NPJ Vaccines最新文献

Zika virus (ZIKV) vaccine development has been hindered by the risk of antibody-dependent enhancement (ADE), particularly in dengue-endemic regions, where sub-neutralizing antibodies can exacerbate disease severity. T cell-based vaccines targeting non-structural (NS) antigens represent a safer alternative that bypasses this risk. Using immunocompetent BALB/c mice, we performed high-resolution in vivo mapping of ZIKV specific CD8⁺ and CD4⁺ T cell responses following ZIKV_PRVABC59 infection, identifying high avidity, polyfunctional memory T cells targeting conserved NS1, NS3 and NS4 proteins. Guided by these data, we developed DNA vaccines encoding full-length NS3 and NS4 and evaluated their efficacy against ZIKV infection alone or combined with a validated construct encoding secreted NS1 (p-tpaNS1). NS3 and NS4 vaccination elicited robust cytotoxic and IFN-γ producing T cell responses, while co-administration with p-tpaNS1 significantly reduced peak serum viremia achieving earlier and stronger viral control. Although NS1 alone conferred strong protection, the multi-antigen formulation demonstrated additive benefits. This T cell-based vaccine approach, targeting conserved NS proteins, offers a scalable, thermostable platform with potential for safe deployment in childbearing women and resource-limited regions. Given NS protein conservation and cross-reactivity across flaviviruses, it also provides a promising foundation for next-generation pan-flavivirus vaccine development, although this remains to be directly tested.

The detection of Japanese encephalitis virus (JEV) genotype V (GV) in humans in Korea in 2015 has raised concerns regarding its potential public health impact. Current JEV vaccines, based on genotype Ⅲ (GⅢ) strains, exhibit suboptimal neutralizing activity against JEV GV, thereby underscoring the need for genotype-specific vaccines. To address this, we developed the KNIH (GV) vaccine strain optimized for enhanced production efficiency. We evaluated its neutralizing activity and protective efficacy in a murine model. The currently available GⅢ-based vaccine (Beijing-1 strain) exhibited limited neutralizing efficacy against JEV GV. Conversely, the KNIH-based vaccine elicited strong neutralizing responses against JEV GV but exhibited reduced cross-neutralization against JEV GⅢ. In conclusion, the K15P38-KNIH strain represents a promising vaccine candidate for mitigating the risk associated with JEV GV reemergence. Future studies will focus on evaluating the efficacy of bivalent vaccination strategies against other circulating JEV genotypes in Korea.

The association between vaccine efficacy (VE) and force of infection (FoI) remains incompletely understood. Previous analyses have been primarily based on trial-level summary data-not accounting for the effect of time and constrained by the number of trials. Here, we leverage individual-level data from three phase 3 randomized, placebo-controlled COVID-19 vaccine trials-the COVE trial (Moderna, CoVPN3001), the AZD1222 trial (AstraZeneca, CoVPN3002), and the ENSEMBLE trial (Janssen/Johnson & Johnson, CoVPN3003)-and contemporaneous geographic-location-specific SARS-CoV-2 surveillance data from the start of the pandemic through November 14, 2021 (including the blinded follow-up periods of the trials) to conduct five cohort- and vaccine-specific analyses: COVE (U.S.), AZD1222 overall (U.S. + non-U.S.), AZD1222 U.S., ENSEMBLE overall (U.S. + non-U.S.), and ENSEMBLE U.S. In AZD1222 U.S., higher VE was associated with higher FoI (p = 0.01). In ENSEMBLE overall, lower VE was marginally associated with higher FoI (p = 0.21), further supported by a region-specific analysis. In COVE, AZD1222 overall, and ENSEMBLE U.S., no VE-FoI association was found. These findings highlighted a new perspective: the VE-FoI association appears complex, potentially influenced by FoI levels, with patterns suggesting an inverted U-shaped relationship, showing a positive association at low FoI levels and a negative association at high levels.

