The Lancet Infectious Diseases

BackgroundChikungunya virus (CHIKV) is an Aedes transmitted arbovirus. Demographic changes coupled with the expanding footprint of the mosquito from climate change have the potential to shift the global burden from the virus. MethodsHere we use projections of human demography and Aedes mosquitoes distribution to estimate baseline and future burden from CHIKV under different climate change scenarios in 178 countries. We then estimate the potential of vaccines to mitigate the growing burden. FindingsWe found that under RCP2.6 (an optimistic climate change scenario), the global population at risk from CHIKV will increase by 30.2% to 5.4 billion individuals. We estimated a 35% increase in annual infections, 49% increase in cases and a 128% increase in deaths. A similar impact was found under the more pessimistic RCP8.5 climate change scenario. In Europe and the Americas, the growing presence of Aedes will drive the growing case burden, with increases in human population size being key elsewhere. Ageing populations will result in major increases in the number of CHIKV-related deaths in all continents outside Africa. Vaccinating 50% of individuals aged 12y+ with a vaccine providing 70% protection against disease and 40% protection against infection would avert 29% of cases and 31% of deaths. InterpretationThese findings highlight how climate change will expand the footprint of CHIKV circulation, while demographic changes will lead to substantially increased case burden in affected countries. Vaccines will be critical to minimising this changing global burden. FundingCEPI

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.

A balanced and safe vaccine against all four-dengue virus (DENV) serotypes is urgently needed. Although the currently licensed DENV vaccines demonstrate efficacy, they also raise concern about vaccine-associated disease enhancement, particularly in DENV-naive individuals. The conserved, immunodominant fusion loop (FL) epitope is the target of cross-reactive, weakly neutralizing antibodies (Abs) which are associated with antibody-dependent enhancement (ADE). Previously, we developed D2-FLM, a highly mature DENV2 strain containing modification in the FL epitope making it unrecognizable to FL-Abs. Here, we grafted the FLM modification to another serotype and adapted them to replicate in Vero cells for live-attenuated vaccine (LAV) manufacturing while retaining favorable antigenic profiles, generating two new strains: D2-vFLM and D4-vFLM. Deep sequencing revealed mutations at the junction of envelope domains I and II (EDI and EDII) that appeared during adaptation of the engineered FL in mammalian cells. Importantly, both D2-vFLM and D4-vFLM showed no evidence of ADE in the presence of FL-targeting Abs. Sera from D2-vFLM immunized mice displayed strong homotypic and reduced heterotypic neutralization compared to wild-type viruses, with minimal to no ADE potential in vitro. Moreover, D2-vFLM immunization completely protected AG129 mice from lethal challenge with mouse-adapted D220. Collectively, these findings demonstrate that the FLM modification platform is transferable across serotypes and yields strains with favorable immunogenicity and reduced ADE risk. Our FLM approach provides a promising path toward the development of a safer tetravalent DENV LAV.

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.

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.

The seasonal circulation of respiratory syncytial virus (RSV) in countries such as Japan, together with the transient nature of passive immunity conferred to infants via maternal vaccination or monoclonal antibody administration, may warrant a differential strategy for those born during the RSV inter-seasonal period. Maximal effectiveness may be achieved by deferring immunisation of this cohort from birth until entry into their first RSV season using catch-up administration of monoclonal antibody through a seasonal and catch-up programme, compared with year-round administration. To estimate the benefit of seasonal and catch-up programmes in reducing RSV infant hospitalisations in Japan, we developed a static cohort model following infants through their first year of life, parameterised by Japanese data on weekly and municipality-specific RSV incidence during 2018 to 2025 and on RSV case hospitalisation risk from a health claims database study. We used Bayesian inference to estimate the effectiveness and its waning for maternal vaccine (RSVpreF) and long-acting monoclonal antibody (nirsevimab) from trial data. We estimate that year-round programme of RSVpreF or nirsevimab could reduce RSV hospitalisations from the status quo, under which only high-risk infants are eligible for monoclonal antibodies, by 46% (95% uncertainty range (UR): 31%, 65%) or 58% (95%UR: 39%, 79%) respectively. Seasonal and catch-up programmes could achieve percentage reductions of 1.1-fold (95%UR: 0.82, 1.6) or 0.98-fold (95%UR: 0.83, 1.2) compared with the year-round programme. If seasonality matches the seasonal immunisation timing, using 2024 as an example, the percentage reduction was 1.2-fold (95%UR: 0.95, 1.6) or 1.1-fold (95%UR: 0.97, 1.2), respectively, compared with the year-round programme. If protection from nirsevimab remained substantial after six months, the year-round programme would likely to be more effective. RSVpreF and nirsevimab may substantially reduce RSV infant hospitalisations in Japan. The benefit of the seasonal programmes depends on predictability of RSV seasonality and potential logistical challenges.

