NPJ Vaccines最新文献

Streptococcus agalactiae is a major pathogen threatening global tilapia aquaculture, causing severe economic losses due to high mortality. The rise of antimicrobial resistance necessitates the development of effective vaccines for streptococcosis control. Here, we generated an auxotrophic mutant through the targeted deletion of the aroA gene, which encodes a key enzyme in aromatic amino acid biosynthesis. The aroA mutant (ΔaroA) exhibited reduced intracellular survival within macrophages, a phenotype that was not restored by supplementation with exogenous aromatic amino acids under our experimental conditions. These findings suggest that aroA contributes to intracellular survival through mechanisms extending beyond its role in aromatic amino acid biosynthesis. In zebrafish, Nile tilapia and mouse models, ΔaroA demonstrated stable attenuation, reduced endothelial cell damage, and mitigated blood-brain barrier disruption and neuroinflammation, confirming its safety. The ΔaroA strain provided dose-dependent protection against lethal S. agalactiae challenges in both tilapia and mice, with 100% protection in tilapia conferred at a dose of 10⁶ CFU following intraperitoneal administration. This study represents the first investigation into the role of aroA in S. agalactiae pathogenicity, providing valuable insights into the mechanisms of micronutrient utilization during bacterial pathogenesis. Also, our findings strongly support auxotrophic mutation as a promising attenuation strategy for vaccine development against streptococcosis in aquatic species.

Benefit-risk assessment (BRA) plays a vital role in the development and approval of drugs and biologics, including vaccines. The U.S. Food and Drug Administration recently published the final guidance "Benefit-Risk Assessment for New Drugs and Biological Products", which presents a structured framework for evaluating the benefit-risk (BR) of drugs and biological products and encourages the use of quantitative BR analysis (qBRA) to support complex decision-making. Unique challenges arise when assessing the BR of prophylactic vaccines, including the extrapolation of clinical trial data to real-world outcomes. To address these challenges, qBRA has been used to assist in some cases of decision-making related to vaccines. This article explores key steps and considerations for the qBRA of vaccines within the FDA BR framework. We explore the processes of "Framing the Research Question and Scope," "Identifying Key Benefit and Risk Endpoints," "Selecting the Quantitative Approach and Characterization of Uncertainties," "Gathering Data and Establishing qBRA Model Assumptions," and "Interpreting and Communicating the BRA Results," highlighting major considerations for each step. By carefully considering these processes and their challenges, we aim to help develop qBRAs that effectively inform decisions, ensuring that the benefits of authorized and licensed vaccines outweigh their risks.

The role of T-cell-mediated immune responses is recognized as pivotal in achieving functional cure in chronic hepatitis B (CHB) patients. We aimed to assess safety and T-cell responses induced by JNJ-6430535 (JNJ-0535); a hepatitis B virus (HBV)-specific therapeutic DNA vaccine administered via electroporation-mediated intramuscular injection. JNJ-0535 comprises 2 plasmids, encoding HBV core and polymerase (pol) proteins, respectively. We describe the safety, tolerability, and immunogenicity results of JNJ-0535 from an open-label, single arm phase 1 study in healthy volunteers (HVs) (64300535HPB1003, NTC04736147) and a randomized, placebo controlled phase 1 study in CHB patients (64300535HPB1001, NTC03463369). HBV-specific T-cell responses were evaluated using enzyme-linked immunospot (ELISpot) and intracellular cytokine staining (ICS). We performed baseline single-cell RNA sequencing (scRNA-seq) to explore immune correlates associated with vaccine response in HVs, and baseline serum proteomics (Olink Explore^® 3072) to explore differences in soluble immune markers between responders and non-responders in both HVs and CHB patients. JNJ-0535 was safe and well tolerated in both HVs and CHB patients. Compared to CHB patients, HVs showed a higher proportion of participants with vaccine-induced HBV-specific T-cell responses (92% versus 50%), a greater increase from baseline (24× [interquartile range=40×;9×] versus 4.8× [interquartile range=5×;6×]) and a broader response in terms of number of antigens. Serum proteomics revealed few differential circulating host biomarkers between CHB and HVs, but these could not be linked to differences in immunogenicity. In addition, whole-blood scRNA-seq was performed in HVs to explore differences between participants with a strong vaccine response and those with low or no response. Our research showed a decrease in vaccine-induced responses in CHB patients compared to HVs and may provide preliminary insights into immune-related biomarkers that could influence vaccine immunogenicity but require further confirmation in future larger studies. trial numbers: 64300535HPB1001 (NCT03463369) First posted: 18. April 2018; ULR: https://clinicaltrials.gov/study/NCT03463369?term=JNJ-64300535&rank=2 and 64300535HPB1003 (NCT04736147) First posted: 03. Feb. 2021; URL: https://clinicaltrials.gov/study/NCT04736147?term=JNJ-64300535&rank=1.

