NPJ Vaccines最新文献

Influenza remains a significant global public health concern. Live-attenuated influenza vaccines (LAIVs) are recognized as effective interventions for influenza prevention. Currently, two types of LAIVs are licensed for human use: one developed through cold-adapted viral gene mutation and the other through the deletion of the viral NS1 gene. However, the similarities and differences in these two LAIVs' efficacy, safety, and immune responses have not been thoroughly studied. This study constructed a gene-deficient live-attenuated vaccine strain, CA4-dNS1, and a gene locus-mutated attenuated vaccine strain, CA4-cold, to compare their in vivo and in vitro replication capacity, broad-spectrum protective efficacy, safety, and immunogenicity. The results showed that both LAIVs provide comparable broad-spectrum protection against lethal H1N1 and H5N1 influenza challenges in mice and induce similar humoral and mucosal immune responses. Notably, the CA4-cold vaccine strain induces superior influenza memory T-cell responses, while the CA4-dNS1 vaccine strain demonstrates greater safety. These findings underscore the importance of gene modification in LAIVs in striking a balance between their safety and efficacy. The NS1 gene-deficient CA4-dNS1 strain may offer a more advantageous approach for developing next-generation LAIVs and other intranasal influenza virus vectored vaccines due to enhanced safety.

Vaccination against human cytomegalovirus (HCMV) to protect transplant recipients and prevent congenital infection remains highest priority. Follow-up analyses of a vaccine directed against the fusion protein glycoprotein B (gB/MF59) identified a vaccine-specific response (AD-6) that correlated with protection. Subsequently, it was demonstrated that AD-6 antibodies are anti-viral by preventing cell-associated spread. Here we now demonstrate AD-6 antibodies limit HCMV reactivation - an event critical for pathogenesis via hematogenic spread in vivo. To better understand the AD-6 immunogen, we use structural homology to identify putative AD-6 regions in related herpesviruses and show, despite limited sequence similarity, they share key physico-chemical properties. Of note was that AD-6 mapped to a region under high molecular frustration within gB - arguing AD-6 antibodies inhibit gB function by targeting activity dependent on conserved conformational changes. Consistent with structural conformation being crucial, we observe that both rabbit and human HCMV AD-6 antibodies recognise other herpesvirus AD-6s and that AD-6 antibodies are potently antiviral against HSV-1. Thus, a combinatorial in silico, biochemical and immunological approach reveals conformational epitopes within AD-6 are critical components of the gB/MF59 vaccine, represent crucial conserved elements of AD-6 in gB structure and function which makes it an attractive target of multiple herpesviruses.

Taquet et al. evaluated the impact of AS01-adjuvanted vaccines on subsequent dementia diagnosis¹. The authors conclude: "No difference was observed between the two AS01-adjuvanted vaccines, suggesting that the AS01 adjuvant itself plays a direct role in lowering dementia risk". Although the study offers promising evidence, the inference regarding the role of AS01 adjuvant in dementia prevention is not convincingly supported by the presented data or other published literature².

Infants born to HBsAg/HBeAg-positive mothers remain risk for hepatitis B virus vaccine breakthrough infection (VBI). In this multicenter prospective cohort study, we assessed whether increased neonatal vaccine dose (20 μg vs. 10 μg) or booster immunization could reduce VBI among these children. Infants were vaccinated after birth and followed up to age 5. The 20 μg non-booster group sustained higher anti-HBs levels and lower seronegative rates at all follow-ups compared to the 10 μg non-booster group. Booster immunization increased antibody levels in both dose groups. By age 5, VBI incidence was highest in the 10 μg non-booster group, whereas all overt/occult infections occurred among non-booster children. Multivariate analysis suggested that both higher neonatal dose and booster immunization were associated with a reduced VBI risk, with the lowest risk observed when both strategies were combined. These findings suggest that increased neonatal vaccine dose and booster immunization may help sustain anti-HBs and reduce VBI in high-risk population.

There is currently no Lyme disease (LD) vaccine available for use in humans. Outer surface protein C (OspC) of the causative agent, Borrelia burgdorferi, is a promising LD vaccine target. However, the extensive genetic variation of OspC poses a challenge in affording broad protection. Here, we developed a monovalent mRNA vaccine encoding OspC type A and a polyvalent vaccine encoding OspC types A, C, I, K, and N. The monovalent vaccine conferred complete protection against homologous challenge in mice, inducing functional OspC-specific antibodies and CD4⁺ T cell responses. The polyvalent formulation elicited antibodies to all encoded OspC types and protected against strains expressing OspC types A, I, and K, but not C or N. Increasing the dose enhanced protection against the OspC type C strain. This study is the first demonstration of an effective OspC-targeted mRNA vaccine and supports the development of OspC-based vaccines for broad LD prevention.

