npj Vaccines

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

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.

IntroductionMalaria is a leading health problem with high disease burden and mortality rates worldwide. Currently approved vaccines target the sporozoite form of Plasmodium falciparum that initially infects the liver, but only provide modest protection against malaria in young children. There is an urgent need to develop next-generation malaria vaccines that target multiple parasite developmental stages for greater efficacy. Antibodies to merozoites, which are involved in blood-stage replication, and are associated with clinical illness, have multiple functional activities and can protect against malaria. A promising merozoite vaccine candidate is Merozoite Surface Protein 2 (PfMSP2). Antibodies to PfMSP2 can promote multiple antibody Fc-mediated functional activities to clear merozoites. MethodsWe developed and evaluated monovalent and bivalent (3D7 and FC27 variants) PfMSP2-based mRNA vaccines. We designed and codon-optimised mRNA, which was validated for in vitro expression in mammalian cells, and subsequently formulated as lipid nanoparticles for vaccination of mice in a 3-dose regimen. Vaccination with recombinant PfMSP2 protein with adjuvant was performed for comparison. We evaluated the induction of antibodies and functional activities relevant to protective immunity. ResultsmRNA vaccines induced prominent IgG responses using monovalent (3D7 allele) and bivalent (3D7 and FC27 alleles) vaccines encoding near full-length PfMSP2, and antibodies recognised the surface of whole merozoites. Vaccine responses were equivalent to, or superior than, a recombinant protein-based PfMSP2 vaccine. The bivalent vaccine induced equivalent antibodies to the two PfMSP2 alleles. Vaccination induced cytophilic IgG subclasses with multiple functional activities, including complement fixation, binding of human Fc{gamma}-receptors I and IIa, and opsonic phagocytosis. ConclusionsPfMSP2 is highly immunogenic using the mRNA vaccine platform and induces antibodies with multiple functional activities associated with protective immunity in humans. Combining PfMSP2 with other merozoite and sporozoite antigens is a promising strategy to develop highly efficacious vaccines to achieve malaria control and elimination goals.

Background: Induction of HIV envelope (Env)-specific broadly neutralizing antibodies (bnAbs) is considered a key objective for HIV-1 vaccine development. One approach is to vaccinate with HIV Env immunogens that initially target the naive B cell receptors of a bnAb type and boost with a series of HIV Env variants. We chose a priming immunogen, the CH505 transmitted/founder Env with high affinity for the naive B cell receptor of the prototype CD4 binding site (bs) bnAb lineage, CH103, as a candidate priming immunogen to induce the initial critical step in CD4bs bnAb development. Methods: HVTN 300 is a first-in-human, open-label Phase 1 study evaluating the safety and immunogenicity of a CH505 TF chimeric (ch) Trimer adjuvanted with 3M-052-AF (a TLR7/8 agonist) + Alum. The immunogen is a recombinant, stabilized chimeric Env trimer protein with the N-terminal sequence of CH505 TF gp120 Env transplanted into the BG505 SOSIP sequence. Participants received the adjuvanted protein administered in both deltoid muscles at months 0, 2, 4, 8, and 12. Results: Adults (n=18) aged 18 to 55 were screened at a single site in Boston, USA, and 13 were enrolled. Local and systemic reactogenicity was typically mild to moderate. One participant had severe pain/tenderness, and five participants reported transient severe systemic symptoms at least once. Five participants chose to stop further vaccination due to reactogenicity. No vaccine-related SAEs occurred. Vaccine-specific B-cell response rates reached 100% two weeks post third and fifth vaccinations. Antibody blocking experiments with monoclonal antibodies demonstrated that most participants had antibodies directed to the CD4bs. Four out of 11 participants had serum neutralization signatures for CD4bs bnAb precursors. Conclusions: No safety concerns were identified. The adjuvanted CH505 TF chTrimer elicited serum antibodies capable of CD4bs-mediated neutralization against strains designed to detect early precursors of the CD4bs B-cell lineages. Trial Registration: NCT04915768 Disclosure: Presented in part at HIVR4P 2024, Lima, Peru, October 6-10, 2024