The approved, live-attenuated tetravalent dengue vaccine TAK-003 has undergone extensive preclinical and clinical assessment. This review provides an overview of the rationale for some key decisions made during TAK-003 development. These include decisions around vaccine composition, assessment of factors that may be associated with the safety of live-attenuated viral vaccines, dosing schedule, immunogenicity assessments, and design of the pivotal phase 3 efficacy study.

mRNA-lipid nanoparticle (LNP) vaccines induce robust adaptive immune responses and have proven highly effective against SARS-CoV-2. However, their long-term effectiveness is limited by waning humoral responses, which decline substantially within the first six months post-boost vaccination. DNA-LNPs are being investigated as an alternative vaccine platform, offering prolonged antigen expression and robust immunity. Here, we compare DNA- and mRNA-LNP vaccines encoding CD40L-adjuvanted SARS-CoV-2 XBB.1.5 Spike (S_XBB.1.5-CD40L) in a long-term in vivo challenge model. Both nucleic acid vaccines induced strong neutralizing antibody responses and conferred equivalent protection in Syrian hamsters challenged three weeks post-boost. Notably, DNA-LNP vaccination maintained high binding and neutralizing antibody titers six months post-boost, whereas mRNA-LNPs exhibited a marked decline. Correspondingly, while S_XBB.1.5-CD40L DNA-LNP vaccination completely protected from weight loss, viral replication, and lung pathology at this late timepoint, S_XBB.1.5-CD40L mRNA-LNP vaccination conferred minimal protection. These findings demonstrate that DNA-LNPs can sustain durable immunity, highlighting their potential as a next-generation vaccine platform that could reduce the need for frequent boosters.

Reducing the latent HIV-1 reservoir is essential to achieving a functional cure, and therapeutic vaccination is a promising strategy. While most approaches emphasize cytotoxic CD8⁺ T-cell responses, the role of antibodies-particularly Fc-mediated effector functions-remains incompletely defined. We evaluated the immunogenicity and functional antibody responses induced by Ad26- and MVA-based HIV-1 mosaic vaccines in SHIV-infected rhesus macaques and ART-suppressed people with HIV. In nonhuman primates, vaccination significantly increased Env-specific antibody titers, Fcγ receptor binding, and Fc-dependent functions, including cellular phagocytosis, complement deposition, and NK cell activation. Responses peaked following MVA boosting and, although they declined over time, remained elevated compared with unvaccinated controls. Humoral responses did not predict viral rebound during analytic treatment interruption but correlated inversely with post-ART viral setpoints, suggesting a role in viral control. In a parallel human study, therapeutic vaccination similarly elicited functional antibody responses, with the strongest effects observed following Ad26 mosaic vaccination combined with a gp140 protein boost, whereas Ad26 and MVA alone induced more modest responses. Ad26-based HIV vaccines, especially with protein boosting, elicit robust, multifunctional antibody responses; although human virologic outcomes remain untested, these findings support exploring Fc-mediated humoral immunity for viral control and cure strategies.

Individuals exhibit considerable heterogeneity in vaccine-induced antibody responses, yet commonly used binary classifications may overlook intermediate patterns. More nuanced grouping could better capture inter-individual differences. Here, we analyzed longitudinal neutralizing antibody (NAb) trajectories in 73 adults after inactivated SARS-CoV-2 vaccination. Unsupervised analysis identified three phenotypes: Low-Delayed Responders (LR), with a modest, delayed NAb rise to day 30; Rapid-Stabilizing Responders (RS), peaking at day 7 and plateauing thereafter; and Continuous Increase Responders (CI), exhibiting sustained increases. Between days 0 and 7, these groups diverged in immune activation: LR showed limited pathway activation or cell shifts; RS exhibited early innate activation with reduced dendritic cells; CI mounted innate and adaptive responses with increased naive B cells. These differences culminated at day 7, when CI exhibited enhanced antigen presentation and Th1-related pathways, accompanied by higher IFN-γ and IL-2 T cell responses. CI also showed post-transcriptional regulation of innate signaling, including HLA-F/H splicing, 3'UTR shortening in IKBKE and HRAS, and biased IGHV4-59-IGHJ4 usage. Finally, we developed a baseline gene model accurately predicting LR individuals. Our work refines responder classification and provides molecular insights into antibody heterogeneity, laying groundwork for early stratification and personalized vaccination.