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Dengue virus (DENV) is an arboviral disease affecting more than 400 million people annually. Only a single vaccine formulation is available commercially and many others are still under clinical trials. Despite all the efforts in vaccine designing, the improvement in vaccine formulation against DENV is very much needed. In this study, we used a roboust immunoinformatics approach, targeting all the four serotypes of DENV to design a multi-epitope vaccine. A total of 13501 MHC II binding CD4+ epitope peptides were predicted from polyprotein sequences of four dengue virus serotypes. Among them, ten conserved epitope peptides that were interferon-inducing were selected and found to be conserved among all the four dengue serotypes. The vaccine was formulated using antigenic, non-toxic and conserved multi epitopes discovered in the in-silico study. Further, the molecular docking and molecular dynamics predicted stable interactions between predicted vaccine and immune receptor, TLR-5. Finally, one of the mapped epitope peptides was synthesized for the validation of antigenicity and antibody production ability where the in-vivo tests on rabbit model was conducted. Our in-vivo analysis clearly indicate that the imunogen designed in this study could stimulate the production of antibodies which further suggest that the vaccine designed possesses good immunogenicity.

Emerging data have suggested that single short peptides have limited success as a cancer vaccine; however, extending the short peptides into longer multi-epitope peptides overcame the immune tolerance and induced an immune response. Moreover, the combination of adjuvants such as lenalidomide and anti-programmed cell death protein 1 (PD1) with a peptide vaccine showed potential vaccine effects in previous studies. Therefore, the effects of a long multi-epitope peptide vaccine in combination with lenalidomide and anti-PD1 were analyzed in this study. Long multi-epitope peptides from two MHCI peptides (BIRC5 97-104 and EphA2 682-689 ) and the pan-human leukocyte antigen-DR isotype (HLA-DR) binding epitope (PADRE) were synthesized. The therapeutic effects of long multi-epitope peptides in combination with lenalidomide and anti-PD1 were confirmed in the murine GL261 intracranial glioma model. Immune cells’ distribution and responses to the long multi-epitope peptides in combination with these adjuvants were also estimated in the spleens, lymph nodes, and tumor tissues. The difference between long multi-epitope peptides and a cocktail of multi-epitope peptides combined with lenalidomide and anti-PD1 was also clarified. As a result, long multi-epitope peptides combined with lenalidomide and anti-PD1 prolonged the survival of mice according to the suppression of tumor growth in an intracranial mouse model. While long multi-epitope peptides combined with these adjuvants enhanced the percentages of activated and memory effector CD8 + T cells, the increase in percentages of regulatory T cells (Tregs) was observed in a cocktail of multi-epitope peptides combined with lenalidomide and anti-PD1 group in the tumors. Long multi-epitope peptides combined with these adjuvants also enhanced the function of immune cells according to the enhanced pro-inflammatory cytokines and cytotoxicity against GL261 cells in ex vivo . In conclusion, long multi-epitope peptides composed of MHCI peptides, BIRC5 and EphA2, and the MHCII peptide, PADRE, in combination with lenalidomide and anti-PD1 has the potential to improve the therapeutic effects of a vaccine against GBM.

Neospora caninum (NC) is a protozoan infection causing neosporosis, a disease that leads to substantial economic loss in livestock, especially in cattle, sheep, and goats. Unfortunately, there is presently no viable vaccination or authorized therapy available. Our research applied a bioinformatics approach to design a multi-epitope peptide (MEP) vaccine aimed at the pathogenic proteins GRA2 and Nc-p43 of NC, which are critical in parasite-mediated antigenicity and host interactions. Consequently, our research employs an in-silico methodology, including protein sequence retrieval, epitope prediction, vaccine design, structural analysis, molecular docking, molecular dynamics simulations, immunological simulation, and codon optimization using in silico cloning. We conducted analyses of antigenicity, allergenicity, toxicity, topology, and immunogenicity using multiple bioinformatics methods and identified 4 CTL, 4 HTL, and 2 B-cell epitopes. The vaccine design was created by integrating an adjuvant and a PADRE sequence to enhance immunogenicity, along with linkers (AAY, GPGPG, KK) to facilitate appropriate structural assembly, which was then analyzed for optimal complete profiles. Molecular docking with the Bos taurus (cattle) TLR9 receptor demonstrated a robust binding affinity, scoring − 1183.4, while molecular dynamics (MD) simulations over 50 ns validated persistent interactions between the vaccine and immune receptors. Moreover, immunological models forecasted a robust adaptive immune response, marked by an increase in the production of cytokines and the establishment of memory T-lymphocytes. Ultimately, codon optimization and in silico cloning validated the capacity for effective expression in E. coli . The results demonstrate that the developed vaccine has considerable immunogenic potential against NC. Nonetheless, more in vitro and in vivo studies are necessary to confirm its efficiency.