Blocking transmission of Borrelia burgdorferi (Bb), the causative agent of Lyme disease (LD), from reservoir hosts to humans via Ixodes scapularis ticks represents an alternative strategy to reduce LD incidence. Here, we evaluated Purified Borrelial Lipoproteins (PBL) with a combination of adjuvants, for their ability to limit Bb transmission using C3H/HeN mice and Peromyscus leucopus reservoir models. Immunization with PBL as oral gavage, either alone or nanoparticle-encapsulated, elicited increased antibody responses and reduced pathogen burden in fed larvae and select host tissues. A formulation combining PBL with a recombinant fusion protein adjuvant consisting of Cholera Toxin B subunit, Outer surface protein A, and two-tandem repeats of an M-cell-targeting peptide (rCOM) induced durable protective immunity for up to 10 months in C3H/HeN mice. This oral regimen significantly reduced Bb burden in host tissues, in fed larvae from vaccinated hosts, molted nymphs, and nymph-challenged naive mice. Immunization with PBL+rCOM elevated peripheral levels of Bb-specific IgG isotypes and increased antigen-specific T cell responses producing IFN-{gamma} and IL-4 at days 28 and 65 post-immunization. Significant protective responses were observed in P. leucopus, including strong antibody responses, reduced Bb burden in tissues and reduced Bb transmission to naive larvae, independent of sex but influenced by challenge dose. Sodium chloride content in oral formulation modulated vaccine induced protective responses. Notably, Bb burden in infected nymphs was reduced during the bloodmeal on vaccinated hosts with decreased pathogen transmission to both vertebrate hosts. These findings support PBL+rCOM as a promising oral, reservoir-targeted, transmission-blocking biologic for controlling Lyme disease. Lay AbstractNumerous vertebrate hosts serve as reservoirs of pathogens that are transmitted to humans via the bite of blood feeding vectors such as ticks. Lyme disease, caused by Borrelia burgdorferi (Bb), is the most common tick-borne disease in the US. Bb is transmitted to humans following the bite of infected Ixodes scapularis ticks. In nature, ticks acquire Bb and other pathogens from a variety of reservoir hosts, notably Peromyscus leucopus. Therefore, strategies that limit pathogen burden in reservoir hosts or block their transmission via ticks are options to prevent human infectious diseases, circumventing need for human vaccines and therapeutics. An oral, reservoir host-targeted, pathogen-derived, biologic prepared by extracting immunogenic lipoproteins (Purified Borrelial Lipoproteins) from Bb and combining them with a mucosal adjuvant derived by fusing Cholera-Toxin B subunit, Outer surface protein A of Bb and 2 repeats of an M-cell targeting peptide was tested in C3H/HeN mice and Peromyscus leucopus hosts. Single or two dose regimens via the oral route resulted in significant increases in peripheral Bb specific antibody responses, select T cell responses, blocking the transmission of Bb to naive Is larvae, reducing pathogen burden in vaccinated hosts, and interfering with the infectious cycle of the agent of Lyme disease.

Neonatal sepsis caused by Klebsiella pneumoniae is a major cause of under-five mortality in sub-Saharan Africa, and the rapid increase of infections caused by bacteria resistant to most or all available antimicrobials severely limits treatment options. An effective, maternally-administered vaccine could make a substantial reduction in neonatal sepsis and associated negative outcomes, as well as reduce the overall need for antimicrobials, a key driver of antimicrobial resistance. This study explored the potential for a maternally administered protein-based vaccine to provide neonatal protection via antibodies transferred transplacentally and through breastfeeding. A case-control study of mother and baby dyads was designed with 20 neonates developing K. pneumoniae sepsis and 80 uninfected control neonates to analyse breastmilk IgA, cord blood IgG and maternal serum IgA and IgG antibodies on a protein microarray with 161 selected K. pneumoniae proteins representing 152 unique genes. This analysis identified a set of proteins eliciting antibody responses, some associated with lack of K. pneumoniae sepsis, that indicate the presence of potentially protective antibodies. This is an essential first step in exploring surface protein accessibility, despite the large capsule. We highlight fimbrial structures, conjugative pili, and small lipoproteins associated with large outer membrane complexes as potential protein vaccine targets.

