Human Vaccines & Immunotherapeutics

Introduction: Adenoviral vectors such as chimpanzee ChAdOx1 were selected for COVID-19 vaccines due to their low seroprevalence in humans, minimizing the impact of neutralising anti-vector immunity that could attenuate vaccine responses. However, the influence of pre-existing adenoviral immunity on vaccine response remains incompletely understood. We have previously shown that SARS-CoV-2 spike-specific T cells were enhanced in ChAdOx1 nCoV-19 vaccinated immunodeficient patients compared to mRNA-based BNT162b2. Here, we assess immune cross-reactivity between ChAdOx1 and human adenovirus 5 (HuAd5), and test the hypothesis that in antibody-deficient individuals, cross-neutralisation may be impaired, allowing bystander enhancement of SARS-CoV-2 spike-specific T cell responses following ChAdOx1 nCoV-19 vaccination. Methods: We studied healthy healthcare workers (HCWs) and immunodeficient patients (IDPs) who received homologous ChAdOx1 nCoV-19 or BNT162b2 vaccines. HCWs samples were collected pre-vaccination and 4-6 weeks after the second dose, while IDP samples were obtained 4-6 weeks after the second dose. Serum anti-HuAd5 hexon IgG was quantified using a Luminex multiplex assay, and neutralizing antibodies were assessed using a replication-deficient HuAd5-GFP virus neutralization assay with flow cytometry readout. Ex vivo ELISpot and flow cytometry assays were used to measure T cell responses to HuAd5 hexon. These data were compared with previously published ChAdOx1 nCoV-19 vaccine responses in the same cohorts. Results: HuAd5 hexon-binding IgG titres were significantly higher in ChAdOx1 nCoV-19 compared to BNT162b2 vaccine recipients in both HCWs (p = 0.0043) and IDPs (p = 0.0328). Within ChAdOx1 nCoV-19 vaccine group, titres were lower in IDPs than HCWs (p = 0.0015) but not within the BNT162b2 group (p = 0.1261). HuAd5 neutralisation titres did not differ between cohorts or vaccine groups. In ChAdOx1 nCoV-19 vaccinated IDPs and HCWs, there was a significant negative correlation between HuAd5 hexon IgG titres and SARS-CoV-2 spike-specific T cell responses. Similarly, HuAd5 neutralisation titres showed an inverse correlation with spike-specific T cell responses in ChAdOx1 nCoV-19 vaccinated IDPs and HCWs. ChAdOx1 nCoV-19 vaccination induced significantly higher frequencies of HuAd5 hexon-reactive T cells compared with BNT162b2 vaccination in IDPs (p < 0.0001), consistent with cross-reactive adenoviral T cell responses. In IDPs, HuAd5 hexon-specific T cell frequencies positively correlated with SARS-CoV-2 spike-specific T cell responses following ChAdOx1 nCoV-19 vaccination but not following BNT162b2 vaccination. Functional profiling in ChAdOx1 nCoV-19 vaccinated IDPs demonstrated expansion of HuAd5 hexon-specific CD4IFN-{gamma}TNF T cells in high SARS-CoV-2 spike responders (p = 0.0002) compared to low responders, and the frequency of these cells strongly correlated with spike-specific T cell response. Discussion: ChAdOx1 nCoV-19 has been associated with stronger T cell responses than BNT162b2 in certain populations, including immunodeficient and elderly individuals. While this has been attributed to antigen persistence and innate adjuvant effects, our findings support a mechanism whereby heterologous pre-existing adenovirus immunity modulates vaccine-induced responses. Specifically, cross-reactive HuAd5-specific T cells may enhance spike-specific T cell responses via bystander enhancement, while cross-reactive binding antibodies may exert opposing effects. An implication of this study is that vaccine protocols could incorporate therapies that suppress vector-specific or cross-reactive antibodies while preserving T cell responses especially in cases where T cell-specific responses are most desirable. Also, safe vector-based vaccines can be developed for patient groups with predominant antibody deficiency. Targeted vaccination strategy could be implemented for clinical cohorts based on immune competence.

