New England Journal of Medicine

Background Killed whole-cell oral cholera vaccines require multiple doses and have reduced efficacy in young children, limiting their utility. PanChol is a single-dose, oral live-attenuated cholera vaccine engineered from a current seventh pandemic El Tor O1 Vibrio cholerae strain. PanChol was shown to be safe and immunogenic in a previous phase 1a trial. In participants from this first-in-human trial, we aimed to assess the durability of the initial PanChol dose and the safety and immunogenicity of a second dose. Methods This open-label phase 1a booster study was conducted at Brigham and Women's Hospital (Boston, MA). Eligible participants were healthy adults aged 18-55 years without a history of cholera or gastrointestinal disorders and had received a PanChol dose ranging from 105-1010 colony-forming units (CFU) within the previous 322-1111 days. All participants received a booster dose of 2x107 CFU. The primary outcome was safety, including solicited, unsolicited, and serious adverse events following the second dose of PanChol. Secondary endpoints were the magnitude of pre- and post-vaccination serum vibriocidal titers to both Inaba and Ogawa V. cholerae, including seroconversion (4-fold rise in titers over baseline), and stool shedding of PanChol organisms using quantitative and qualitative stool cultures. Comparisons of the amount of vaccine shedding in stool following primary and secondary immunization were used to assess the intestinal mucosal immunity elicited by the initial PanChol dose. All outcomes were assessed in all participants. This trial is registered with ClinicalTrials.gov, NCT05657782, and is complete. Findings Between Aug 25, 2025, and Feb 20, 2026, 20 healthy adults who previously received a single oral dose of PanChol were enrolled to receive a booster dose of 2x107 CFU. Eleven (55%) of 20 participants were male and the median age was 43{middle dot}6 (IQR 30{middle dot}2-49{middle dot}5). Ten (50%) were White and 17 (85%) were not Hispanic or Latino. Nine (45%) of 20 boost recipients reported at least one solicited adverse event; 13 (93%) of 14 events were mild, and all were transient. The most common solicited adverse event was nausea, reported by 4 (20%) participants; all cases were mild. Most unsolicited adverse events were mild; one was grade 3 and was deemed unrelated to vaccination. Two unsolicited adverse events were deemed related to vaccination (mild gassy sensation and heartburn, both of which occurred on day 1 and resolved the same day). In most participants, vibriocidal antibody titers measured on the day of boosting exceeded baseline titers prior to the initial dose (17 (85%) for Inaba and 14 (70%) for Ogawa). Fifteen (75%) of 20 boost recipients seroconverted vibriocidal antibody titers to both serotypes. After the boost, 17 (85%) participants had no or self-limited vaccine shedding, compared with 10% after the first PanChol dose. Interpretation A second oral dose of PanChol had a favorable safety profile and induced vibriocidal seroconversion to both serotypes in 75% of boost recipients. Intestinal colonization of PanChol following the boost serves as a proxy for measuring mucosal immunity targeting V. cholerae. The decrease in in the abundance of PanChol fecal shedding following the second dose, compared with the first, suggests that a single dose of PanChol is sufficient to confer durable protective immunity against a cholera challenge. These observations underscore the need for further clinical development of PanChol. Funding Wellcome Trust.