We evaluated 2024/25 KP.2 vaccine effectiveness (VE) against COVID-19 hospitalization among adults >60 years old eligible for publicly-funded vaccination during fall and/or spring campaigns in the province of Quebec, Canada. We included Quebec residents tested for COVID-19-compatible symptoms in an acute-care hospital between October 13, 2024 (epi-week 2024-42) and August 23, 2025 (2025-34), linking vaccine, hospital, chronic diseases and laboratory administrative records to assess VE through test-negative design. We compared the odds of being COVID-19 test-positive versus test-negative among vaccinated versus non-vaccinated participants, adjusting for sex, age, comorbidities, place of residence, and epidemiological week. Overall, 49,949 (43%) participants were vaccinated. Over an analysis period spanning up to ten months, including median time since vaccination of 16 weeks (interquartile range 9-24 weeks), VE was 34% overall, declining from 43% <8 weeks to negligible by the 32nd week post-vaccination. Findings confirm meaningful but short-lived COVID-19 vaccine protection against hospitalization in older adults.

Influenza viruses present a significant public health risk, causing substantial illness and death in humans each year. Seasonal flu vaccines must be updated regularly, and their effectiveness often decreases due to mismatches with circulating strains. Furthermore, inactivated vaccines do not provide protection against shifted influenza viruses that have the potential to cause a pandemic. The highly pathogenic avian influenza H5N1 clade 2.3.4.4b is prevalent among wild birds worldwide and is causing a multi-state outbreak affecting poultry and dairy cows in the United States (US) since March 2024. In this study, we have generated a NS1 deficient mutant of a low pathogenic version of the cattle-origin human influenza A/Texas/37/2024 H5N1, namely LPhTXdNS1, and validated its safety, immunogenicity, and protection efficacy in a prime vaccination regimen against wild-type (WT) A/Texas/37/2024 H5N1. The attenuation of LPhTXdNS1 in vitro was confirmed by its reduced replication in cultured cells and inability to control IFN{beta} promoter activation. In C57BL/6J mice, LPhTXdNS1 has reduced viral replication and pathogenicity compared to WT A/Texas/37/2024 H5N1. Notably, LPhTXdNS1 vaccinated mice exhibited high immunogenicity that reach its peak at weeks 3 and 4 post-immunization, leading to robust protection against subsequent lethal challenge with WT A/Texas/37/2024 H5N1. Altogether, we demonstrate that a single dose vaccination with LPhTXdNS1 is safe and able to induce protective immune responses against H5N1. Both safety profile and protection immunity suggest that LPhTXdNS1 holds promise as a potential solution to address the urgent need for an effective vaccine in the event of a pandemic for the treatment of infected animals and humans.

