NPJ Vaccines最新文献

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.

Streptococcus pneumoniae and influenza A virus (IAV) are significant agents of pneumonia cases and severe respiratory infections globally. Secondary bacterial infections, particularly by Streptococcus pneumoniae, are common in IAV-infected individuals, leading to critical outcomes. Despite reducing mortality, pneumococcal vaccines have high production costs and are serotype specific. The emergence of new circulating serotypes has led to the search for new prevention strategies that provide a broad spectrum of protection. In this context, vaccination using antigens present in all serotypes, such as Pneumococcal Surface Protein A (PspA), can offer broad coverage regardless of serotype. Employing the reverse genetics technique, our research group developed a recombinant influenza A H1N1 virus that expresses PspA (Flu-PspA), through the replacement of neuraminidase by PspA. This virus was evaluated as a bivalent vaccine against infections caused by influenza A and S. pneumoniae in mice. Initially, we evaluated the Flu-PspA virus's ability to infect cells and express PspA in vitro, its capacity to multiply in embryonated chicken eggs, and its safety when inoculated in mice. Subsequently, the protective effect against influenza A and Streptococcus pneumoniae lethal challenge infections in mice was assessed using different immunization protocols. Analysis of the production of antibodies against PspA4 protein and influenza, and the binding capacity of anti-PspA4 antibodies/complement deposition to different strains of S. pneumoniae were also evaluated. Our results demonstrate that the Flu-PspA virus vaccine efficiently induces PspA protein expression in vitro, and that it was able to multiply in embryonated chicken eggs even without exogenous neuraminidase. The Flu-PspA-based bivalent vaccine was demonstrated to be safe, stimulated high titers of anti-PspA and anti-influenza antibodies, and protected mice against homosubtypic and heterosubtypic influenza A and S. pneumoniae challenge. Moreover, an efficient binding of antibodies and complement deposition on the surface of pneumococcal strains ascribes the broad-spectrum vaccine response in vivo. In summary, this innovative approach holds promise for developing a dual-protective vaccine against two major respiratory pathogens.

The limited but recurrent outbreaks of the zoonotic Nipah virus (NiV) infection in humans, its high fatality rate, and the potential virus transmission from human to human make NiV a concerning threat with pandemic potential. There are no licensed vaccines to prevent infection and disease. A recombinant Hendra virus soluble G glycoprotein vaccine (HeV-sG-V) candidate was recently tested in a Phase I clinical trial. Because NiV outbreaks are sporadic, and with a few cases, licensing will likely require an alternate regulatory licensing pathway. Therefore, determining a reliable vaccine correlate of protection (CoP) will be critical. We assessed the immune responses elicited by HeV-sG-V in African Green monkeys and its relationship with protection from a NiV challenge. Data revealed values of specific binding and neutralizing antibody titers that predicted survival and allowed us to establish a mechanistic CoP for NiV Bangladesh and Malaysia strains.

Leishmaniasis is a tropical disease caused by Leishmania parasites and currently has no licensed vaccines. We developed a dermotropic Leishmania major centrin gene-deleted strain (LmCen^-/-) as a live attenuated vaccine. Recent studies have shown that type I interferons (IFNs) play important roles in immunity to parasitic and viral pathogens. However, their relevance in protective immunity following vaccination is not understood. We found that immunization with LmCen^-/- induces a transient increase in type I IFN response along with its regulatory factor IRF7 that is downregulated 7-21 days post-immunization, coincided with the induction of a robust Th1 adaptive immune response. Challenge infection with virulent L. donovani parasites showed a significant reduction of splenic and hepatic parasite burden in IRF7^-/- mice than wild type mice following immunization with LmCen^-/-, suggesting that ablation of type I IFN response is a pre-requisite for the induction of LmCen^-/- mediated Th1 immunity against L. donovani infection.