(1) Background: Brain cancer is the ninth leading cause of cancer death in the US, with approximately 76,000 newly diagnosed cases annually. Studies show that at time of diagnosis, up to six-months post-treatment, 50%-80% of brain cancer survivors (BCS) report cognitive dysfunction. Mild cognitive impairment (MCI) has gained increasing attention as a persistent disability experienced by up to 75% of all BCS, which affects memory, concentration, executive function, etc. Studies show cognitive training with computerized gaming as improving cognitive function for patients with stroke, dementia, and Parkinsons. It is of significant clinical interest to develop innovative interventions that reduce MCI. Aim: To improve cognitive performance of BCS suffering with MCI by evaluating the feasibility, acceptability and effect of a Virtual Reality Cognitive Rehabilitation Training (VR-CRT) platform during four weeks of cognitive training. (2) Methods: We employed a quasi-experimental pretest/posttest non-randomized/non-blinded single-arm design for 4 weeks, with an experimental group (n=6, after attrition) using VR-CRT. Participants were selected based on convenience sampling using the electronic medical record to identify qualified patients, guided by inclusion/exclusion criteria. Feasibility was defined by retention as >80%, with usability testing using the System Usability Scale (SUS) and NASA-TLX surveys. The Hopkins Verbal Learning Test (HVLT), Controlled Oral Word Association (COWA) test, and Trail Making A-B (TM-A/B) test were used to measure cognitive performance, comparing baseline to post week-four. (3) Results: The feasibility criteria of >80% was met. All SUS and NASA scores were in the higher index, suggesting a high degree of usability, with low workload demand. For effect, the COWA findings showed a significant improvement (41.38%), with a paired sample T-Test confirming that the participants COWA scores improved significantly from pre- to post-intervention (p = 0.03), indicating enhanced verbal fluency and executive functioning after intervention. HVLT (combined) showed improvements of 18.75% for Form A and 11.32% for Form B, which also showed a significant improvement (p = .04) in the retention discrimination index from pre- to post-test. The TM-A/B test showed an improvement (25.97%), suggesting that the participants spent less time completing both parts A and B, but was not statistically significant. (4) Conclusion: This study fulfilled our aim to demonstrate modest to significant cognitive improvement using VR-CRT with brain cancer patients with MCI. Despite the small sample size, we believe the use of virtual reality will lead to important advances for patients with MCI, particularly the frontal lobe brain region, expressed in executive function.

Background: High school students may be able to communicate health topics to peers and adults. Yet, few studies have evaluated the role of high school students in community health initiatives, making them an underutilized group for disseminating health information. We pilot tested stroke education across five high schools using varied delivery approaches as a preliminary step toward evaluating youth stroke education to improve community health. Methods: In April-May 2025, five high schools in Connecticut and New York participated in stroke education. The format was designed to fit the needs of each school and included an 8-session classroom curriculum (Derby, CT), after-school club meetings (New Haven, CT; Long Island, NY), and one large assembly (Bridgeport, CT). Developed by teachers and neurology providers, the curriculum covered stroke risk factors, symptoms, and emergency response. Students completed a 15-point assessment adapted from the validated Stroke Action Test before, immediately after, and 4-6 weeks post-intervention; data were collected between April and July 2025. Results: Of 112 students completing the pre-test, 99 (88%) completed the immediate post-test and 51 (46%) the delayed follow-up. Average scores rose from 47% pre-intervention to 75% post and 70% at 4-6 weeks. All schools scored <50% on pre-tests suggesting poor baseline stroke knowledge. Conclusion: This pilot suggests that stroke education can be delivered to high school students across varied settings and may support knowledge gains up to 6 weeks. Limitations included small sample sizes and missing follow-up data. If validated in larger studies, this adaptable, teacher-supported approach could offer a scalable public health strategy for improving community stroke preparedness.

Anti-polyethylene glycol (PEG) hyperimmune pigs, immunized against PEG, provide a sensitive experimental model for the rare anaphylactic reactions induced by mRNA-PEGylated lipid nanoparticle (LNP)-based COVID-19 vaccines, such as Comirnaty. These pseudo-allergic infusion reactions can usually be prevented or attenuated by multicomponent anti-inflammatory premedication regimens; however, no established protocol exists for mRNA-LNP-based COVID-19 vaccines. The aim of the present study was to identify an effective premedication strategy capable of preventing or attenuating these reactions in hypersensitive subjects, using the hyperimmune porcine model. We compared the protective effects of individual pretreatment components; dexamethasone, famotidine, levocetirizine, acetaminophen, diclofenac, indomethacin, by analyzing hemodynamic endpoints (systemic and pulmonary arterial pressure, pulse pressure). All tested compounds modulated Comirnaty-induced anaphylactic responses; however, only cyclooxygenase (COX) inhibitors provided complete protection against anaphylaxis and other abnormal processes. This finding is consistent with the low incidence of infusion reactions to cancer nanomedicines at the Shaare Zedek Oncology Center in Israel which uses COX-inhibitors as premedication. Given that most currently used human infusion-reaction prevention protocols do not include COX inhibitors, and that steroid-containing regimens may potentially counteract vaccine efficacy, our results suggest that COX inhibitors may offer a clinically effective standalone option or form the basis of simplified premedication regimens for preventing this life-threatening condition.