The emergence of new SARS-CoV-2 variants and breakthrough infections underscores the need for next-generation vaccines capable of protecting from natural infection and/or preventing virus transmission to others. Intranasal vaccination offers a promising approach by eliciting local immune responses in the nasal mucosa, the primary site of infection and reservoir for transmissible virus. We evaluated two live-attenuated, respiratory syncytial virus vectored vaccines in which the RSV F and G surface glycoproteins were replaced with a chimeric SARS-CoV-2 Spike protein from either the ancestral USA/WA-1/2020 strain (MV-014-212) or the Delta variant (MV-014-212-delta). A single intranasal dose of either vaccine elicited systemic and mucosal immunity in K18-hACE2 mice, including serum neutralizing antibodies, Spike-specific memory B cells and plasmablasts, and Spike-specific CD8 lung-resident memory T cells. Although MV-014-212-delta vaccination provided the best protection against Delta variant virus challenge, both vaccines decreased viral loads in nasal discharge, lung and brain, and reduced weight loss and mortality. In naturally acquired infection studies, vaccinated hamsters exposed to infected cagemates exhibited minimal weight loss, limited viral replication within the nasal mucosa, and attenuated lung pathology. Therefore, intranasal RSV-vectored vaccines can elicit broad protective respiratory immunity, suggesting that this platform could be leveraged for other respiratory pathogens.

West Nile virus (WNV) is the causative agent of fatal West Nile encephalitis. To date, no human vaccine against WNV has been approved. Adjuvants are important for developing effective and affordable vaccines that enhance the immunogenicity and decrease the required antigen doses. In this study, we assessed the efficacy of AddaS03, a synthetic adjuvant analogous to AS03, in a WNV subunit vaccine composed of soluble recombinant envelope protein (sEnv). Using a passive immunization mouse model, we defined the neutralizing antibody titer threshold required for protection against lethal WNV infections and applied this threshold as a surrogate marker to evaluate adjuvant efficacy. AddaS03-adjuvanted formulations elicited markedly higher neutralizing antibody titers compared to Alhydrogel adjuvant 2% (Alhydrogel), even at suboptimal antigen doses, and consistently exceeded the defined protective threshold titer. Moreover, in a sequential challenge mouse model, AddaS03-adjuvanted vaccines completely protected mice from symptomatic WNV infections, whereas Alhydrogel-adjuvanted vaccines failed to confer full protection. Collectively, these findings demonstrate that AddaS03 is a promising adjuvant for WNV subunit vaccine development and highlights the utility of a passive immunization model for defining protective antibody thresholds as a surrogate marker for vaccine evaluation.

In a confirmatory study, we evaluated the immunogenicity and protective efficacy of a heterologous prime-boost vaccination strategy against respiratory syncytial virus (RSV) in non-human primates. Building on prior evidence of protective mucosal immunity induced by intramuscular DNA priming followed by an oropharyngeal adenoviral boost, we conducted a randomized, blinded, dual-centre study across two European primate research facilities. Rhesus macaques received a codon-optimized RSV-F DNA vaccine via electroporation, followed by two mucosal administrations of a recombinant adenovirus serotype 5 vector encoding the same antigen. Control groups included animals vaccinated with irrelevant influenza antigens and a comparator group mimicking natural immunity induced by primary RSV infection. Systemic and mucosal immune responses, including RSV-F-specific antibodies and tissue-resident memory T cells, were monitored longitudinally. Here, we detected robust immune responses, but with some variability between the two centres. However, following experimental RSV challenge performed 22 weeks after the final immunization, RSV-vaccinated animals demonstrated markedly reduced viral replication in both upper and lower respiratory tracts. However, unexpected RSV-specific immunity in the control group at one single study site prevented confirmation of the predefined primary endpoint. Overall, these results support the potential of mucosal adenoviral boosting following DNA priming to induce protective immunity against RSV, while highlighting challenges associated with multi-centre preclinical vaccine studies.

