NPJ Vaccines最新文献

Evidence regarding the high-dose (HD) vaccine's relative vaccine effectiveness (rVE) and absolute benefit in reducing influenza-related hospitalizations compared to the standard-dose (SD) vaccine is warranted. We estimated the adjusted rVE and the number needed to vaccinate (NNV) of the HD vaccine compared to the SD vaccine among Clalit Health Services members aged ≥65 years. Among 418,603 and 393,125 members vaccinated in the 2022-2023 and 2023-2024 influenza seasons, the adjusted rVE was 27% (95% CI: -12% to 61%) for 2022-2023 and 7% (95% CI: -36% to 42%) for 2023-2024, with NNV to prevent one hospitalization event being 2262 (95% CI: 1004 to ∞) and 7662 (95% CI: 1293 to ∞), respectively. Even among the highest-risk subgroup, the NNV was 1289 (95% CI: 571 to ∞) for 2022-2023 and 4719 (95% CI: 797 to ∞) for 2023-2024. The HD vaccine exhibited a limited incremental benefit, even for individuals at the highest risk.

Influenza B viruses pose a significant threat to global public health, leading to severe respiratory infections in humans and, in some cases, death. During the last 50 years, influenza B viruses of two antigenically distinct lineages (termed 'Victoria' and 'Yamagata') have circulated in humans, necessitating two different influenza B vaccine strains. In this study, we devised a novel vaccine strategy involving reciprocal amino acid substitutions at sites where Victoria- and Yamagata-lineage viruses differ, leading to the generation of 'hybrid' vaccine viruses with the potential to protect against both lineages. Based on antigenic characterization, we selected two candidates and assessed their protective efficacy in a ferret model. Notably, both recombinant HA proteins conferred enhanced protection against heterologous challenges compared to their respective wild-type antigens. These findings show the potential of our novel strategy to develop cross-lineage protective influenza B virus vaccines.

Hepatocellular carcinoma (HCC) is a highly prevalent malignancy with limited treatment efficacy despite advances in immune checkpoint blockade (ICB) therapy. The inherently weak immune responses in HCC necessitate novel strategies to improve anti-tumor immunity and synergize with ICB therapy. Kinesin family member 20A (KIF20A) is a tumor-associated antigen (TAA) overexpressed in HCC, and it could be a promising target for vaccine development. This study confirmed KIF20A as a promising immunogenic antigen through transcriptomic mRNA sequencing analysis in the context of HCC. Therefore, we developed a thermosensitive hydrogel vaccine formulation (K/R^Lip@Gel) to optimize antigen delivery while enabling sustained in vivo release. The vaccine efficiently elicited robust immune responses by activating DCs and T cells. Moreover, K/R^Lip@Gel improved the therapeutic efficacy of PD-L1 blockade in subcutaneous and orthotopic cell-derived xenograft (CDX) models, along with immune-humanized patient-derived xenograft (PDX) HCC models, which was evidenced by improved maturation of DCs and elevated infiltration and activation of CD8⁺ T cells. These findings highlight the potential of KIF20A-based vaccines to synergistically improve ICB therapy outcomes in HCC, providing a promising approach for enhancing anti-tumor immunity and improving clinical outcomes.

DS-Cav1, SC-TM, and DS2 are distinct designer pre-fusion F proteins (pre-F) of respiratory syncytial virus (RSV) developed for vaccines. However, their immunogenicity has not been directly compared. In this study, we generated three recombinant vaccines using the chimpanzee adenovirus vector AdC68 to express DS-Cav1, SC-TM, and DS2. All three vaccines elicited robust serum binding and neutralizing antibodies following intramuscular priming and boosting. DS2 induced the strongest antibody responses, followed by SC-TM and DS-Cav1. DS2 also provided strong protection against live RSV challenge. Monoclonal antibodies (mAbs) isolated from long-lived antibody-secreting cells (ASCs) in the bone marrow six months post-immunization with AdC68-DS2 predominantly targeted site Ø as well as site II. One neutralizing antibody against site II, mAb60, conferred strong protection against live RSV infection in mice. These findings highlight the strong ability of the DS2 design in eliciting long-lived antibody responses and guide the development of next-generation RSV vaccines.

Pneumococcal infections are a serious health issue associated with increased morbidity and mortality. This systematic review evaluated the efficacy, effectiveness, immunogenicity, and safety of the pneumococcal conjugate vaccine (PCV)15 compared to other pneumococcal vaccines or no vaccination in children and adults. We identified 20 randomized controlled trials (RCTs). A meta-analysis of six RCTs in infants showed that PCV15 was non-inferior compared with PCV13 for 12 shared serotypes. Based on a meta-analysis of seven RCTs in adults, PCV15 was non-inferior to PCV13 for 13 shared serotypes. For the unique PCV15 serotypes, 22F and 33F, immune responses were higher in infants and adults vaccinated with PCV15 compared to those receiving PCV13. Regarding safety, meta-analyses indicated comparable risks of adverse events between PCV15 and PCV13 in infants. Adults receiving PCV15 had a slightly higher risk of adverse events, though serious events were similar between groups.

We previously reported that mice immunized twice with a lipid nanoparticle vaccine comprising four monkeypox viral mRNAs raised neutralizing antibodies and antigen-specific T cells and were protected against a lethal intranasal challenge with vaccinia virus (VACV). Here we demonstrated that the mRNA vaccine also protects mice against intranasal and intraperitoneal infections with monkeypox virus and bioluminescence imaging showed that vaccination greatly reduces or prevents VACV replication and spread from intranasal, rectal, and dermal inoculation sites. A single vaccination provided considerable protection that was enhanced by boosting for at least 4 months. Protection was related to the amount of mRNA inoculated, which correlated with neutralizing antibody levels. Furthermore, immunocompetent and immunodeficient mice lacking mature B and T cells that received serum from mRNA-immunized macaques before or after VACV challenge were protected. These findings provide insights into the mechanism and extent of mRNA vaccine-induced protection of orthopoxviruses and support clinical testing.