Background: The Vaccine Safety Datalink (VSD) detected a statistical signal for ischemic events (ischemic stroke or transient ischemic attack) following bivalent mRNA COVID-19 vaccination through prospective surveillance during 2022-2023. Although multiple studies from other surveillance systems and countries reported no increased risk, important methodological limitations remained. This U.S. study addressed those limitations by evaluating the ischemic stroke risk following bivalent mRNA COVID-19 vaccination, influenza vaccination, and their same-day coadministration using event-dependent self-controlled case series (SCCS) design. Methods: Study outcomes included first-ever ischemic stroke (primary outcome), first-in-1-year ischemic stroke (secondary outcome), and ischemic events (exploratory outcomes), identified using ICD-10-CM codes in inpatient and emergency department settings during September 1, 2022-March 31, 2023, among individuals aged>=12 years across eight VSD sites. Analyses were conducted separately for Pfizer-BioNTech and Moderna bivalent vaccines, with relative incidences (RI) and 95% confidence intervals (CI) estimated for 1-21-day and 1-42-day risk intervals, using person-time outside these intervals as the control period. Subgroup analyses were performed by age group (12-64, >65 years) and history of documented SARS-CoV-2 infection. Results: A total of 6,510 first-ever ischemic strokes were identified among more than 6.8 million participants. Among recipients of Pfizer-BioNTech bivalent COVID-19 and influenza vaccines, no statistically significant increased risk of first-ever ischemic stroke was observed following bivalent COVID-19 vaccination (RI=0.94; 95% CI: 0.63-1.41), influenza vaccination (RI=0.95; 95% CI: 0.82-1.10), or same-day coadministration (RI=1.15; 95% CI: 0.88-1.49) within 1-21-day risk intervals; findings were similar for 1-42-day intervals. Comparable null results were observed for Moderna vaccines and across all subgroups, secondary, and exploratory outcomes. Conclusion: No increased risk of ischemic stroke was found following bivalent mRNA COVID-19 vaccination, influenza vaccination, or their coadministration in this multi-site SCCS study. These findings are consistent with previous studies and underscore the importance of continued vaccine safety monitoring.

Background: Incomplete childhood vaccination undermines individual and herd immunity and increases vulnerability to vaccine-preventable diseases. Understanding local determinants of vaccination adherence is essential for targeted interventions. This study assessed routine immunization completion and dropout patterns among children aged 0-15 months in Bayelsa State, Nigeria. Objectives: To determine vaccination completion rates, identify factors influencing adherence, analyze temporal patterns across immunization milestones, and provide evidence-based recommendations for improving coverage. Methods: A comparative longitudinal study was conducted from March 2023 to July 2024 across three Local Government Areas (LGAs), representing each senatorial district. A total of 369 mother-child pairs (123 per LGA) were enrolled. Data were obtained from health facility immunization registers and supplemented with semi-structured questionnaires. Children were followed through the 6th week, 10th week, 14th week, 9th month, and 15th month immunization visits. Completion rates were analyzed using descriptive statistics and chi-square tests. Ethical approval was obtained from the State Ministry of Health, and informed consent was obtained from all mothers. Results: Completion rates varied across LGAs, with the highest in LGA C (86.2%) and lowest in LGA B (61.0%). Phone-based reminders achieved the highest adherence, outperforming routine and home visit strategies. Progressive attrition was observed along the immunization schedule, with dropout exceeding completion by the 15th month. Principal reasons for non-completion included forgetfulness, travel, and caregiver busyness. Maternal age, education, and occupation significantly influenced adherence, indicating disparities across LGAs. Conclusion: Vaccination adherence is shaped by maternal characteristics and operational strategies. While early-stage coverage is high, attrition increases at later milestones, particularly in LGAs with lower resource engagement. Recommendations: Implement targeted phone-based reminders, milestone-specific outreach, and community engagement programs to reduce dropout, enhance timely completion, and strengthen childhood immunity.

