NPJ Vaccines最新文献

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.

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.