Scrub typhus, caused by the intracellular bacterium Orientia tsutsugamushi, remains a major public health concern in endemic regions, and no licensed vaccine is currently available. Antigenic diversity of the major surface antigen TSA56 has hindered vaccine development. Here, we evaluated a recombinant TSA56 antigen containing conserved regions (cTSA56) and the autotransporter protein ScaA as candidate vaccines and identified an adjuvant formulation capable of inducing robust cellular immunity. Adjuvant screening in mice showed that the GLA-SE + QS21 formulation elicited strong polyfunctional T-cell responses and provided significant protection following challenge. Using this formulation, we compared cTSA56 and ScaA vaccines in rhesus macaques. Although both vaccines induced antigen-specific antibody and T-cell responses, cTSA56 vaccination generated stronger cellular immunity and accelerated reduction of bacteremia in peripheral blood after O. tsutsugamushi challenge, accompanied by reduced systemic inflammatory responses. These findings support conserved TSA56 combined with Th1-inducing adjuvants as a promising strategy for scrub typhus vaccine development.
Japanese encephalitis (JE), a mosquito-borne, vaccine-preventable disease, is a risk in parts of Asia and Oceania. A previous study showed that after a primary 2-dose series and booster dose of the Vero cell-derived JE vaccine (JE-VC; IXIARO), high seroprotection rates in adults persisted through 6 years. We used serum samples from U.S. military personnel aged 29–55 years to investigate seroprotection at 10 years after the booster dose (based on a 50% plaque reduction neutralization test titer of ≥10). Overall, 97% (95% confidence interval [CI]: 94–98%) of 300 individuals were seroprotected at approximately 10 years with a geometric mean titer of 165 (95% CI: 140–195). Neutralizing antibody titers were not significantly associated with age, intervals between primary series or booster doses, or previous yellow fever vaccination. Young and middle-aged adults who have completed a JE-VC primary series and booster maintain high seroprotection rates for at least 10 years.
In 2025, a mutated H3N2 lineage, subclade K, emerged, showing high activity in many regions. Mutations in the hemagglutinin (HA) may affect cell entry and antibody-mediated neutralisation. Using pseudovirus particles, we show that subclade K-HA drives augmented entry into certain cell lines and displays significant antibody evasion. Both phenotypes were linked to mutation A186D. Influenza vaccination significantly boosted H3N2 subclade K neutralisation, suggesting that current vaccines may provide considerable protection.
Seasonal influenza remains a leading cause of global morbidity and mortality, highlighting the need for vaccination strategies that improve coverage and streamline vaccine delivery. In this systematic review and meta-analysis, we searched PubMed, Embase, Web of Science, Scopus, and the Cochrane Central Register of Controlled Trials for randomised controlled trials (RCTs), cohort, case-control, and cross-sectional studies, evaluating immunogenicity and safety of same-day co-administration of influenza vaccines with COVID-19 or other vaccines, compared with non-concomitant administration. Comparators included sequential administration, single vaccine administration or placebo-controlled delayed vaccination. Risk of bias was evaluated using the Cochrane Risk-of-Bias tool for Randomized Trials and Risk of Bias In Non-randomized Studies of Interventions; certainty of evidence was evaluated using Grading of Recommendations, Assessment, Development and Evaluation. Immunogenicity was assessed using geometric mean fold rise (GMFR) in antibody titres and seroprotection rate. Safety was assessed by adverse event (AE) incidence. 52 eligible studies were included. Influenza immunogenicity was comparable between the co-administration and non-concomitant comparator group across all strains (H1N1 GMFR ratio of means (ROM): 1.02 [95% CI: 0.95–1.10]; H3N2, 1.05 [95% CI: 0.97–1.13]; B strain, 1.01 [95% CI: 0.97–1.05]). Pooled risk ratio (RR) for seroprotection was 1.00 for all three strains with 95% CIs ranging from 0.99–1.01. GMFR for COVID-19 vaccines was modestly reduced under co-administration (ROM 0.84 [95% CI: 0.74–0.95]; p = 0.006). Serious AEs were more frequent in the co-administration group compared to the non-concomitant group (RR 1.41 [95% CI: 1.07–1.86]; p = 0.014; absolute risk difference: 1.56 percentage points). Overall, co-administration preserves influenza immunogenicity but modestly reduces COVID-19 vaccine GMFR. Although safety findings warrant cautious interpretation, the low absolute risk difference supports its feasibility as a strategy to streamline vaccination schedules and improve uptake.