Adenoviruses (Ads) are widely used as vaccine vectors. However, pre-existing immunity to commonly used serotypes, like Ad5, can reduce vaccine immunogenicity, with neutralizing antibody titers >200 previously shown to impact vaccine efficacy. Gorilla adenovirus (GRAd) vectors have been developed to evade pre-existing anti-vector responses, but their seroprevalence in southern Africa is poorly defined. Here, we assessed seroprevalence to GRAd32, Ad26 and Ad5 before (baseline) and after COVID-19 vaccination, in cohorts from South Africa and Zimbabwe. Sera from South African participants enrolled in the Sisonke sub-study (n=100, prior to Ad26.COV2.S vaccination) and the follow-up "Booster after Sisonke" (BaSiS) study (n=226) were tested for neutralizing antibodies to Ad5, Ad26, and GRAd32. These samples included paired pre/post boost samples for 27 donors. We also tested sera from the Zimbabwean Mutala cohort (n=131, of which 44 were unvaccinated, and 87 vaccinated with inactivated vaccines). Participants living with HIV (PLWH) comprised 30-50% of each cohort. In the pre-vaccination samples from the Sisonke cohort, geometric mean titers (GMT) for anti-GRAd32, Ad26, and Ad5 antibodies were 78, 142, and 459, with neutralization titers >200 observed in 14%, 32%, and 68% of participants, respectively. Similarly, in the unvaccinated participants in the Mutala cohort, GMTs for GRAd32, Ad26, and Ad5 were 117, 245, and 536, with neutralizing titers >200 in 22%, 42%, and 69% of participants. We observed no significant difference in Ad antibody titers between PLWH and those living without HIV. We next assessed the impact of COVID-19 vaccination on titers. Vaccination with inactivated COVID-19 vaccines (Sinopharm/Sinovac) did not significantly affect Ad5, Ad26 or GRAd32 titers in an unpaired analysis. In contrast, [~]9 months after Ad26.COV2.S vaccination, anti-Ad26 titers for longitudinally sampled participants (n=27) increased 10-fold from a GMT of 141 to 1,426. By comparison, GRAd32 responses were not significantly altered by Ad26.COV2.S vaccination, while anti-Ad5 responses showed a modest <2-fold increase. Our data support previous findings that, whereas anti-Ad5 neutralizing antibody responses are commonly detected globally, GRAd32 responses are less frequent. Importantly, GRAd32 neutralizing responses remained unchanged after Ad26.COV2.S vaccination. HIV status had no significant effect on antibody titers. These results support the use of the GRAd32 vector in upcoming HIV vaccine trials, including in regions where Ad26-based COVID-19 vaccines were widely deployed.

Objectives In Quebec, Canada, vaccination against human papillomavirus (HPV) has been publicly-funded since January 2016 for gay, bisexual, and other men who have sex with men (GBM) aged [&le;]26 years. The study aimed to analyze data collected in Greater Montreal (Engage study) to evaluate the HPV vaccination program for GBM in Quebec. Study Design Engage is a cohort of sexually active GBM aged [&ge;]16 recruited via respondent-driven-sampling (RDS) in Canada. Participants completed a questionnaire and tested for sexually transmitted infections. Methods RDS-II weights were applied to adjust for recruitment. Subgroups were compared using standardized mean differences. Odds ratios of HPV vaccination and prevalence ratios of anal HPV infection adjusted for potential confounders were estimated using robust regression models. Results Of 1179 participants, 309 were eligible for free HPV vaccination. Vaccine coverage among eligible GBM was 42%. Among those who disclosed same-sex sexual activity and discussed HPV vaccination with their healthcare provider, coverage reached 82%. Anal HPV prevalence among eligible GBM was 26.5% for [&ge;]1 HPV-6/11/16/18 genotypes without significant difference between vaccinated and unvaccinated individuals. Among unvaccinated GBM aged [&le;]26 who were aware of the vaccine, 60% intended to get vaccinated within the next year. Conclusions One to two years after GBM aged [&le;]26 were included in the Quebec HPV vaccination program, 42% of eligible GBM in Greater Montreal had been vaccinated. Anal HPV prevalence was high among GBM. Vaccinees were more likely to self-report a prior STI diagnosis. Offering vaccination to all preadolescents in schools appears essential to maximize vaccination benefits.