SARS-CoV-2 antigenic evolution continues to challenge strain-matched vaccination. For the 2026-27 season, the European Medicines Agency (EMA) identified XFG as the preferred antigen within the JN.1 family and Comirnaty XFG was authorised in the European Union in July, 2026. We studied 22 participants who received 30 microg of mRNA encoding XFG (Comirnaty XFG, BioNTech/Pfizer, Mainz, Germany) in September, 2026 and had paired serum available before vaccination and median 14 days afterwards. Median Wuhan-Hu-1 S1-specific IgG increased from 1600 BAU/mL (IQR 1118-2926) to 2914 BAU/mL (2117-4468), a 1.8-fold increase. Median RBD-binding ED50 increased from 116 (51.4-212) to 305.6 (170.8-434.6) for LP.8.1 and from 354.3 (129.2-558.2) to 832.9 (429-1175) for NB.1.8.1, corresponding to 2.6-fold and 2.4-fold increases, respectively (all p<0.0001). XFG-adapted vaccination increased neutralising activity against each tested variant. The GMT against XFG increased from 180 before vaccination to 894 afterwards (5.0-fold), and that against RV.1.3 increased from 121 to 599 (4.9-fold). GMTs increased from 117 to 386 for PQ.16.1.1 (3.3-fold), from 101 to 316 for XFG.1.1 (3.1-fold), from 629 to 1772 for LP.8.1 (2.8-fold), from 221 to 611 for NB.1.8.1 (2.8-fold), and from 228 to 642 for PJ.2.1 (2.8-fold). Neutralisation of BA.3.2.2 increased more modestly, from GMT 78 to 126 (1.6-fold; p=0.0009). Pre- versus post-vaccination neutralisation titres differed significantly for all variants (p<0.001). Despite the broad increase, post-vaccination neutralisation remained heterogeneous. Relative to LP.8.1, GMTs were 2.0-fold lower for XFG, 2.8-fold lower for PJ.2.1, 2.9-fold lower for NB.1.8.1, 3.0-fold lower for RV.1.3, 4.6-fold lower for PQ.16.1.1, 5.6-fold lower for XFG.1.1, and 14.1-fold lower for BA.3.2.2. These findings provide early human immunogenicity data after XFG-adapted mRNA vaccination. The largest relative increases were observed for XFG and RV.1.3, whereas LP.8.1 remained the most strongly neutralised variant after Comirnaty XFG vaccination and BA.3.2.2 the least. This pattern suggests broad boosting of cross-reactive humoral immunity without elimination of between-variant differences. The small, extensively pre-immunised cohort, short follow-up, absence of a contemporaneous vaccine-comparator group, and use of a pseudovirus assay limit inference. Our data characterise early antibody binding and neutralisation but do not establish durability or clinical effectiveness.

In this test-negative study, the effectiveness of the maternal RSVpreF vaccine among infants <6 months was 73.9% against medically attended respiratory syncytial virus (RSV) infection and 86.3% against RSV-associated hospitalization. Maternal RSVpreF and nirsevimab had comparable initial effectiveness, but effectiveness of RSVpreF waned approximately 1.7 times more rapidly.

Background: Invasive non-typhoidal Salmonella (iNTS) disease causes an estimated 605,000 cases and 76,000 deaths each year, concentrated in sub-Saharan Africa, where the African Salmonella Typhimurium sequence type 313 (ST313) lineage predominates. Vaccine development is hampered by an absence of efficacy data and undefined correlates of protection. Methods: We conducted a phase 1, randomised, double-blind, dose-escalation controlled human infection model (CHIM) in healthy UK-resident adults, who were randomly assigned 1:1 to oral challenge with S. Typhimurium 4/74 (ST19, associated with gastrointestinal disease) or D23580 (ST313, associated with invasive disease). Dose-escalation was guided by a Bayesian continual reassessment method (CRM). The primary endpoint was Salmonella diagnosis, defined as sustained fever [&ge;]38{degrees}C on [&ge;]2 occasions [&ge;]12 hours apart and/or bacteraemia. Trial registration ClinicalTrials.gov (NCT05870150). Findings: Between August 2023 and December 2024, 50 participants were enrolled (25 per strain). 105 CFU was the maximum feasible dose, with CRM-estimated attack rates of 57.9% (95% credible interval 37.3 - 73.8) for D23580 and 47.4% (26.7 - 65.7) for 4/74. There were no serious adverse events. We found no clinical, microbiological, or immunological difference between the two pathovariants. Higher baseline serum anti-O-antigen IgG was associated with reduced disease (adjusted OR 0.42, 95% CI 0.17 - 0.90) and higher baseline faecal anti-lipopolysaccharide IgA with reduced colonisation (OR 0.12, 95% CI 0.01 - 0.59). Interpretation: This S. Typhimurium CHIM is safe, reproducible, and provides a platform to generate early efficacy signals and candidate correlates of susceptibility, thereby de-risking future iNTS vaccine trials. The absence of a phenotypic difference between the invasive and gastrointestinal pathovariants in immunocompetent adults suggests that host factors, rather than pathogen adaptation alone, shape the invasive phenotype seen in endemic settings. Funding: Wellcome Trust.

