The Lancet Infectious Diseases

Background: Mucosal immunity is critical for preventing poliovirus transmission. Despite evidence that infant immunisation protects against poliovirus infection into adulthood, the duration of vaccine-induced intestinal antibody responses remains poorly characterised. Methods: We evaluated poliovirus type-specific neutralising activity and immunoglobulin levels in stool and serum from children in Tanzania who completed routine poliovirus vaccine series (bivalent oral polio vaccine at birth, 6, 10, and 14-weeks, and inactivated polio vaccine at 14-weeks). The study included a longitudinal cohort with four visits over 6 months and a cross-sectional sample of children recruited 1 to 108-months after vaccine series completion. Potential modification by nutritional factors, gastrointestinal infections, and environmental enteropathy was explored. Findings: Among 103 longitudinal and 246 cross-sectional participants enrolled, 33% and 18% had positive poliovirus type-1 (PV1) stool neutralisation, and 66% and 56% had positive poliovirus type-3 (PV3) neutralisation 1 month after vaccination. All were seropositive for PV1 and PV3 across timepoints. Infants followed longitudinally who were stool neutralisation-positive at enrolment had no boost in neutralisation after vaccination, while those stool neutralisation-negative at enrolment experienced a weak boost at 1 month. Stool neutralisation half-life among longitudinal cohort infants was 3.4 months [95% CI 2.6-5.0] for PV1 and 1.7 months [1.4-2.3] for PV3. Moderate evidence suggested concurrent viral intestinal infections were associated with lower neutralisation responses (PV1 p=0.153; PV3 p=0.052). Interpretation: Intestinal antibody responses to poliovirus vaccination were short-lived. The impact of waning intestinal antibodies on transmission risk remains unclear and research is needed to identify vaccination strategies that induce durable mucosal immunity.

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: The World Health Organization has expanded its recommendations for prophylactic Ebola vaccination for at-risk populations. Durable vaccine-induced immunity is important for sustaining outbreak preparedness in regions with recurrent Ebola virus disease (EVD). We assessed five-year persistence of vaccine-induced immune responses in adults and children from the PREVAC trial. Methods: Two large randomised phase 2 trials (NCT02876328), in adults and children aged [≥]1 year, were conducted in four west African countries. Participants were randomly assigned to placebo or to one of three Ebola vaccine strategies: Ad26.ZEBOV followed by MVA-BN-Filo at 56 days; rVSV{Delta}G-ZEBOV-GP followed by placebo; or rVSV{Delta}G-ZEBOV-GP followed by a homologous booster dose at 56 days. After 12 months of follow-up, the primary results were published, participants unblinded to their vaccine assignment, and follow-up continued for 60 months. After Month 24, placebo group recipients were offered active vaccination. Anti Ebola virus glycoprotein Immunoglobulin G (IgG) concentrations were measured for 5 years. Findings: 1401 adults and 1401 children were initially randomized, and 1315 (93.9%) adults and 1322 (94.4%) children attended at least one long-term visit. Retention was high, with 95% followed beyond 1 year and 83% completion at 5-year follow-up. For the three vaccine strategies, antibody geometric mean concentrations (GMC) declined modestly between Months 12 and 24, followed by a stable plateau from Months 24 to 60. At Month 60, antibody GMC were higher in the rVSV-based groups (1099 and 1216 EU/ml for adults; 1982 and 2347 EU/ml for children) than in the Ad26.ZEBOV, MVA-BN-Filo group (252 adults and 645 EU/ml children). Antibody persistence at Month 60 was heterogeneous, varying by age, sex, country, and baseline IgG concentration. Interpretation: Licensed Ebola vaccines induced sustained antibody responses in adults and children for up to 5 years. While the protective antibody level is unknown, these data demonstrate long-lasting immune responses from currently employed vaccine strategies.

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(R) adjuvant using two different booster dosing regimens: 10-10-10 {micro}g versus 50-50-10 {micro}g RH5.1, both delivered in a 0-1-6-month schedule with 50{micro}g Matrix-M(R) 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(R) 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.

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.

