NPJ Vaccines最新文献

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.

A novel vaccine modality is needed to generate both systemic and mucosal immunity in the respiratory tract, where pathogens are most likely to colonize and to initiate infection. Here, we demonstrated that intranasal immunization with probiotic Escherichia coli-derived membrane vesicles displaying serotype-14 pneumococcal capsule (CPS14⁺MVs) elicited potent IgG responses without adjuvant in mice, which were comparable and significantly superior to those of the injected CPS14⁺MVs and two licensed pneumococcal vaccines (conjugate and polysaccharide types), respectively. Notably, IgA class-switch recombination occurred only with intranasal CPS14⁺MVs immunization, resulting in robust secretory IgA (SIgA) production throughout a one-year-long-term study. Furthermore, the intranasal CPS14⁺MV vaccine induced both systemic and mucosal immunity regardless of mouse age at vaccination. Whereas opsonophagocytic activities were detected in sera of all immunization groups, only the intranasal CPS14⁺MV vaccine achieved dramatic pneumococcal clearance in the nasal cavity. Nevertheless, it failed to protect isogenic pIgR^-/- mice, which are genetically impaired for SIgA translocation, from colonization of the respiratory tract. In conclusion, the present study could offer a novel vaccination strategy using chimeric probiotic E. coli MVs to provide antibody-mediated protection against pneumococcal colonization and infection.

High-throughput sequencing (HTS) can detect known and novel adventitious viruses in biological materials that might be missed by the conventional in vitro and in vivo assays. We compared HTS with the conventional assays using the same sample preparation of CHO cell harvest spiked with human respiratory syncytial virus (RSV) and mammalian orthoreovirus (Reo1). The viruses were selected with the expectation that one would produce a positive result in each test. The study results indicated both RSV and Reo1 were detected by HTS and in vitro assays, albeit with inter-assay and intra-lab differences in sensitivity of virus detection, and only Reo1 was detected by the in vivo assays. The results support using HTS to replace the in vivo assays. Additionally, based on capabilities of HTS for non-targeted virus detection, it may supplement or replace the in vitro assays. The study further highlighted that the analytical sensitivity of HTS can be improved.

Concomitant administration of coronavirus disease (COVID-19) and influenza vaccination schedules has been widely adopted. However, long-term data on the immunological impact, particularly on variant-specific responses, remain limited. In this 10-month prospective study, 80 participants (40 per group) received either a concomitant bivalent COVID-19 mRNA booster and quadrivalent influenza vaccination (Group C) or separate vaccinations (Group S) at least 4 weeks apart. Immunogenicity was evaluated using an anti-S IgG electrochemiluminescence immunoassay, anti- receptor-binding domain (RBD) IgG enzyme-linked immunosorbent assay, focus reduction neutralisation test (FRNT), and hemagglutination-inhibition assay. Both Groups C and S elicited robust immune responses for up to 10 months with no immune interference, as antibody responses against wild-type (WT) and Omicron BA.5 remained comparable between the groups. Notably, neutralising antibody titre against Omicron BA.5 were higher in Group C at 1 month post-vaccination, with significantly higher neutralising potency (FRNT₅₀/anti-RBD IgG titer ratio) against Omicron BA.5 and a higher BA.5-to-WT ratio in FRNT. These findings may suggest alleviated immune imprinting, although this remains exploratory and requires further validation. For influenza, the overall antibody responses were comparable between the two groups. These findings support the feasibility of concomitant influenza and COVID-19 vaccination, without evidence of immune interference. Moreover, the enhanced variant-specific immune responses with concomitant administration suggest a potential immunological benefit, warranting future investigation.

Adjuvants play an important role in modulating antigen-specific immune responses. We conducted a comparative adjuvant immunogenicity study in Rhesus macaques using HIV-1 subtype B gp120 envelope protein, B.63521, formulated with aluminum hydroxide gel (AH), or a family of liposomal adjuvants known as Army Liposome Formulation (ALF). ALF comprises saturated phospholipids, cholesterol, and monophosphoryl lipid A. Inclusion of QS-21 or adsorption of the antigen to AH, followed by the addition of ALF, generates ALFQ and ALFA, while inclusion of both immunostimulants generates ALFQA. Priming with canarypox vector ALVAC, followed by boosting with ALVAC and gp120 formulated with each of the four adjuvants, resulted in ALFQ and ALFQA outperforming AH and ALFA vaccine formulations with a high frequency of antigen-specific plasma cells in the bone marrow, robust antibodies, and Env-specific polyfunctional CD8⁺ T cell responses. Transcriptomic analyses revealed upregulation of antiviral and innate immune pathways, thus highlighting ALFQ as a highly potent adjuvant.

Nipah virus (NiV) is a zoonotic pathogen that causes severe encephalitis and respiratory disease in humans and multiple mammalian species. However, no licensed vaccines or therapeutics are currently available against NiV infection. In this study, we developed three mRNA vaccine candidates using a lipid nanoparticle (LNP) delivery platform: mRNA-F-LNP, comprising mRNA encoding the fusion protein (F); mRNA-G-LNP, containing mRNA encoding the attachment glycoprotein (G); and mRNA-GF-LNP, in which mRNAs encoding both F and G proteins were co-encapsulated at a 1:1 molar ratio. All three mRNA-LNPs induced robust and sustained immune responses in both mice and Syrian hamsters. Sera from immunized Syrian hamster showed high levels of cross-neutralizing antibodies against both NiV-Malaysia (NiV-M) and NiV-Bangladesh (NiV-B) strains. Notably, all three mRNA-LNPs conferred complete protection against a lethal challenge with NiV-M in Syrian hamsters. These findings demonstrate that these mRNA-based vaccines are highly immunogenic and efficacious, highlighting their potential as promising candidates for NiV vaccine development.