BackgroundCoronavirus outbreaks remain a persistent threat to global health, and vaccines based primarily on spike-specific immune responses are susceptible to antigenic variation. T-cell immunity directed against conserved internal viral proteins may provide a complementary and more variant-tolerant strategy for next-generation coronavirus vaccines. MethodsWe combined machine learning-guided antigen prioritization with ex vivo functional immunological validation to identify conserved non-spike T-cell targets across betacoronaviruses. Candidate sequences were screened for immunogenicity using primary human peripheral blood mononuclear cells from healthy donors using intracellular cytokine staining and activation-induced marker assays. Top-ranked conserved regions were incorporated into multiepitope mRNA constructs, and their intracellular expression and HLA class I presentation were confirmed by immunopeptidomics. Immunogenicity was further evaluated ex vivo and in vivo using mRNA immunization of mice and T-cell FluoroSpot assays. FindingsAcross a panel of 97 peptides derived from 19 viral proteins, evolutionary conservation across distinct betacoronavirus taxa was strongly associated with functional T-cell immunogenicity in human donors. Highly conserved peptides elicited significantly stronger and more frequent CD4 and CD8 T-cell responses than taxon-restricted peptides. Multiepitope mRNA constructs encoding conserved regions were efficiently expressed and presented on HLA class I molecules and induced T-cell responses in human PBMCs. In mice, mRNA immunization with conserved multiepitope constructs generated robust interferon-{gamma}- and interleukin-2-producing T-cell responses that exceeded those induced by unconserved control constructs. InterpretationThese results link evolutionary conservation to functional cellular immunogenicity and demonstrate the feasibility of multiepitope mRNA delivery for inducing conserved coronavirus-directed T-cell responses. Although protective efficacy remains to be established, conservation-guided antigen selection represents a scalable strategy for developing T-cell-focused vaccines with broad lineage coverage, supporting pandemic preparedness beyond spike-centered immunity. FundingThe research was supported by CEPI, NEC, University of Oslo and Oslo university hospital. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSPrior coronavirus vaccine development has focused predominantly on spike protein-directed neutralizing antibodies. While highly effective against matched strains, spike-centered immunity is vulnerable to antigenic drift and lineage-specific escape. Multiple observational and experimental studies have shown that T-cell responses, particularly against internal viral proteins, are more conserved and correlate with reduced disease severity and cross-variant recognition. Epitope prediction algorithms and immunoinformatics approaches have been widely used to nominate candidate T-cell targets; however, systematic functional validation of conserved non-spike antigens across betacoronaviruses in primary human immune systems, combined with antigen presentation data and in vivo vaccine testing, has remained limited. Searches of PubMed and bioRxiv up to December 2025 using terms including "coronavirus T-cell vaccine," "conserved coronavirus epitopes," "betacoronavirus cross-reactive T cells," and "mRNA T-cell vaccine" identified studies demonstrating cross-reactive T-cell immunity and computational epitope selection, but few integrated machine-learning-guided antigen prioritization with ex vivo human functional screening, immunopeptidomics, and in vivo mRNA immunization in a unified workflow. Added value of this studyThis study provides an integrated experimental and computational framework for identifying and validating conserved non-spike T-cell antigens across betacoronaviruses. We functionally screened a panel of candidate peptides derived from multiple viral proteins and demonstrated that evolutionary conservation across species is strongly associated with T-cell immunogenicity. We further demonstrate that multiepitope mRNA constructs encoding these top-ranked conserved regions can be intracellularly expressed, presented on HLA class I molecules to induce polyfunctional T-cell responses in primary human PBMCs. Finally, in vivo mRNA immunization in mice induces robust interferon-{gamma} and interleukin-2 T-cell responses exceeding those induced by unconserved control constructs. Together, these findings link evolutionary conservation to functional cellular immunogenicity and extend beyond in silico prediction by demonstrating antigen processing, presentation, and immunogenicity across human and murine systems. Implications of all the available evidenceCollectively, the available evidence indicates that T-cell immunity directed toward conserved internal coronavirus proteins represents a complementary and potentially more variant-tolerant axis of vaccine design than spike-only strategies. Our findings suggest that evolutionary conservation can serve as a practical selection principle for prioritizing T-cell antigens with broad lineage coverage and that multiepitope mRNA delivery is a feasible platform for inducing such responses. While direct protection and heterologous challenge studies will be required to establish clinical efficacy, the integration of computational prioritization with functional validation supports a scalable approach to pandemic preparedness that may be applicable to other rapidly evolving viral families.

