentation, hospital mortality and virological characteristics of patients with laboratory-confirmed influenza infection included in French intensive care units during the 2025-2026 epidemic season with those of patients admitted during the 2024-2025 season. We also aimed at measuring the impact of the A(H3N2) subtype on hospital mortality during the 2025-2026 season. DesignProspective, multicenter, observational SEVARVIR cohort study including patients admitted during the 2024-2025 and 2025-2025 influenza seasons. SettingForty-two French ICUs ParticipantsAdult patients with laboratory-confirmed influenza infection Interventionsnone Main Outcomes and MeasuresThe primary outcome measure was in-hospital mortality. ResultsPatients admitted in intensive care units for influenza in 2024-2025 (n=360) and 2025-2026 (n=325) were included in the French nationwide prospective multicentre SEVARVIR study. There was no significant difference in day-28 mortality between the seasons (12.7%, n=45/355 vs 16.5% n=28/170; p=0.28). In the 2025-26 season, 49% had the A(H1N1) subtype and 51% the A(H3N2) subtype (k subclade: 77%). The univariable Cox analysis revealed that patients infected with A(H3N2) viruses were at greater risk of death over time. Multivariable Cox analysis revealed that during the 2025-2026 season, age (adjusted hazard ratio, aHR=1.05 [1.00;1.11]; p=0.046) and the clinical frailty scale (aHR=1.82 [1.26;2.72]; p=0.001) were associated with an increased risk of death. The A(H3N2) subtype was not associated with an increased risk of death (aHR=1.13 [0.32;4.51]; p=0.85). Phylogenetic analyses from our ICU cohort together with 300 contextual sequences from community-acquired influenza cases collected during the same period showed no clustering according to severity. Conclusions and RelevanceThis French national prospective observational study, found that the emergence of the influenza A(H3N2) subclade K was associated with an increased risk of death in univariable but not multivariable analysis, adjusting for host-related factors. Trial RegistrationNCT051625 Key PointsQuestion: What impact did the 2025-26 influenza epidemic and the A(H3N2) variant have on the mortality of patients admitted to intensive care units? Findings: In this prospective, nationwide cohort study of 685 patients admitted to intensive care units with severe influenza during the 2024-25 or 2025-26 seasons, no difference in hospital mortality was observed between the two seasons. Patients infected with the A(H3N2) virus, 77% of which corresponded to clade k, were at higher risk of death in univariable but not in multivariable analysis after adjusting for age and clinical frailty scale. Meaning: Patients in intensive care units with severe A(H3N2) infection during the 2025/2026 season were not at higher risk of death after adjusting for confounding variables.

Influenza H3N2 subclade K (J.2.4.1) is a genetic branch of H3N2 with 11 mutations in hemagglutinin and currently represents the dominant circulating influenza strain. We evaluated antibody responses to H3N2 subclade K before and after influenza vaccination in 46 healthy individuals. Our data show that baseline antibody responses to two H3N2 subclade K variants were lower than to other H1N1 and H3N2 strains and that antibody responses following vaccination were also less robust to the H3N2 subclade K variants. These data indicate that the H3N2 subclade K strain partially evades both prior H3N2 immunity and the current inactivated influenza vaccine.

