Vaccines最新文献

Background/objectives: RSV is a major cause of mortality in infants, and despite recent progress to prevent RSV in the very young, an RSV vaccine for this population is still highly warranted. Clinical studies in infants in the 1960s using formalin-inactivated RSV (FI-RSV) led to life-threatening enhanced respiratory disease (ERD). Therefore, a thorough safety assessment of RSV vaccine candidates intended for RSV seronegative infants is crucial.

Methods: Prior to clinical pediatric development of Ad26.RSV.preF, an adenovirus type 26 vector-encoding RSV F protein stabilized in its prefusion conformation, predisposition to ERD was extensively assessed in cotton rat and mouse models.

Results: Cotton rats intramuscularly immunized with a wide dose range of Ad26.RSV.preF, including low and sub-protective vaccine doses, and challenged with vaccine homologous RSV A2 or heterologous RSV B Wash 18537, did not show signs of predisposition to ERD. Histopathology scores for alveolitis, peribronchiolitis, interstitial pneumonia, and perivasculitis after challenge were significantly lower for Ad26.RSV.preF-immunized cotton rats compared to FI-RSV-immunized cotton rats and comparable to or lower than scores in cotton rats intranasally pre-exposed to RSV prior to challenge to mimic natural repeated infection. These results were observed in animals with or without viral replication in the lung after RSV challenge, in the presence or absence of vaccine-induced antibodies. Similar results were observed in mice, where more extensive assessment of mono- and polymorphonuclear cell alveolitis, mucus cell hyperplasia, and mucus accumulation was performed.

Conclusions: Based on these extensive analyses, we conclude that there are no indications of ERD predisposition after Ad26.RSV.preF vaccination in rodent models, irrespective of the vaccine dose, challenge virus strain, or presence of viral replication in the lung. These results are crucial for the pediatric development of this vaccine.

During the COVID-19 pandemic, substantial changes occurred that may have either facilitated or hindered efforts to promote vaccination [...].

Background/Objectives: Despite clonal expansion during a primary immune response, or after subsequent antigen encounters, the frequency of memory B cells (B_mem) specific for an antigen remains low, making their detection difficult. However, unlike serum antibodies, which have a short half-life in vivo and thus require continuous replenishment to maintain stable titers, circulating B_mem are long-lived; they preserve immunological preparedness through their ability to rapidly engage in recall responses and differentiate into antibody-secreting cells (ASCs) upon antigen encounter. To this end, development of assays suited for the reliable detection of rare antigen-specific B_mem is critical and can provide insights into an individual's antigen exposure history and immune status beyond that offered by traditional serum antibody measurements alone. Methods: ImmunoSpot^® has emerged as a suitable technique for the detection of individual antigen-specific B cells through visualizing their antibody-derived secretory footprints. Here, we report the theoretical and practical foundations for detecting rare antigen-specific B_mem in human peripheral blood mononuclear cells (PBMC). Leveraging the unique availability of verifiably naïve vs. antigen-experienced human samples, we used SARS-CoV-2 Spike (S-) and Nucleocapsid (NCAP) antigens to interrogate the presence of B_mem with these respective specificities. Results: While 100% diagnostic accuracy was achieved for both antigens, detection of NCAP-specific B_mem required reducing the lower detection limit of the standard assay. Specifically, this was achieved by testing a total of 2 million PBMC across multiple replicate assay wells and assessing the cumulative number of secretory footprints detected. Conclusion: The protocols described here should facilitate the reliable detection of ASCs present at varying precursor frequencies and serve as guidance for routine immune monitoring of rare B_mem with specificity for any antigen.