The impact of social parameters on brain health among people with traumatic brain injury (TBI) has been extensively documented. However, translation of this evidence into policy and clinical practice remains limited. This may reflect a lack of coordinated and equity-driven approaches to brain health that integrate diverse stakeholder perspectives, limiting progress toward equity-oriented research and service delivery models. We conducted a convergent parallel mixed-methods study guided by the REporting guideline for PRIority SEtting of health research (REPRISE). We utilized the PROGRESS-Plus framework (Place of residence, Race/ethnicity, Occupation, Gender/sex, Religion, Education, Socioeconomic status, Social capital, and context-specific parameters) to ensure systematic consideration of social parameters in the study. For Objective 1, we synthesized existing evidence on social parameters and brain health outcomes. For Objective 2, we surveyed people with lived experience of TBI, family members/friends, clinicians, researchers, and community leaders across the globe to assess their prioritization of social parameters relevant to brain health. For Objective 3, we integrated evidence synthesis and stakeholder input through a structured Round Robin consensus activity to prioritize actionable areas for feasibility and impact. The activity culminated in the development of a knowledge mobilization agenda designed to inform equity-centred policy, research, and clinical practice. In Objective 1, we identified 59 publications with evidence on the effect of PROGRESS-Plus parameters on brain health outcomes following TBI. Meta-research highlighted that education, age, and country-level indicators are prognostic for brain health after TBI. In Objective 2, the highest-ranked priorities of 113 stakeholders across four continents (North America, Europe, Africa, and Oceania) were education, access to benefits, and income. These priorities were at the centre of discussion in Objective 3, which comprised idea sharing, refinement and thematic clustering, and a final prioritization poll. The resulting final 15 priorities were organized into two tracks: Track A, actions feasible in the short term, and Track B, longer-term implementation priorities. Building on this priority-setting process, co-created with stakeholders around the globe, the findings provide a roadmap for integration of social parameters in TBI research, knowledge exchange, policy, and practice.

Introduction: Synthetic oligopeptides provide a rapid and cost-efficient approach to developing antibodies and diagnostics for emerging viral variants. Methods: This study computationally and experimentally characterized a synthetic peptide analog of the SARS-CoV-2 spike subdomain 2 major disulfide loop (SD2MDL), designated S621 (CPVAIHADQLTPTWRVYSTC). Binding affinity was computationally estimated using the Heuristic Affinity Prediction Tool for Immune Complexes (HAPTIC), while experimental validation was performed using enzyme-linked immunosorbent assay (ELISA) with rabbit-derived antipeptide antibodies. Clinical diagnostic accuracy testing was done using plasma samples from RT-PCR-confirmed COVID-19 patients and pre-COVID-19 controls. Results: S621 demonstrated nanomolar binding affinity (Kdapp = 1.14 nM) and high avidity (3.67 nM), closely matching HAPTIC predictions (3.54 nM). Diagnostic evaluation yielded a sensitivity of 89.92% and specificity of 27.79%, corresponding to an overall accuracy of 71.79%. Discussion: These findings demonstrate that a single synthetic peptide derived from a conserved spike subdomain can function as a high-affinity surrogate for full-length antigens, supporting its potential application in rapid peptide-based immunodiagnostics.

Introduction-India's immunization initiatives are among the largest globally, characterized by a substantial birth cohort of 27 million children annually, and have achieved significant progress in increasing coverage through the UIP. However, there are still challenges that persist, and multiple determinants contribute to the existing challenges; parental migration is one of them. Migration has always been a key driver of socio-economic and demographic changes, particularly in low and middle-income countries (LMICs). Specifically, there is a need to better understand the vulnerabilities of immunization among recent migrants. To examine this, the study explores the association between a mother's recent migration and the full immunization coverage of children aged 12-23 months in India. Data & Methods-Our study utilized data from the National Family Health Survey-5 (2019-21). The outcome variable of interest in this study is the receipt of all basic vaccinations (full immunization) for children. The primary predictor variable in this study is the children's migration status. We used a series of multivariate logistic regression models to examine the relationship between full Immunization and recent migration of children, with some data restrictions in the models. Results - The results show a 17% difference in full immunization between migrant and non-migrant children. The odds ratios for children who had recently migrated were lower for full immunization (OR: 0.39, 95% CI: 0.35-0.43) compared to children who had not recently migrated. Even across the household wealth quintile and social groups, the recent migration of children was associated with being less likely to be fully immunized among children 12-23 months. Conclusion- The findings of this study provide significant quantitative evidence that recent migration (less than 3 years) of children is a key factor influencing Immunization coverage and is a predictor of full vaccination among children aged 12-23 months in India. The recent migration was consistently linked to a lower likelihood of full immunization coverage across different household wealth levels and social groups. This study suggests that recently migrated children are a vulnerable subgroup of the population at risk of not receiving all basic vaccinations by their first birthday.