BackgroundCoronavirus outbreaks remain a persistent threat to global health, and vaccines based primarily on spike-specific immune responses are susceptible to antigenic variation. T-cell immunity directed against conserved internal viral proteins may provide a complementary and more variant-tolerant strategy for next-generation coronavirus vaccines. MethodsWe combined machine learning-guided antigen prioritization with ex vivo functional immunological validation to identify conserved non-spike T-cell targets across betacoronaviruses. Candidate sequences were screened for immunogenicity using primary human peripheral blood mononuclear cells from healthy donors using intracellular cytokine staining and activation-induced marker assays. Top-ranked conserved regions were incorporated into multiepitope mRNA constructs, and their intracellular expression and HLA class I presentation were confirmed by immunopeptidomics. Immunogenicity was further evaluated ex vivo and in vivo using mRNA immunization of mice and T-cell FluoroSpot assays. FindingsAcross a panel of 97 peptides derived from 19 viral proteins, evolutionary conservation across distinct betacoronavirus taxa was strongly associated with functional T-cell immunogenicity in human donors. Highly conserved peptides elicited significantly stronger and more frequent CD4 and CD8 T-cell responses than taxon-restricted peptides. Multiepitope mRNA constructs encoding conserved regions were efficiently expressed and presented on HLA class I molecules and induced T-cell responses in human PBMCs. In mice, mRNA immunization with conserved multiepitope constructs generated robust interferon-{gamma}- and interleukin-2-producing T-cell responses that exceeded those induced by unconserved control constructs. InterpretationThese results link evolutionary conservation to functional cellular immunogenicity and demonstrate the feasibility of multiepitope mRNA delivery for inducing conserved coronavirus-directed T-cell responses. Although protective efficacy remains to be established, conservation-guided antigen selection represents a scalable strategy for developing T-cell-focused vaccines with broad lineage coverage, supporting pandemic preparedness beyond spike-centered immunity. FundingThe research was supported by CEPI, NEC, University of Oslo and Oslo university hospital. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSPrior coronavirus vaccine development has focused predominantly on spike protein-directed neutralizing antibodies. While highly effective against matched strains, spike-centered immunity is vulnerable to antigenic drift and lineage-specific escape. Multiple observational and experimental studies have shown that T-cell responses, particularly against internal viral proteins, are more conserved and correlate with reduced disease severity and cross-variant recognition. Epitope prediction algorithms and immunoinformatics approaches have been widely used to nominate candidate T-cell targets; however, systematic functional validation of conserved non-spike antigens across betacoronaviruses in primary human immune systems, combined with antigen presentation data and in vivo vaccine testing, has remained limited. Searches of PubMed and bioRxiv up to December 2025 using terms including "coronavirus T-cell vaccine," "conserved coronavirus epitopes," "betacoronavirus cross-reactive T cells," and "mRNA T-cell vaccine" identified studies demonstrating cross-reactive T-cell immunity and computational epitope selection, but few integrated machine-learning-guided antigen prioritization with ex vivo human functional screening, immunopeptidomics, and in vivo mRNA immunization in a unified workflow. Added value of this studyThis study provides an integrated experimental and computational framework for identifying and validating conserved non-spike T-cell antigens across betacoronaviruses. We functionally screened a panel of candidate peptides derived from multiple viral proteins and demonstrated that evolutionary conservation across species is strongly associated with T-cell immunogenicity. We further demonstrate that multiepitope mRNA constructs encoding these top-ranked conserved regions can be intracellularly expressed, presented on HLA class I molecules to induce polyfunctional T-cell responses in primary human PBMCs. Finally, in vivo mRNA immunization in mice induces robust interferon-{gamma} and interleukin-2 T-cell responses exceeding those induced by unconserved control constructs. Together, these findings link evolutionary conservation to functional cellular immunogenicity and extend beyond in silico prediction by demonstrating antigen processing, presentation, and immunogenicity across human and murine systems. Implications of all the available evidenceCollectively, the available evidence indicates that T-cell immunity directed toward conserved internal coronavirus proteins represents a complementary and potentially more variant-tolerant axis of vaccine design than spike-only strategies. Our findings suggest that evolutionary conservation can serve as a practical selection principle for prioritizing T-cell antigens with broad lineage coverage and that multiepitope mRNA delivery is a feasible platform for inducing such responses. While direct protection and heterologous challenge studies will be required to establish clinical efficacy, the integration of computational prioritization with functional validation supports a scalable approach to pandemic preparedness that may be applicable to other rapidly evolving viral families.