The continued evolution of SARS-CoV-2 has led to regular updates of the COVID-19 vaccine immunogen. However, the exact benefits of these updates for vaccine effectiveness in a real world context are difficult to evaluate. We performed a comprehensive meta-analysis of booster vaccine effectiveness in studies identified through the ViewHub systematic review. We integrated evidence from 44 studies reporting on effectiveness of mRNA booster vaccines containing XBB.1.5, JN.1 and KP.2 immunogens to assess the combined impact of booster immunogen, time since vaccination and calendar time at which a study was conducted. We estimate that the relative risk of severe disease increases by 9% [95%CI 7.4-10.5] each month following booster administration, likely due to antibody waning, and by an additional 2.4% [95%CI 1.2-3.6] for each calendar month, likely due to antigenic drift. Our findings show that COVID-19 booster vaccine effectiveness declines both with time after vaccination as well as calendar time since the vaccine immunogen emerged. This reinforces the need for regularly and timely vaccine immunogen updates.

Background: The 2025/26 influenza season included A(H3N2) subclade K predominance with A(H1N1)pdm09 co-circulation and subsequent prolonged influenza B activity. The Canadian Sentinel Practitioner Surveillance Network reports vaccine effectiveness (VE) in the context of genetic and antigenic relatedness to circulating viruses. Methods: We estimated VE by test-negative design among outpatients with medically-attended acute respiratory illness between November and April. We characterized case viruses by whole genome sequencing and hemagglutination inhibition assay. Results: Among 2809/9047 (31%) influenza-positive specimens, 82% (2306/2809) were influenza A with 18% (504/2809) influenza B. Of subtyped influenza A, 85% (1848/2169) were A(H3N2). We sequenced 59% (1099/1848) of A(H3N2) viruses, with 87% (956/1099) subclade K, antigenically-mismatched to subclade J.2 vaccine. VE against A(H3N2) and subclade K was 38% (95% confidence interval: 27%-47%) and 33% (19%-45%). We sequenced 69% (222/323) of A(H1N1)pdm09 viruses, virtually all (n=218) clade 5a.2a.1, including subclades D.3.1 (21%; n=47) and D.3.1.1 (77%; n=171), antigenically-matched to subclade D vaccine. VE against A(H1N1)pdm09, subclades D.3.1 and D.3.1.1 was 28% (4%-47%), -21% (-144%-40%) and 44% (14%-64%). We sequenced 82% (413/504) of influenza B viruses, all B/Victoria, including antigenically-mismatched subclade C.3 (18%; n=74) with D197N gain-of-glycosylation, and antigenically-matched subclade C.5 (82%; n=339) relative to subclade C vaccine. VE against influenza B, subclades C.3 and C.5 was 55% (41%-66%), 10% (-60%-49%) and 68% (51%-79%). Conclusions: The 2025/26 influenza vaccine reduced the risk of A(H3N2), A(H1N1)pdm09 and B/Victoria by over one-third, one-quarter and one-half, respectively. Laboratory-based indicators of vaccine match remain uncertain proxies for actual vaccine protection, reinforcing importance of annual epidemiological monitoring of VE.

Background Mupirocin, a widely used topical agent for decolonization of Staphylococcus aureus, is increasingly compromised by resistance. Although plasmid-mediated mupirocin resistance is a recognized cause of decolonization failure, its role in facilitating hospital-wide transmission is unknown. Methods We conducted genomic surveillance of S. aureus at two interconnected urban hospitals where mupirocin decolonization is routine. Genome sequencing of >10,000 isolates was integrated with patient data to identify transmission and resistance determinants. Bacterial phenotypes and fitness were evaluated in vitro and in murine colonization models. Findings Genome sequencing identified 475 hospital transmission events; none were detected by conventional surveillance. The mupA (ileS2) resistance determinant, carried on conjugative plasmids, was enriched eightfold in methicillin-resistant S. aureus (MRSA) relative to methicillin-susceptible strains. mupA was associated with nearly a threefold greater chance of hospital transmission, especially within endemic healthcare-associated MRSA lineages, and was enriched twofold in hospital-onset infections compared with admission colonizing isolates. Multiple independently evolved inactivating mutations in the essential chromosomal gene ileS1 co-occurred with mupA, creating plasmid addiction in which mupA became indispensable for bacterial survival. Addiction arose most frequently within the dominant community-acquired MRSA lineage, where plasmid carriage reduced colonization fitness in mice. Plasmid-containing strains exhibited stringent-response activation, explaining the fitness costs and collateral tolerance to disinfectants, such as ethanol and peroxide. Although addiction reduced S. aureus fitness, it increased plasmid transfer, and addicted variants spread across hosts, demonstrating adaptation that mitigates these costs. Unexpectedly, we identified a mupirocin-dependent vulnerability to isoleucine limitation, revealing a potential strategy to target mupA-mediated resistance. Interpretation Plasmids promote hospital transmission of mupirocin-resistant S. aureus and create an evolutionary trap in which antibiotic use selects for bacterial dependence on otherwise costly resistance elements. This dependence revealed a collateral bacterial vulnerability that could be exploited to target resistant strains and preserve the effectiveness of mupirocin.