Spinal fractures are an important contributor to disability worldwide, particularly in aging populations. However, comprehensive long-term comparisons between China and other major economies remain limited. Using data from the Global Burden of Disease (GBD) 2021 study, we analyzed temporal trends in the incidence, prevalence, and years lived with disability (YLDs) of spinal fractures in China and the overall G20 from 1990 to 2021. Age-standardized rates were assessed using Joinpoint regression and age-period-cohort analysis. Future burden through 2050 was projected using autoregressive integrated moving average modeling, and decomposition analysis was performed to quantify the contributions of demographic and epidemiological factors. Between 1990 and 2021, China experienced substantial increases in absolute burden. Incident cases increased by 52.27%, prevalent cases by 113.66%, and YLDs by 107.21%. The age-standardized prevalence rate (ASPR) and age-standardized YLD rate (ASYR) increased significantly, whereas the age-standardized incidence rate (ASIR) showed a non-significant upward trend. In contrast, the overall G20 aggregate showed increasing absolute case numbers but significantly declining age-standardized rates. Age-period-cohort and age-specific analyses indicated that older adults represented the main burden-bearing population. Projections suggested that Chinas ASIR may decline by 2050, whereas prevalence and YLD burden, particularly among males, may remain relatively high compared with the overall G20 level. Decomposition analysis identified population aging as the major driver of burden growth. China experienced a rising burden of spinal fractures over the past three decades, in contrast to declining age-standardized trends in the overall G20 aggregate. These findings highlight the substantial role of population aging in shaping spinal fracture burden and provide epidemiological evidence for prevention planning and aging-related health policy.

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.

Activation of innate immunity enhances adaptive immune responses and underlies the mechanism of action of vaccine adjuvants. First-generation mRNA vaccines lack a dedicated adjuvant, relying instead on the self-adjuvanting properties of lipid nanoparticles (LNPs), and are thus expected to benefit from additional engagement of innate immune pathways not activated by LNPs. Among innate immune modulators, TLR5 agonists are particularly promising adjuvants due to their ability to induce a balanced Th1/Th2 immune response and their relatively favorable safety profile. Here we tested whether supplementing mRNA vaccines with mRNA encoding a TLR5 agonist could enhance immunization efficacy by induction of TLR5 signaling coordinated with vaccine antigen expression. We designed FL711, an mRNA encoding a derivative of Salmonella flagellin optimized for mammalian expression, functionally active in TLR5 signaling, deimmunized for pre-existing human T and B cell epitopes, and engineered for secretion to stimulate the TLR5 pathway in the local tissue microenvironment. We characterized FL711 in vitro and in vivo for functional and pharmacological parameters and assessed its adjuvant effect as a component of experimental anti-influenza and anti-SARS-CoV-2 mRNA vaccines. Supplementation with small amounts of FL711 mRNA (up to 30-fold less than antigen-encoding mRNA) significantly enhanced vaccine immunogenicity and protective efficacy, stimulating local NF-{kappa}B induction, boosting antibody production and T cell activation, and prolonging the durability of the response -- while enabling a marked reduction in mRNA dose per vaccine. These findings support the potential of FL711 as a broadly applicable mRNA-encoded adjuvant to improve the potency, durability, and dose efficiency of next-generation mRNA vaccines.

Background and Objectives: SARS-CoV-2 (COVID-19) continues to mutate, circulate, and adversely impact health and quality of life. While COVID-19 vaccines remain safe and effective, uptake remains low, especially among children, the youngest of whom were not vaccine-eligible until after Omicron and are underrepresented in published research. This study estimated vaccine effectiveness (VE) among under-5-year-olds. Methods: We used Virginia Department of Health surveillance data from June 2022 through October 2022 to conduct a test negative case-control study. We estimated VE derived from odds ratios (ORs) of reported infections using logistic regression among children aged 6-months to 5-years. Results: Using the earliest positive (cases) or negative (controls) post-vaccine-eligible test results, the VE associated with two doses of a COVID-19 vaccine was 78% (95% CI=45%, 93%; p=0.004) in unadjusted analyses and 70% (95% CI=25%, 91%, p=0.023) when adjusting for age, sex, prior testing behavior, and prior reported infections. The adjusted VE was 74% (95% CI=28%, 94%; p=0.025) among those with no prior positives reported and 45% (95% CI=-302%, 97%; p=0.569) among those with a prior positive reported. Conclusions: These results show that even though the vaccine was not closely matched to the dominant variants circulating during the time period analyzed, it was effective at reducing the risk of reported infections. This study adds to the body of knowledge on pediatric COVID-19 VE in an underrepresented age-group and in a rural region, illustrates the utility of surveillance data for evaluation, and can inform vaccine decisions to improve vaccine uptake for young children.

