NPJ Vaccines最新文献

Effective respiratory mucosal vaccines remain urgently needed to mitigate the rapid mutation and transmission of SARS-CoV-2. Here, we demonstrated that the spike protein (S-2P) of ancestral SARS-CoV-2 acted as a self-adjuvanted antigen for intranasal immunization, inducing robust systemic and mucosal immunity via integrin- and STING-dependent pathways. In contrast, H1N1 influenza hemagglutinin (HA) failed to generate measurable serum IgG or mucosal IgA following intranasal immunization. In mice, intranasal S-2P vaccination conferred complete protection against lethal ancestral SARS-CoV-2 challenge and partial cross-protection against heterologous Omicron variants, with both effects being IFN-γ- and CD8 + T cell-dependent. Co-administration of S-2P with the clinical immunomodulator lentinan (LNT) achieved complete protection against Omicron variants, mediated by IFN-γ but largely independent of CD8 + T cells. These findings establish S-2P + LNT as a safe, broad-spectrum mucosal vaccine candidate against emerging SARS-CoV-2 variants and reveal novel protection mechanisms beyond neutralizing antibodies and T cell immunity.

Recent advances in our understanding of immune tolerance, particularly the role of immune checkpoints in peripheral tolerance, have opened promising new avenues for therapeutic interventions in immune-related disorders. In this study, we developed a novel class of tolerogenic vaccines based on recombinant virus-like particles (tVLPs), engineered to display the immune checkpoint molecule CTLA-4 on their surface and incorporate specific antigens. These tVLPs promote the differentiation of tolerogenic dendritic cells (DCs) in vitro, characterized by a distinct functional phenotype and associated transcriptomic alterations. Furthermore, tVLPs inhibit DC activation and specifically modulate the antigen-specific T cell compartment, inducing a hyporesponsive state in effector T cells while promoting the activation of regulatory T cells (Tregs). The therapeutic efficacy of tVLPs was demonstrated in a murine model of food allergy, where five consecutive daily injections conferred protection against allergic symptoms and anaphylactic shock. Importantly, this effect was antigen-specific, long-lasting, and dependent on Tregs, as evidenced by the transfer of protection to naïve mice following adoptive transfer of Tregs from vaccinated animals. These findings establish tVLPs as a promising platform for the development of targeted immunotherapies for allergies and autoimmune diseases.

Coronaviruses remain a challenge due to the limited or incomplete protection provided by existing vaccines, highlighting the need for improved antigen-based designs that can reduce mortality, block transmission, and provide long-lasting, broad-spectrum protection. In this study, we adapted artificial antibody strategies to display receptor-binding domains (RBDs) from representative human coronaviruses, utilizing an engineered human IgG1 framework modified at the Fab and Fc domains to support diverse antigen presentation and enhanced immunopotentiation. The results indicate that bivalent, tetravalent, and multivalent RBD constructs developed within this framework confer broad-spectrum immune protection against severe acute respiratory syndrome coronavirus 2 and other pathogenic coronaviruses. Moreover, Fc-mediated antigen delivery, primarily engaging the neonatal Fcγ receptor, enhances mucosal, cellular, and sustained immune responses. This underscores the versatility and practical utility of the modified IgG1 framework, based on artificial antibody strategies, for developing broad-spectrum mucosal vaccine antigens, representing promising vaccine candidates targeting human coronaviruses.

The benefits of adjuvants for enhancing vaccine immunogenicity and efficacy are well known. Numerous novel adjuvants are at advanced levels of characterization, including some in clinical trials. However, understanding the relative benefits of each is hindered by a lack of comparative studies between adjuvants within the same study. To address this, we have performed a side-by-side comparison of 5 novel combination adjuvants (Alhydroxyquim-II, T-VANT, TRAC-478, IVAX-1 and IVAX-3) by formulating each with two approved seasonal influenza vaccines, Flublok® and Fluzone HD®, and assessing immunogenicity and efficacy in female and male C57Bl/6 mice. Although all tested adjuvants were immunogenic and protective against H1N1 challenge, T-VANT, TRAC-478 and IVAX-1 and -3 were associated with systemic inflammatory cytokines and robust Th1 responses, while Alhydroxyquim-II elicited lower levels of inflammatory cytokines and a Th2 response. Greater morbidity after challenge was also detected in males compared to females. Side-by-side comparisons of existing and novel adjuvants with the same antigen and model system will help inform rational adjuvant selection and guide vaccine development for influenza and other infectious diseases.