The global spread of highly pathogenic avian influenza A(H5N1) viruses poses a serious pandemic threat. While sustained human-to-human transmission has not occurred, widespread circulation in birds, increased detection in mammals, and occasional human spillovers underscore the need for safe and effective vaccines. We evaluated an H5 mRNA vaccine candidate in ferrets using recent clade 2.3.4.4b A(H5N1) human isolates. Vaccination elicited strong neutralizing antibodies, conferred robust protection against lethal challenge, and significantly reduced viral titers. In a direct contact transmission model, mRNA vaccination decreased virus shedding in inoculated ferrets and reduced onward transmission; it also protected vaccinated contact ferrets from infection following exposure to virus-shedding, unvaccinated ferrets. Additionally, sera from vaccinated animals cross-neutralized clade 2.3.2.1e human viruses to varying degrees, depending on the strain. These findings demonstrate that H5 mRNA vaccination not only protects against disease but also reduces transmission, supporting its potential as a key tool for pandemic preparedness.

Prophylactic human papillomavirus vaccines such as Cervarix® and Gardasil®9 induce robust and sustained antibody responses over time. One driver of such responses is memory B-cells (MBCs), primed during initial HPV-vaccine exposure. As part of the Dose Reduction Immunobridging and Safety Study (DoRIS), MBCs were evaluated in peripheral blood mononuclear cells by enzyme-linked immunosorbent spot assay at baseline and at 5 visits post-first vaccine dose to Month 36 in 930 Tanzanian girls randomly allocated to 3, 2, or 1 doses of either vaccine. Most ( > 90%) participants had detectable MBCs at all time points, with maximum responses by Month 7. Geometric mean frequency HPV-specific MBCs and the proportion responding declined thereafter for both vaccines in the 2 and 3-dose arms. MBC frequencies were lower in single-dose than in 2- and 3-doses recipients at all time points subsequent to Month 1. By Month 36, MBC responses to both vaccines for both HPV16 and 18 were similar across all dosing arms. The clinical significance of the dose response remains to be evaluated; however, the presence of MBCs in the circulation after 3 years with a single vaccine dose is encouraging in terms of generating long-lasting protection with a one-dose vaccination strategy.

The SARS-CoV-2 spike receptor binding domain (RBD) is the major target for neutralising antibodies. However, subdomains like RBD may constrain the availability of CD4 T follicular helper (TFH) cells and impact immunogenicity. We engineered a chimeric trimeric RBD (CTR) glycoprotein, replacing the RBD of HKU-1 spike with SARS-CoV-2 RBD (ancestral WT/Omicron BA.2). This maintains trimerised RBD, while providing CD4 help via the HKU-1 scaffold. In C57BL/6 mice, CTR-BA.2 elicited high anti-BA.2-RBD IgG and neutralising titres, matching native spike responses. Germinal centre B cells were predominantly WT⁺/BA.2⁺ cross-reactive, and TFH predominantly recognised HKU-1 epitopes, demonstrating scaffold-directed help. In macaques, CTR-WT elicited comparable anti-RBD IgG, anti-spike IgG and neutralising responses to native spike, with elevated RBD-specific GC B cells in draining lymph nodes. Macaque TFH responses targeted RBD, NTD/S2 or HKU-1 peptides. This chimeric design overcomes poor RBD immunogenicity by engaging CD4 TFH, maintaining neutralising responses that is non-inferior to native spike.

Nipah virus (NiV) and Hendra virus (HeV), two highly pathogenic Henipaviruses (HNVs), pose a significant public health threat. The attachment glycoprotein (G) plays a crucial role in viral attachment and entry, making it an attractive target for vaccine and therapeutic antibody development. However, the antigenic landscape and neutralization sensitivity of the diverse HNV G proteins remain poorly defined. Here, we systematically characterize 27 monoclonal antibodies (mAbs) elicited by NiV G head (G^H) nanoparticle-immunized mice. Among these, 25 mAbs exhibit neutralizing activity against two major NiV strains, NiV-Malaysia and NiV-Bangladesh, with five mAbs also cross-inhibiting HeV infection. Notably, mAbs from two distinct groups conferred complete protection to hamsters against lethal NiV-Malaysia challenge. Structural analysis of NiV G^H in complex with representative Fabs reveals four non-overlapping epitopes, including two novel antigenic sites and one public protective epitope shared across species. MAbs targeting the novel sites bind to the top or side faces of G protein's β-propeller and inhibit viral infection by blocking either receptor engagement or membrane fusion. MAbs recognizing the public epitope block the receptor binding directly. Our study provides a comprehensive antigenic map of the NiV G^H and offers new insights and opportunities for antibody-based therapies and rational vaccine development.

Avian influenza continues to be a major threat to poultry and public health. This study investigated the efficacy of a bivalent H9N2/H5N2 modified live virus (MLV) vaccine delivered through a sequential aerosol priming and drinking water boosting in chickens. We hypothesized that this vaccination strategy would induce robust protective immunity against both low pathogenic H9N2 and high pathogenic H5N1 avian influenza viruses. The results demonstrated that the bivalent MLV vaccine provided sterilizing immunity against homologous and antigenically drifted H9N2 virus challenges. While anti-H5 antibody responses after MLV vaccination were generally weak, a robust anti-N2 antibody response was observed. Notably, the bivalent MLV prime-boost group demonstrated 90% survival against a high-dose H5N1 HPAI challenge. These findings highlight the potential of this mass vaccination approach, utilizing aerosol delivery complemented by drinking water administration, as a convenient and cost-effective method for avian influenza control, particularly H9N2 and H5N1 HPAI.