Background Rifampicin-resistant tuberculosis (RR-TB) is a major threat to public health in Viet Nam, with nearly 10,000 incident cases estimated annually. It is uncertain whether these cases are driven by transmission of resistant strains or de novo resistance acquisition during treatment. Methods We undertook dense, city-wide sampling of adults newly diagnosed with pulmonary RR-TB in Ho Chi Minh City, Viet Nam's largest city, between March 2020 and April 2024. Participants provided sputum for culture and whole-genome sequencing (WGS), and demographic and clinical data were collected at enrolment. Phylogenetic analyses were combined with clinical histories to infer transmitted versus acquired rifampicin resistance. Estimates were corrected for sampling coverage using simulation-extrapolation (SIMEX). Temporal emergence of rifampicin resistance was reconstructed by lineage using Bayesian phylogenetic dating, and the geographic and demographic structure of transmission networks was assessed using geocoded residential data and commute time-based analyses. Findings Among 2,319 RR-TB cases diagnosed during the study period, 1,491 (64%) isolates were successfully sequenced. After accounting for sampling and phylogenetic uncertainty, we estimated that between 72% and 87% of all RR-TB arose through transmission of already-resistant strains with the remainder due to de novo acquired resistance. Bayesian dating analyses revealed that resistance emergence events occurred repeatedly from the 1980s to the present, with early events seeding long-lived, city-wide transmission networks. Transmission networks were geographically dispersed across the city, with limited household clustering, and only weakly structured by host demographics, consistent with diffuse, city-wide transmission rather than localised or assortative spread. Interpretation RR-TB in Ho Chi Minh City is driven predominantly by ongoing transmission, but a substantial minority of cases arise from newly acquired resistance. Alongside promoting early diagnosis and treatment to interrupt transmission, the main drivers of acquired resistance need to be identified to control RR-TB.

The portfolio of next generation COVID-19 vaccines would benefit from candidates that induce durable systemic and mucosal immune responses that would lessen person-to-person transmission. We constructed an intranasal (IN) replication-competent adenovirus type 4 recombinant platform to express SARS-CoV-2 Spike variants (Ad4-S) and assessed immunogenicity and efficacy in the Syrian hamster model. Although both IN Ad4-S and intramuscular (IM) vaccines (Ad26.CoV2.S and mRNA-1273) induced serum binding antibodies, only Ad4-S induced a robust mucosal response in the nasal cavity. IN Ad4-S vaccination induced serum neutralizing titers equivalent to or greater than IM vaccination but more durable up to 6 months. Upon challenge, IN immunization also resulted in less weight loss, greater breadth and durability of restriction of viral replication, and less lung pathology than IM immunization up to 268 days after immunization. These data support the potential of the IN Ad4 vaccine platform to reduce transmission of SARS-CoV-2 and other respiratory viruses with pandemic potential.

BackgroundThe LP.8.1-containing COVID-19 mRNA vaccines were recommended for the 2025 seasonal vaccination campaigns in Europe and the United States. Safety data on these vaccines are limited. MethodsWe conducted a nationwide register-based cohort study in Denmark including all adults aged 65 years and older or at high risk of severe COVID-19 who had received previous COVID-19 vaccine doses. The study period was July 1, 2025, to December 3, 2025. We estimated incidence rate ratios using Poisson regression comparing rates of 30 adverse events within 28 days following LP.8.1-containing vaccination with reference period rates, adjusted for age, sex, region of residence, high risk of severe COVID-19, calendar time, and comorbidities. Self-controlled case series analysis was conducted as a complementary approach. ResultsAmong 1,565,697 individuals (mean age 69.5 years; 53.8% female), 958,633 received an LP.8.1-containing vaccine. Receipt of an LP.8.1-containing vaccine was not associated with a statistically significant increased rate of any of the 30 adverse events within 28 days after vaccination. The incidence rate ratio was 0.95 (95% CI, 0.86-1.06) for ischemic cardiac event, 0.83 (95% CI, 0.76-0.92) for cerebrovascular event, and 0.32 (95% CI, 0.04-2.50) for myocarditis. Results from the self-controlled case series analysis were similar. ConclusionsIn a nationwide cohort of more than 1.5 million adults, no increased risk of 30 adverse events was observed following vaccination with LP.8.1-containing COVID-19 mRNA vaccines.