Background: Salmonella is a major zoonotic foodborne pathogen. Conventional poultry vaccines may present limitations in terms of efficacy, safety, and practicality. Objectives: This study focuses on enhancing the immunogenicity and improving the safety of a novel oral vaccination employing inducible toxin-antitoxin (TA) systems, which lead to self-destruction of virulent Salmonella Enteritidis. Methods: A Hok/Sok (HS) TA system was designed to induce cell death upon absence of arabinose. Point mutations were introduced to the Hok toxin promoter to moderate toxin production. A combination of HS and CeaB/CeiB (CC) TA systems was designed to induce cell death both in low di-cation levels or anaerobic conditions. Survival of Salmonella-carrying TA systems was tested in culture and in the Raw264.7 macrophage cell line. One-day old chicks were inoculated with Salmonella carrying the TA system to evaluate bacterial persistence and induction of a protective immune response. Results: Attenuation of the Hok toxin promoter prolonged bacterial survival in vitro. Salmonella carrying the combined TA systems was eliminated completely both in vitro and in inoculated chickens, eliciting high levels of antibodies and conferring protection against challenge with wild-type Salmonella. Conclusions: These findings highlight the potential of the adaptable TA-based vaccination platform to generate safe and efficacious Salmonella vaccines for poultry, contributing to reduced transmission in the food chain.

Background: Nirsevimab, a monoclonal antibody for respiratory syncytial virus (RSV), reduces medically attended RSV infections. It was introduced in the 2023-24 RSV season. This study examined the association between caregiver vaccination (seasonal influenza vaccine (SIV), COVID-19, and boosters) and intent to immunize infants against RSV. Methods: Data from 118 caregivers with infants ≤ 8 months were analyzed. Chi-squared tests and logistic regression assessed the relationship between caregiver vaccination and intent to immunize against RSV. Results: In total, 74.6% of caregivers intended to immunize their infants against RSV. Intent was positively associated with caregiver receipt of a seasonal influenza vaccine (p < 0.001), COVID-19 vaccine (p < 0.001), and COVID-19 booster (p < 0.001). Intent was also associated with older child seasonal vaccination. Caregiver receipt of both COVID-19 vaccinations and boosters had a strong relationship with RSV immunization intent (OR 7.91 (1.90-33.0, p = 0.004)). Conclusions: Caregiver vaccination behaviors are linked to RSV immunization intent, helping physicians identify hesitant families and prepare for immunization conversations.

Great strides have been made in the area of immunization over the past several decades [...].

Background: Nipah virus (NiV), a zoonotic paramyxovirus with high case fatality and pandemic potential, remains without a licensed vaccine for humans to date. Although there has been progress in vaccine development, it remains limited, and peptide vaccines have rarely been validated in vivo. Methods: Here, we report the rational antigen selection, synthesis, and preliminary immunogenicity evaluation of NiV fusion glycoprotein (NiV-F)-derived linear peptides as vaccine candidates. Candidate epitopes were identified by in silico, and a total of 18 B- and T-cell epitope-derived peptides were shortlisted for synthesis and antigenicity validation by ELISA. Results: Antigenicity evaluation showed that 9 of the synthesized peptides have A_450nm of over 1 (8 from the F11 group, A_450nm: 1.13-3.6; 1 from the F18 group, A_450nm: 1.51), with the peptide constructs F11-3 (A_450nm: 3.5) and F11-4 (A_450nm: 3.6) showing the highest antigenicity. Interestingly, peptides from F11 with amidation increased antibody binding (F11-4-NH2, A_450nm: 3.05; F11-4-9mer-1-NH2, A_450nm: 0.87). The lead peptide candidates, F11-3 and F11-4, were subsequently used for the immunization experiment, and mouse sera were assessed against their homologous peptide antigens or recombinant NiV-F protein. ELISA result showed detectable antibody reactivity against their homologous antigen for the intramuscular (IM) F11-3 vaccinated group (A_450nm: 0.30 ± 0.35), whereas increased binding was observed for both IM-administered F11-3 (A_450nm: 1.62 ± 0.97) and F11-4 (A_450nm: 2.0 ± 0.77) against NiV-F protein, albeit without statistical significance compared to the negative control (NC, p > 0.05), and were markedly lower compared to mice immunized with NiV-F recombinant protein (PC, p < 0.01), underscoring the need for further optimization procedures. Conclusions: Collectively, these results support an exploratory antigen discovery and prioritization framework for NiV-F-derived peptide candidates and provide a foundation for future studies aimed at optimizing immunogenicity and evaluating protective relevance in appropriate preclinical models.