Filoviruses pose a threat to individuals and the global community as pathogens of pandemic potential. The scientific community faces an ongoing challenge of developing effective vaccines with unpredictable outbreaks concentrated in countries with lower healthcare resources. Given these limitations, it is important to ensure that existing filovirus research is used as efficiently as possible. To enable rapid identification and use of this research, we have developed evidence maps of existing filovirus publications to enable further analysis and synthesis. We systematically identified and categorised existing immunological and clinical publications on Bundibugyo (BDBV), Marburg (MARV), Sudan (SUDV) and Ebola (EBOV) viruses. We captured studies that reported on animal or human immune responses to infection, outcome of infection, or human vaccine safety data. Initial searches of PubMed, Embase and Europe PMC were run between November 2024 and January 2025 and the MARV, SUDV and EBOV searches were updated on 1 August 2025. A BDBV search was conducted on 18 May 2026 in response to the WHO declaration of a Public Health Emergency on 17 May 2026. The initial searches retrieved 208, 1646, 534 and 3963 manuscripts for BDBV, MARV, SUDV and EBOV, respectively. After screening using an a priori exclusion criteria, 49 BDBV, 198 MARV, 149 SUDV and 850 EBOV publications were included on each evidence map. These maps provide a comprehensive, transparent and reproducible structure to categorise existing studies of filovirus vaccination and immunity. They allow rapid identification of the totality of available evidence and the existing experimental tools to support vaccine development for these priority pathogens.

SARS-CoV-2 continues to evolve from the Omicron serotype, with BA.2.86 sublineage JN.1 and descendants such as KP.2 predominating in 2025-26. By early 2026, the JN.1-derived NB.1.8.1 and XFG variants had largely replaced other variants globally, with a more recent emergence of the highly divergent BA.3.2 saltation variant. Elderly individuals continue to be at greatest risk of clinical complications from COVID-19, yet contemporary data on kinetics of immune potency and breadth following multiple vaccinations remain very limited in this group. We studied a cohort of forty-three healthy older adults (median age = 85 years, IQR 75-88, 40% female). Using both pseudotyped virus (PV) and surrogate virus neutralisation (SVNT) based assays, we demonstrate that JN.1 and KP.2 vaccinations six months apart elicit high potency neutralisation across all studied variants except BA.3.2.2, which escaped neutralisation almost completely in all individuals. Waning of neutralising activity in serum was observed to be modest in the [~]6 months between vaccine doses, suggesting sustained immunity following multiple vaccines. While absolute neutralisation titres remained highest against ancestral Wu-1 at all timepoints due to multiple historical exposures and accumulation, the recall responses revealed a shift in immunodominance. After the recent KP.2 vaccine dose, neutralisation against full-length Wu-1 spike was not boosted, whereas all tested JN.1 descendants and BA.3.2.2 showed significant boosts, indicating that immune imprinting against ancestral Wu-1 was partially overcome. Interestingly, RBD-specific neutralising responses experienced a boost following KP.2 vaccination, suggesting that RBD responses remain imprinted but that they constitute a small proportion in the overall Wu-1 neutralising response as immune imprinting is alleviated.

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.

Background Community-wide active case-finding (ACF) is being increasingly implemented as a tuberculosis (TB) elimination intervention. However, conventional site selection strategies may result in low yields from screening. We evaluated whether an artificial intelligence (AI) software guided targeting strategy could improve detection of TB during screening activities (called camps) relative to routine approaches to site selection in the programmatic setting in Pakistan. Methods We conducted a stepped-wedge cluster-randomised trial embedded within Global Fund supported ACF activities implemented by Pakistan s National TB Program and private sector partners. Thirty mobile X-ray van teams operating in 68 districts were randomly assigned to transition from routine site selection approaches (based on field-staff experience and historical data) to an AI-guided targeting strategy, using the software MATCH-AI. We assessed the effect of the intervention on the primary outcome, Camp Positivity Yield, defined as the number of individuals diagnosed with bacteriologically confirmed TB per camp, using generalised linear mixed models. The primary analysis was by intention to treat. Camps conducted within a 5-km radius of the AI selected locations were included in a validated per-protocol analysis. We conducted several district-level subgroup analyses. This trial is registered, number NCT06017843. Findings Between August 2023 and September 2024, 3,936 screening camps were conducted (2,046 control, 1,890 intervention), screening 269,254 individuals. In the intention-to-treat analysis, Camp Positivity Yield was 7% higher in the intervention group relative to the control group, however this difference was not statistically significant (adjusted risk ratio [RR] 1.07, 95% CI: 0.94 -1.22). In the validated per-protocol analysis, Camp Positivity Yield was 32% higher in the intervention group relative to the control group (adjusted RR 1.32, 95% CI: 1.12-1.54). Yields were highest in districts that had moderate baseline yields of 0.5-1% per population screened prior to the trial (adjusted RR: 1.57, 95% CI: 1.13 - 2.18) and in rural districts (adjusted RR 1.43, 95% CI: 1.23 -1.65). Interpretation The use of an AI-guided targeting strategy significantly increased detection of bacteriologically confirmed TB during active case-finding in the validated per-protocol analysis, relative to conventional site-selection approaches employed by field-staff. This software may be considered as a supportive tool to improve the efficiency of community-based TB case-finding interventions in other high burden countries.