Extraintestinal pathogenic Escherichia coli (ExPEC) is a major cause of urinary tract infections (UTIs) and invasive disease. Rising antimicrobial resistance highlights the need for preventive strategies such as vaccination. The conserved D-mannose-specific adhesin FimH is essential during early UTI pathogenesis, making it an attractive vaccine target. We rationally designed a FimH lectin domain antigen stabilized in a low-affinity, tense conformation by two amino-acid substitutions (LAFimHLD), thereby exposing epitopes within the mannose-binding pocket relevant for functional immunity. Multiple vaccine formats incorporating LAFimHLD were generated, including fimbrial tip constructs, carrier protein fusions or conjugates and a nanoparticle. In rats, monomeric LAFimHLD induced functional antibody responses comparable to a clinically tested FimCH reference, while four LAFimHLD variants elicited superior inhibition of ExPEC binding to human bladder cells. A multimeric LAFimHLD –CRM197 conjugate further demonstrated robust functional immunogenicity in minipigs. These data show enhanced FimH vaccine potency and identify candidates for UTI prevention.
OSPREY was a single-arm, open-label, phase 1b study that assessed whether reduction of viral antigens by the small-interfering RNA daplusiran/tomligisiran (DAP/TOM) could enhance HBV-specific T-cell and/or HBsAg responses to the DNA vaccine JNJ-64300535 (JNJ-0535) in participants with virologically suppressed, HBeAg-negative chronic hepatitis B. All participants received DAP/TOM (200 mg, Q4W) for 24 weeks and 4 doses of JNJ-0535 from Week (W)14 to W26. NA was given until W36 and continued to Follow-up W48, unless stopping criteria were met. Of 24 participants enrolled, 11 (45.8%) achieved the primary endpoint of ≥2 log10 HBsAg reduction at W36. JNJ-0535 vaccination enhanced core/polymerase-specific T-cell responses in 22% of participants by W28, and 39% during follow-up. Seven participants stopped NA based on W36 results and had more polyfunctional CD4 T-cells targeting ≥2 HBV antigens and a greater mean reduction in HBsAg at Follow-up W48 versus those who continued NA (2.42 log10 IU/mL vs 0.96 log10 IU/mL).
Tuberculosis (TB) vaccine development remains challenging due to the complex biology of M. tuberculosis infection and the absence of established correlates of protection. mRNA platforms can induce strong systemic humoral and effector immunity and offer several potential advantages; however, limited lung-localised immunity may restrict current formulations. This Perspective examines these challenges and discusses strategies to optimise mRNA vaccine design, formulation and delivery to improve protective immunity against TB.
Cholera remains a significant public health concern globally. To address this, the World Health Organization and Gavi have coordinated an oral cholera vaccine (OCV) stockpile since 2013, enabling timely vaccine access for countries experiencing outbreaks. Using comprehensive shipment data and a transmission model, the current study assessed the impact of vaccination campaigns across all recipient nations over time. The analysis estimated health outcomes under both real-world conditions—with observed delays and supply shortages—and ideal scenarios where these constraints were eliminated. Under actual shipments, vaccination campaigns prevented approximately 8.1 million cholera cases and 146,013 deaths, averting 6.7 million disability-adjusted life years (DALYs) and reducing the economic burden by US$1.05 billion. In scenarios without delays or supply limitations, the benefits were even greater, with an estimated 17.4 million cases, 321,730 deaths, and 15.1 million DALYs averted. Enhanced timeliness and sufficient vaccine supply are key to maximizing public health impact.