Background: Tanzania introduced the human papillomavirus (HPV) vaccine in 2018 for girls aged 9-14 years; however, coverage remains suboptimal. Missed opportunities (MOs) for vaccination are an important but understudied barrier, particularly in urban settings. This study assessed factors associated with MOs and explored healthcare providers perspectives on barriers and potential solutions in Dar es Salaam. Methods: An embedded mixed-methods study was conducted in public health facilities in Temeke Municipal Council from June - July 2025. The quantitative component involved a cross-sectional survey of 252 parents or caregivers of eligible adolescent girls using structured exit interviews. The qualitative component included in-depth interviews with 20 healthcare providers using a phenomenological approach. Multivariable logistic regression identified factors associated with MOs. Qualitative data were analyzed thematically using Braun and Clarkes framework. Results: The prevalence of MOs for HPV vaccination was 71.4%. Factors independently associated with MOs included caregiver age [&ge;]40 years (aOR 1.87, 95% CI: 1.02-3.42), female caregiver gender (aOR 1.61, 95% CI: 1.00-2.59), primary education (aOR 2.14, 95% CI: 1.03-4.45), married status (aOR 1.72, 95% CI: 1.01-2.94), and receiving care at health centers or dispensaries versus hospitals (aOR 1.83, 95% CI: 1.05-3.19). Qualitative findings identified key drivers of MOs, including limited caregiver knowledge, vaccine hesitancy, time constraints, failure to routinely offer vaccination, stock-outs, poor documentation, high workload, and limited outreach. Proposed strategies included routine eligibility screening, reminder systems, community engagement, and supportive supervision. Conclusion: MOs for HPV vaccination are highly prevalent and driven by both caregiver and health system factors. Strengthening routine screening, reminder systems, community engagement, and supervision may improve vaccine uptake.

Introduction Care home (CH) influenza vaccination of staff improves resident health, yet uptake remains low at just over 11% (England, 2025/2026). We report an economic evaluation (EE) of "FluCare", an intervention to increase staff influenza vaccination through: vaccination clinics at CHs; promotional materials; and CH financial incentives. Method Seventy-five CHs were randomised to FluCare or control. A cost-consequence analysis took the influenza vaccination programme funder perspective, but also extended to the National Health Service (NHS) and CH perspective. Costs included: influenza vaccination; administration fee; FluCare components; CH resident NHS utilisation. Outcomes were: staff influenza vaccination rates; staff sickness; and resident mortality. Sensitivity analyses excluded intervention CHs that did not host vaccination clinics. Results Compared to control CHs, adjusted analysis found intervention homes with a mean absolute increase in vaccination rates of 1.8% (95% CI: -6.0%, 10.8%; p=0.572) at an increased cost of {pound}451 (95% CI: {pound}239, {pound}675; p<0.001) to the vaccination programme funders: {pound}249 per additional percentage point (PAPP) per CH. Vaccination clinics were delivered late in the influenza season, with 80% taking place from February 2023. Including only intervention CHs that hosted staff flu vaccination clinics (23/35), increases the mean difference to 10.1% (95% CI: 0.9%, 21.9%; p=0.018) and costs to {pound}805 (95% CI: {pound}603, {pound}1,079; p<0.001): {pound}79 PAPP per CH. Differences between trial arms in other costs and outcomes were marginal and generally non-significant. Conclusions FluCare delivered little improvement when staff flu vaccination clinics did not occur and had little impact on other costs/outcomes. Cost-effectiveness depends on willingness-to-pay for increased staff vaccination, but cost PAPP per CH improved from {pound}249 to {pound}79 when only CHs hosting clinics were considered. Late implementation, likely reduced impact by limiting clinic delivery, as reflected in sensitivity analysis. Future evaluations should implement FluCare earlier in the season.

BackgroundBispecific T-cell Engagers (TCEs) targeting B7H3 (CD276) show promise for solid tumors but are limited by systemic toxicities and poor tumor penetration. Intratumoral (IT) delivery is proposed as a solution, but the safety and spatial pharmacodynamics (PD) remain poorly defined in these malignancies. Spontaneous canine tumors serve as a highly translatable model for human therapeutic development due to its clinical, genetic, and immunological similarities to human patients. This study evaluates the feasibility of an IT-delivered B7H3:CD3 TCE in a trial that enrolls companion dogs with solid tumors. MethodsWe engineered a canine B7H3:CD3 TCE and validated its ability to induce T-cell activation and T-cell mediated cytotoxicity in vitro on several B7H3-expressing canine tumor cell lines. Two STS canine patients received intratumoral columnar injections of the TCE and saline (internal control) at fixed distance of 1.5cm using a custom-engineered multi-needle assembly. Safety was evaluated by physical examinations and hematological and biochemical changes in peripheral blood. PD response was analyzed by H&E and immunohistochemistry. ResultsIn vitro assays validated the cytotoxicity of the B7H3:CD3 TCE on B7H3+ canine tumor cell lines. TCE IT administration (7.83 g / 148.2 pmol) was well tolerated with no adverse events greater than Grade 1 and no evidence of systemic cytokine release or organ toxicity. Immunohistochemistry of tumors collected 7 days after TCE administration revealed a significant five-fold increase in CD3+ T-cell density at the TCE injection site (within 0.5 cm radius) compared to internal saline controls. ConclusionsThis study demonstrated the feasibility of evaluating pharmacodynamic response to IT delivery of B7H3:CD3 TCE, namely local T-cell accumulation. T-cell localization around the TCE injection site supports our hypothesis that effective IT immunotherapy might require enhanced volumetric coverage using multi-needle injections and/or co-stimulatory strategies to convert T-cell localization into a robust, sustained anti-tumor response.