Eilat (EILV)/chikungunya virus (CHIKV), an insect-based chimeric alphavirus was previously reported to protect mice months after a single dose vaccination. The underlying mechanisms of host protection are not clearly defined. Here, we assessed the capacity of EILV/CHIKV to induce quick and durable protection in cynomolgus macaques. Both EILV/CHIKV and the live attenuated CHIKV 181/25 vaccine protected macaques from wild-type (WT) CHIKV infection 1 year after a single dose vaccination. Transcriptome and functional analyses reveal that EILV/CHIKV triggered T cell, memory B cell and antibody responses in a dose-dependent manner. EILV/CHIKV induced more robust, durable, and broader repertoire of CHIKV-specific T cell responses than CHIKV 181/25; whereas the latter group induced more durable memory B cells and comparable or higher CHIKV -specific neutralization and binding antibodies. EILV/CHIKV and an inactivated WT CHIKV protected macaques from WT CHIKV infection and CHIK fever (CHIKF) within 6 days post vaccination. Transcriptome analysis showed that the chimeric virus induced multiple innate immune pathways, including Toll-like receptor signaling, antigen presenting cell activation, and NK receptor signaling. EILV/CHIKV triggered quicker and more robust type I interferon and NK cell responses than the inactivated WT virus vaccine. Lastly, we developed a guinea pig sensitization model and demonstrated that the chimeric virus produced in insect cells, did not cause skin hypersensitivity reactions. Overall, EILV/CHIKV is safe, and confers rapid and long-lasting protection in cynomolgus macaques via preferential induction of robust innate immune signaling and superior T cell immunity.

Spread by Hyalomma genus ticks, Crimean-Congo hemorrhagic fever virus (CCHFV) causes a severe hemorrhagic disease endemic throughout Southern and Eastern Europe, Asia, and Africa. To date, there are no widely approved vaccines for CCHFV and treatment for disease is largely supportive. Due to this lack of intervention, the WHO lists CCHFV as a high-priority pathogen. Recently, we described a highly efficacious self-replicating RNA vaccine which is protective against CCHFV disease in mice and non-human primates. This vaccine induces high titers of non-neutralizing anti-nucleoprotein (NP) antibodies and a robust T-cell response against the viral glycoprotein. Here, we assess the durability of this vaccine in mice by monitoring the immunogenicity and efficacy of this vaccine up to 1 year post vaccination. We found that while glycoprotein-specific T-cell responses and anti-NP antibody titers waned over time, mice remained protected against lethal CCHFV challenge for at least 1 year post vaccination.

Development of an efficacious universal influenza vaccines remains a long-sought goal. Current vaccines have shortfalls such as mid/low efficacy and needing yearly strain revisions to account for viral drift/shift. Horses undergo bi-annual vaccines for the H3N8 equine influenza virus, and surveillance of sera from vaccinees demonstrated very broad reactivity and neutralization to many influenza strains. Subsequently, vaccinating mice using the equine A/Kentucky/1/1991 strain or recombinant hemagglutinin (HA) induced similar broadly reactive and neutralizing antibodies to seasonal and high pathogenicity avian influenza strains. Challenge of vaccinated mice protected from lethal virus challenges across H1N1 and H3N2 strains. This protection correlated with neutralizing antibodies to the HA head, esterase, and stem regions. Vaccinated ferrets were also protected after challenge with H1N1 influenza A/07/2009 virus using whole viral or HA. These data suggest that equine H3N8 induces broad protection against multiple influenzas using a unique antigen that diverges from other universal vaccine approaches.

Hepatitis E virus (HEV) infection is a major cause of acute viral hepatitis worldwide. The efficacy and safety of the HEV239 vaccine have been validated, with protection lasting at least 10 years. This study extended the phase 3 trial of HEV239 (NCT01014845), presenting data on the durability of the anti-HEV IgG response elicited by one or two doses in the participants with different baseline serostatus. Over half of baseline seronegative individuals retained detectable antibodies at month 91 after two doses, with geometric mean concentration levels above the detection limit at month 67 (no available data for month 91). Seropositive individuals exhibited more prolonged and higher anti-HEV IgG response. After a single dose, individuals with pre-existing immunity achieved high and sustained antibody levels for over 103 months, comparable to the two-dose regimen. Both single-dose and two-dose HEV239 regimens demonstrated notable immunogenicity and persistence, potentially offering substantial protective benefits.