Subdominant B-cell immune responses to conserved epitopes are major obstacles in eliciting broadly neutralizing antibodies (bnAbs) against HIV-1 through natural infection or vaccination. Although the sequence conserved membrane proximal external region (MPER) of HIV-1 gp41 is partially occluded on the virion surface, epitope-focused immunogens could mitigate access limitations. Here, we found that a MPER/liposome vaccine delivered with a single CD4 T cell helper epitope results in a post-priming response hierarchy, eliciting low-affinity MPER-specific B cells. Heterologous boosting, however, promotes MPER-specific B cell clonal expansion and enhances plasma antibody functionality. This improvement is associated with increased B-cell affinity for MPER and reduced competition from B cells targeting the helper epitope. While helper peptide co-delivery increases the affinity of serum antibodies, the outcome of subsequent MPER antibody responses is shaped by the priming antigen. Our results offer insights into heterologous immunization strategies to potentiate subdominant B cell responses against frequently mutating viruses.

Tick-borne pathogens (TBPs) are expanding globally, with their impact on public health expected to rise due to climate change. Immunizing livestock offers a cost-effective alternative or adjunct to human vaccination. We evaluated two DNA vaccines, one targeting Crimean-Congo hemorrhagic fever virus (CCHFV) and another targeting Hyalomma tick infestation. The Hyalomma-targeting vaccine was designed to disrupt tick feeding by targeting midgut proteins essential for blood digestion and survival; however, its direct role in preventing CCHFV transmission remains unconfirmed. Here, we demonstrate that two doses of the CCHFV vaccine significantly reduced the risk of CCHFV infection in naturally exposed sheep. We further investigated whether the Hyalomma vaccine provided cross-protection against Wad Medani virus (WMV) and Rickettsia conorii, two TBPs endemic to Senegal. Sheep were vaccinated intramuscularly with two doses of DNA vaccine, followed by electroporation, and monitored under natural farming conditions in an endemic region of Senegal. Natural infection with CCHFV, WMV, and R. conorii was assessed longitudinally using pathogen-specific IgG seroconversion as the primary endpoint. The Hyalomma vaccine reduced WMV acquisition, whereas its effect on R. conorii was less pronounced. These findings underscore the potential of veterinary vaccines to mitigate multiple TBPs and reinforce their established role in reducing tick-borne diseases.

This retrospective cohort study evaluated the risk of maternal safety outcomes, including preterm birth, following prefusion F protein (RSVpreF) during pregnancy compared with an unvaccinated cohort using large-scale real-world data. Propensity score matching was performed to compare the risks of preterm delivery, hypertensive disorder of pregnancy (HDP), gestational diabetes (GDM), oligohydramnios, placental abruption, intrauterine growth restriction (IUGR), and intrauterine fetal death (IUFD) to calculate the odds ratio (OR). Following the propensity score matching, 11,265 and 11,265 pregnant women with and without RSVpreF vaccination were included, respectively. After matching, the ORs in the vaccinated group compared with the unvaccinated group were 0.98 [0.84-1.14], p = 0.789; 1.01 [0.96-1.08], p = 0.644; 0.98 [0.90-1.06], p = 0.570; 0.77 [0.63-0.95], p = 0.015; 0.99 [0.77-1.27], p = 0.949; 0.94 [0.86-1.03], p = 0.189; and 0.68 [0.38-1.22], p = 0.189 for pre-term delivery, HDP, GDM, oligohydramnios, placental abruption, IUGR, and IUFD, respectively. Maternal RSV vaccination did not increase the risk of selected maternal outcome events. However, further safety monitoring with larger sample size is required to detect rare events or small risk differences.