Importance: Acute mountain sickness (AMS) is a common high-altitude illness partly preventable by acetazolamide, but sex-specific efficacy and tolerability have not been prospectively evaluated. Objective: To test the a priori hypothesis that preventive acetazolamide achieves a 20% greater relative risk reduction (RRR) of AMS in female vs male lowlanders ascending to 3600 m. Design: Randomized, double-blind, placebo-controlled, parallel-group trial conducted from March 2024 to August 2025; participants, outcome assessors, and statistician were blinded until analysis was complete. Setting: Baseline at 760 m in Bishkek and altitude exposure at the Kumtor High Altitude Facility (3600 m), Kyrgyz Republic. Participants: Healthy female and male low-altitude residents (age 18-44 years, BMI 18-30 kg/m2, residence <1000 m); females were premenopausal, eumenorrheic, and not using hormonal contraception. Exclusion criteria included pre-existing disease, regular medication, pregnancy, anaemia, and altitude sojourn >2500 m within 4 weeks. Intervention: Acetazolamide 125 mg or matching placebo twice daily, from 24 hours before ascent and throughout the 2-day, 2-night stay at 3600 m. Main Outcomes and Measures: Primary outcome was the between-sex difference in RRR of AMS, defined as a 2018 revised Lake Louise Score of 3 or higher including headache. Secondary outcomes included absolute risk reduction (ARR) and drug tolerability. Results: Of 303 randomized participants (180 females, 123 males; mean [SD] age, 23 [4] years), AMS incidence under placebo (n=155) was 34% (females 42% vs males 23%; P=.02) and under acetazolamide (n=148) was 24% (females 30% vs males 14%; P=.02). Overall RRR was 31% (95% CI, 0% to 52%) and ARR was 10% (95% CI, 0% to 22%). Sex-stratified RRR was 27% (95% CI, -9% to 52%) in females and 42% (95% CI, -28% to 74%) in males; between-sex RRR difference, -15% (95% CI, -65% to 57%). Females had a 4.8-fold higher risk of moderate-to-severe drug-related side effects than males. Conclusions and Relevance: Preventive acetazolamide reduced overall AMS incidence at 3600 m, but the pre-specified 20% greater RRR in females (trial powered at 90%) was not observed. The nearly 5-fold higher risk of moderate-to-severe side effects in females warrants further investigation of sex-specific dosing. Trial Registration: ClinicalTrials.gov Identifier: NCT06499727

The World Health Organization has called for malaria vaccines with > 90% efficacy against Plasmodium falciparum (Pf) infection. The live, non-attenuated PfSPZ-CVac (chloroquine) vaccine provides the strongest protection against controlled human malaria infection (CHMI). Its 100% protective efficacy at 12 weeks against genetically distant Pf stems from a highly amplified immune stimulus. After inoculation, each invading sporozoite (SPZ) replicates up to 50,000 times within a hepatocyte. Over six days of development, these parasites express thousands of distinct proteins, presenting a vast and diverse array of antigens to the host immune system. The late liver stage parasites then rupture into the bloodstream, where they are killed by the co-administered drug, chloroquine. To engineer a Pf parasite that develops to the late liver stage like PfSPZ-CVac (chloroquine), but then arrests before transitioning to the blood stage, two genes required for transition from non-pathogenic liver to pathogenic blood stages were identified and deleted, creating late-liver stage arresting, replication-competent (LARC) PfSPZ. In a first-in-human, randomized, double-blind, placebo-controlled clinical trial, we assessed PfSPZ-LARC2 Vaccine in 75 malaria-exposed Burkinabe 1- to 48-year-olds. No vaccine-strain breakthrough blood-stage infections were detected; safety and tolerability profiles were similar in vaccinees and placebo recipients; and the highest immunogenicity was observed in the youngest recipients. Based on these findings, PfSPZ-LARC2 Vaccine has progressed to Phase 2 testing with the goal of rapidly advancing this genetically attenuated whole parasite vaccine to licensure and deployment.

