NPJ Vaccines最新文献

Despite evidence of varying vaccine effectiveness, T cell responses to rotavirus (RV) vaccines remain incompletely studied. To address this research gap, RV-specific T cells in the blood of infants pre- and post-monovalent RV vaccination (RV1) were analyzed for memory recall and functionality using RV-specific peptide pool stimulation. We find that RV vaccine elicits heterogenous responses with respect to cellular and humoral immunity. T cell responses to RV vaccine are detectable in the periphery, though poorly functional. Vaccination induces Th2-biased conventional effector memory and central memory CD4 + T cells, as suggested by chemokine receptor profiles, though the response wanes by 8 months post vaccination. The presence of preexisting immunity results in no significant increase in either RV-specific IgA or T cells after vaccination. Our data provides the first in-depth assessment of RV-specific T cell responses induced by vaccine, demonstrating patterns of negative and positive association with response that may play a role in protection against rotavirus disease.

Respiratory viral infections, such as influenza and coronavirus, are major threats to humankind. Injectable vaccines for SARS-CoV-2 protect against severe disease but fail to induce immunity in the upper airway mucosa, the virus entry site, thus not preventing infection and transmission. This highlights the urgent need for mucosal-targeted vaccination systems. While intranasal immunization holds promise, achieving local antigen delivery for mucosal immunity remains challenging. To address this, we designed an innovative nanoparticle system to deliver intranasal vaccines, using the receptor-binding domain (RBD) and multiple T-cell epitopes of SARS-CoV-2 antigens. Nonporous silica-based nanoparticles (SiNP) functionalized with a mucoadhesive cyclodextrin polymer (MaP) were selected as a delivery vehicle capable of adhering to and penetrating mucus. In a 3-dose regimen, the nanovaccine induced and sustained high systemic and neutralizing antibody levels for at least 1 year, with robust cellular responses, as well as IgA secretion in the oral and nasal cavities, providing strong protection against SARS-CoV-2 and substantially reducing viral loads in both upper and lower respiratory tracts. Our findings provide evidence that an intranasal vaccination platform combining two distinct nanoscale strategies might be crucial for inducing lasting and broad systemic and upper airway immunity, potentially controlling SARS-CoV-2 infection and transmission.

Neisseria gonorrhoeae imposes a substantial global health burden due to its high incidence and escalating multidrug resistance. This study investigated the immunogenicity and efficacy of a peptide-based vaccine and a monoclonal antibody (mAb) targeting the conserved Loop2 epitope of the outer membrane protein MtrE. Two multiple antigenic peptide (MAP) vaccines, displaying four copies of MtrE Loop2 with or without a Cathepsin S cleavage site, were formulated with CpG1826 adjuvant. Immunization of mice elicited robust Loop2-specific IgM-dominant antibody responses with complement-dependent anti-gonococcal serum bactericidal activity. In a murine vaginal tract infection model, both vaccines demonstrated significant prophylactic and single-dose therapeutic efficacy. Furthermore, a human-mouse chimeric mAb (M01), consisting of mouse variable domains and human IgG1 constant domains, was generated from a dominant B-cell clonotype obtained from MAP vaccine-immunized mice. M01 exhibited high-affinity binding to MtrE and potent complement-dependent bactericidal activity. In a murine infection model, intravaginal administration of M01 significantly enhanced gonococcal clearance. Furthermore, Fc-engineered M01 variants confirmed that this efficacy was critically dependent on complement activity. These findings identify MtrE Loop2 as a promising target for both active and passive immunization strategies against N. gonorrhoeae, and underscore the critical role of complement-mediated activity as a mechanistic correlate of protection.