An efficacious blood-stage malaria vaccine would serve as a highly useful public health tool alongside licensed vaccines targeting the pre-erythrocytic life cycle stage of the Plasmodium falciparum parasite. RH5 is the leading blood-stage malaria vaccine candidate antigen due to its highly-conserved sequence and non-redundant role in merozoite invasion of red blood cells. Following encouraging immunogenicity data in UK and Tanzanian Phase Ia/b vaccine trials, RH5-based vaccines have progressed to Phase IIb evaluation in Burkina Faso in recent years. Here, we report a Phase Ia clinical trial in malaria-naive UK adults to assess the safety and immunogenicity of the malaria vaccine candidate RH5.1 soluble protein with Matrix-M adjuvant using two different booster dosing regimens: 10-10-10 micrograms versus 50-50-10 micrograms RH5.1, both delivered in a 0-1-6-month schedule with 50 micrograms Matrix-M adjuvant per dose (ClinicalTrials.gov NCT06141057). A total of n=24 participants were recruited to this study, with n=23 completing all follow-up visits through to 1 year following final vaccination. The RH5.1/Matrix-M formulation was well-tolerated in this population, with injection site pain, myalgia and fatigue being the most commonly reported symptoms up to 7 days post-vaccination. There were no serious adverse events, adverse events of special interest, or suspected unexpected serious adverse reactions reported over the course of the trial. Both vaccination regimens were similarly immunogenic; no differences were observed in peak anti-RH5.1 serum IgG concentrations, in vitro functional anti-parasitic activity, avidity, or durability. Our findings build on other observations from clinical trials of adjuvanted RH5.1 indicating that humoral immunogenicity can be enhanced by delaying the final booster vaccination, but that there is limited impact of fractionation of the final dose. These insights can help to guide the next steps of multi-antigen, multi-stage malaria vaccine development in malaria-endemic settings.

Infection with pnuemococcus bacteria is generally mild but can be more severe in the young and elderly, causing invasive pneumococcal disease (IPD) and community-acquired pneumonia (CAP). Although paediatric pneumococcal conjugate vaccine (PCV) programmes and elderly pneumococcal polysaccharide vaccine (PPV) programmes have reduced cases, we estimate that pneumococcal infection still leads to direct health care costs of around {pound}68M and approximately 16 thousand QALY losses in England per year. The public health situation is complicated by the large number of interacting serotypes, such that while serotype-specific vaccines reduced the target serotypes others arose to replace them. Here we develop a novel (relatively) low-dimensional model to capture the interaction of 26 common pneumococcal serotypes. The model is matched to English IPD data from 2000-2023 and to five carriage studies (conducted in 2001/02, 2008, 2012, 2015 and 2018). When combined with a health economic approach, this model allows us to calculate the willingness to pay for paediatric vaccination with PCV7 (introduced in England in 2006), PCV13 (introduced in England in 2010) and the future vaccination of both the young and elderly with PCV20, which offers protection against 20 serotypes. Due to rapid serotype replacement, we find that the introduction of PCV7 vaccination in 2006 was not cost effective - a result that could not have been anticipated at the time, but is supported by simple statistical fits to the IPD data. In contrast, switching to PCV13 in 2010 and switching to PCV20 in 2026 are both associated with a high willingness to pay for a single dose. Given pneumococcal disease has shifted over time to become predominantly in the older adult population, we find that switching from PPV23 to PCV20 vaccination in those aged 65 and introducing an additional PCV20 vaccine at age 75 are both cost effective for a sufficiently low vaccine price. The inference that underpins our model is unfortunately limited by the available data and the high-dimensional nature of multiple interacting serotypes. Future sampling of carriage from older adults would greatly improve our confidence, as would national estimates of CAP.

Dementia affects tens of millions of people worldwide, yet disease-modifying treatments remain strikingly limited. Although the recombinant zoster vaccine Shingrix has been associated with reduced dementia incidence, its potential influence on individuals already living with dementia is unknown. Here, we followed a propensity-score matched cohort of 68,960 US dementia patients using a nationwide electronic health record network, comparing Shingrix recipients within two years of diagnosis to recipients of any other vaccine. Shingrix was associated with substantially reduced all-cause mortality across the first three years of follow-up (hazard ratios 0.74, 0.88, and 0.89; P[&le;]0.006), robust across multiple sensitivity analyses. Furthermore, within-individual subgroup analyses of repeated Mini-Mental State Examinations conducted 3-6 years apart revealed significantly divergent cognitive decline rates across groups (time-by-group interaction P=0.002). Interval vaccination was associated with more stable cognition, contrasting with steeper declines in unvaccinated individuals. These findings support prospective evaluation of recombinant zoster vaccination as a potential strategy to improve outcomes in patients with established dementia.