Pneumococcal vaccination of older adults is primarily guided by age and clinical eligibility, despite substantial variation in individual risk of severe pneumonia. Here, we used longitudinal electronic health records from 787,538 adults aged [&ge;]65 years to evaluate the real-world effectiveness of the 20-valent pneumococcal conjugate vaccine (PCV20) and quantify clinical benefit according to baseline risk of pneumonia hospitalization. We developed and validated a machine-learning model using pre-PCV20 data to estimate individual 12-month hospitalization risk and integrated these predictions into a propensity score matching framework. Overall vaccine effectiveness against pneumonia hospitalization was 16.5% (95% CI, 10.6-22.1), but this population-level estimate masked substantial heterogeneity in clinical benefit. The 60% at lowest predicted risk, characterized by younger age and fewer pulmonary and other chronic conditions, showed no measurable reduction in hospitalization (VE, 3.1%; 95% CI, -14.4 to 18.0) and had an estimated 1-year number needed to vaccinate (NNV) of 7,423, compared with 184 and 115 in the intermediate- and high-risk groups, respectively. These findings suggest that incorporating baseline risk into adult pneumococcal vaccination strategies could enable more targeted and potentially better-timed vaccination.

Importance: Pharmacological targeting of host mechanisms that limit sepsis-induced organ dysfunction represents a new therapeutic approach. Preclinical studies showed that low-dose epirubicin enhances tissue damage control and attenuates sepsis severity independently of pathogen burden, thereby promoting disease tolerance to infection. Yet epirubicin can cause myelotoxicity when used in cancer therapy. Objective: To investigate whether low-dose epirubicin can safely be administered to patients with sepsis and septic shock. Design, Setting, and Participants: A randomized, double-blind, placebo-controlled clinical trial conducted in five German University hospitals. Patients with sepsis, defined by Sepsis-3 criteria, were eligible within 48 hours after diagnosis. The first patient was enrolled on October 19, 2022, and the last follow-up was conducted on May 21, 2025. Interventions: Eligible patients were randomized in a 4:1 ratio to receive either placebo or low-dose epirubicin in addition to standard care. There were three consecutive phases. Patients in the epirubicin group received a single dose of epirubicin (either 3.75 mg/m2, 7.5 mg/m2 or 15 mg/m2, depending on study phase). Main Outcomes and Measures: The primary endpoint of the trial was the 14-day myelotoxicity. Secondary and explorative outcomes included 90-day mortality, the degree of organ dysfunction as assessed by SOFA score, PK/PD modelling and cytokine release. Results: Of 854 patients assessed for eligibility, 32 were randomized and 31 were included in the primary analysis population. Six participants received placebo, nine participants received 3.75 mg/m2, nine received 7.5 mg/m2 and eight individuals received 15 mg/m2 epirubicin, respectively. There was no myelotoxicity in any group. Mortality at 90 days and SOFA-scores were not significantly different between groups. Two of 39 SAEs in the epirubicin group were assessed by the investigators as possibly related to epirubicin, Conclusions and Relevance Among patients with sepsis and septic shock, low dose epirubicin was not associated with increased myelotoxicity.