We conducted the first pooled analysis of two randomised controlled vaccine trials on experimental pneumococcal serotype 6B carriage, registered in Malawi (PACTR202008503507113) and the UK (ISRCTN45340436). This post-hoc exploratory study examined the sex-based differences in carriage, vaccine efficacy and vaccine-induced responses. PCV-13 reduced colonisation by 76% (p < 0.001) with non-significant interaction by sex (RR = 1.549, p = 0.413). Females showed a higher carriage rate than males (28% vs. 19%, p = 0.066). Baseline anti-6B Capsular Polysaccharide Immunoglobulin G (IgG) titres were higher in females, significantly in Malawi (2.62 µg/ml vs males 2.05 µg/ml, p = 0.015). Post-vaccination titres did not differ by sex. The pooled fold change in IgG pre-post vaccination, was higher in vaccinated females (5.47 vs 3.30, p = 0.053). This analysis demonstrates the utility and challenges of integrating CHIM data between diverse settings to evaluate vaccine efficacy, describe inter-setting differences, investigate biological and immunological factors influencing protection against pneumococcal carriage and ultimately inform future vaccine development strategies.

Current lipid nanoparticles (LNPs) used in mRNA vaccines typically incorporate polyethylene glycol (PEG) as a stabilizing material; however, safety concerns have prompted the search for non-PEG alternatives. Severe Fever with Thrombocytopenia Syndrome (SFTS) is a life-threatening zoonotic disease with a case fatality rate of up to 30%, and its incidence is rising in East Asia, including China, South Korea, and Japan. Despite its growing public health impact, no licensed vaccine or specific antiviral therapy is available, highlighting the urgent need for vaccine development. Human serum albumin (HSA) is a promising stabilizer, yet an HSA-based LNP mRNA vaccine has not been reported. Here, we developed SFTSV HSAmvac, an HSA-LNP mRNA vaccine encoding a modified Gn protein of SFTSV. Immunization of BALB/c and C57BL/6 mice elicited robust humoral and cellular immune responses, and vaccination of IFNAR^-/^- mice provided complete protection against a lethal challenge, demonstrating the potential of HSA-LNP as a safe and effective mRNA vaccine delivery platform.

The inherent instability of poliovirus capsids presents a formidable challenge for developing next-generation vaccines suitable for a post-eradication world. Here, we address this by engineering a thermally stabilized virus-like particle (sVLP) derived from the poliovirus serotype 1 (PV1) Mahoney-SC7 mutant and elucidating its atomic-level structure. Produced at remarkably high yields in Pichia pastoris yeast, our engineered sVLP maintains a native, D-antigenic conformation and elicits a potent neutralizing antibody response in mice, in sharp contrast to unstable wild-type VLP (wtVLP) which adopts an expanded, non-immunogenic form. Our 2.43 Å resolution cryo-EM structure reveals precisely how seven stabilizing mutations cooperatively enhance inter-protomer contacts and rigidify surface loops to lock the particle in its immunogenic state. We further define a critical D-antigenic epitope by determining the 2.60 Å structure of the sVLP in complex with a novel D-antigen-specific, neutralizing monoclonal antibody, 3G10, elucidating the structural mechanisms of D-antigen recognition and virus neutralization by 3G10. These findings provide a definitive structural blueprint for engineering stable, immunogenic vaccines for PVs and other enteroviruses and also deliver a vital reagent for ensuring vaccine quality control.

Multiple doses of HPV vaccines induce durable, antibody-mediated protection against HPV infections and HPV-associated diseases. Although actual protection against disease by a single HPV vaccination dose has not been confirmed in randomised trials, this regimen induces protection against incident and persistent HPV infection, similar to multi-dose schedules. However, the cellular mechanisms driving durable antibody responses to subunit vaccines remain poorly understood. B cells and T follicular helper (Tfh) cells play central roles in long-term antibody-mediated immunity. We characterised plasmablast, memory B cell (Bmem), and Tfh cell responses to assess the effects of dose number and age following HPV vaccination in Gambian females aged 4-26 years. A significant induction of HPV16/18-specific IgM plasmablasts occurred after the first dose, while robust HPV16/18-specific IgG plasmablast, Bmem, and Tfh responses were observed after two or three doses. Activation within the total Tfh pool increased with decreasing age, whereas HPV16/18-specific Tfh activation was higher in older vaccinees. These findings demonstrate the potential of multi-dose HPV vaccination schedules to sustain antibody protection through coordinated B cell and Tfh responses and highlight the need for continued monitoring of single-dose regimen. Exploring HPV vaccination in children under nine years may improve delivery and uptake.