Despite the availability of effective vaccines, vaccination uptake remains suboptimal, particularly for “low-awareness” vaccines. Whether informational nudges can increase vaccination intention in such contexts, and among whom they are most effective, remains unclear. Using herpes zoster vaccination (HZV) as a case study, we conducted a pre-registered randomized survey experiment among 4730 unvaccinated adults aged ≥40 years in China. Participants were randomly assigned to receive one of several informational nudge messages, including clinical evidence, expert recommendations, descriptive social norms, and gain- or loss-framed messages, before reporting their intention to receive HZV on a 0-10 scale. Compared with a no-message control group, messages emphasizing clinical evidence, descriptive social norms, and gain-framed family protection significantly increased vaccination intentions. By contrast, expert recommendation messages and loss-framed messages were not associated with higher intentions. Direct comparisons within intervention categories revealed no significant differences between clinical evidence and expert recommendation messages or between weak and strong descriptive norm messages, whereas gain-framed messages produced modestly stronger effects than loss-framed messages in some specifications. Subgroup analyses revealed stronger responses among females, urban residents, individuals with lower perceived socioeconomic status, and those reporting better health. Our findings suggest that informational nudges can increase intentions to receive a “low-awareness” vaccine, but their effects depend on message content and population characteristics. The results provide the potential of targeted communication strategies for improving vaccination uptake.
Vaccine hesitancy has long been recognized as a global health concern and has become an even greater challenge during and after the COVID-19 pandemic. Although extensive research has examined hesitancy toward COVID-19, how the general population would respond to vaccination in a future pandemic remains unclear. Furthermore, little is known about the conditions that may reduce hesitancy. In this study, we conducted a nationwide internet survey in Japan in 2024-2025 involving 28,000 participants to assess vaccination intentions in a hypothetical future pandemic, identify factors associated with vaccine hesitancy, and examine conditions that may increase willingness to be vaccinated. We analyzed associations between individual characteristics and vaccination intention using logistic regression and explored heterogeneity in prioritized factors to determine vaccination intention using unsupervised clustering analysis. We found that only 53.1% of respondents reported intending to be vaccinated in a future pandemic-a marked decline from observed COVID-19 vaccination coverage. Notably, 35.8% of individuals who were vaccinated during the COVID-19 pandemic expressed hesitancy. Vaccination intention was lower among adults aged 20-40 years, women, individuals with lower income or educational attainment, and those endorsing misinformation or conspiracy statements. Cluster analysis identified eight distinct groups with heterogeneous priority structures. Free vaccination and evidence from clinical trials were prioritized across all clusters, whereas the prioritization of trust in authorities, social influence, domestic vaccine production, and convenience varied substantially across clusters. Public intentions to vaccinate in a future pandemic are shaped by diverse perspectives and values. Tailored strategies and risk communication approaches that address these heterogeneous concerns may be critical to strengthening preparedness for future pandemics.
Vaccination decreases bacterial shedding and reduces the incidence and severity of infection by Mycobacterium avium subsp. paratuberculosis (Map), the causative agent of paratuberculosis (PTB), a chronic granulomatous enteritis that economically impacts the dairy industry. An inactivated Map vaccine exhibits features suggestive of trained immunity in cattle, along with enhanced neutrophil (PMN) activation in rabbits. Although PMNs from healthy cattle exhibit antimicrobial effects against Map, the impact of vaccination on bovine PMN function remains undetermined. This study has further explored the mechanisms of trained immunity mediated by PMNs elicited by this vaccine in calves. PMN mediated phagocytosis, ROS production and NET release showed a significant increase in vaccinated calves upon stimulation in ex vivo assays. Furthermore, PMNs from vaccinated animals exhibited decreased motility that was partially restored upon ex vivo stimulation with Map. Upregulation of phagocytosis receptors such as TREM2 and PBDL1, genes related to NETosis TREM2, LYZ and F13A1 and downregulation of genes involved in chemotaxis, adhesion, and motility in vaccinated animals support these findings. Altogether, these findings support that this inactivated Map vaccine induces changes consistent with trained immunity in calves.