Norovirus can cause severe and potentially fatal gastroenteritis in infants. Mucosal vaccination of breastfeeding women may promote infant protection by enriching antibody responses in consumed breast milk. Here, we report a double-blind, placebo-controlled phase 1 trial in South Africa (SANCTR: DOH-27-072023-7893) to evaluate a single-dose oral bivalent vaccine against norovirus genotypes GI.1 and GII.4 in post-partum breastfeeding women. Safety and reactogenicity (primary outcome), breast milk and serum norovirus-specific antibodies (primary outcome), and passive transfer of antibodies to infants as measured in infant stool (exploratory outcome) were assessed. The vaccine was safe and well tolerated with similar reports of mild or moderate adverse events between placebo (n = 16) and vaccine groups (5 × 10¹⁰ or 1 × 10¹¹ IU/genotype, n = 30/group). Functional norovirus-specific breast milk and serum antibodies were significantly enriched in vaccinated groups. Norovirus-specific IgA in infant stool increased post-vaccination and positively correlated with breast milk IgA, indicating passive transfer. Thus, oral vaccination of breastfeeding women generates robust mucosal and systemic functional maternal antibodies. Our study presents a promising vaccination strategy to provide mucosal anti-norovirus immunity to infants.

Influenza causes substantial morbidity and mortality worldwide. This randomized, open-label, phase 1 trial (ClinicalTrials.gov, NCT05397223, date of registration: May 31, 2022) compared the immunogenicity of an mRNA-based quadrivalent influenza hemagglutinin (HA) vaccine (mRNA-1010) with a licensed comparator (FLUAD) in adults aged 18-75 years. We evaluated humoral and cellular immune responses using hemagglutination inhibition assays, flow cytometry-based memory B cell (MBC) profiling, and intracellular cytokine staining for T-cell characterization. Both vaccines elicited durable hemagglutination inhibition titers and increased HA-specific MBC responses across four vaccine strains. Compared with FLUAD, mRNA-1010 induced higher frequencies of classical and activated MBCs specific to the H3 HA included in the vaccine, while inducing similar MBC responses to the other strains. mRNA-1010 and FLUAD generated strong HA-specific CD4⁺ T-cell responses; a trend toward higher CD8⁺ T-cell responses was observed in mRNA-1010 recipients compared with FLUAD recipients for two of the four strains. These findings support the potential of the mRNA platform for seasonal influenza vaccination.

We preclinically characterize BNT162b3, a nucleoside-modified mRNA-based coronavirus disease 2019 (COVID-19) vaccine encoding a trimerized, cell surface-tethered severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike receptor-binding domain (RBD-foldon), formulated in lipid nanoparticles. Intramuscular immunization with BNT162b3 induced high antigen-specific antibody titers with early seroconversion kinetics in mice and rhesus macaques. One dose of BNT162b3 induced high neutralizing antibody titers against pseudoviruses harboring the spike of the SARS-CoV-2 Wuhan-Hu-1 strain and early variants of concern up to Delta, but lower titers against Omicron, the phylogenetically more distant variant. In mice, a second immunization boosted Omicron neutralizing antibody titers to levels comparable to those of other tested variants. The cellular immune response was T helper 1 cell driven. The cell surface-tethered RBD-foldon was more immunogenic than its soluble counterpart. This study demonstrated the suitability of BNT162b3 as COVID-19 vaccine and supported its evaluation in a phase I/II clinical trial (BNT162-04, NCT04537949).

The emergence and broad circulation of highly pathogenic avian influenza (HPAI) H5N1 virus in wild birds and its spillover into dairy cows with sustained transmission in this species pose a major risk to felines, which are highly susceptible and often succumb to the infection. Here, we developed a novel recombinant hemagglutinin H5-based vaccine and evaluated its safety, immunogenicity, and protective efficacy against HPAI H5N1 virus in domestic cats. Immunization of cats with H5-vaccine candidate elicited robust levels of neutralizing antibodies against H5N1 virus and protection against disease, mortality, and infection upon H5N1 virus challenge. The vaccine-elicited immunity significantly reduced virus shedding and viremia, limiting systemic spread and disease severity in immunized animals. Importantly, beyond protecting susceptible felids, vaccinating cats against the H5N1 virus could also reduce the risk of human exposure - underscoring the One Health impact of implementing such a vaccination strategy in feline populations.