NPJ Vaccines最新文献

Antibiotics are essential for treating bacterial infections, but the growing problem of antimicrobial resistance (AMR) undermines their effectiveness. Vaccines targeting multidrug-resistant (MDR) bacteria are urgently needed. Here, we developed next-generation mRNA vaccines encoding two novel target antigens: phosphate-specific transport protein (PstS) and DUF3748 domain-containing protein (YidR). The resulting fusion proteins exhibited high expression and secretion in vitro and provided strong protective efficacy in mice against Klebsiella pneumoniae (K. pneumoniae) and enterohemorrhagic Escherichia coli (EHEC), significantly reducing bacterial loads and organ damage. Moreover, the K. pneumoniae-based mRNA vaccine (KV3), encoding the PstS-YidR fusion protein, elicited notable cross-protection against four Enterobacteriaceae species, including K. pneumoniae, EHEC, Salmonella enterica (S. enterica), and Shigella flexneri (S. flexneri). In conclusion, this study demonstrates the potential of mRNA vaccines employing fusion protein containing a novel target antigen to combat MDR Enterobacteriaceae with significant cross-protective effects.

Mycoplasma synoviae (MS) is a significant pathogen mentioned by the World Organisation for Animal Health (WOAH) and has caused substantial economic losses to the global poultry industry. The prevention and control strategies are primarily based on flock purification, antibiotic treatment, and vaccination. Given the high cost and extended timeline of flock purification, along with the growing antibiotic resistance, vaccination remains the most effective strategy for preventing MS transmission. This study employed pangenome analysis combined with reverse vaccinology (RV) to identify protective antigens against MS. At last, three proteins namely VY320 (elongation factor P), VY430 (50S ribosomal protein L6), and VY930 (YbhB/YbcL family Raf kinase inhibitor-like protein), were selected to assess their potential as candidate subunit vaccines. Furthermore, a lesion scoring method using a foot pad challenge model was established to evaluate the protective efficacy of the MS vaccine. The results indicated that the VY930 protein is an effective antigen and can activate strong humoral and cellular immunity responses in immunized flocks, superior to the inactivated vaccine. The screening strategy, evaluation methods, and related findings of this study may provide valuable insights into the prevention and control of MS.

Wild poliovirus remains endemic in Pakistan and Afghanistan despite global progress. We quantified immunity to poliovirus types 1-3 among children aged 6-23 months in 44 high-risk districts (2022-2023) using a cross-sectional serosurvey with probability proportional to size (PPS) cluster sampling. We enrolled 20,680 children (10,112 aged 6-11 months; 10,568 aged 12-23 months). Seroprevalence among 6-11-month-olds was 94.5% (type 1), 44.6% (type 2), and 88.0% (type 3); among 12-23-month-olds, it was 95.9%, 53.8%, and 91.2%, respectively. Type 1 seropositivity was highest across provinces; type 3 exceeded 90% except in Balochistan and KP; type 2 was lowest everywhere. Younger children have lower immunity. In multivariable models, residence in Balochistan predicted reduced seroprotection (AOR 0.178, 95% CI 0.066-0.484); older age (AOR 1.356, 1.161-1.583), full immunization (AOR 2.004, 1.643-2.444); and receiving <4 oral poliovirus vaccine (OPV) doses showed higher odds (AOR 1.25, 1.021-1.529) of seroprotection. Wealth showed a non-linear association. Gaps in types 2-3 warrant stronger routine immunization, expanded inactivated polio vaccine (IPV), and tailored supplementary immunization activities (SIAs).

SARS-CoV-2 immunity and innate immune training may influence influenza vaccine immunogenicity. We investigated this in India. Adult volunteers with hybrid SARS-CoV-2 immunity were administered Fluarix^TM Tetra (GlaxoSmithKlein) 2022/2023 NH Vaccine in 2022. Significant induction of hemagglutinin inhibition-specific antibodies and polyfunctional central memory CD4⁺ T-cells (TCM) were observed 1-week post-vaccination with variable induction of CD8⁺T-cell and innate effectors. Vaccination also expanded Flu-specific regulatory T-cells (Treg), which negatively correlated with CD4 responses, highlighting vaccine immunogenicity may be subject to Treg dampening. Fluarix^TM did not boost SARS-CoV-2 immunity. However, SARS-CoV-2-specific T-cell responses correlated positively with vaccine-induced T-cell responses. We evaluated trained immunity post-COVID-19 as a potential regulatory mechanism linking SARS-CoV-2 and heterologous vaccine immunogenicity. We observed, elevated frequencies of basal bacterial Lipopolysaccharide (LPS)-induced IL-6⁺IL1β⁺HLA-DR⁺CD14⁺CD16^- frequencies post-COVID-19 correlated positively with vaccine-induced Fluarix-specific CD4 T-cell frequencies. Our study highlights a potential positive role for COVID-19-driven immune imprinting on heterologous vaccine immunogenicity in a post-COVID-19 era.