Background: Israel was among the first countries to implement rapid nationwide BNT162b2 vaccination and became a major source of early real-world evidence on COVID-19 vaccine effectiveness. Early Israeli studies reported approximately 90-95% effectiveness against documented SARS-CoV-2 infection, but over relatively short epidemiological periods. This study examines the national trajectory from the pre-vaccination period through the end of the global COVID-19 emergency. Methods: Five publicly available Israeli Ministry of Health surveillance datasets were analyzed longitudinally from February 2020 through May 2023. National trajectories of documented infection and test positivity were characterized before and after vaccine rollout, which began on December 20, 2020. Vaccinated-unvaccinated differences were then examined in two ways: first, using routine-surveillance case rates by vaccination status; and second, using an age-adjusted test-positivity analysis among individuals without documented prior infection, with testing denominators stratified by vaccination status. The second analysis, designed to address potential biases from prior-infection history and differential testing, began 19 weeks later, when the required data became available on May 30, 2021. Results: The two completed pre-rollout waves declined to [&le;]10% of their peaks within 32 and 43 days, respectively. The winter 2020-2021 wave, which was already underway when vaccination began, required 68 days. Subsequent major peaks were larger than the January 2021 peak, with Delta 17% higher and Omicron approximately nine times higher. Routine surveillance reached an early apparent vaccine-effectiveness peak of 94.4% in mid-February 2021 and declined to 61.5% by late May, with substantial rebounds thereafter. By early December it was 79.9%, before falling to 37.4% two weeks later and 8.2% by late December; it became persistently negative in February 2022. The test-positivity analysis showed a generally lower trajectory. After unstable estimates during the low-incidence summer weeks, it reached 62.1% in early December, fell to 26.8% one week later and -14.5% the next, and remained negative thereafter. Conclusions: These observational data cannot establish causal vaccine effects and do not address protection against hospitalization, severe disease, or death. Within the domain of documented infection, however, the early vaccination-associated advantage attenuated substantially within months and was further reduced when prior-infection history and vaccination-stratified testing were incorporated; in the latter analysis, the contrast reversed by late 2021 and remained negative thereafter. At the population level, national surveillance showed no sustained reduction in the magnitude or resolution of documented-infection waves after rollout. The Israeli experience may therefore be informative for future public-health emergencies, in which early short-window effectiveness estimates may change substantially as population immunity, testing practices, and the pathogen itself evolve.

Importance Several influenza vaccine products are available for older adults, but evidence combining both their absolute effectiveness and head-to-head comparisons within the same large population remains scarce, limiting product-specific vaccination guidance for this high-risk group. Objective To estimate the relative and absolute effectiveness of influenza vaccines against influenza-related hospitalization and in-hospital mortality among older adults. Design, Setting, and Participants Nationwide cohort study using the French National Health Data System (SNDS), including all adults born in 1958 or earlier, living in metropolitan France, at the start of the 2023-2024 campaign. Relative effectiveness (rVE) was assessed using a landmark design with exposure fixed before epidemic onset. Absolute effectiveness (VE) was assessed using a sequential trial emulation with weekly matching of newly vaccinated individuals to yet unvaccinated controls. Follow-up ran from December 5, 2023 to April 19, 2024. Exposures Vaccination with a high-dose (Efluelda) or one of three standard-dose quadrivalent vaccines (Influvac, Fluarix, Vaxigrip), compared individually or by dosage category, and against no vaccination. Main Outcomes and Measures Hospitalization with a diagnosis of influenza and death during such hospitalization. Effectiveness was estimated as 1 minus the hazard ratio from weighted Cox models, with corresponding numbers needed to vaccinate to prevent one case. Results Among 13.8 million eligible individuals, 5.7 million (41%) were vaccinated at the beginning of follow-up. The high-dose vaccine showed greater rVE than standard-dose vaccines against hospitalization (27% [95%CI, 23 to 31%]) and in-hospital death (27% [95%CI,14 to 38%]). Absolute VE was 39% (95%CI, 38 to 41%) against hospitalization and 45% (95%CI, 40 to 49%) against in-hospital death, and was higher for the high-dose vaccine (50%) than standard-dose vaccines (36%) against hospitalization. This difference was most evident among adults 70 years and older, while overall effectiveness declined with age. Conclusions and Relevance In this study, influenza vaccination conferred moderate protection against severe outcomes in older adults, and high-dose vaccination was associated with significantly greater effectiveness than standard-dose vaccines, particularly among adults 70 years and older. These findings support product-level differentiation in vaccination strategy for this population.

We compared the immunogenicity of three licensed egg-based inactivated influenza vaccines, including TetrAnflu (Sinovac quadrivalent), Fluarix Tetra (GSK quadrivalent), and Vaxigrip (Sanofi trivalent), in adult healthcare workers in Hong Kong during the 2025/26 season. Paired pre- and post-vaccination sera from age- and sex-matched recipients (n=30 to 40 per group) were tested by hemagglutination-inhibition assays against vaccine strains. After adjustment for age, sex, and sampling interval, the vaccines induced broadly comparable rises in antibody titers, proportions achieving titers >=40, and seroconversion rates, with a superior response to A(H1N1) after TetrAnflu. These real-world findings support the interchangeability of these vaccines for influenza vaccination programs.