The emergence of the SARS-CoV-2 Omicron BA.2.86 subvariant, a lineage derived from the BA.2 strain, led to the 2024-2025 COVID-19 vaccine update to include KP.2 or related JN.1-lineage spike antigens. We evaluated the magnitude, breadth, and durability of humoral immune responses following a single KP.2 vaccine dose in a longitudinal cohort of 21 individuals up to six months. KP.2 vaccination increased spike-specific binding and neutralizing antibodies against the ancestral WA1 strain, alongside the BA.5, XBB.1.5, and KP.2 variants. Power law modeling estimated half-lives for WA1- and KP.2-specific IgG responses at 770 and 248 days, respectively. Additionally, the KP.2 dose increased IgG1 and IgG4 subclasses more than IgG2 and IgG3 responses to both spike proteins. Serum depletion experiments using WA1 or KP.2 proteins demonstrated most vaccine-elicited antibodies were cross-reactive. Consequently, KP.2 vaccine-induced antibodies retained broad neutralizing activity against recently circulating Omicron subvariants (BA.2.86, KP.3.1.1, XEC, LP.8.1, LF.7, XFG.3.12, PQ.1, BA.3.2.1, and RE.2). Using a live virus neutralization assay, XFG.3.12 showed the greatest reduction in neutralizing titers relative to KP.2 (4.2-fold). In a small subset, an LP.8.1 vaccine dose increased neutralizing activity against the matched variant while maintaining WA1 and KP.2 cross-reactivity, but only modestly increased antibodies to divergent variants BA.3.2.1 and RE.2. Ultimately, these data indicate the KP.2 mRNA vaccine generates durable, cross-reactive responses against current Omicron subvariants. However, ongoing spike evolution impacts neutralization of emerging lineages, highlighting the need for continued viral monitoring and timely vaccine updates. IMPORTANCESARS-CoV-2 continues to evolve, raising ongoing concerns about how well updated vaccines protect against emerging variants. This study evaluates antibody responses after KP.2 spike mRNA vaccine dose and shows that a single dose induces durable and broadly cross-reactive immunity against both earlier strains and recently circulating Omicron subvariants. Despite this breadth, reduced neutralizing activity against certain emerging variants indicates that ongoing antigenic changes can impact vaccine induced antibody effectiveness. These findings provide insight into how current vaccines perform over time and highlight the need to track viral evolution and update vaccine antigens to maintain broad protection against severe disease, hospitalization, and death.

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.

Background: The ongoing Bundibugyo virus disease (BDBV) outbreak in Central Africa highlights the absence of approved vaccines specifically targeting BDBV. Whether licensed Zaire ebolavirus (EBOV) vaccines induce cross-reactive immunity against BDBV remains largely unknown. Methods: We performed an immunogenicity analysis using serum samples from participants enrolled in the PREVAC randomized clinical trial evaluating licensed Ebola vaccine strategies in West Africa. Samples collected at day 28 (D28) and month 3 (M3) following vaccination with rVSV{Delta}G-ZEBOV-GP or Ad26.ZEBOV/MVA-BN-Filo were assessed using a multiplex Luminex assay against glycoproteins from multiple filoviruses, including EBOV Kikwit, EBOV Mayinga, BDBV, Sudan virus, Reston virus, and Marburg virus. Results: A total of 179 samples were analysed. Detectable cross-reactive antibody responses against BDBV were observed across vaccine groups, timepoints, and age categories. However, BDBV responses remained substantially lower than homologous EBOV responses. In rVSV recipients, median BDBV responses (net MFI) reached 282 (IQR 164-644) at D28 compared with 1788 (832-3311) against the homologous Kikwit antigen. Similar patterns were observed following rVSV booster vaccination and Ad26.ZEBOV/MVA-BN-Filo vaccination. The heterologous Ad26/MVA regimen demonstrated increasing BDBV responses between D28 and M3. Conclusions: Licensed EBOV vaccines induced detectable but quantitatively reduced cross-reactive antibody responses against BDBV. Although no direct assessment of vaccine efficacy against BDBV disease was possible, these findings support the plausibility of partial heterologous immunity following EBOV vaccination. In the absence of approved BDBV-specific vaccines, these data support the urgent evaluation of currently available Ebola vaccines during BDBV outbreaks and reinforce the importance of developing broadly protective pan-filovirus vaccines.

