Next-generation Vaccines Research Articles

Next-Generation Coronavirus Disease 2019 Vaccines: Clinical Data and Future Directions.

Next-Generation Coronavirus Disease 2019 Vaccines: Clinical Data and Future Directions.

E3 ubiquitin ligase MARCH5 positively regulates Japanese encephalitis virus infection by catalyzing the K27-linked polyubiquitination of viral E protein and inhibiting MAVS-mediated type I interferon production.

Membrane-associated RING-CH-type finger (MARCH) proteins, a class of E3 ubiquitin ligases, have been reported to be involved in the infection of multiple viruses and the regulation of type I interferon (IFN) production. However, the specific role and mechanisms by which MARCH proteins influence Japanese encephalitis virus (JEV) infection remain poorly understood. Here, we systematically investigate the functional relevance of MARCH proteins in JEV replication by examining the effects of siRNA-mediated knockdown of MARCHs on viral infection. We identified MARCH5 as a positive regulator of JEV replication. The knockout of MARCH5 dramatically reduced viral yields, whereas its overexpression significantly enhanced JEV replication. Mechanistically, MARCH5 specifically interacts with the JEV envelope (E) protein and promotes its K27-linked polyubiquitination at the lysine (K) residues 136 and 166. This ubiquitination enhances viral attachment to permissive cells. Substituting these lysine residues with arginine (R) attenuated JEV replication in vitro and reduced viral virulence in vivo. Furthermore, JEV infection upregulated the expression of MARCH5. We also discovered that MARCH5 degrades mitochondrial antiviral-signaling protein (MAVS) through the ubiquitin-proteasome pathway by catalyzing its K48-linked ubiquitination, thereby inhibiting type I IFN production in JEV-infected cells. This suppression of type I IFN further facilitates JEV infection. In conclusion, these findings disclosed a novel role of MARCH5 in positively regulating JEV infection and revealed an important mechanism employed by MARCH5 to regulate the innate immune response.IMPORTANCEJEV is the leading cause of viral encephalitis in many countries of Asia with an estimated 100,000 clinical human cases and causes economic loss to the swine industry. Until now, there is no clinically approved antiviral for the treatment of JEV infection. Although vaccination prophylaxis is widely regarded as the most effective strategy for preventing Japanese encephalitis (JE), the incidence of JE cases continues to rise. Thus, a deeper understanding of virus-host interaction will enrich our knowledge of the mechanisms underlying JEV infection and identify novel targets for the development of next-generation live-attenuated vaccines and antiviral therapies. To the best of our knowledge, this study is the first to identify MARCH5 as a pro-viral host factor that facilitates JEV infection. We elucidated two distinct mechanisms by which MARCH5 promotes JEV infection. First, MARCH5 interacts with viral E protein and mediates the K27-linked ubiquitination of E protein at the K136 and K166 residues to facilitate efficient viral attachment. Furthermore, double mutations of K136R-K166R attenuated JEV infection in vitro and reduced viral virulence in mice. Second, the upregulated expression of MARCH5 induced by JEV infection further suppresses the RIG-I-like receptor (RLR) signaling pathway to benefit viral infection. MARCH5 downregulates type I IFN production by conjugating the K48-linked polyubiquitin at the K286 of MAVS, which leads to MAVS degradation through the ubiquitin-proteasome pathway. In summary, this study provides novel insights into the role played by MARCH proteins in JEV infection and identifies specific ubiquitination sites on JEV E protein that could be targeted for viral attenuation and the development of antiviral therapeutics.

The saponin monophosphoryl lipid A nanoparticle adjuvant induces dose-dependent HIV vaccine responses in non-human primates.

The induction of durable protective immune responses is the main goal of prophylactic vaccines, and adjuvants play a role as drivers of such responses. Despite advances in vaccine strategies, a safe and effective HIV vaccine remains a significant challenge. The use of an appropriate adjuvant is crucial to the success of HIV vaccines. Here we assessed the saponin/MPLA nanoparticle (SMNP) adjuvant with an HIV envelope (Env) trimer, evaluating the safety and impact of multiple variables including adjuvant dose (16-fold dose range), immunization route, and adjuvant composition on the establishment of Env-specific memory T and B cell responses (TMem and BMem) and long-lived plasma cells in non-human primates (NHPs). Robust BMem were detected in all groups, but a 6-fold increase was observed in the highest SMNP dose group vs. the lowest dose group. Similarly, stronger vaccine responses were induced in the highest SMNP dose for CD40L+OX40+ CD4 TMem (11-fold), IFN-γ+ CD4 TMem (15-fold), IL21+ CD4 TMem (9-fold), circulating TFH (3.6-fold), bone marrow plasma cells (7-fold), and binding IgG (1.3-fold). Substantial tier-2 neutralizing antibodies were only observed in the higher SMNP dose groups. These investigations highlight the dose-dependent potency of SMNP in NHPs, which are relevant for human use and next-generation vaccines.