mRNA platforms have been proposed for delivery of malaria vaccine candidates capable of inducing protective immunity. Here, we demonstrate that mammalian cells transfected in vitro with mRNA constructs encoding regions of Plasmodium vivax circumsporozoite protein (PvCSP) fused to hepatitis B surface antigen (HBsAg) secrete virus-like particles (VLPs). Immunization of mice with such mRNA constructs elicits PvCSP-specific immune responses that confer significant protection against challenge with transgenic P. berghei sporozoites expressing PvCSP. Feature selection and regression analyses identified immune correlates associated with protection. These include IgG2b titers, IgA levels, and presence of IgGs targeting PvCSP tandem repeat vk210. These findings establish mRNA-delivered PvCSP-HBsAg VLPs as a viable strategy for development of a P. vivax pre-erythrocytic stage vaccine and provide insights into immune correlates of protection.
Porphyromonas gingivalis (P. gingivalis) is a keystone pathogen in chronic periodontal disease, primarily colonizing the oral mucosa. Current therapeutic strategies are limited in efficacy, emphasizing the need for preventive vaccination approaches capable of eliciting both systemic and mucosal immunity. This study evaluated the immunogenicity of an intranasal protein-based vaccine targeting P. gingivalis. Mice were intranasally immunized twice with a multi-antigen vaccine composed of three key P. gingivalis proteins produced using a cell-free protein synthesis platform and adjuvanted with double-mutant heat-labile toxin. Two vaccine doses (low: 5 µg per antigen; and high: 10 µg per antigen) were tested. We found that vaccine elicited robust and functional systemic IgG and mucosal IgA responses. Higher dose did not further enhance humoral responses. Importantly, both doses induced strong antigen-specific IFNγ production and generated CD4+ and CD8+ tissue-resident memory T cells (CD69+CD103+) in the lungs. These findings provide proof-of-concept that targeting P. gingivalis via mucosal immunization can generate systemic and mucosal immune responses with functional antibody activity, supporting further efficacy testing in P. gingivalis oral challenge models, offering a promising strategy to prevent colonization and reduce the risk of periodontal disease.
Respiratory syncytial virus (RSV) is a leading cause of respiratory illness and there is no universally accepted serological correlate of protection (CoP). We evaluated serum pre-fusion immunoglobulin G binding (preF-IgG) and RSV-A2 neutralizing antibodies (RSV-nAb) in adults aged >60 years following vaccination with investigational Ad26.RSV.preF–RSV preF vaccine. PreF-IgG and RSV-nAb measured pre-vaccination (Day 1) and Day 15 post-vaccination were assessed as CoPs against RSV-mediated acute respiratory infection (ARI) and lower respiratory tract disease (LRTD). An increase in both preF-IgG and RSV-nAb at Day 15 was significantly associated with reduced occurrence of RSV-mediated ARI and LRTD during follow-up. Based on controlled vaccine-efficacy curves and Prentice criteria, both markers were identified as CoPs for RSV-mediated ARI and LRTD. These results were validated using samples from a second randomized, phase 3 efficacy trial. Comprehensive profiling of preF-specific antibody responses showed that preF IgG3 and IgG2 may also contribute to protection from RSV.
The Asia-UK maternal-neonatal infection and iMMunity Network (AMMuNet) convened its first international symposium in Kathmandu, November 2025, to address global and regional burden of maternal-neonatal infections. Primary objective of the symposium was to share the latest research and evidence on perinatal infections and immunization, alongside a focused workshop to develop an outline for potential studies targeting priority pathogens: group B Streptococcus, respiratory syncytial virus, Bordetella pertussis, and Klebsiella pneumoniae.