Emerging tick-borne orthonairoviruses pose a growing public health threat, yet few animal models fully recapitulate human disease. Here, we report the development of a mouse-adapted Yezo virus (MA-YEZV) strain that causes lethal infection in immunocompetent mice, mirroring key clinical features of human infection, including thrombocytopenia, leukopenia, and severe liver injury. Serial passaging of YEZV in C57BL/6J mice selected for 31 non-synonymous mutations, enhancing viral replication and pathogenicity. MA-YEZV exhibited broad tissue tropism, with the highest viral loads in the liver, and induced a robust inflammatory response marked by elevated proinflammatory cytokines (e.g., IFN-{gamma}, TNF-, IL-6) and inflammasome activation. Ribavirin treatment effectively suppressed viral replication, prevented mortality, and mitigated tissue damage, whereas remdesivir showed no efficacy. This model provides a critical tool for studying YEZV pathogenesis and antiviral development, while the identified mutations offer insights into viral adaptation and virulence mechanisms. Our findings underscore the potential of MA-YEZV as a platform for evaluating countermeasures against emerging orthonairoviruses.

The prospective design of vaccine efficacy trials for deployment in outbreaks requires advance consideration of plausible outbreak scenarios, anticipated vaccine characteristics, and logistical and ethical constraints. As part of CEPIs 100 Days Mission to accelerate vaccine development against a novel Disease X, we evaluated trial designs for a hypothetical Nipah-X outbreak. We assumed Nipah-X would share key features with Nipah, including high case fatality rates and substantial super-spreading, but with sustained human-to-human transmission. Using simulations based on infection models, including an extended chain-binomial model incorporating super-spreading, we compared ring-trials using cluster-randomisation with individual-randomisation within rings. High levels of super-spreading markedly reduced the power of cluster-randomised designs due to strong intra-cluster correlations in case numbers, whereas individual-randomisation retained power. These findings highlight that understanding and accounting for super-spreading is critical when designing ring-trials, as cluster-randomised designs may fail unless vaccine efficacy is nearly complete.

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.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSPrevious cost-effectiveness analyses have examined tuberculosis (TB) infection testing and latent TB infection (LTBI) treatment among migrants in high-income, low TB-incidence countries, including the United States, Canada, and Australia. These studies found that cost-effectiveness varied by setting, population risk, and intervention design. Refugees and asylum seekers--populations with higher TB exposure and reduced healthcare engagement post-arrival--were identified as high-priority groups. Studies suggested that diagnosis and treatment of LTBI before migrants depart their origin country could improve retention along the care cascade and yield better health and economic outcomes compared to post-arrival interventions. A recent pilot study demonstrated the feasibility of pre-departure TB infection testing and voluntary LTBI treatment among U.S.-bound immigrants in Vietnam. However, a cost-effectiveness analysis examining the addition of pre-departure LTBI treatment to pre-departure testing and post-arrival LTBI treatment for refugee and asylee populations is lacking. Added value of this studyThis model-based cost-effectiveness analysis extends prior work by evaluating the addition of pre-departure LTBI treatment to pre-departure testing and post-arrival LTBI treatment. It demonstrates that a pre-departure offer of LTBI treatment could increase overall treatment completion and enhance both health outcomes and cost-effectiveness. Implications of all the available evidenceIn many settings, recently arrived refugees have some of the highest risks of developing TB disease. Therefore, identifying preventive interventions that can reduce TB risk among the refugee population--in ways that are cost-effective, feasible, and respectful of individual autonomy--is a high public health priority. This study found that pre-departure TB infection testing and voluntary LTBI treatment would be a cost-effective addition to current post-arrival prevention approaches, reducing TB risk for a traditionally underserved population at high risk of TB disease. BackgroundIn the United States, preventing TB among refugee populations is a public health priority. We assessed the health impact and cost-effectiveness of strategies to diagnose and treat latent TB infection (LTBI) among U.S.-bound refugees from high TB incidence countries. MethodsUsing mathematical modelling, we simulated TB-related health outcomes and costs (2023 USD) among individuals entering the United States as refugees, from pre-departure medical evaluation until death. LTBI diagnosis was made via interferon-gamma release assay (IGRA), after ruling out TB disease. We compared three intervention strategies: (1) pre-departure IGRA testing for children (2-14 years) and post-arrival IGRA testing for adults (>14 years), with LTBI treatment offered in the United States; (2) pre-departure IGRA testing for children and adults, with LTBI treatment offered post-arrival; (3) pre-departure IGRA testing for children and adults with LTBI treatment offered pre-departure, then re-offered in the United States for individuals not completing treatment before U.S. arrival. FindingsThe intervention strategies were projected to avert 32-60% lifetime TB cases for children and adults, compared to no IGRA testing or LTBI treatment ( no intervention). Compared to Strategies 1 and 2, Strategy 3 produced greater health gains with lower incremental costs. Compared to no intervention, Strategy 3 had an incremental cost-effectiveness ratio of $45,000 per QALY gained for children, and $21,111 per QALY gained for adults. InterpretationPre-departure IGRA testing and voluntary LTBI treatment could be cost-effective for preventing TB disease among U.S.-bound refugees, when provided in conjunction with existing services to diagnosis and treat TB disease. FundingCDC.