Influenza virus infection poses a significant health risk to newborns, with this population experiencing higher hospitalization and mortality rates compared to older children. The heightened vulnerability of this age group results from a combination of an altered immune system and lack of a licensed vaccine for children under six months of age. mRNA-LNP vaccines have shown remarkable efficacy, including the capacity to induce antibodies in poorly responding populations. This makes them a promising candidate for addressing the unique immunological environment of newborns. Here, we leveraged the close immunological and physiological similarity of NHP to evaluate the efficacy of an influenza hemagglutinin mRNA-LNP vaccine in newborns. Our findings show the HA mRNA-LNP vaccine elicits robust, multi-functional antibody responses in newborn NHP that result in significantly reduced viral load and disease severity following challenge. These results highlight the potential of mRNA-based vaccines as a transformative approach to protect the vulnerable newborn population against influenza. Continued development and optimization of this platform could address the critical gap in influenza virus and other pathogen vaccine coverage for infants under six months of age.

Due to antigenic drift and shift, influenza A viruses may cause new future pandemics. Currently used seasonal influenza vaccines are of little use against novel viruses with pandemic potential. Genetic vaccines can be rapidly produced and could therefore mitigate pandemic outbreaks. Here, we present preclinical proof of protective efficacy of a DNA vaccine encoding a vaccine protein that targets influenza hemagglutinin (HA) to human leukocyte antigen class II (HLAII) molecules on antigen presenting cells (APC). Vaccination of mice raised robust levels of neutralizing antibodies, and protection against a lethal challenge with influenza H7N1 virus. In ferrets, we observed induction of neutralizing antibodies and T-cell responses after a single vaccination, with levels increasing after a second dose. Protection of vaccinated ferrets against a viral challenge with influenza H7N9 was dose dependent, with ferrets receiving the highest vaccine dose being completely protected from clinical disease. In sum, these results warrant progression to a human clinical Phase I trial.

Controlled human malaria infections after immunization via mosquito bites with radiation attenuated Plasmodium falciparum sporozoites are necessary tools to decipher immune signatures of malaria protection. The phenotype of circulating mononuclear innate cells and the PBMC response to in vitro stimulation unraveled correlates of protection from baseline immune response to sporozoite stimulation (IFN-ƴ secretion and HLA-DR^high expression) to vaccine-induced immune factors (IL-4 secretion and CD57^- γδ T cell frequency).

Influenza vaccination is central to reducing morbidity and mortality. However, vaccine-induced immune responses vary considerably across vaccine platforms. Hemagglutination inhibition (HAI) titers are widely used as correlates of protection, but do not fully capture the complexity of memory B-cell (MBC) responses. This study employed an integrated analysis of humoral and MBC responses elicited by three licensed influenza vaccines: inactivated Fluzone standard dose (FluZ), recombinant protein-based FluBlok (FluB), and live-attenuated intranasal FluMist (FluM). FluB-vaccinees had the most robust HAI and MBC responses, with increased frequencies of switched memory and IgG memory across all HA components (H1, H3, and IBV), along with increased IgA resting memory and IgG activated memory to H1 and H3, and IgG resting memory to H1 and IBV. FluZ-vaccinees had robust, but comparatively lower responses, including increased IgG memory to H1 and IBV, but reduced switched memory compared to FluB-vaccinees. FluM-vaccinees had the lowest HAI titers but increased unswitched memory and IgA memory to H1 and IBV, along with higher IgM memory to H3. Notably, FluM-vaccinees showed greater inter-correlation among multiple MBC subsets, particularly for H3. These findings uncover distinct platform-specific immune landscape and demonstrate that FluB induces superior MBC responses, providing a framework for designing next-generation vaccines.

Potent cellular immune responses are crucial for the development of effective vaccines against cancer and chronic infectious diseases. Here, we formulate Nexavant (NVT), a well-characterized TLR3 agonist, into lipid nanoparticles (LNPs) using either the ionizable lipid SM-102 or the cationic lipid DOTAP, and characterize their physicochemical properties and adjuvant potential. Both formulations achieve high encapsulation efficiency and enhance cellular uptake. In contrast to the stronger in vitro potency of DOTAP-based NVT/LNPs, SM-102-based NVT/LNPs (NVT/SM-LNPs) induce greater dendritic cell activation, cytokine production, and systemic T cell responses in vivo, likely due to more efficient delivery of NVT to the spleen. As an adjuvant for peptide vaccines, NVT/SM-LNP enhances antigen-specific CD4⁺ and CD8⁺ T cell responses and demonstrates potent therapeutic efficacy across subcutaneous, orthotopic, and metastatic TC-1 and B16-OVA tumor models, while also reducing viral titers in a chronic LCMV infection model. Compared to conventional adjuvants (poly(I:C), CpG, GM-CSF, IFA) and current mRNA vaccine platforms at clinically relevant doses, NVT/SM-LNP elicits stronger T cell immunity and enables effective neoantigen responses without requiring peptide-carrier conjugation. These findings establish NVT/SM-LNP as a potent adjuvant for T cell-targeted vaccines, with the lipid composition critically influencing immune targeting and efficacy, thereby guiding the design of next-generation vaccines.