There are currently no approved vaccines or medical countermeasures for use in prevention or treatment of Bundibugyo virus disease. A critical question is whether the existing vaccines approved for use against Ebola virus disease could provide sufficient cross-reactivity and cross-protection against Bundibugyo virus disease. We performed a systematic review and meta-analysis of published studies of antibody cross-reactivity to Bundibugyo virus (BDBV) after vaccination with previously approved Ebola vaccines (Ervebo or Zabdeno/Mvabea). We find on average a 2.8-fold (95% predictive interval, PI: 2.6-3.0) drop in binding (n = 8 observations from 4 studies) and 3.1-fold drop (95% PI: 2.0-4.8) in neutralization (n = 2 observations from 1 study) between Ebola virus and BDBV antigens after Ervebo vaccination, which appears maintained over time after vaccination. Very limited data on cross reactivity after Zabdeno/Mvabea vaccination suggests a higher drop in recognition of BDBV (39.7-fold, 95% PI: 24.8-63.8; n = 3 observations from 2 studies). In addition to analysis of antibody recognition in humans, we also investigated evidence for vaccine protection from BDBV challenge in animal models after Ervebo or other recombinant vesicular stomatitis virus (rVSV) based vaccines containing only Ebola antigen. A single study in NHP showed non-significant vaccine protection from BDBV challenge, while a study in ferrets showed significant protection after both one and two doses. The available data demonstrate immune cross-reactivity and some evidence for protection in animals, although further clinical and pre-clinical data is urgently needed to inform decisions on the use of Ervebo to protect against Bundibugyo virus disease.

Bundibugyo ebolavirus (BDBV) is causing an ongoing outbreak in the Democratic Republic of Congo (DRC) with no licensed vaccine available. Recent reports have shown the presence of BDBV-cross-reactive antibody responses in humans vaccinated against the related Ebola virus (EBOV). Here, we used an IFN-{gamma} ELISpot assay to assess T cell responses against the EBOV, BDBV and SUDV glycoproteins in clinical trial participants vaccinated with the licensed VSV-EBOV vaccine. We could show that BDBV-cross-reactive T cell responses are detectable in the majority of individuals and that conserved regions within the glycoprotein are targeted. In the absence of a BDBV-specific vaccine, these data support efficacy trials of the VSV-EBOV vaccine during the current outbreak.

Rationale. Guidelines disagree on antibacterial treatment for adults with community-acquired pneumonia and a positive respiratory viral test, particularly hospitalized patients and outpatients with comorbidities. Objectives. To estimate associations between antibacterial treatment selected for community-acquired pneumonia and outcomes in adults with virus-positive, imaging-evaluated nonsevere pneumonia. Methods. We conducted a retrospective multicenter study using Epic Cosmos data from 2016-2025. Hospitalized patients treated empirically by 24 hours were compared by continuation during hours 24-48; outpatients were compared by prescription at emergency-department discharge. Analyses were stratified by guideline-defined comorbidity and used propensity-score overlap weighting with source-cluster bootstrap confidence intervals. Exploratory analyses assessed respiratory virus, antiviral treatment, antibacterial class, and outpatient timing. Measurements and Main Results. The cohort included 376,320 adults: 275,604 inpatients and 100,716 outpatients. Inpatients who continued treatment had higher 30-day adverse-event risk without guideline comorbidity (adjusted risk difference, 1.70 percentage points; 95% confidence interval, 0.80-2.39) and with guideline comorbidity (2.56; 1.88-3.14), and longer post-landmark stay (adjusted mean ratios, 1.14 and 1.08). Exploratory class-specific analyses showed the largest adverse-event and mortality associations with broad therapy targeting resistant staphylococci or Pseudomonas; macrolide-containing and other atypical coverage showed no consistent adverse signal. Outpatient prescribing was associated with lower risks, but care-transition and residual confounding remained. Conclusions. Continued inpatient therapy after the empiric period showed no evidence of benefit and was associated with worse observed outcomes. Outpatient associations favored prescribing but remained vulnerable to care-transition and residual confounding.

