NPJ Vaccines最新文献

Vaccines against Salmonella Typhi are available, while vaccines against invasive non-typhoidal Salmonella are in development. Investments in vaccine development and introduction need to be informed by a full value of vaccines assessment, including consideration of broader societal impacts of salmonellae disease. We reviewed literature on these broader impacts in low- and middle-income countries to inform a conceptual framework. We found 16 studies relevant to Salmonella, but only one study on non-typhoidal Salmonella. Despite variations in study design, methodology, and study quality, salmonellae infections were largely associated with negative broader societal impacts, including detriments in childhood physical development (very weak association), childhood educational development (strong to very strong association), household security (moderate association), public health spending (moderate association), and national income (moderate to strong association). Study quality was low for all impacts except childhood physical development. There were no studies measuring economic impact of antimicrobial resistance, changes in household behaviour or health inequalities.

Enterotoxigenic Escherichia coli (ETEC) diarrhea is associated with a high burden of disease globally, for which no licensed vaccine is available. A Phase 1, double-blind, dose-escalation (0.1-2.0 µg) study was conducted to evaluate the safety and immunogenicity of double mutant heat-labile toxin LTR192G/L211A (dmLT) delivered intradermally (ID) to healthy adults. Subjects received up to three immunizations at three-week intervals. The vaccine was safe, although it induced mild local and some gastrointestinal adverse events, as well as frequent hyperpigmentation at the injection site. High levels of serum IgG and IgA, LT neutralizing antibodies, and IgG and IgA antibodies in lymphocyte supernatant were elicited post-vaccination, most prominently at the largest dose (2.0 μg). Rates of responses were the highest in subjects who received the largest dose (2.0 μg) and multiple immunizations. The ETEC dmLT vaccine was safe and highly immunogenic, inducing long-lasting systemic and mucosal responses when administered by the ID route. Trial registration Clinical Trials NCT02531685.

Burkholderia cenocepacia causes life-threatening infections in immunocompromised patients. Treatment is challenging due to intrinsic antibiotic multiresistance, so vaccination provides an alternative approach. We aimed to identify vaccine candidates using reverse vaccinology and evaluate their efficacy as protein-loaded chitosan: pectin nanoparticles (C:P NPs) in a vaccine model. Applying strict subtractive channels, three proteins were shortlisted: WP_006481710.1 (LY), WP_012493605.1 (KT), and WP_006492970.1 (BD). Proteins were cloned, purified as His-tagged proteins, and loaded onto C:P NPs. Vaccinated mice had significantly higher systemic IgG and mucosal IgA antibody responses and induced IL-6 and IL-17A. 6x-His-LY-CS:P NPs and 6x-His-KT-CS:P NPs vaccines induced TNF-α. Vaccines conferred significant protection against B. cenocepacia intranasal infections. In conclusion, cyclic-di-AMP phosphodiesterase (WP_012493605.1) is a promising vaccine candidate that elicited IgG and IgA antibodies, Th1, Th2, and Th17 cellular immunity in BALB/c mice and protected against B. cenocepacia infection. This provides hope for saving lives of people at high risk of infection.

While many novel candidates for tuberculosis vaccines are presently undergoing pre-clinical or clinical trials, none of them have been able to eliminate infection entirely. In this study, we engineered a potent chimeric protein vaccine candidate, Rv2299cD2D3-ESAT-6-Ag85B (REA), which induced Th1 and Th17 responses via dendritic cell maturation. REA-activated macrophages operated the killing mechanisms of Mycobacterium tuberculosis (MTB), such as phagosomal maturation and phagolysosome fusion, through the (PI3K)-p38 MAPK-Ca²⁺-NADPH oxidase pathway. Dendritic cells and macrophages activated by REA elicited synergistic anti-mycobacterial responses. Notably, REA-immunized mice suppressed MTB growth to undetectable levels at 16 weeks post-infection, which was supported by gross and pathologic findings and acid-fast staining of the lung tissues, and maintained antigen-specific multifunctional IFN-γ⁺IL-2⁺TNF-α CD4⁺ T and long-lasting T cells producing cytokines in the tissues. Our findings suggest that REA is an outstanding prime prophylactic vaccine candidate against tuberculosis.

The rapid development and worldwide distribution of COVID-19 vaccines is a remarkable achievement of biomedical research and logistical implementation. However, these developments are associated with the risk of a surge of substandard and falsified (SF) vaccines, as illustrated by the 184 incidents with SF and diverted COVID-19 vaccines which have been reported during the pandemic in 48 countries, with a paucity of methods for their detection in supply chains. In this context, matrix-assisted laser desorption ionisation-time of flight (MALDI-ToF) mass spectrometry (MS) is globally available for fast and accurate analysis of bacteria in patient samples, offering a potentially accessible solution to identify SF vaccines. We analysed the COVISHIELD™ COVID-19 vaccine; falsified versions of which were found in India, Myanmar and Uganda. We demonstrate for the first time that analysis of spectra from the vaccine vial label and its adhesive could be used as a novel approach to detect falsified vaccines. Vials tested by this approach could be retained in the supply chain since it is non-invasive. We also assessed whether MALDI-ToF MS could be used to distinguish the COVISHIELD™ vaccine from surrogates of falsified vaccines and the effect of temperature on vaccine stability. Both polysorbate 80 and L-histidine excipients of the genuine vaccine could be detected by the presence of a unique combination of MALDI-ToF MS peaks which allowed us to distinguish between the genuine vaccines and falsified vaccine surrogates. Furthermore, even if a falsified product contained polysorbate 80 at the same concentration as used in the genuine vaccine, the characteristic spectral profile of polysorbate 80 used in genuine products is a reliable internal marker for vaccine authenticity. Our findings demonstrate that MALDI-ToF MS analysis of extracts from vial labels and the vaccine excipients themselves can be used independently to detect falsified vaccines. This approach has the potential to be integrated into the national regulatory standards and WHO's Prevent, Detect, and Respond strategy as a novel effective tool for detecting falsified vaccines.