Filoviruses, including Ebola, Marburg, Sudan, and Taï Forest viruses, are zoonotic pathogens that can cause severe viral hemorrhagic fever and death. Developing vaccines that provide durable, broad immunity against multiple filoviruses is a high global health priority. In this Phase 1 trial, we enrolled 60 healthy U.S. adults and evaluated the safety, reactogenicity and immunogenicity of homologous and heterologous MVA-BN®-Filo and Ad26.ZEBOV prime-boost schedules followed in select arms by MVA-BN®-Filo boost at 1 year (NCT02891980). We found that all vaccine regimens had acceptable safety and reactogenicity. The heterologous prime-boost strategy elicited superior Ebola binding and neutralizing antibody, antibody-dependent cellular cytotoxicity (ADCC), and cellular responses compared to homologous prime-boost. The MVA-BN®-Filo boost administered at 1 year resulted in robust humoral and cellular responses that persisted through 6-month follow-up. Overall, our data demonstrated that a heterologous Ad26.ZEBOV/MVA-BN®-Filo prime-boost was safe and immunogenic and established immunologic memory primed to respond after re-exposure. Clinicaltrials.gov, NCT02891980, registered September 1, 2016.

The intestinal microbiota plays a critical role in host immunity and might contribute to the significant variation between individuals' vaccine responses. A systematic search was done using MEDLINE and Embase to identify original human studies investigating the association between intestinal microbiota composition and humoral and cellular vaccine responses. In total, 30 publications (26 studies, 14 in infants, 12 in adults), were included. Of these, 26 publications found an association between intestinal microbiota composition and vaccine responses. A beneficial effect of Actynomycetota (particularly Bifidobacterium) and a detrimental effect of Pseudomonadota (particularly Gammaproteobacteria) were observed across studies. Study designs were highly heterogenous, with variation in vaccine type, outcome measure, timing of stool analysis and analysis methods. Overall, studies support the concept that the composition of the intestinal microbiota influences vaccine responses. Further adequately powered studies are needed to confirm this association and inform potential microbiota-targeted interventions to optimise vaccine responses.

Protein subunit vaccines, lacking pathogen-associated molecular patterns that trigger immune responses, rely on adjuvants to induce robust immune responses against the target pathogen. Thus, selection of adjuvants plays a crucial role in the design of protein subunit vaccines. Recently, there has been growing interest in utilizing cGAS-STING agonists as vaccine adjuvants. In this study, we investigated the adjuvant effect of manganese (Mn), a cGAS-STING agonist, on the tuberculosis subunit vaccine Bfrb-GrpE (BG) in a mouse model. Initially, mice were administered with BG-Mn(J), and its immunogenicity and protective efficacy were assessed six weeks after the final immunization. The results showed that Mn(J) enhanced both the cellular and humoral immune responses to the BG vaccine and conferred effective protection against M. tuberculosis H37Ra infection in mice, leading to a significant reduction of 2.0 ± 0.17 Log₁₀ CFU in spleens and 1.3 ± 0.17 Log₁₀ CFU in lungs compared to the PBS control group. Additionally, we assessed the BG-Mn(J) vaccine in a surrogate model of tuberculosis in rabbit skin model. The vaccination with BG-Mn(J) also provided effective protection in the rabbit model, as indicated by a decreased bacterial load at the infection site, minimal pathological damage, and accelerated healing. These findings suggest that Mn(J) holds promise as an adjuvant for tuberculosis vaccines, underscoring its potential to enhance vaccine efficacy and offer protection against tuberculosis infection.

In the aim of designing and developing a novel saponin-based adjuvant system, we combined the QS21 saponin with low microgram amounts of the fully synthetic TLR4 agonist, E6020, in cholesterol-containing liposomes. The resulting adjuvant system, termed SPA14, appeared as a long-term stable and homogeneous suspension of mostly unilamellar and a few multilamellar vesicles, with an average hydrodynamic diameter of 93 nm, when formulated in citrate buffer at pH 6.0-6.5. When compared in an in vitro human innate immunity construct to AS01B, the QS21/MPL® liposomal adjuvant system of GSK, and with QS21-Liposomes used as benchmarks, SPA14 displayed the strongest immunostimulatory potential based on antigen-presenting cell (APC) activation and cytokine secretion, which was essentially driven by the highly active E6020 agonist in this assay. When tested as an adjuvant in vivo with human cytomegalovirus glycoprotein B (gB) and pentamer complex (PC) as test antigens, SPA14 was generally well tolerated and as active as AS01B for the induction of long-lasting CMV-neutralizing antibodies in mice and non-human primates (NHPs). Both adjuvants promoted the induction of Th-1 responses based on IgG2c production in mice and IFN-γ production in mice and NHPs, but in mice, a higher level of Th-2 cytokines (IL-5) and higher IgG1 over IgG2c secreting cells ratios were obtained with SPA14 indicating that the adjuvant profile of SPA14 could be less Th-1 biased than that of AS01B. From a developability standpoint, SPA14 could be manufactured by a simple and scalable ethanol injection method, owing to the high solubility in ethanol of all its lipidic components, including E6020. Furthermore, E6020 is a single molecule, well-characterized fully synthetic TLR4 agonist constructed in eight synthetic steps from entirely crystalline starting materials and intermediates via an optimized high-yield synthetic route. Overall, our data suggest that SPA14 is a viable, easy-to-manufacture, potent novel adjuvant system that could be broadly applicable as a ready-to-mix adjuvant in the form of a long-term stable liquid formulation.