Development and validation of the Oxford Benchmark Scale for Rating Vaccine Technologies (OBSRVT), a scale for assessing public attitudes to next-generation vaccine delivery technologies

ABSTRACT Next-generation vaccine delivery technologies may provide significant gains from both a technical and behavioral standpoint, but no scale has yet been developed to assess public attitudes to novel vaccine delivery technologies. We therefore performed a cross-sectional validation study that included 1,001 demographically representative participants from the UK and US to develop and validate a novel scale, the Oxford Benchmark Scale for Rating Vaccine Technologies (OBSRVT). A sample of 500 UK participants was used to perform exploratory factor analysis with categorical variables (using a polychoric correlation matrix) followed by promax oblique factor rotation to develop the initial model. This yielded a 15-item 4-domain scale with domains including acceptance (6 items), effectiveness (4 items), comfort (3 items), and convenience (2 items). This model was tested for robustness on a 501-participant demographically representative sample from the US. A confirmatory factor analysis with a Satorra-Bentler scaled test statistic was performed, which demonstrated adequate goodness of fit statistics including the root mean squared error of approximation (0.057), standardized root mean squared residual (0.053), and comparative fit index (0.938). Reliability as internal consistency was excellent (alpha = 0.92). Convergent validity with the Oxford Needle Experience Scale was supported by an adequate correlation (r = 0.31, p < .0001), while discriminant validity was supported by a lack of correlation with an unrelated question (r = -0.03, p < .0001). These findings suggest that the OBSRVT scale represents a feasible, valid, and reliable scale that could be used to gauge the acceptability of existing and future vaccine delivery technologies, and further investigation and testing should be considered.

Transformative approaches in SARS-CoV-2 management: Vaccines, therapeutics and future direction.

Transformative approaches in SARS-CoV-2 management: Vaccines, therapeutics and future direction.

Towards developing multistrain PEDV vaccines: Integrating basic concepts and SARS-CoV-2 pan-sarbecovirus strategies.

Towards developing multistrain PEDV vaccines: Integrating basic concepts and SARS-CoV-2 pan-sarbecovirus strategies.

Self-assembling of coiled-coil peptides into virus-like particles: Basic principles, properties, design, and applications with special focus on vaccine design and delivery.

Self-assembling of coiled-coil peptides into virus-like particles: Basic principles, properties, design, and applications with special focus on vaccine design and delivery.

A novel platform for engineered AAV-based vaccines.

A novel platform for engineered AAV-based vaccines.

From protein to immunology: comprehensive insights into Marburg virus vaccines, mechanism, and application.

The Marburg virus (MARV), a member of the Filoviridae family, is a highly lethal pathogen that causes Marburg virus disease (MVD), a severe hemorrhagic fever with high fatality rates.Despite recurrent outbreaks, no licensed vaccine is currently available. This review explores MARV's genomic architecture, structural proteins, and recent advancements in vaccine development. It highlights the crucial role of MARV's seven monocistronic genes in viral replication and pathogenesis, with a focus on structural proteins such as nucleoprotein (NP), glycoprotein (GP), and viral proteins VP35, VP40, and VP24. These proteins are essential for viral entry, immune evasion, and replication. The review further examines various vaccine platforms, including multi-epitope vaccines, DNA-based vaccines, viral vector vaccines, virus-like particles (VLPs), and mRNA vaccines. Cutting-edge immunoinformatics approaches are discussed for identifying conserved epitopes critical for broad-spectrum protection. The immunological responses induced by these vaccine candidates, particularly their efficacy in preclinical trials, are analyzed, showcasing promising results in generating both humoral and cellular immunity. Moreover, the review addresses challenges and future directions in MARV vaccine development, emphasizing the need for enhanced immunogenicity, safety, and global accessibility. The integration of omics technologies (genomics, transcriptomics, proteomics) with immunoinformatics is presented as a transformative approach for next-generation vaccine design. Innovative platforms such as mRNA and VLP-based vaccines offer rapid and effective development opportunities. In this study, underscores the urgent need for a licensed MARV vaccine to prevent future outbreaks and strengthen global preparedness. By synthesizing the latest research and technological advancements, it provides a strategic roadmap for developing safe, effective, and broadly protective vaccines. The fight against MARV is a global priority, requiring coordinated efforts from researchers, policymakers, and public health organizations.