Next-generation vaccine adjuvants, including live bacterial platforms such as Salmonella, must enhance antigen-specific immune responses while maintaining an optimal safety profile, particularly for mucosal delivery. We report a rationally engineered live attenuated Salmonella adjuvant platform, self-destructing attenuated adjuvant Salmonella (SDAAS), designed for effective innate immune stimulation with built-in biosafety. Three candidate strains, χ12612, χ12621, and χ12626, were developed incorporating programmed auxotrophy for self-limiting growth, lipid A and lipopolysaccharide carbohydrate modifications to reduce endotoxin activity, and engineered flagellin. The SDAAS strains exhibited self-limiting growth, high LD₅₀ values across injection routes, and complete safety following parenteral and mucosal administration. In vitro assays showed minimal cytotoxicity, while functional analyses demonstrated robust TLR4 activation with reduced endotoxin activity from lipid A engineering and strong TLR5 signaling mediated by modified flagellin. Using ovalbumin as a model antigen, transcriptomic analysis revealed broad activation of proinflammatory, pattern recognition receptor, and antigen presentation pathways, most prominently in strain χ12621. These innate signatures correlated with elevated IL-6 and TNF-α, low IL-10, and strong antigen-specific IgG responses comparable to or exceeding those induced by alum and other commercial adjuvants. Collectively, these findings establish SDAAS strains as safe, tunable, and broadly applicable adjuvant platforms for mucosal and systemic vaccine delivery.

The recurrent emergence of ACE2‑using sarbecovirus underscores the need for a broadly protective vaccine. Here, we mapped the antigenic landscape of sarbecovirus receptor-binding domains (RBDs) and identified three distinct clusters. We then engineered a single "three‑in‑one" immunogen, 3Rs-NC, incorporating representative RBDs from each cluster into a single scaffold. Intranasal administration of 3Rs-NC with a flagellin-derived mucosal adjuvant (KFD), which possess excellent safety profile potential for clinical usage, elicited high titers of RBD-specific serum IgG and mucosal IgA, as well as potent neutralizing antibody responses in mice. Furthermore, KFD-adjuvanted 3Rs-NC conferred sustained protection in both the upper and lower respiratory tracts against SARS-CoV-2 Omicron BA.1 and SARS-like coronavirus WIV1. Additionally, 3Rs-NC immunization protected mice from lethal challenge of SARS-like coronavirus rRsSHC014S, with more efficient protection observed in female mice than male mice. This needle-free formulation offers a potent, broad-spectrum vaccine candidate against current and emerging ACE2-using sarbecoviruses, functioning as a modular "three-in-one" vaccine platform ready for rapid deployment in future coronavirus outbreaks.

Emergency vaccination programs face unique challenges requiring effective social mobilization strategies, yet comprehensive evaluations of mobilization effectiveness across population settings and temporal phases remain limited. This cross-sectional study conducted from September 2024 to January 2025 included 3048 healthcare workers and 3722 non-healthcare workers in China using multi-stage stratified sampling across eastern, central, and western regions. Participants retrospectively evaluated vaccination attitudes across three COVID-19 vaccination phases: pre-mobilization (2020), in-mobilization (2021-2022), and post-mobilization (2023). Healthcare workers showed increased vaccination willingness in-mobilization (53.5% to 56.2%, p < 0.05), while non-healthcare workers demonstrated sustained increases from 45.1% to 48.1% and 46.5% (p < 0.05). In-mobilization, collective responsibility remained the strongest predictor for healthcare workers (OR = 2.69, 95% CI: 1.85-3.89), while social identity emerged for non-healthcare workers (OR = 3.24, 95% CI: 2.10-4.99). These findings suggest that association between social mobilization and vaccination willingness depends on population-specific intervention strategies acknowledging distinct motivational frameworks and temporal dynamics in emergency vaccination contexts.