Of the two influenza A virus (IAV) subtypes circulating endemically in humans, A/H3N2 and A/H1N1pdm09, A/H3N2 has historically been the dominant driver of disease burden in older adults. Based on an analysis of publicly available global surveillance data from 2015 to 2025 (>300,000 subtyped, age-stratified infections), we report a substantially increased contribution of A/H1N1pdm09 to influenza morbidity in older adults since approximately 2022. Birth cohort-stratified analyses suggest elevated A/H1N1pdm09 burden among individuals born before 1955-1959, consistent with erosion of pre-existing immunity originally generated by exposure to historical A/H1N1 strains. Pooled estimates across datasets and analytical approaches indicate the increase in A/H1N1pdm09 burden rises with earlier birth year, ranging from 1.22-fold (95% CI 1.08-1.37) for the 1955-1959 birth cohort to 3.10-fold (95% CI 2.58-3.72) for the 1930-1934 cohort. These findings point to a substantial rise in the overall influenza burden among the most vulnerable age groups, with implications for vaccine policy, clinical management, and public health planning.

Background. Despite the decline of the 2022 global outbreak, mpox remains an ongoing public health concern, with persistent transmission and emerging viral clades sustaining resurgence risk. Improving preparedness and response is a priority, yet it remains unclear how best pre-exposure vaccination and community response can effectively limit transmission under realistic conditions and whether behavioral adaptation is critical. Methods. We used a data-driven network model of mpox transmission among men who have sex with men in the Paris region, parameterized with sexual behavioral data and calibrated to surveillance data from the 2022 outbreak. We evaluated counterfactual scenarios by varying vaccination timing, rollout speed, prioritization, and behavioral responses. Results. Here we show that, with respect to the 2022 epidemic in the Paris region, vaccination alone delivered at the observed rollout speed would not have reproduced the observed epidemic decline, even if initiated the day of the first European alert, corresponding to 12 days before the first case was reported in France. Achieving comparable control through vaccination alone would have required more than a fourfold increase in rollout speed. Large-scale and long-term reductions in sexual contacts remain instrumental to limit the epidemic size, although earlier vaccination reduces the proportion of MSM needing to change behavior. In contrast, short-term behavioral measures adopted by the vaccinees, such as sexual abstinence during the 14-day immunity-building period, combined with moderately faster vaccine rollout, (+68% for 50% compliance; +34% for 75% compliance) could achieve comparable epidemic control. Targeting individuals with higher sexual activity further improved intervention efficiency. Conclusions. Under realistic reactive vaccination scenarios, mpox control still requires strong behavioral responses. Combining timely vaccination with short-term behavioral change guidance at vaccine administration offers a feasible path to limit transmission and strengthen outbreak preparedness and response.

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 Sub-clades 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-Nigeria, CAR-Cameroon or CAR-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.

BackgroundNovel HIV prevention interventions such as long-acting pre-exposure prophylaxis (PrEP) could substantially reduce HIV transmission in Africa. However, efficient implementation in high-prevalence settings where incidence has declined requires an understanding of the contemporary dynamics driving new infections. MethodsWe identified incident HIV cases from a longitudinal, population-based cohort in Uganda. We individually matched cases to HIV-negative controls; traced and enrolled reported sexual partners; and enrolled female sex workers (FSWs) from reported venues. Conditional logistic regression, transmission modeling, and phylogenetics were used to characterize transmission networks. FindingsFrom 2021-2024, 38,899 HIV tests among 22,255 people identified 187 people with incident infections (47.6% male); 164 (88%) were enrolled and matched to 164 HIV-negative controls. Overall, 593 non-sex-worker partners (371 enrolled,62.6%), 146 FSW partners (21 enrolled,14.4%), and 28 venues (208 FSWs enrolled) were reported. Incident infection was most strongly predicted by partnership with a FSW (odds ratio:15.5; 95%CI:3.7-64.8), identified in 43.0% of male cases versus 6.3% of controls. Men with FSW partners had larger sexual networks than men without (median:6 vs 2 partners), and 91.2% of men with FSW partners also had non-sex-worker partners. Transmission modeling attributed 34.4% (95%CI:31.5-36.8%) of all male infections and 80.0% (95%CI:73.2-84.4%) of infections among male clients to sex with FSWs. Oral PrEP use among HIV-negative partners of incident cases was low (8.9% in women; 2.1% in men). InterpretationMen with FSW partners accounted for a substantial share of incident HIV infections and had markedly higher odds of infection than men without such partnerships. Together with the high potential for onward transmission within male client networks, these findings suggest that inclusion of male clients in long-acting HIV prevention strategies could be highly efficient and impactful. FundingNational Institutes of Health, United States; Gates Foundation; National Health and Medical Research Council, Australia

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.