A recombinant protein vaccine induces protective immunity against SARS-CoV-2 JN.1 and XBB-lineage subvariants

The emergence of XBB- and JN.1-lineages with remarkable immune evasion characteristics have led to rises in breakthrough infections within populations. In addition, the unfavorable impacts of immune imprinting, stemming from continuous exposure to antigens from circulated viruses, have been observed to incline immune response against earlier lineages, thereby declining the neutralization to newly emerged Omicron subvariants. In response to this, the advancement of next-generation vaccines against COVID-19 targeting components from new subvariants such as XBB-lineage is imperative. In the current study, a self-assembled trimeric recombinant protein (RBDXBB.1.5-HR) was generated by concatenating the sequences of the receptor binding domain (RBD) derived from XBB.1.5 with heptad-repeat 1 (HR1) and HR2 sequences from the spike S2 subunit. Adjuvanted-RBDXBB.1.5-HR induced robust humoral and cellular immune responses, characterized by elevated neutralization against JN.1-inculuded subvariants and a substantial population of antigen-specific T memory cells. Protective immunity conferred by RBDXBB.1.5-HR vaccine was preserved post-immunization, as evidenced by germinal center B (GC B) and T follicular helper (Tfh) responses, sustained neutralization potency, and an increase in memory B cells (MBCs) and long-lived plasma cells (LLPCs). The RBDXBB.1.5-HR vaccine showed a favorable boosting effect when administered heterologously after three doses of inactivated virus (IV) and mRNA vaccines. Significantly, it provided protection against live Omicron EG.5.1 viruses in vivo. The monovalent RBDXBB.1.5-HR vaccine showed favorable safety and immunogenicity, boosting neutralizing antibodies against JN.1- and XBB-lineage subvariants in individuals with prior COVID-19 vaccinations. These findings highlight its clinical potential in safeguarding against circulating Omicron subvariants.

Immunogenicity of Rabies Virus G-Protein mRNA Formulated with Muscle-Targeting Lipid Nanoparticles in Mice

Background: Rabies is a preventable zoonotic disease caused by the rabies virus (RABV) with a high mortality rate. Most vaccines on the market or under development have issues, such as low single-dose neutralization titer, complex processes, and high costs. During the COVID-19 pandemic, the successful development of mRNA vaccines opened up a new avenue for preventive vaccines. As a new technology, mRNA has higher scalability. Methods: In this study, we designed an mRNA encoding the RV-G protein, encapsulated by our own muscle-targeting lipid nanoparticles (LNPs), and evaluated the expression of the RV-G protein in vitro, its immunogenicity, and its protection against virus infection in vivo. Results: The results show that RV-G mRNA was significantly expressed in vitro. High Virus-IgG binding titers and virus-neutralizing antibody titers (VNT) were induced by immunization with RV-G mRNA-LNP. Additionally, our results showed that the RV-G mRNA vaccine is better than commercially available vaccines in mice. Conclusions: Our research highlights the potential of the mRNA-LNP platform in developing next-generation rabies vaccines.

Which Proteins? The Challenge of Identifying the Protective Antigens for Next-Generation Capripoxvirus Vaccines

Sheeppox, goatpox, and lumpy skin disease continue to negatively impact the sheep, goat, and cattle industries in countries where these diseases are present and threaten to spread into new regions. Effective vaccines are available for disease control and eradication. However, commercial vaccines are based on live attenuated virus isolates and therefore it is not currently possible to differentiate between infected and vaccinated animals (DIVA), which severely limits the use of these vaccines in countries that are free from disease and at risk of an incursion. The development of next-generation vaccines, including recombinant protein, viral-vectored, and mRNA, has been limited due to the lack of understanding of the protective antigen(s) of capripoxviruses. The complexity of capripoxviruses, with up to 156 open reading frames, makes the identification of protective antigen(s) difficult. This paper identifies the most promising antigens by first considering the membrane-associated proteins and then further selecting proteins based on immunogenicity and their role in immunity by comparing them to known orthopoxvirus homologues. From the 156 potential antigens, 13 have been identified as being the most likely to be protective. Further evaluation of these proteins, as immunogens, would be required to identify the optimal combination of immunodominant antigen(s) for the development of next-generation capripoxvirus vaccines.

