NPJ Vaccines最新文献

Cell-mediated immunity contributes to durable protection against severe COVID-19, particularly as antibody responses wane or viral variants partially evade neutralization. Here, we characterize SARS-CoV-2-specific T cell responses elicited by a next-generation COVID-19 vaccine, mRNA-1283, which encodes the receptor-binding and N-terminal domains of the spike protein, in a phase 1 randomized clinical trial (NCT04813796). COVID-19-naïve, healthy adults (18-55 years) received two doses of mRNA-1283 (10 µg, 30 µg, or 100 µg), two doses of mRNA-1273 (100 µg; full-length spike comparator), or a single-dose regimen of mRNA-1283. Using intracellular cytokine staining, we show that two-dose regimens of mRNA-1283 or mRNA-1273 induce Th1-biased, polyfunctional spike-specific CD4+ and CD8+ T cell responses that were maintained through Day 209. TCRβ sequencing demonstrated significant increases in the breadth and frequency of SARS-CoV-2-associated TCRs, which correlated with functional spike-specific T cell responses. Therefore, the low-dose (10 µg) regimen of the next-generation COVID-19 vaccine, mRNA-1283, induces polyfunctional and durable CD4+ and CD8+ T cell immunity comparable to the standard 100 µg mRNA-1273 vaccine, supporting a dose-sparing strategy without compromising long-term cellular protection against severe COVID-19.

A quarter of the world's population harbours latent Mycobacterium tuberculosis, yet current vaccines, including BCG, offer limited protection against latency or reactivation. Multi-stage or post-exposure vaccines targeting antigens expressed during these phases may mitigate TB burden. This review screens late-stage Mtb antigens, evaluating their antigenicity, immunogenicity, and protective efficacy, summarizes in silico analyses, and discusses challenges and examples of vaccine design, highlighting candidates for incorporation into next-generation TB vaccines.

To successfully complete an infection lifecycle, viruses have to avoid activating host antiviral and transcriptional responses to avoid disrupting cellular processes and cause premature host cell death. How the host transcriptional response to dengue virus (DENV) infection and its impact on pathogenesis, however, remain unclear. Herein, we examined a pair of DENV-2, where the wild-type strain (16681) elicited few host transcriptional responses following infection, in contrast to its clinically tested attenuated derivative (PDK53 strain). Site-directed mutagenesis studies revealed a single D29V substitution on the pre-membrane (prM) protein, present not in 16681 but in PDK53, that altered transcriptional response to infection. Mechanistically, prM D29V substitution impaired interaction of prM protein with host high mobility group box 1 (HMGB1) protein; wild-type prM-HMGB1 interaction prevented HMGB1 cytoplasmic-nuclear translocation to support transcriptional response to infection. Remarkably, HMGB1 knockdown not only reduced transcriptional response but also slowed virus replication rate, suggesting that HMGB1 also controlled the expression of host factors necessary for DENV replication. Indeed, introducing 29 V to prM increased virus replication rate and transcription of antiviral response genes in both wild-type DENV-3 as well as chimeric DENV-3/-2, the DENV-3 component of TAK-003. Our findings suggest exploiting this interaction to improve immunogenicity and potentially efficacy of current vaccines.

Achieving high vaccination coverage is a critical challenge during both crisis and routine outbreaks of infectious diseases. Previous studies have largely focused on single vaccination behaviors and vaccine-specific attitudes. A three-wave prospective longitudinal study was conducted to investigate the complex relationships between influenza vaccination behavior, COVID-19 vaccination behavior, and general vaccine hesitancy across different peri-pandemic phases. Uptake of pre-pandemic influenza vaccination was associated with uptake of full COVID-19 vaccination during the outbreak of COVID-19, which was further associated with uptake of influenza vaccination in the post-emergency phase when a strong resurgence of seasonal influenza occurred. The specific vaccination behaviors and negative general attitudes toward vaccination had reciprocal relationships across the peri-pandemic phases. Reduced negative attitudes toward vaccination mediated the spillover between influenza and COVID-19 vaccination behaviors. This suggests that general vaccine hesitancy could have a profound impact on shaping specific vaccination behaviors across target diseases and risk communication contexts. Two-tier promotion strategies can help effectively promote vaccinations and better prepare for future pandemics.

Dengue continues to pose a significant global health threat. However, the development of a safe and effective tetravalent vaccine is impeded by complex serotype-specific and cross-reactive immune responses. This review assesses licensed and advanced dengue vaccines, emphasizing serostatus-dependent safety, serotype imbalance, and the durability of protection. It also critically evaluates immunological correlates of protection and addresses remaining obstacles, such as vector-mediated immune modulation and orthoflavivirus cross-reactivity, to guide future dengue vaccine strategies.