The current production of the Japanese encephalitis virus (JEV) vaccine is based on animal cells, where various risk factors for human health should be resolved. This study used a transient expression system to express the chimeric protein composed of antigenic epitopes from the JEV envelope (E) protein in Nicotiana benthamiana. JEV multi-epitope peptide (MEP) sequences fused with FLAG-tag or 6× His-tag at the C- or N-terminus for the purification were introduced into plant expression vectors and used for transient expression. Among the constructs, vector pSK480, which expresses MEP fused with a FLAG-tag at the C-terminus, showed the highest level of expression and yield in purification. Optimization of transient expression procedures further improved the target protein yield. The purified MEP protein was applied to an ICR mouse and successfully induced an antibody against JEV, which demonstrates the potential of the plant-produced JEV MEP as an alternative vaccine candidate.

Zoonotic leishmaniases are a worldwide public health problem for which the development of effective vaccines remains a challenge. A vaccine against leishmaniases must be safe and affordable and should induce cross-protection against the different disease-causing species. In this context, the DNA vaccine pHisAK70 has been demonstrated to induce, in a murine model, a resistant phenotype against L. major, L. infantum, and L. amazonensis. Moreover, a chimeric multiepitope peptide, HisDTC, has been obtained by in silico analysis from the histone proteins encoded in the DNA vaccine and has showed its ability to activate a potent CD4+ and CD8+ T-cell protective immune response in mice against L. infantum infection. In the present study, we evaluated the plasmid DNA vaccine pHisAK70 in comparison with the peptide HisDTC (with and without saponin) against L. major and L. infantum infection. Our preliminary results showed that both formulations were able to induce a potent cellular response leading to a decrease in parasite load against L. infantum. In addition, the DNA candidate was able to induce better lesion control in mice against L. major. These preliminary results indicate that both strategies are potentially effective candidates for leishmaniases control. Furthermore, it is important to carry out such comparative studies to elucidate which vaccine candidates are the most appropriate for further development.

Colorectal cancer (CRC) is one of the most common cancers and is the second-highest in cancer-related deaths worldwide. The changes in gut homeostasis and microbial dysbiosis lead to the initiation of the tumorigenesis process. Several pathogenic gram-negative bacteria including Fusobacterium nucleatum are the principal contributors to the induction and pathogenesis of CRC. Thus, inhibiting the growth and survival of these pathogens can be a useful intervention strategy. Fibroblast activation protein-2 (Fap2) is an essential membrane protein of F. nucleatum that promotes the adherence of the bacterium to the colon cells, recruitment of immune cells, and induction of tumorigenesis. The present study depicts the design of an in silico vaccine candidate comprising the B-cell and T-cell epitopes of Fap2 for improving cell-mediated and humoral immune responses against CRC. Notably, this vaccine participates in significant protein–protein interactions with human Toll-like receptors, especially with TLR6 reveals, which is most likely to be correlated with its efficacy in eliciting potential immune responses. The immunogenic trait of the designed vaccine was verified by immune simulation approach. The cDNA of the vaccine construct was cloned in silico within the expression vector pET30ax for protein expression. Collectively, the proposed vaccine construct may serve as a promising therapeutic in intervening F. nucleatum-induced human CRC.