Foot-and-mouth disease (FMD) is a fast-spreading, economically devastating veterinary viral disease. While inactivated vaccines have contributed to FMD control worldwide, recent outbreaks in Europe and Asia highlight the need for new control strategies. Live-attenuated virus (LAV) vaccines provide strong and long-lasting protection. We previously demonstrated that deoptimization of various viral coding regions results in attenuated foot-and-mouth disease virus (FMDV). Here, an FMDV A24Cruzeiro LAV with codon deoptimized P2/P3 regions (A24-P2/P3Deopt) and markers differentiating infected from vaccinated animals (DIVA) was tested for safety/efficacy in cattle. Animals inoculated intradermolingually (IDL) with 10⁶ or 10⁷ pfu of A24-P2/P3Deopt for safety testing exhibited no clinical signs, viremia or viral shedding for 28 days post inoculation (DPI). To assess efficacy, cattle were subcutaneously inoculated either once with 10⁵ pfu or twice (0- and 14-dpi) with 10⁴, 10⁵ or 10⁶ pfu A24-P2/P3Deopt. No animal developed signs of disease post-inoculation. All prime-boost vaccinated animals developed strong neutralizing antibody responses that were protective against challenge with WT FMDV A24. Moreover, vaccinated sera showed strong cross-reactivity against several A strains and serotype Asia1. Our work demonstrates that codon deoptimization is a viable technology to derive novel LAV candidates that are safe, immunogenic and efficacious against FMD in cattle.

The African Swine Fever Virus (ASFV) poses a major threat to global livestock production by infecting both domestic and wild pigs, causing significant economic loss. Despite promising protective results observed with live attenuated viruses, the safety concern blocked its extensive application. In this study, we developed a novel vaccine combining two recombinant vaccinia viruses-rTTV-D-A and rTTV-K-J-that together express eight ASFV genes, including EP402R (CD2v), B646L (p72), B602L (pB602L), D117L (p17), H240R (pH240R), B438L (p49), E183L (p54), CP204L (p30), and a synthetic T antigen composed of conserved T cell epitopes from multiple ASFV proteins, aiming to induce both humoral and T-cell immune responses against different viral antigens. After demonstrating that this vaccine induced antigen-specific humoral and cellular responses in both mice and swine, its protective efficacy in swine was examined using a lethal challenge model. The vaccinated pigs showed a promising protection against the lethal challenge of a virulent genotype II ASFV strain (100 HAD₅₀/pig), with 4 out of 6 surviving, while all control animals succumbed from 9 to 15 days post challenge. Importantly, the protection was further evidenced by the recovery to normal temperature and no ASFV infection-related clinical signs or virus shedding in surviving pigs over a 21-day observation period. Our results support the potential of rTTV-D-A and rTTV-K-J as a novel multi-immunogen vaccinia-vectored ASFV vaccine. Further studies are warranted to explore and improve its use as a standalone vaccine or in combination with other vaccine platforms to achieve broad and effective protection against ASFV.