A next-generation SARS-CoV-2 vaccine must address the currently inadequate prevention of virus transmission, particularly against emerging variants of concern, a challenge that none of the licensed commercial vaccines fully meet. Effective control of respiratory pandemics necessitates vaccines that 1) can be rapidly adapted, 2) have high patient compliance with simple and non-invasive administration, and 3) block transmission in a virus challenge. We describe here the characterization of an updated single-cycle SARS-CoV-2 vaccine candidate (scVac), engineered as a replication-defective virus with targeted deletions of the E gene and ORF6 and ORF7a, along with a truncation of ORF3a. The candidate carries an Omicron XBB.1.5 Spike (scVacXBB), maintaining all essential antigenic properties. The vaccine demonstrated an excellent safety profile in K18-hACE2 transgenic mice, the most sensitive virulence model, with no clinical signs or adverse events observed. In the Syrian hamster model, potent systemic and mucosal immune responses were induced, along with a strong neutralizing antibody response. Notably, there was no virus transmission to co-housed naive animals, which outperforms a bivalent Omicron mRNA vaccine reference. Our results demonstrate that scVacXBB-induced immunity not only prevents disease but also effectively blocks transmission. Furthermore, the successful introduction of the XBB.1.5 Spike protein into the scVac platform demonstrates the pipelines ability to adapt quickly to any emerging variant. These findings highlight the potential of this single-cycle concept as a next-generation COVID-19 vaccine, offering robust protection with a strong safety profile.

The recent MPXV epidemic across Africa revealed extensive viral diversity and complex transmission dynamics, prompting a continent-wide genomic investigation. We analysed 3,450 high-quality MPXV virus whole genomes from 24 African Union Member States, revealing the complex and concurrent circulation of Subclades Ia, Ib, IIa, and IIb. Subclade Ia showed high levels of virus diversity in reservoir hosts in Central Africa, detected through zoonotic transmission and some sustained human outbreak lastly detected. In contrast, Clade Ib exhibited signatures of sustained human to human transmission across Eastern and Southern Africa. Clade IIa remains largely zoonotic in West Africa. Like Ia, IIb shows continued zoonotic transmission, and sustained human outbreak linked to lineage G1 and G2 circulation. Phylogeographic analyses revealed frequent cross border transmission and interconnectedness, which was aligned with both human mobility corridors and international boundaries. For instance, the Democratic Republic of the Congo or Sierra Leone seems to emerge as a source of regional exportation, while the Cameroon and Nigeria, CAR and Cameroon or CAR and DRC interfaces reflected ongoing cross border zoonotic spillovers. These findings underscore the need for harmonised genomic surveillance, APOBEC3-aware triage, and integrated One Health strategies to prevent local outbreaks from escalating into regional epidemics and to inform vaccine deployment and public health preparedness.