Orthoparamyxoviruses such as human parainfluenza virus type-3 (HPIV3) and measles virus (MeV), are a major health threat. We discovered an orally efficacious broad-spectrum inhibitor of orthoparamyxovirus polymerases. However, here we found that tolerability in higher mammals was limited. We report development of clinical candidate analog GHP-88310 (EIDD-3608), which combines improved oral efficacy with favorable tolerability in non-rodents (ferrets and dogs). GHP-88310 was active against HPIV3, Sendai virus (SeV), MeV, and related canine distemper virus (CDV). In 7-day tolerability studies, daily doses of 2,000 mg/kg were well tolerated. Pharmacokinetic analysis revealed altered plasma exposure of GHP-88310 compared to the original hit. In HPIV3-infected cotton rats, GHP-88310 lowered respiratory tract viral load. Dosing of ferrets infected with CDV, causing lethal measles-like disease, resulted in complete survival, reduction of viremia and shed viral load, and alleviated lymphocytopenia. Once-daily GHP-88310 was efficacious in the CDV-ferret and HPIV3-cotton rat models. The compound was sterilizing against HPIV3 at physiological concentrations in human airway epithelium organoids.

BackgroundEvidence from real-world implementation of follow-up and pharmacovigilance for Plasmodium vivax treatment in population scale interventions targeting asymptomatic individuals remains limited, especially among highly mobile, hard-to-reach groups. This study describes the follow-up strategy used in the CUREMA project and assesses its implementation, as well as safety, tolerability, and adherence outcomes. MethodsThe CUREMA project implemented a PvTDA (P. vivax targeted drug administration) intervention in cross-border Amazonian settings, consisting in a full course treatment with chloroquine and primaquine (7 days) or tafenoquine (single dose), after screening its main contraindications (including semiquantitative G6PD testing); its target population was represented by artisanal and small scale migrant miners evaluated as at risk for asymptomatic P. vivax carriage. Treatment follow-up was mandatory for PvTDA participants and combined in-person visits or telephone interviews, and/or a tailored smartphone application, to be compatible with target population high mobility. Planned follow-up visits were scheduled 2, 5, and 14 days after treatment initiation. Univariate analyses described app uptake, follow-up completion, adverse events and treatment declared adherence; multivariable regression models explored factors associated with these outcomes. ResultsAmong 294 participants who received PvTDA, 269 (91.5%) configured the smartphone application, 100 (34.0%) selected telephone follow-up and/or 44 (15.0%) selected in-person follow-up. Overall, 210/294 participants (71.4%) completed at least one follow-up questionnaire, and 81/294 (27.6%) completed the three follow-up visits At least one adverse event was recorded in 49/294 participants (16.7%); events were generally mild to moderate, and no serious adverse event was identified. The declared adherence to the 7-days chloroquine and primaquine treatment was 79.2% [95% CI 72.5-86.4]. ConclusionsActive follow-up of P. vivax radical treatment was feasible in a highly mobile, remote population when multiple complementary tools were combined. This supports pharmacovigilance and safe implementation of radical cure strategies in similarly challenging settings.

The recurrent outbreaks and geographical expansion of mosquito-borne arboviruses pose a significant challenge to public health worldwide. The disease outcome for arboviral infections ranges from acute febrile illness to severe conditions such as encephalitis, hemorrhagic shock, and mortality. Current treatment options for these viruses are limited to supportive care, necessitating an urgent need for a safe and effective broad-spectrum antiviral. In this study, we have identified Trifluoperazine (TFP), an FDA-approved antipsychotic, as a potent broad-spectrum antiviral against Japanese encephalitis Virus (JEV), Dengue virus (DENV) and Chikungunya virus (CHIKV) infections. The antiviral effect of TFP was also seen in the animal models of JEV and CHIKV with significantly reduced disease severity. Mechanistically, TFP treatment increased the phosphorylation of eIF2a and induced an adaptive ER stress response in diverse cell types. Alleviation of TFP-induced ER stress by chemical chaperone 4PBA abolished the antiviral activity of the drug and rescued virus replication in cells. The robust in vitro and in vivo efficacy of the drug against arboviruses highlights the potential for repurposing TFP as a broad-spectrum antiviral candidate.