Background: The value proposition for Shigella vaccines is strengthened by the potential for vaccines to prevent linear growth faltering. However, because expected effect sizes in Phase 3 vaccine trials are small due to limited Shigella incidence, a simple comparison of growth by randomized vaccine arm is likely underpowered and may yield null or even inverse results. Methods: We consider a new approach that estimates vaccine effects in the subgroup that would be infected in absence of vaccination, termed the naturally infected. In simulations parameterized by multi-site studies of diarrhea, we compare power for detecting linear growth effects in the naturally infected versus the full study. We further quantified how power is impacted by trial design choices including immunization schedule, study site, and timing of growth measurements. Findings: Simple comparisons of height-for-age z-score (HAZ) by randomized vaccine arm have extremely limited power (<15%) at realistic trial sizes (n=2,500 to 20,000) and carry risk of showing an inverse effect due to random chance. In contrast, naturally infected effects were five to ten times larger and power was up to three times higher. Using a twelve month immunization schedule with a single growth endpoint in high-incidence settings maximized power to detect an effect. Interpretations: While realistically sized clinical trials may be underpowered to detect an effect of vaccination on growth, estimation using the naturally infected subpopulation and careful trial design improve chances of detecting an effect while mitigating risks of null or inverse results.

Background Catch-up vaccination will be pivotal for achieving WHOs cervical cancer elimination goals in low- and middle-income countries (LMICs). We assessed the health-economic impact of catch-up HPV vaccination for females in LMICs. Methods Using IARCs METHIS modelling platform and data from 132 LMICs, we simulated HPV catch-up vaccination beyond the primary target age, varying the maximum age up to 30 years. Budget impact was expressed as a share of national five-year immunization budgets and current health expenditure. We conducted cost-effectiveness analyses for a smaller subset of countries for which high-quality cervical cancer treatment costs were available. Findings Catch-up HPV vaccination up to age 30 in LMICs could prevent 9.2 million cervical cancer cases over the lifetime among females aged 9-30 years. Across countries, budget impact ranged from 0.007%-2.24% of five-year health expenditure and 0.002%-236.65% of immunization budgets, with vaccine procurement comprising about 70% of costs. Gavi support could reduce costs by nearly 70% for catch-up up to age 18. Catch-up vaccination up to age 30 was cost-effective in almost all evaluated countries, except in one where cost-effectiveness was achieved up to age 21. Interpretation In LMICs, after achieving adequate coverage in the primary target group (9-14 years), expanding HPV catch-up vaccination would be impactful and cost-effective. Sustainable financing, Gavi support, and cost-minimization strategies are crucial for successful catch-up programmes and progress toward cervical cancer elimination.

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.