Currently used influenza vaccines primarily induce antibody responses against hemagglutinin (HA). Neuraminidase (NA) has been proposed as a complementary antigen to improve and potentially expand the breadth of influenza vaccine protection. Here, we assessed the immunogenicity and protective potential of adjuvanted recombinant protein- and mRNA-LNP-based octavalent influenza vaccine formulations in naïve mice. The vaccine candidates contained HA and NA derived from the viruses recommended for the 2018-2019 Northern Hemisphere quadrivalent influenza vaccine. Both adjuvanted recombinant protein and mRNA-LNP formats fully protected mice against challenge with homologous H1N1, influenza B, and HxN2 viruses. However, the octavalent mRNA-LNP vaccine elicited higher serum IgG titers against both HA and NA compared with the adjuvanted octavalent recombinant protein vaccine in this animal model. Furthermore, the octavalent mRNA-LNP vaccine also protected mice against challenge with the historical H3N2 virus strains X31, X47, and X79. This protection correlated with the presence of HA cross-reactive serum antibodies and was confirmed by passive transfer of immune serum into unvaccinated mice.

Therapeutic cancer vaccines (TCVs) remain limited in their capacity to elicit robust CD8⁺ cytolytic T lymphocyte responses. An effective cancer vaccine adjuvant should promote expansion of antigen-specific T cells through cross-presentation by type 1 conventional dendritic cells (cDC1s). For anti-PD-1 immune checkpoint inhibitor therapy, being frequently combined with cancer vaccines, requires an expanded pool of precursor-exhausted CD8⁺ T (Tpex) cells. Here, we report Flt3L-FlaB (FB), a hybrid adjuvant that integrates FMS-like tyrosine kinase 3 ligand (Flt3L) with the TLR5 agonist flagellin B (FlaB). FB significantly expanded and activated cDC1s, accompanied by increased CD8⁺ T cells with stem-like memory (Tscm) and Tpex phenotypes in tumors and draining lymph nodes. FB-adjuvanted TCVs, combined with anti-PD-1 therapy, achieved potentiated tumor suppression and provided durable protection against metastasis and high-dose tumor rechallenge. These results establish FB as a potent TCV adjuvant with strong translational potential, particularly the combination with anti-PD-1 immune checkpoint inhibitors.

The respiratory syncytial virus (RSV) burden and cost-effectiveness of infant RSV immunisation was evaluated by comparing seven strategies in terms of costs and Quality-Adjusted Life Years (QALYs) from health care payer's perspective: no universal immunisation, year-round or seasonal maternal vaccination (MV), year-round or seasonal nirsevimab (NmAb) at birth, seasonal NmAb+catch-up for infants ≤ 6-month and a combined MV+NmAb with catch-up strategy. Seasonal NmAb+catch-up averted the most disease, while seasonal MV averted the least, but had the lowest incremental cost-effectiveness ratio (€11,276/QALY gained) at current list prices (MV €186, NmAb €778). Extensive trade-offs between NmAb and MV show at which cost per dose which strategy would be deemed cost-effective. At a willingness to pay of €35,000/QALY gained, seasonal NmAb + catch-up was preferred if NmAb < €210; otherwise, seasonal or year-round MV was preferred when MV < €220 or <€75, respectively. The combined strategy became preferred at low MV and NmAb costs. Besides price level, cost-effectiveness was most sensitive to RSV hospital burden.

Whilst COVID vaccines proved to be effective in preventing severe COVID disease, they failed to control the emergence of variant viruses and antibody responses waned quickly. We report the findings of a recombinant β-SARS-CoV-2 variant virus-like particle (VLP) vaccine composed of the viral spike (S), membrane (M) and envelope (E) proteins produced in Vero cell factories. The β-SARS-CoV-2 VLP vaccine formulated with Addavax or MF59 produced strong antibody and CD4 + T cell responses and was protective in mice against pulmonary infection with Beta, Delta and Omicron BA.5 variant viruses. Multiplex RBD-ACE2 binding inhibition assay was performed as a surrogate virus neutralisation test and revealed immune sera from immunised mice produced low-titre broad-inhibitory anti-RBD-ACE2 antibodies (sNAb) to Alpha, Delta, Beta, Gamma, Mu, Omicron BA.1, BA.2, BA.5 and XBB1.5. However, microneutralisation assays did not show the presence of sNAb. The β-SARS-CoV-2 VLP is strongly immunogenic producing broad antibody and T cell responses and is protective against infection with SARS-CoV-2 variant viruses.