Computational design and evaluation of multiepitope vaccines against herpes simplex virus type 1

Abstract

Introduction: Herpes simplex virus type 1 (HSV-1) is a prevalent human pathogen, causing infections in various tissues and leading to severe complications such as herpes simplex encephalitis and cognitive impairments. Despite existing antiviral treatments, recurrent infections and the lack of effective vaccines highlight the need for new preventive measures.

Methods: We employed immunogenomic and bioinformatics methods to design two multi-epitope vaccine constructs 1 and 2 against HSV-1. The Immune Epitope Database was used to identify B-cell and T-cell epitopes from HSV-1 glycoproteins. The IFN epitope server and the IL4pred/IL-10pred server were used to ascertain the activation possibility of IFN-γ, IL-4, and IL-10. The NetMHC-4.0 and NetMHCII2.3 servers were used to identify MHC epitopes. The constructed vaccine was analyzed for antigenicity and allergenicity using the VaxiJen v2.0 and AllergenFP servers. The three-dimensional structure of the vaccine construct was constructed using the AlphaFold3 tool. The ClusPro 2.0 server was utilized for molecular docking and the Desmond module in Schrodinger 2021-1 was utilized for molecular dynamics and MM/PBSA analysis. The immunogenicity and the corresponding immune response curves were analyzed using the C-ImmSim server.

Results: Bioinformatics analysis demonstrated that these vaccines exhibited both good affinity and immunogenicity, and were non-toxic and non-allergenic to the host. In addition, vaccine construct 2 exhibits superior stability and binding affinity with TLR9, and is more effective in triggering a robust immune response.

Discussion: This approach targets the key mechanisms of HSV-1 entry and TLR-mediated immune responses, providing a potential strategy for preventing and treating HSV-1 infections. Furthermore, the identified and optimized vaccine construct offers a promising avenue for developing a preventive vaccine against HSV-1, addressing the critical need for better control of this widespread virus.

Keywords: HSV-1; immune response; molecular docking; molecular dynamics simulation; multiepitope vaccine.

Figure 1

Vaccine construction. (A) Schematic diagram of vaccine construct. (B, C) Amino acid sequence of vaccine construction V1 and V2.

Figure 2

Spatial structure and structural characteristics analysis of vaccine constructs. (A, B) 3D model of V1 and V2. (C, D) Ramachandran diagram of V1 and V2. (E, F) ERRAT mass value of V1 and V2.

Figure 3

Interactions between TLR9 and vaccine constructs. (A) Interaction between vaccine construct 1 and TLR9. (B) Interaction between vaccine construct 2 and TLR9.

Figure 4

The molecular dynamics simulation of vaccine constructs and TLR9. (A) Root mean square deviation analysis of TLR9, the TLR9-V1 complex, and the TLR9-V2 complex. (B) Root mean square fluctuation analysis of TLR9 bound to V1 and V2. (C) Solvent-accessible surface area analysis of the TLR9-V1 and TLR9-V2 complex. (D) Hydrogen bond analysis of the TLR9-V1 and TLR9-V2 interaction. (E, F) Radius of gyration (Rg) analysis of the TLR9-V1 complex (E) and the TLR9-V2 complex (F). (G, H) Binding free energy analysis of the TLR9-V1 (G) and the TLR9-V2 (H) interaction.

Figure 5

Key amino acids between TLR9 and vaccine constructs. (A) The binding energy between the vaccine constructs and TLR9 is evaluated by MM/PBSA Analysis, with different colors indicating various types of binding energy. (B) Key residues of TLR9 binding to the V1. (C) Key residues of V1 binding to TLR9. (D) Key residues of TLR9 binding to the V2. (E) Key residues of V2 binding to TLR9.

Figure 6

The immune system′s reaction to a simulated vaccine construct 1. (A) Response of antigen and immunoglobulines. (B) Cytokine response patterns. The ‘D’ in the insert plot represents the danger signal. (C) Total count of B lymphocytes and its different subtypes, including memory cells, IgM-, IgG1- and IgG2- isotypes, were shown. (D) CD4 T-helper lymphocytes count. (E) Total and memory CD8 T-cytotoxic lymphocytes. (F) Natural Killer cells.

Figure 7

The immune system′s reaction to a simulated vaccine construct 2. (A) Response of antigen and immunoglobulines. (B) Cytokine response patterns. The ‘D’ in the insert plot represents the danger signal. (C) Total count of B lymphocytes and its different subtypes, including memory cells, IgM-, IgG1- and IgG2- isotypes, were shown. (D) CD4 T-helper lymphocytes count. (E) Total and memory CD8 T-cytotoxic lymphocytes. (F) Natural Killer cells.