For millions of immunocompromised individuals, vaccines may not elicit adequate protection from infections, so alternative strategies for pre-exposure prophylaxis are essential. There is only one non-vaccine product authorized in the U.S. as pre-exposure prophylaxis against COVID-19: the monoclonal antibody pemivibart. We previously showed that pemivibart had lower neutralizing activity in vitro against many recent dominant SARS-CoV-2 variants, such as KP.3.1.1, NB.1.8.1, and LP.8.1.1, than it had against JN.1, which was dominant when the antibody was first authorized. The manufacturer of pemivibart (Invivyd) recently initated clinical testing of a new monoclonal antibody derived from pemivibart, VYD2311, but there are no available studies of the activity of VYD2311 against dominant and emerging SARS-CoV-2 variants. Here, using pseudovirus neutralization assays, we measured the neutralizing activity of laboratory-synthesized VYD2311 and pemivibart against dominant and emerging SARS-CoV-2 variants, including XFG, NB.1.8.1, and the genetically distant BA.3.2.2. We found that VYD2311 potently neutralized all tested variants in vitro, dramatically more so than pemivibart. Combined with interpretation of earlier clinical trials of a parental antibody product, we conclude that VYD2311 is a promising candidate for passive immunoprophylaxis against COVID-19, particularly for those who do not respond well to vaccination.

BackgroundWidespread immunity from vaccination and infection has reduced COVID-19 morbidity and mortality, but this immunity varies across the population. Understanding how repeated antigenic exposures influence antibody responses helps to inform future vaccination strategies. MethodsSerum samples collected one and six months after XBB.1.5 vaccination from 25 generally healthy healthcare workers with varying exposure histories were assessed for neutralizing activity against a range of variants, from pre-Omicron variants to latest Omicron JN.1 sublineage variants and divergent BA.3.2 variants, using lentiviral pseudoviruses. Participants were stratified by vaccination and infection history. ResultsXBB.1.5 vaccination elicited broad neutralizing responses, with strong boosting against previously encountered antigens relative to vaccine-matched XBB.1.5 and newer variants. Geometric mean neutralization titers were generally comparable across exposure groups, indicating limited influence of prior Omicron infection or bivalent vaccination, though intra-group heterogeneity was observed. At six months, overall titers declined by 36-62%. Titers remained highest against the pre-Omicron and lowest against JN.1 sublineage variants. N-terminal glycosylation (DelS31, T22N) modestly affected neutralization. ConclusionsXBB.1.5 vaccination elicited broad neutralizing antibody responses against previously encountered and vaccine-matched antigens regardless of exposure history, but titers waned after six months. This waning, compounded by continued emergence of immune-evasive variants and heterogenous population immunity, underscores the need for continually monitoring neutralizing antibody durability and breadth to guide evidence-based COVID-19 vaccine formulation updates.

Background Post-licensure vaccine effectiveness and impact studies provide evidence on how vaccines perform under routine programme conditions in the real world. In sub-Saharan Africa (SSA), vaccine introductions frequently coincide with concurrent public health and social measures that may influence disease risk and transmission. Failure to account for these concurrent interventions may affect the interpretation of vaccine effects. Methods We conducted a systematic review of post-licensure vaccine effectiveness and impact studies conducted in children under five years of age in SSA. Electronic databases were searched for peer-reviewed studies published between January 2000 and December 2019. Eligible studies used observational designs to estimate vaccine effectiveness or population-level impact. Two reviewers independently screened studies, extracted data, and assessed methodological quality using Joanna Briggs Institute tools. We examined study designs, vaccines evaluated, outcomes assessed, and whether public health and social measures (PHSMs) were measured or adjusted for. A narrative synthesis was undertaken. In addition, we conducted a meta-analysis for rotavirus and pneumococcal conjugate vaccines where we explored the heterogeneity in individual-level effectiveness estimates where designs and outcomes were comparable. Results Sixty-four studies met the inclusion criteria, covering eight vaccine-preventable diseases. Rotavirus vaccines were most frequently evaluated, followed by pneumococcal conjugate vaccines. Case-control and ecological designs were most common, while cohort and time-series analyses were less frequently used. None of the included studies collected, reported, or adjusted for PHSMs such as nutrition, WASH, or access to healthcare. The implications of this omission varied by pathogen. Rotavirus vaccine effectiveness estimates from comparable individual-level designs were consistent across settings, with no evidence of between-study heterogeneity. Pneumococcal vaccine effectiveness estimates showed substantial heterogeneity, which appeared to reflect differences in outcome definitions, host risk profiles, and study context. Estimates for other vaccines were generally protective in direction, although the magnitude and precision varied across studies. Conclusions Post-licensure vaccine effectiveness and impact studies in SSA rarely account for concurrent PHSMs. The consequences of this omission are not uniform across vaccines. For some pathogens, effectiveness estimates appear robust to unmeasured contextual change, while for others they are highly sensitive to outcome choice and setting. Future evaluations should prioritise systematic measurement of key PHSMs and consider study designs that better account for time-varying context. Strengthening routine data systems to capture these factors is essential for generating interpretable evidence to inform immunisation policy.

