Immunological Considerations for the Development of an Effective Herpes Vaccine
Abstract
:1. Introduction
2. Overview of HSV Route of Infection and Clinical Complications
2.1. Transmission of the HSV Infection
2.2. Ocular Herpes Infection
2.3. Genital Herpes Infection
2.4. Neonatal Herpes Infection
3. Mechanism of Viral Latency
4. Immune Reactions against HSV
4.1. Innate Immunity
4.2. Adaptive Immunity against HSV
4.3. Cellular Immunity
4.4. Humoral Immunity
4.5. Cytokines
5. Current Approaches for Design of HSV Vaccines
Classification | Vaccine Design | Year | Stage | Study Model | Benefits | Disadvantages | References |
---|---|---|---|---|---|---|---|
Replication-defective | Deletion of HSV-1 gH coding sequences (SC16∆gH) Deletion of HSV-2 UL5 gene or UL4 ORF (dl5) or UL29 gene or UL5 and UL29 genes (dl5-29) or ICP10∆PK | 1994–2019 | Preclinical and clinical | Mice Guinea pigs Human | Establishes a self-limiting infection. Protects against acute infection, local viral replication, primary disease, and recurrence and shortens disease episodes. Long-lasting immune responses over 6 months. Better potency for complete protection. Induces defective viral replication and latent infection by reducing viral titer and shedding. Safe for immunocompromised individuals. Induces memory T cells by eliciting HSV-specific T-helper type 1 and increases IL-12 production by DCs. Promotes increased T-cell responses and anti-HSV neutralizing antibody production. Effective against a wide range of HSV strains. | No improvements in duration of viral shedding, frequency and severity of recurrences, and lesion healing time. Non-efficient during first recurrence of genital HSV. Induces delayed-type hypersensitivity responses. Some of the antigens only induce CD4+ T cells in HSV-seropositive individuals. | [110,111] |
Replication-defective | HSV-2 ICP8− with B7 co-stimulation molecules Deletion of HSV-2 glycoprotein D | 2007–2020 | Preclinical | Mice | Boosts FcγR-activating responses and increases IgG2 antibodies. Increases effector T-cell production of IFN–γ. Decreases viral replication and spreading in mucosa and to the sacral ganglia. Improved overall survival. | Patients still show signs of genital and neurological disease. Not applicable for measuring reactivation of latent virus. | [112,113] |
Live-attenuated | Live rHSV (R7017, R7020, RAV9395, VC2 with mutations in gK, membrane protein, R2) HSV-1 0∆NLS, HSV-2 0gD∆NLS | 1998–2020 | Preclinical | Mice Guinea pigs Rabbits | Reduces viral shedding and recurrent disease in ocular and vaginal herpes, TG, and brain neurons. gB induces expression and release of IFN-γ, granzyme B, and CD107a and decreases T-cell exhaustion (LAG-3, PD-1, and TIM-3). Protects against severe infections and lethal IV antigen challenge. | Option as a prophylactic vaccine, not as a therapeutic vaccine. Not sufficient to provide broad protection against HSV infection. | [72,76,78,114,115] |
Protein-based subunit | gD2t, gD, gB, gE2 (mixed with adjuvants) | 2002–2020 | Preclinical and clinical | Mice Guinea pigs Human | Protects against acute and recurrent HSV-2. Induces antigen-specific CD8+ T cells and high antibody levels and reduces viral shedding. Induces mobilization of DCs. Sustained durability of response for up to 21 months. | [79,116,117] | |
Peptide-based | Neutralizing epitope of CD8, CTL, and T helper HLA-A2 epitopes, HSP + 32-35 mer peptides | 2011–2021 | Preclinical clinical | Mice | Reduces vaginal lesions. Generates high levels of mucosal antibodies (IgA). Able to block viral infection. | Toxicological studies are absent and not tested against latent infections. | [91,92,118] |
Naked DNA vaccine | pDNA encoding several genes | 1995–2020 | Preclinical and clinical | Mice Guinea pigs Human | Decreases viral shedding. Prevents pathological progression after infection, improves survival, and increases infiltration of leukocytes. Induces specific cytotoxic T cells and is safe and well tolerated. Reduces latent viral load. | Limited protection against lethal dose in the animal model. | [76,119,120] |
mRNA-based HSV vaccine | Tri-HSV mRNA encoding the ectodomains of gC1, gD1, and gE1 proteins | 2023 | Preclinical and clinical | Mice Human | Stimulates robust CD4+ T-helper cells and germinal center B-cell responses and produces high levels of antibodies. BNT163 (BioNtTech, Mainz, Germany) (ClinicalTrials.gov Identifier, NCT05432583), mRNA-1608 vaccine (Moderna Inc., Cambridge, MA, USA). | [121,122,123] | |
Prime-pull vaccine | Adv viral peptides + T-cell chemokines (CXCL-x) | 2018 | Preclinical clinical | Mice Guinea pigs Rabbit Human | Mobilizes tissue-resident and effector T-cell subsets to the site of infection. Can prime with different peptides or adenoviral vectors. Shows humoral and cellular immune activation against active and latent infection. | Toxicological studies are absent. | [118] |
6. T-Cell Epitope Vaccines
6.1. Identification of T-Cell Immunophenotypes to Evaluate T-Cell Vaccines
6.2. Functional Assays to Evaluate T-Cell Vaccines
6.3. Transcriptome Analysis for T-Cell Vaccines
7. Conventional Method for Evaluating Efficacy of Herpes Vaccine by Differential CD8+ T-Cell Interactions against HSV
7.1. Resident Functional Memory CD8+ T-Cell Epitopes
7.2. Types of Memory CD8+ T Cells
8. Important Perspectives of Immune Aspects for Designing a Successful Vaccine against Herpes
9. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Singer, M.; Husseiny, M.I. Immunological Considerations for the Development of an Effective Herpes Vaccine. Microorganisms 2024, 12, 1846. https://doi.org/10.3390/microorganisms12091846
Singer M, Husseiny MI. Immunological Considerations for the Development of an Effective Herpes Vaccine. Microorganisms. 2024; 12(9):1846. https://doi.org/10.3390/microorganisms12091846
Chicago/Turabian StyleSinger, Mahmoud, and Mohamed I. Husseiny. 2024. "Immunological Considerations for the Development of an Effective Herpes Vaccine" Microorganisms 12, no. 9: 1846. https://doi.org/10.3390/microorganisms12091846