Epitope-focused vaccine immunogens design using tailored horseshoe-shaped scaffold

The continuous emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants highlights the need to update coronavirus 2019 disease (COVID-19) vaccine components. Epitope-based vaccine designs targeting conserved and immunorecessive regions of SARS-CoV-2 are critically needed. Here, we report an engineered epitope-focused immunogen design based on a novel horseshoe-shaped natural protein scaffold, named ribonuclease inhibitor 1 (RNH1), that can multiply display of conserved neutralizing epitopes from SARS-CoV-2 S2 stem helix. The designed immunogen RNH1-S1139 demonstrates high binding affinity to S2-specific neutralizing antibodies and elicits robust epitope-targeted antibody responses either through homologous or heterologous vaccination regimens. RNH1-S1139 immune serum has been proven to have similar binding ability against SARS-CoV, SARS-CoV-2 and its variants, providing broad-spectrum protection as a membrane fusion inhibitor. Further studies showed that RNH1 has the potential to serve as a versatile scaffold that displays other helical epitopes from various antigens, including respiratory syncytial virus (RSV) F glycoprotein. Our proposed immunogen engineering strategy via tailored horseshoe-shape nano-scaffold supports the continued development of epitope-focused vaccines as part of a next-generation vaccine design.Graphical abstract

Indirect comparison of the relative vaccine effectiveness of mRNA-1283 vs. BNT162b2 vaccines against symptomatic COVID-19 among US adults

Background COVID-19 continues to pose a significant health burden, particularly among older adults. mRNA-1283 is a next-generation COVID-19 mRNA vaccine developed to enhance immune response. Findings from the Phase 3 NextCOVE trial comparing bivalent versions of mRNA-1273 and mRNA-1283 vaccines have recently become available. However, there are no head-to-head trials comparing mRNA-1283 and the BNT162b2 vaccine. Objective To indirectly compare the effectiveness of mRNA-1283 and BNT162b2 against symptomatic COVID-19 among adults in the U.S. Methods A targeted literature review was conducted to identify relevant studies comparing the mRNA-1273 and BNT162b2 bivalent vaccines. A real-world evidence (RWE) study by Kopel et al. (2023) assessing the relative vaccine effectiveness (rVE) of mRNA-1273 vs. BNT162b2, was selected for an indirect treatment comparison (ITC) against the NextCOVE trial using the Bucher method. Analyses were stratified by age group, and sensitivity analyses were conducted using alternative outcome definitions. Results Despite differences between NextCOVE and the Kopel study, comparability assessments supported a robust ITC. Among participants ≥18 years of age, the indirect rVE of mRNA-1283 vs. BNT162b2 against symptomatic COVID-19 was 15.3% (95% CI: 4.7–24.8%, p = 0.006). For adults ≥65 years of age, the rVE was 22.8% (95% CI: 3.7–38.1%, p = 0.022). Sensitivity analyses with alternative outcome definitions supported these estimates. Conclusion This analysis provides consistent and statistically significant evidence indicating the next-generation mRNA-1283 vaccine is more effective in preventing symptomatic COVID-19 than BNT162b2, with the largest effect in individuals aged ≥65. Consistent results across sensitivity analyses underscore the robustness of the findings, offering important evidence to inform vaccination decisions by policymakers, providers, and payers.

Tick Control Strategies: Critical Insights into Chemical, Biological, Physical, and Integrated Approaches for Effective Hard Tick Management.

Ticks and tick-borne diseases significantly impact animal health, public health, and economic productivity globally, particularly in areas where the wildlife-livestock interface complicates management. This review critically examines the current control strategies, focusing on chemical, biological, physical, and integrated pest management (IPM) approaches. Chemical acaricides, while effective, are increasingly challenged by resistance development and environmental concerns. Biological approaches, including natural predators and entomopathogenic fungi, and physical interventions, such as habitat modification, provide sustainable alternatives but require further optimization. IPM stands out as the most promising long-term solution, integrating multiple approaches to enhance efficacy while reducing environmental risks. Emerging innovations, such as nanotechnology-enhanced acaricides and next-generation vaccines, offer promising avenues for improved tick control. Addressing the complex challenges of tick management requires tailored strategies, interdisciplinary collaboration, and sustained research investment in both veterinary and public health contexts.

Genetically attenuated parasites show promise as a next-generation malaria vaccine.