Live-attenuated vaccines represent a promising strategy for preventing herpes simplex virus type 1 (HSV-1) infection, but achieving an optimal balance between attenuation and immunogenicity remains a significant challenge. Here, we engineered a replication-tunable HSV-1 strain, M4, by fusing the essential replication factor UL54 to a destabilizing domain, enabling ligand-dependent control of viral replication. Additionally, we deleted four viral genes (UL23, LAT, UL13 and US12) to reduce neurovirulence and enhance immune activation. Without the stabilizing ligand, M4 exhibited severely impaired replication, while ligand addition restored replication, facilitating efficient production of virions. In vivo studies confirmed that M4 is highly attenuated, eliciting robust HSV-1-specific humoral and cellular immune responses that conferred full protection against lethal viral challenge. Transcriptomic and immune profiling revealed that M4 preferentially activated adaptive immunity while minimizing inflammatory responses associated with neurovirulence. This study provides a novel strategy for developing safe and effective live-attenuated herpesvirus vaccines.
This study aimed to assess the kinetics of antibody and T cell response to seasonal influenza vaccination in patients with immune-mediated inflammatory diseases (IMID) and tumor necrosis factor inhibitor (TNFi) therapy compared to patients on methotrexate therapy and healthy controls (HC). Thirty-three IMID patients on TNFi therapy, 13 on methotrexate therapy, and 29 HC were enrolled in the seasons 2022/2023 and 2023/2024. At baseline, 1 week, 3 months and 6 months after vaccination, serum antibody levels and T-cell response were assessed. Antibody titers increased markedly by one week after vaccination in all three groups. In patients on TNFi, titers peaked at week-1, stayed elevated throughout 3 months, and approached baseline by 6 months, demonstrating similar kinetics to HC, but at lower levels. Titers of methotrexate group peaked at 3 months and stayed elevated at 6 months. T cell response trajectories were similar. IMID patients with TNFi or methotrexate therapy mount humoral and cellular responses to seasonal influenza vaccination. This study indicates humoral and cellular immune response kinetics under TNFi treatment similar to HC, but at lower levels. Methotrexate therapy may induce a delayed peak in antibody levels at 3 months and prolonged elevation of humoral responses throughout 6 months.
While a growing number of invasive non-typhoidal Salmonella (iNTS) vaccine candidates, including trivalent formulations with typhoid conjugate vaccine (TCV), are in early development, the market demand and commercial potential remain unclear. This study presents a novel demand and financial forecast model for a hypothetical trivalent iNTS-typhoid vaccine, designed for introduction in sub-Saharan Africa (sSA). The model includes projected vaccine demand, revenue and profit forecasts, and net present value (NPV) analysis of return on investments required for development, licensure and manufacturing of the trivalent vaccine. By year 12 after forecasted introduction, annual demand for the trivalent vaccine is projected to reach 47 million doses for a 1-dose regimen and 96 million doses for a 2-dose regimen (Scenario 2), generating annual revenues of $94 million USD and $191 million USD, respectively. Despite these projections, the risk-adjusted NPV is negative, suggesting that the market is not commercially viable for industry investment without global health funding to de-risk the investment. This model assumes a significant demand for a trivalent vaccine in sSA and highlights the need for innovative financing to ensure commercial viability of investment in the vaccine’s development and manufacturing, toward addressing a significant public health issue.
The recombinant vesicular stomatitis virus-vectored Zaire ebolavirus (rVSVΔG-ZEBOV-GP) vaccine has been recently approved for children. Here, the transcriptomic response to this vaccine was characterised for the first time in children using a targeted gene panel. In a randomised controlled trial in Lambaréné, Gabon, children (n = 114, age 1–12 years old) were immunised with the rVSVΔG-ZEBOV-GP or varicella-zoster vaccine as control. Gene perturbation peaked at D1, and returned to baseline levels between D2 and D14. Genes related to type I/II interferon-signalling, pattern recognition receptors, myeloid cells and cell activation modules were upregulated, while downregulated genes were related to T cell and cytotoxicity modules. Perturbation of type-I IFN genes positively correlated with children’s age. Correlates of D28 ZEBOV-GP antibody titres were identified at D7 post-vaccination. Concluding, these findings provide insights into the vaccine-induced immune regulation at play in children.