Background The majority of family dementia caregivers in the United States (U.S.) are now young and middleaged adults. However, little research has been conducted to understand how caregiver needs and preferences for support differ depending on their phase of adulthood. This study evaluated differences in mental health, caregiving readiness, desired supports, and intervention preferences among early (<46 years), middle (46 to 60 years), and late (>60 years) adulthood dementia caregivers. Methods A cross sectional survey was conducted with 202 family dementia caregivers aged 22 to 88. Caregivers completed validated measures of burden, anxiety, depression, well being, time pressure, dementia knowledge, caregiving preparedness, and positive aspects of caregiving. Desired supports and preferences for intervention format, program type, and frequency were assessed. Analyses examined both categorical adulthood phase and continuous age associations with caregiver outcomes, with alpha thresholds of p<.05. Results Early adulthood caregivers self reported higher anxiety symptoms (relative to late adulthood caregivers) and perceived time pressure (relative to middle and late adulthood caregivers). Relative to late adulthood caregivers only, early adulthood caregivers more frequently endorsed desired support for supplemental care and safety tools for the person with dementia, as well as willingness to engage in individual counseling and automated, digital supports. Relative to both middle adulthood and late adulthood caregivers, they also more frequently expressed desired support for their own mental health. Conclusions Dementia caregiving in early adulthood is associated with distinct psychological and practical support needs, suggesting life course informed interventions may enhance relevance and engagement.

BackgroundCognitive dysfunction is a prevalent and debilitating symptom of post-COVID-19 condition with limited evidence-based interventions. Here, we assessed the efficacy of cognitive training (CT) alone and combined with transcranial direct current stimulation (tDCS) for cognitive enhancement in post-COVID-19 patients. MethodsNeuromod-COV was a phase IIb, prospective, randomized, open-label, blinded-endpoint trial conducted at University Medicine Greifswald, Germany. The tDCS intervention was evaluated through a double-blind, sham-controlled design. Adults aged 18-60 with confirmed SARS-CoV-2 infection [&ge;] 6 weeks prior and post-infection cognitive complaints were eligible. Participants were randomly assigned (1:1:1) to CT with active tDCS (CT+AtDCS), CT with sham tDCS (CT+StDCS), or progressive muscle relaxation (PMR, non-cognitive control intervention) with sham tDCS. Intervention consisted of nine 20-minute sessions over three weeks of CT (letter updating task) or PMR with 2 mA tDCS (active/sham) applied over the left dorsolateral prefrontal cortex. The primary outcome was untrained working memory (WM; measured by N-back task accuracy) comparing CT with PMR at post-intervention. Secondary outcomes included trained and untrained WM, visuospatial memory, and self-report measures at post-intervention and 1-month follow-up comparing CT vs. PMR and CT+AtDCS vs. CT+StDCS. The trial was registered at ClinicalTrials.gov (NCT04944147). ResultsBetween October 1, 2021, and August 7, 2024, 60 participants were randomized (76.7% female) to CT+AtDCS (n = 20), CT+StDCS (n = 20), or PMR (n = 20). CT did not improve untrained WM at post-intervention compared with PMR (primary outcome: {beta} = 1.59, 95% CI - 1.30 to 4.48, p = 0.278; 1-back: {beta} = 2.52, 95% CI -1.27 to 6.31, p = 0.191; 2-back: {beta} = 0.66, 95% CI -3.12 to 4.44, p = 0.732). However, CT+AtDCS enhanced untrained WM at post-intervention and follow-up, and visuospatial memory at post-intervention compared with CT+StDCS (secondary outcomes). No intervention improved self-report outcomes. No serious adverse events occurred and incidence rate ratios were similar between groups. ConclusionCT alone did not improve untrained WM performance. However, CT with tDCS enhanced untrained WM and visuospatial memory, suggesting potential benefits of combined neuromodulation approaches for cognitive enhancement in post-COVID-19 patients.