Background: Global oral cholera vaccine (OCV) supply shortages and the retirement of Shanchol necessitate absolute reliance on alternative formulations. We conducted a systematic review and meta-analysis to evaluate the immunogenicity and safety of Euvichol variants compared with the historical Shanchol benchmark. Methodology/Principal Findings: A searched PubMed, Embase, MEDLINE, Scopus, and Cochrane CENTRAL up to May 2026 for randomized controlled trials (RCTs) comparing any Euvichol variant against Shanchol in healthy populations aged [&ge;]1 year. Primary outcomes were vibriocidal seroconversion rates at 14 days post-dose 2 pooled as Risk Ratios (RRs) via Mantel-Haenszel fixed-effects models. Five RCTs comprising 7,253 participants were included. Euvichol formulations demonstrated non-inferior, equivalent seroconversion rates compared with Shanchol for both Vibrio cholerae O1 Inaba (RR 1.00, 95% CI 0.98-1.02; I2=0%) and O1 Ogawa (RR 1.01, 95% CI 0.99-1.04; I2=26%). Log-transformed Geometric Mean Titers confirmed clinical equivalence for Inaba (MD 0.02, 95% CI -0.01 to 0.05) and Ogawa (MD 0.00, 95% CI -0.03 to 0.03). Overall safety was balanced between arms, showing no significant variation in the risk of any solicited adverse event (RR 0.91, 95% CI 0.75-1.11) or specific symptoms including fever (RR 0.84, 95% CI 0.52-1.35). Serious adverse events were rare and uniformly unrelated to vaccination. Conclusions/Significance: Euvichol variants demonstrate immunogenic non-inferiority and interchangeable safety thresholds compared with Shanchol. These findings robustly support the large-scale integration of modern Euvichol-Plus and streamlined Euvichol-S formulations to stabilize global OCV stockpiles.

An uncontrolled and rapidly growing outbreak of Bundibugyo virus (BDBV) is currently gripping the Democratic Republic of the Congo and threatening health security across Central Africa. There are no available BDBV-specific vaccines, although emerging evidence suggests that the Ebola virus-specific vaccine, rVSV-EBOV (also known by its tradename ERVEBO), may offer cross-protective immunity. To directly address this question, we evaluated the efficacy of rVSV-EBOV in the uniformly lethal ferret model of BDBV infection. All vaccinated animals survived BDBV challenge and exhibited minimal clinical signs of infection, presumably as a result of a moderate--but protective--humoral immune response. These findings provide critical evidence further supporting the cross-protective efficacy of rVSV-EBOV, and they suggest a potential role for this vaccine in mitigating the ongoing BDBV outbreak.

BACKGROUND Current polio vaccines face challenges including vaccine-derived poliovirus and high-containment manufacturing. We evaluated a recombinant trivalent virus-like particle (VLP)-based poliovirus vaccine (VPV) for safety and immunogenicity in a first-in-human phase 1 trial. METHODS In this randomized, observer-blind, active-controlled trial, 72 healthy adults (18 to 54 years) were assigned (1:1:1:1) to receive a single dose of VPV at low (45:8:25 D-antigen units [DU] + 0.1 mg aluminum phosphate [AP]), medium (45:8:25 DU + 0.3 mg AP), or high (90:12:45 DU + 0.3 mg AP) doses, or conventional inactivated poliovirus vaccine (cIPV). Primary outcomes were safety and tolerability. Secondary outcomes included neutralizing antibody titers through day 180. RESULTS No serious adverse events or Grade 3 reactions were reported. Solicited adverse events were reported in 77.8%, 55.6%, and 72.2% of the low-, medium-, and high-dose VPV groups, respectively, and 66.7% in the cIPV group. By day 29, VPV induced dose-dependent neutralizing antibody responses. For serotypes 1 and 2, the high-dose VPV group achieved geometric mean titers (GMTs) of 73,582 (95% CI, 31,198-173,545) and 110,623 (95% CI, 59,276-206,451), respectively, comparable to cIPV at 45,161 (95% CI, 20,973-97,244) and 112,361 (95% CI, 58,280-216,625). Although serotype 3 GMTs were lower for the high-dose VPV at 18,905 (95% CI, 8737-40,906) than for cIPV at 61,431 (95% CI, 31,123-121,251), 100% of high-dose VPV recipients achieved neutralizing titers [&ge;]1:1024. CONCLUSIONS A single dose of VPV was safe and highly immunogenic, supporting its potential as a next-generation vaccine to advance global polio eradication. (Funded by the Gates Foundation and Tianjin Leading Enterprises Innovative project 23YDLQSY00100; ClinicalTrials.gov number, NCT06101173).