Metabolically active, genetically attenuated Plasmodium falciparum parasite lines are promising second-generation malaria vaccine candidates. Lamers et al. and Roozen et al. demonstrated in recent Phase 1/2a trials that GA2 parasites, designed to arrest late during liver-stage development and transmitted via mosquito bites, can induce substantial protection against sporozoite challenge infection.

A nucleoside-modified rabies mRNA vaccine induces long-lasting and comprehensive immune responses in mice and non-human primates.

A nucleoside-modified rabies mRNA vaccine induces long-lasting and comprehensive immune responses in mice and non-human primates.

Recombinant protein HR212 targeting heptad repeat 2 domain in spike protein S2 subunit elicits broad-spectrum neutralizing antibodies against SARS-CoV-2 and its variants.

SARS-CoV-2 variants are under continuous emergence carry numerous mutations within S1 subunit in spike protein and have escaped neutralization through many currently used vaccines and antibodies. The development of next-generation vaccines is a continuing and long-term need. In our prior research, the recombinant protein vaccine HR121 targeting the heptad repeat (HR) 1 domain of S2 subunit was constructed, which could evoke highly broad-spectrum neutralizing antibodies in vivo and confer efficient protective effect on several SARS-CoV-2 variants within multiple animal models. Compared with HR1, HR2 domain shows a more conservative degree within SARS-CoV-2 and related coronaviruses. Here, we designed a recombinant protein HR212 consisting of HR2-linker1-HR1-linker2-HR2. HR212 showed a high affinity with HR1 and was functionally analogous to HR2 within fusion intermediate in S2 subunit. Immunizing rabbits using HR212-mediated high nAbs for 28 pseudotyped SARS-CoV-2 variants, like currently circulating variants, such as BA.2.86 and JN.1. Transfer of rabbit anti-HR212 sera or immunization with HR212 offered efficient protective effect on SARS-CoV-2 ancestral strain and Omicron BA.2 variant infections of Syrian golden hamsters. According to our results, HR2 domain of S2 subunit is the novel target that can be used to develop broad-spectrum vaccines to resist SARS-CoV-2 variants.

La Vacunología Reversa y Tecnologías Avanzadas en el Desarrollo de Vacunas de Nueva Generación contra Enfermedades Infecciosas

Reverse vaccinology is an innovative methodology for vaccine development that allows the identification of potential antigens without the need to culture the microorganism. Using bioinformatics tools and analysis of genomic and proteomic sequences, this approach has transformed vaccine research by accelerating the antigen discovery process and improving the accuracy of immunological target selection. In this article, recent advances in reverse vaccinology are reviewed, including the bioinformatics techniques employed, current challenges in predicting immunogenic epitopes, and ethical debates related to the use of genomic data. Case studies and key contributions from researchers in the field are also discussed, highlighting the potential of reverse vaccinology to develop next-generation vaccines against emerging diseases. Finally, potential future applications of this technology are explored, which promises to strengthen the global response to infectious diseases by designing more effective and personalized vaccines.

Modern approaches to predicting vaccine hesitancy: A scoping review.

Motivated by the disproportionate burden of infectious diseases on vulnerable populations and the risk of future pandemics, we conducted a scoping review to analyze the state of the literature about "vaccine uptake indices," defined as models that predict vaccination rates by geospatial area. We analyzed novel vaccine uptake indices created in response to the recent COVID-19 pandemic. The aim of this scoping review is to survey the state of the literature regarding vaccine uptake indices relating to COVID-19 and other infectious diseases. We conducted a scoping review with a systematic search strategy to identify relevant articles from the databases Embase, PubMed, and Web of Science with title and abstract screening, full-text review, and data extraction. Database searches resulted in 3,615 potential articles, of which 229 reports were included. Fifteen studies (7%) were determined to be methodologically advanced vaccine uptake indices that had at least three of the following characteristics: the use of individual- and population-level predictor variables (100 [44%]), geo-spatiotemporal analysis (58 [25%]), data usage agnostic to vaccine specificity (50 [22%]), or sociobehavioral frameworks of health (such as the Health Belief Model and Theory of Planned Behavior) (30 [13%]). This scoping review offers suggestions for future research of next-generation vaccine uptake indices before use in vaccination campaigns of recurring or novel infectious diseases. Areas to pursue include utilizing individual-level data about vaccination behaviors in conjunction with administrative data, solving the challenge of implementing small-area spatiotemporal analysis, using vaccine-agnostic methods that consider data from more than one infectious disease, and assisting causal inference with theoretical frameworks.