Brucellosis is one of the neglected endemic zoonoses in the world. Vaccination appears to be a promising health strategy to prevent it. This study used advanced computational techniques to develop a potent multi-epitope vaccine for human brucellosis. Seven epitopes from four main brucella species that infect humans were selected. They had significant potential to induce cellular and humoral responses. They showed high antigenic ability without the allergenic characteristic. In order to improve its immunogenicity, suitable adjuvants were also added to the structure of the vaccine. The physicochemical and immunological properties of the vaccine were evaluated. Then its two and three-dimensional structure was predicted. The vaccine was docked with toll-like receptor4 to assess its ability to stimulate innate immune responses. For successful expression of the vaccine protein in Escherichia coli, in silico cloning, codon optimization, and mRNA stability were evaluated. The immune simulation was performed to reveal the immune response profile of the vaccine after injection. The designed vaccine showed the high ability to induce immune response, especially cellular responses to human brucellosis. It showed the appropriate physicochemical properties, a high-quality structure, and a high potential for expression in a prokaryotic system.

[...]strategies, such as combining peptides as multi-epitope vaccines or presenting peptides on vaccinia virus particles, are employed. On top of that, predicting the strains that must be included in the formulation of vaccines for combating upcoming influenza outbreaks is difficult owing to gene mutations through antigenic drift and shift patterns in influenza viruses (4). [...]the use of hemagglutinin (HA) (5) as the antigen of choice in the present vaccine formulation and the classic manner of producing influenza vaccine in embryonated chicken eggs reduce the efficacy of influenza vaccines (6). [...]its antigenicity is altered and the stimulation of humoral responses that inhibit the binding of virus to host cells is limited. The triepitope peptide vaccine provided greater protection than the single epitope. [...]the immune responses induced by the triepitope peptide vaccine lasted longer and were able to protect vaccinated mice challenged with influenza virus seven months since the last boost (18).

Canine leishmaniosis (CanL) is a growing health problem for which vaccination is a crucial tool for the control of disease. The successful development of an effective vaccine against this disease relies on eliciting a robust and enduring T-cell immune response involving the activation of CD4+ Th1 and CD8+ T-cells. This study aimed to evaluate the immunogenicity and prophylactic efficacy of a novel nanovaccine comprising a multi-epitope peptide, known as HisDTC, encapsulated in PLGA nanoparticles against Leishmania infantum infection in the murine model. The encapsulation strategy was designed to enhance antigen loading and sustain release, ensuring prolonged exposure to the immune system. Our results showed that mice immunized with PLGA-encapsulated HisDTC exhibited a significant reduction in the parasite load in the liver and spleen over both short and long-term duration. This reduction was associated with a cellular immune profile marked by elevated levels of pro-inflammatory cytokines, such as IFN-γ, and the generation of memory T cells. In conclusion, the current study establishes that PLGA-encapsulated HisDTC can promote effective and long-lasting T-cell responses against L. infantum in the murine model. These findings underscore the potential utility of multi-epitope vaccines, in conjunction with appropriate delivery systems, as an alternative strategy for CanL control.

Hyalomma anatolicum is the principal vector for Theileria annulata, T. equi, and T. Lestoquardi in animals and the Crimean–Congo hemorrhagic fever virus in humans. Due to the gradual loss of efficacy of the available acaricides against field tick populations, the development of phytoacaricides and vaccines has been considered the two most critical components of the integrated tick management strategies. In the present study, in order to induce both cellular and humoral immune responses in the host against H. anatolicum, two multi-epitopic peptides (MEPs), i.e., VT1 and VT2, were designed. The immune-stimulating potential of the constructs was determined by in silicoinvestigation on allergenicity (non-allergen, antigenic (0.46 and 1.0046)), physicochemical properties (instability index 27.18 and 35.46), as well as the interaction of constructs with TLRs by docking and molecular dynamics analysis. The immunization efficacy of the MEPs mixed with 8% MontanideTM gel 01 PR against H. anatolicum larvae was determined as 93.3% and 96.9% in VT1- and VT2-immunized rabbits, respectively. Against adults, the efficacy was 89.9% and 86.4% in VT1- and VT2-immunized rabbits, respectively. A significant (p < 0.001) reduction in the anti-inflammatory cytokine (IL-4) and significantly higher IgG response was observed in a VT1-immunized group of rabbits as compared with the response observed in the control group. However, in the case of the VT2-immunized rabbits, an elevated anti-VT2 IgG and pro-inflammatory cytokine (IL-2) (>30 fold) along with a decreased level of anti-inflammatory cytokine IL-4 (0.75 times) was noted. The efficacy of MEP and its potential immune stimulatory responses indicate that it might be useful for tick management.