Although CD4 T cells are critical orchestrators of protective immunity, vaccine strategies that optimize generation of these cells are not yet prioritized. In this manuscript, to mimic the typical human vaccine recipient using a mouse model, we evaluated the impact of previous influenza infection on the adaptive immune response elicited by the recombinant influenza vaccine Flublok, co-delivered with AddaVax, an MF59 mimetic or with a nanolipoparticle innate activator R-DOTAP. In the context of influenza B infection memory, a repolarization and dramatic change in the fate of the vaccine-elicited CD4 T cells was discovered. A rapidly evolving CD4 T cell response enriched in TNF-α and IFN-γ was observed, with the CD4 T cells also displaying increased expression of chemokine receptors associated with lung homing potential and ultimate accumulation in the lung tissue. Unexpectedly, similar shifts in the features of the H3-specific CD4 T cell and antibody response were also observed, drawn from the naïve repertoire. These results suggest that the microenvironment of the vaccine draining lymph node, developed in the context of immune memory, rather than infection-induced CD4 T cell imprinting, plays the decisive role in the functional phenotype, magnitude, and fate of vaccine-elicited CD4 T cells.

African swine fever (ASF) is a lethal disease of swine caused by the ASF virus (ASFV), for which no licensed vaccine is currently available in non-endemic countries. Here, replication-competent adenovirus-vectored ASFV multi-antigen constructs were shown to express ASFV antigens in primary swine cells. Pigs immunized with a cocktail of these constructs, with or without Quil-A adjuvant, tolerated the formulation well. The constructs elicited robust ASFV-specific IgG responses (p < 0.0001), which were boosted upon reimmunization (p < 0.05). Following challenge with the virulent ASFV Georgia 2007/1 strain using a natural transmission model, five of six pigs vaccinated without Quil-A survived, while all pigs receiving adjuvanted constructs succumbed to ASF. Survivors cleared the virus, exhibited only mild clinical signs, gained weight, and remained healthy for the remainder of the study. Histopathological analysis revealed an absence of ASFV-associated lesions in survivors, whereas severe lesions were observed in pigs vaccinated with adjuvanted constructs and in negative controls. Although neutralizing antibodies were undetectable, granzyme B-producing CD8α⁺ T cell responses were observed in survivors, indicating a likely correlation for cellular immunity in protection. These findings highlight the protective potential of ASFV antigen expression constructs and inform subunit vaccine design.

Enterovirus (EV) A71 causes endemic outbreaks of hand-foot-mouth disease (HFMD) and herpangina in young children, occasionally leading to severe complications and fatal outcomes. We evaluated EnVAX-A71, a bioreactor-produced, aluminum-adjuvanted inactivated EV-A71 (B4/E59) vaccine, in a randomized, double-blind, placebo-controlled phase 3 trial in Taiwan and Vietnam. A total of 4011 children aged 2-71 months were randomized 3:2 to vaccine or placebo; the primary endpoint was laboratory-confirmed EV-A71-associated HFMD/herpangina, evaluated from 28 days after dose two over a follow-up of 1 to 2 years (median, 490 days). In the primary analysis (n = 3733), one case occurred in vaccine recipients versus 70 in placebo (0.3 vs 39.2 per 1000 person-years), yielding 99.2% vaccine efficacy (95% CI: 94.3-99.9, p < 0.001). Seroprotection (neutralizing antibody titer ≥1:32) reached 98.7% at day 56 and remained ≥98% through one year. No vaccine-group hospitalizations occurred versus 19 in placebo (100% efficacy, 95% CI: 90.6-100.0). Safety profiles were comparable between groups. These findings support EnVAX-A71 for endemic EV-A71 control (ClinicalTrials.gov NCT05099029).

This study, grounded in the key stakeholders' perspectives, highlights the critical and immediate need for the development of a new iNTS vaccine. An online survey was conducted among government officials and healthcare providers across eight African countries: Burkina Faso, the Democratic Republic of Congo, Ethiopia, Ghana, Kenya, Malawi, Mozambique, and Nigeria. The framework was built on Spring Boot and Java 8, enabling access via personal computers or mobile phones. A total of 74 out of 84 participants completed the survey. Over 50% indicated that iNTS is both a prevalent and serious disease in their respective countries. The majority (n = 70, 94.6%) identified antibiotics as the most effective treatment for iNTS disease, while 55 (67.6%) participants chose vaccination as the preferred preventive option. Respondents ranked the iNTS vaccine third. Notably, 75.7% (n = 56) emphasized the urgent need for an iNTS vaccine. Barriers to vaccine introduction were identified as insufficient funding (n = 61, 81.4%), limited awareness (n = 49, 79.7%), and challenges related to community acceptance (n = 49, 79.7%). The stakeholders' perspectives highlight an urgent need for iNTS vaccine development. Accelerated and focused efforts are essential to address the reported pressing challenges and to pursue innovative and promising pathways for advancing iNTS vaccine development.