Long-acting lenacapavir (LEN) has emerged as a highly effective, potentially game-changing therapy for HIV treatment and prevention1-5. Although its mechanism of action in the early phase of HIV-1 replication, when the capsid directs key post-entry steps such as reverse transcription, nuclear import, and integration, has been well characterized1,2,6-8, its effects during the late phase of replication, when the capsid assembles and matures within budding virions, remain poorly understood. Here, we determine the cryo-electron microscopy structure of the mature HIV-1 capsid lattice assembled within virus-like particles in the presence of LEN. Our structural analyses revealed that LEN alters interhexamer interactions, perturbs capsid lattice curvature, and thereby prevents the formation of a functional cone-shaped capsid. Biochemical analyses further demonstrated that LEN-containing cores lose reverse transcriptase due to a compromised capsid integrity, whereas integrase and viral RNA remain associated. Functionally, viruses produced in the presence of LEN exhibited markedly reduced infectivity, low reverse transcription activity, and poor integration. Together, these findings provide mechanistic insight into the late-phase action of LEN and provide key directions for the design of future inhibitors.

BackgroundRotavirus remains a leading cause of childhood diarrhoeal hospitalisation globally. Malawi introduced the monovalent G1P8 rotavirus vaccine (Rotarix(R)) in October 2012 and in April 2016 switched from trivalent to bivalent oral poliovirus vaccine (tOPV to bOPV). More than a decade after Rotarix(R) introduction, evidence on sustained vaccine effectiveness and population-level impact in high-transmission, low-income settings remains limited, and it is uncertain whether programme changes such as the OPV formulation switch have influenced Rotarix(R) performance over time. MethodsWe estimated the long-term impact and effectiveness of Rotarix(R) on diarrhoea hospitalisation in Malawi and explored whether OPV type changes Rotarix(R) effectiveness. We used interrupted time-series and test-negative case-control analyses to assess the impact and effectiveness of Rotarix(R), respectively, over seven years post vaccine introduction using data from diarrhoeal surveillance studies in children under five years hospitalised with acute gastroenteritis at Queen Elizabeth Central Hospital, in Blantyre, Malawi, between 1997 and 2019. Stool samples from these children were collected and tested for rotavirus A antigen using enzyme immunoassay (EIA). To assess the effect of concurrent vaccination with OPV, we used a test-negative case-control study to estimate the interaction between the two vaccines. FindingsThe interrupted time-series was based on 7,952 hospitalisations and showed a 23% (95% confidence interval (CI): 10 - 34%) reduction in rotavirus hospitalisations rates among children under five years in the post-vaccine introduction period (January 2013 - December 2019) compared with the pre-vaccine period (July 1997 - December 2012). There was a stronger effect among infants under one year (37%; 95% CI: 25 - 47%). Protection declined with age, with little measurable impact beyond infancy. The test-negative analysis enrolled 1,909 children and Rotarix(R) effectiveness for two doses was 52% (95% CI: 18 - 71%) overall, 67% (95% CI: 36 - 82%) among infants and 29% (95% CI: -136 - 74%) in those older than one year. Analyses of the tOPV to bOPV switch (n = 1,622) showed no measurable interaction with Rotarix(R) performance (aOR 1.07; 95% CI: 0.85 - 1.34). InterpretationRotarix(R) provides moderate protection for Malawian infants, and the transition from tOPV to bOPV did not influence vaccine effectiveness. The lower effectiveness of rotavirus vaccination with increasing child age highlights the need to evaluate alternative vaccination strategies alongside strengthened WASH interventions to sustain vaccine impact in LMICs. FundingMRC Discovery Medicine North (DiMeN) Doctoral Training Partnership (UKRI) and National Institute for Health and Care Research (NIHR) Research in contextO_ST_ABSEvidence before this studyC_ST_ABSMultiple reviews have evidenced variable vaccine effectiveness by setting and age. A recent global review and meta-regression of efficacy and effectiveness data by the authors (https://doi.org/10.1016/j.eclinm.2025.103122), updated to October 2024, highlighted lower rotavirus vaccine effectiveness and impact in high-burden, low- and middle-income countries (LMICs) compared with high-income settings. Studies in LMICs including those in sub-Saharan Africa (SSA) consistently indicate that protection is strongest in infants, with impact and effectiveness declining in older children. Multiple factors have been implicated for this variability in effectiveness, including interference from co-administration of oral polio vaccines. We also conducted a systematic review of post-licensure rotavirus vaccine impact and effectiveness studies from sub-Saharan Africa (CRD42023436851). We also assessed the principal study designs used and the extent to which they adjusted for concurrent public health and social measures (PHSMs). We searched PubMed, EMBASE, MEDLINE, CINAHL, and Google Scholar for studies of vaccine impact or effectiveness in children under five years and screened reference lists of included studies. Across all eligible studies, none measured or adjusted for concurrent public health or social measures. To date, most SSA evaluations have focused on the early post-introduction period, with limited evidence on longer-term vaccine performance and no epidemiological evaluation of the potential effect of co-administration of oral polio vaccines on rotavirus vaccine effectiveness. Added value of this studyWe provide a long-term evaluation of the monovalent rotavirus vaccine (Rotarix(R)) in Malawi using a single hospital-based surveillance platform spanning the pre-vaccine and post-vaccine periods. We combine interrupted time-series analyses of population-level impact with test-negative estimates of individual-level effectiveness using consistent age strata. We also examine whether the national switch from trivalent to bivalent oral poliovirus vaccine modified rotavirus vaccine effectiveness, addressing a programme change that has rarely been assessed in rotavirus vaccine evaluations. Implications of all the available evidenceThe available evidence indicates modest rotavirus vaccine benefit in sub-Saharan Africa, with protection concentrated in infancy and little measurable effect in older children. Our findings highlight the need to interpret long-term vaccine impact estimates alongside changes in other PHSMs that influence rotavirus disease burden, including water and sanitation and access to care. The absence of an effect associated with OPV formulation change suggests that modifying OPV valency alone is unlikely to improve rotavirus vaccine performance. Extending protection beyond infancy may require alternative vaccine schedules alongside sustained improvements in broader public health conditions.