Helminths are parasitic worms that secrete a variety of immune-regulating molecules to modulate the hosts inflammatory responses, enabling them to persist within the host over a long period of time, even decades. Their capacity to control host responses has prompted research into helminth-derived molecules as potential therapies for controlling excessive immune and inflammatory activity across a range of diseases. This systematic review with cross-study quantitative analysis aims to synthesize the published data on helminth-derived immunomodulatory peptides/polypeptides/proteins (HDIPs) with a focus on determining the extent of their disease-modifying and anti-inflammatory potential in in vivo animal models of inflammatory disease. In accordance with PRISMA 2020 guidelines, a predefined systematic search of the PubMed, Web of Science and Medline databases identified relevant studies published up to February 2026, and 65 articles were included after screening. We found that, although the HDIPs were assessed in multiple different disease models, most published studies assessed their potential in mouse models of colitis, asthma, arthritis and sepsis. Twenty species from which >65 isolated HDIPs were derived were tested in these models, with the trematode, Fasciola hepatica, and the nematode, Acanthocheilonema viteae, the most explored species. A common property of the HDIPs was the ability to significantly reduce disease severity across the in vivo animal models of inflammatory disease, underpinned by a decrease in pro-inflammatory cytokine levels and an increase in anti-inflammatory cytokine levels. Overall, this systematic review with cross-study quantitative analysis not only synthesizes the existing literature in this field but also highlights the disease-modifying and anti-inflammatory potential of HDIPs for a range of diseases in which immunoregulatory therapeutics may improve disease outcomes. It also encourages accelerated advancement of these helminth-derived molecules into first-in-human clinical trials.

Defining HLA restriction of T cell epitopes is essential for understanding immune responses in infectious disease, autoimmunity, and vaccine design. Current bioinformatic programs, including the IEDB RATE tool, enable inference of single-HLA restrictions from immune response data of HLA-typed donors. However, T cell epitopes are frequently presented by multiple HLA alleles, a phenomenon termed promiscuous restriction, limiting the utility of single-allele approaches. To address this limitation, we developed COMBO-RATE, an extension of RATE that systematically evaluates combinations of HLA alleles to identify multi-allelic restriction patterns. Analysis of three independent datasets spanning distinct antigen systems and different epitope discovery strategies revealed that promiscuous restriction is a near-universal feature of immunodominant epitopes. Focusing on the 43 immunodominant CD4 T cell epitopes identified in a B. pertussis genome-wide screen, COMBO-RATE outperformed conventional RATE, identifying restrictions for 32 of 43 epitopes, compared to 24 by RATE alone, and uncovered 49 additional allele restrictions, including 30 unique alleles. Experimental validation using single-HLA transfected cell lines and antigen presentation assays confirmed COMBO-RATE-inferred restrictions, demonstrating that a single epitope can be independently presented by distinct HLA alleles. Overall, COMBO-RATE provides a robust and scalable framework for defining complete HLA restriction profiles from existing population response data, with important implications for the design of vaccines requiring broad HLA coverage across genetically diverse populations. This pipeline is available as both a Python package and a user-friendly web application.