Background/Objectives: A key disadvantage of DNA vaccines is ineffective uptake of plasmid DNA, resulting in low immunogenicity. A way to overcome it is forced DNA delivery, which requires specialized equipment and/or reagents. Effective delivery of plasmids without specialized devices or using commonly available ones would significantly increase DNA vaccine applicability. Here, we delivered DNA by intradermal injections, facilitating them by optimized sonoporation (SP) or electroporation (EP), and we compared these methods by their capacity to support the production of foreign proteins in mice. Methods: DNA delivery was optimized using the plasmid encoding firefly luciferase (Luc) (pVaxLuc). Luc production was assessed by bioluminescence imaging (BLI) (IVIS, PerkinElmer, Shelton, CT, USA; LumoTrace Fluo, Abisense, Dolgoprudny, Russia). Female BALB/c mice were injected intradermally (id) with pVaxLuc in phosphate buffers of varying ionic strengths. Injection sites were subjected to SP (Intelect Mobile, Chattanooga, UK) or EP (CUY21EDITII, BEX Co., Tokyo, Japan) or left untreated. Optimal delivery protocols were selected based on the highest in vivo levels of photon flux according to BLI. Optimal protocols for id injections with/without EP were applied to DNA-immunized mice with HIV-1 clade A reverse transcriptase. Antibody response induced by DNA immunization was assessed by ELISA. Results: The optimal phosphate buffers for id delivery had ionic strengths from 81 to 163 mmol/L. The optimal SP regimen included an acoustic pressure of 2.4 W/cm² applied in a duty cycle of 2%. The optimal EP regimen included bipolar driving pulses of 100 V, a pulse duration of 10 ms, and an interval between the pulses of 20 ms. Optimized DNA delivery by id/SP injection was inferior to both id/EP and id alone. DNA immunization with HIV-1 RT by id injections induced anti-RT antibodies in a titer of 10⁴ and by id/EP in a titer of 10⁵. Conclusions: Electroporation of the sites of id DNA injection provided the highest levels of production of luciferase reporters and induced a strong antibody response against HIV-1 RT.

Plant viruses are useful tools for quickly and easily producing recombinant proteins in plants. Compared to systems that use genetically modified plants, viral vectors are easier to work with and can produce recombinant proteins faster and in larger amounts. Recently, there has been growing interest in using plant viruses as vectors to make vaccines, either as whole proteins or as small parts displayed on plant virus particles. The best examples for this purpose are tobacco mosaic virus, cowpea mosaic virus and potato virus X. Vaccines made using these viruses target various human and animal diseases and have often triggered immune responses and provided protection against infections. This review looks at the benefits of using plant virus vectors, the progress in developing different viral vector systems, and immune studies that support the idea of vaccines made from plant viruses.

Background: mRNA LNP technology is now being widely applied as a highly effective vaccine platform. Antigen multimerization is a well-established approach to enhance the antibody titers and protective efficacy of several protein subunit vaccines. However, this approach has been less explored for mRNA LNP vaccines. Methods: Here, within the context of mRNA LNP vaccination, we used mStrawberry (mSb) as a model antigen to conduct a comprehensive, head-to-head comparison of the ability of the foldon (3-mer), IMX313 (7-mer), and ferritin (24-mer) multimerization domains to enhance immunogenicity in mice. Results: We compared multimerized antigen to monomeric secreted antigen and monomeric surface-displayed antigen and observed that the IMX313 domain efficiently multimerized mSb protein and significantly enhanced anti-mSb antibody titers, whereas the foldon and ferritin domains failed to multimerize or improve antibody levels. Conclusions: Our results extend the observation of improved immunogenicity from antigen multimerization to mRNA LNP vaccines and indicate that the 7-mer forming IMX313 multimerization domain may be an ideal candidate for multimer formation in the context of mRNA LNP vaccination. Future studies are needed to evaluate the multimerization of pathogen-derived antigens, in the mRNA LNP format, for the enhancement of neutralization and protective efficacy.