Tumor-derived exosomes (TDEs) mediate oncogenic communication, which modifies target cells to reinforce a tumor-promoting microenvironment. TDEs support cancer progression by suppressing anti-tumor immune responses, promoting metastasis, and conferring drug resistance. Thus, targeting TDEs could improve the efficacy of anti-cancer treatments and control metastasis. Current strategies to inhibit TDE-mediated oncogenic communication including drug-based and genetic modification-based inhibition of TDE release and/or uptake, have proved to be inefficient. In this work, we propose TDE surface engineering to express foreign antigens that will trigger life-long anti-TDE immune responses. The possibility of combining the anti-TDE vaccines with other treatments such as chemotherapy, radiotherapy, targeted therapy, and surgery is also explored.

Severe fever with thrombocytopenia syndrome (SFTS) caused by the SFTS virus (SFTSV) is an emerging tick-borne disease with a high mortality rate. Haemaphysalis longicornis is the primary reservoir and vector of SFTSV. Here, we found that targeting subolesin (SUB), an anti-tick vaccine candidate, affects the infection and transmission of SFTSV in H. longicornis. RNAi-mediated knockdown of SUB repressed SFTSV infection in the salivary glands but not in the gut of H. longicornis, which may be associated with the modulation of protein processing in endoplasmic reticulum revealed by transcriptomic analysis. Knockdown of SUB decreased the survival and engorgement rates of ticks and impaired the horizontal and co-feeding transmission of SFTSV. Furthermore, active immunization with recombinant SUB inhibited the co-feeding transmission of SFTSV, although it had no significant effect on the blood-feeding behavior of infected ticks. Collectively, these results provide a potential target for controlling SFTS and other tick-borne viral diseases.

Saponin-based adjuvants (SBAs) distinguish themselves as vaccine adjuvants by instigating a potent activation of CD8+ T cells. Previously, we discovered SBA's ability to induce cross-presentation in dendritic cells (DCs) leading to CD8+ T cell activation. Moreover, the MHCII^loCD11b^hi bone marrow-derived DC (BMDC) subset was identified to be the most responsive DC subset to SBA treatment. To further investigate SBA's mode of action, labeling of SBAs was optimized with the fluorescent dye SP-DiIC₁₈(3). Efficient uptake of SBAs occurs specifically by MHCII^loCD11b^hi BMDCs and bone marrow-derived macrophages (BMDMs) in vitro and cDC2s and macrophages ex vivo. Furthermore, SBAs are primarily taken up by clathrin-mediated endocytosis and uptake induces lipid bodies and antigen translocation to the cytosol in MHCII^loCD11b^hi BMDCs and BMDMs. Importantly, BMDMs treated with SBAs exhibit cross-presentation leading to potent CD8+ T cells activation. Our findings explain the potency of SBAs as vaccine adjuvants and contribute to vaccine development.

Group A Streptococcus (Strep A) is a human-exclusive bacterial pathogen killing annually more than 500,000 patients, and no current licensed vaccine exists. Strep A bacteria are highly diverse, but all produce an essential, abundant, and conserved surface carbohydrate, the Group A Carbohydrate, which contains a rhamnose polysaccharide (RhaPS) backbone. RhaPS is a validated universal vaccine candidate in a glycoconjugate prepared by chemical conjugation of the native carbohydrate to a carrier protein. We engineered the Group A Carbohydrate biosynthesis pathway to enable recombinant production using the industry standard route to couple RhaPS to selected carrier proteins within Escherichia coli cells. The structural integrity of the produced recombinant glycoconjugate vaccines was confirmed by Nuclear Magnetic Resonance (NMR) spectroscopy and mass spectrometry. Purified RhaPS glycoconjugates elicited carbohydrate-specific antibodies in mice and rabbits and bound to the surface of multiple Strep A strains of diverse M-types, confirming the recombinantly produced RhaPS glycoconjugates as valuable vaccine candidates.

The primary immunological readout for clinical trials of R21/MatrixM™ malaria vaccine, is total IgG antibody specific to the central four amino acid NANP repeat region of the circumsporozoite protein. A multiplexed assay, which includes NANP, was developed and validated for four antigens representing components of the R21 immunogen. Initial assay optimisation included validation of the HBsAg international standard. Further validation performed in Oxford covered intra and inter-assay, and inter-operator variability, accuracy of QC and standard curve material, and included bridging to a singleplex NANP6 ELISA. The assay was shown to be robust and specific, with a broad dynamic range. We report a strong linear relationship between NANP6 IgG as measured by the singleplex ELISA and the multiplexed assay with rho values of 0.89 and 0.88 for two separate clinical trials (both p < 0.0005). This assay can be used to measure antibodies specific to the CSP NANP repeat region, CSP C-term region, full length R21 and HBsAg.