Background Use of oral cholera vaccine (OCV) is globally recommended as a public health response to cholera outbreaks, alongside water, sanitation and hygiene (WASH) interventions. Estimating vaccine effectiveness during emergencies in low-and middle-income countries is challenging because vaccination campaigns are often implemented over short time frames, while individual-level data are frequently incomplete due to constraints in infrastructure, resources and data systems. There is a need for pragmatic approaches that can generate timely, policy-relevant evidence using routinely collected data. Methods We analysed routine surveillance data from a large 2022-2023 cholera outbreak in Blantyre District, Malawi. The EpiEstim framework was used to generate estimates of the time-varying reproduction number (Rt) from line-listed case data. We modelled changes in Rt as a function of cumulative OCV coverage using a log-linear framework and propagated uncertainty through posterior sampling. Lagged WASH exposure variables were incorporated in the model to generate adjusted vaccine effectiveness estimates and to explore potential interaction effects. Sensitivity analyses assessed robustness to alternative lag structures. Findings The Blantyre outbreak was characterised by an initial period of low-level transmission followed by a sharp increase in cases from late November 2022, after which transmission declined steadily through April 2023. This decline coincided with the implementation of a reactive OCV campaign. The majority of the cases were among middle-aged men living in urban Blantyre. The unadjusted vaccine-associated reduction in transmission was estimated at 53.52% (95% credible interval (CrI):42.5-64.1%). After adjusting for a 7-day rolling average WASH activity, total vaccine effectiveness increased to 62.1% (95% CrI: 49.3-74.9%). Sensitivity analyses using alternative lag structures for WASH exposure produced comparable adjusted estimates. Interpretation Implementation of OCV contributed to a substantial reduction in cholera transmission during the outbreak. This study demonstrates a feasible approach for estimating vaccine-attributable impact whilst accounting for public health and social measures, such as WASH interventions. The methods described will be useful in outbreaks where classical observational designs are not possible, providing actionable evidence to policy makers for outbreak response in resource-limited settings.