Introduction The link between Human Papillomavirus (HPV) and cancer is well-established. In Singapore, bivalent HPV vaccines are subsidised for females, but not males. Economic analysis of HPV vaccination has generally assessed the costs to the health system, but this may not be as relevant to individual decision-making as potential lost income. We estimated the impact of bivalent HPV 16/18 vaccination on sick leave, unemployment, and premature mortality as a function of age and sex to understand the broader impact of HPV-related cancers. Methods We developed a population-level economic model to estimate lifetime income losses by diagnosis age, sex and cancer type. We applied sex- and cancer-specific Cox regressions to the Singapore Cancer Registry for annual predicted survival from 1992 to 2022. These were combined with census and employment data to estimate HPV-associated income losses in Singapore. Attributable fractions and vaccine effectiveness data for HPV 16/18 from the literature were used to estimate the effectiveness of bivalent HPV vaccination. Structural sensitivity analysis examined the role of 80% population coverage conferring herd immunity. Results The registry contained 17,294 individuals with an HPV-associated cancer diagnosis. Lost income was greatest for cervical cancer due to its high prevalence, however the losses per diagnosis were highest for oropharyngeal cancer. Bivalent HPV vaccination led to income benefits of $SGD1,397 [$895 to $1,838] in girls and -$62 [-$76 to -$48] in boys. A gender-neutral HPV vaccination of 80% of 15-year-old Singaporeans, conferring herd immunity, would have lifetime income protective benefits of $24.4m [$14.2m, $33.7m] per cohort, a five-fold return on investment. Conclusions In addition to avoiding healthcare costs and lost quality of life, parents should consider vaccination as a means of avoiding potential income losses. A national policy of gender-neutral HPV vaccination could deliver substantial income protection due to both individual vaccine protection and herd immunity.

Cameroon introduced Human papilloma virus vaccine (HPVV) into the routine immunization schedule in October 2020. By the end of 2022, coverage remained low. To increase coverage, Cameroon switched to a country-wide, gender-neutral vaccination (GNV) approach in 2023, coupled with a revamped delivery strategy consisting of Community Dialogues (CDs) and Periodic Intensification of Routine Immunization (PIRIs) activities in selected health districts (HDs). We assessed the impact of these programmatic changes, notably the GNV approach, on HPVV coverage. This retrospective, cross-sectional study measured the effect of GNV and CDs + PIRIs on HPVV coverage among 9-year-old girls in Cameroon (2022-2023). Data on HPVV coverage from all 203 HDs were extracted from DHIS2, and coverage was calculated at the HD level, based on the estimated population eligible of 9-year-old girls. Descriptive statistics and multiple regression models were employed to assess the impact of GNV on vaccination coverage while adjusting for CDs + PIRIs and urban/rural status. In 2023, of the 203 HDs, 115 (56.7%) conducted GNV only, 74 (36.5%) implemented GNV & CDs + PIRIs, and 75.9% (154) were classified as rural. Among age-eligible girls, there was an overall increase in HPV vaccination coverage, with coverage rising 39.2 percentage points from 2022 to 2023. Following multiple linear regression, there was a significant increase in HPVV coverage in HDs with GNV & CDs + PIRIs compared to those with no GNV and no CDs + PIRIs ({beta}:55.5%, 95%CI: 38.7, 72.3, p=0.000). Furthermore, there was a significant increase in HPVV coverage in HDs with GNV only compared to those with no GNV or no CDs + PIRIs ({beta}:28.7%, 95%CI: 12.5, 45.0 p=0.001). Overall, the GNV approach increased HPVV coverage for girls significantly, particularly when implemented alongside CDs + PIRIs.