Greater Durability and Protection against Herpes Simplex Viral Disease following Immunization of Mice with Single-Cycle ΔgD-2 Compared to an Adjuvanted Glycoprotein D Protein Vaccine
Herpes simplex viruses (HSV) cause chronic infections with significant morbidity. Prior vaccines, designed to generate neutralizing antibodies (nAbs) targeting glycoprotein D (gD), failed to provide durable protection. We adopted a different strategy and evaluated a single-cycle virus deleted in gD...
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MDPI AG
2023-08-01
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| Series: | Vaccines |
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| Online Access: | https://www.mdpi.com/2076-393X/11/8/1362 |
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| author | Aakash Mahant Mahant Matthew S. Gromisch Leah Kravets Clare Burn Aschner Betsy C. Herold |
| author_facet | Aakash Mahant Mahant Matthew S. Gromisch Leah Kravets Clare Burn Aschner Betsy C. Herold |
| author_sort | Aakash Mahant Mahant |
| collection | DOAJ |
| description | Herpes simplex viruses (HSV) cause chronic infections with significant morbidity. Prior vaccines, designed to generate neutralizing antibodies (nAbs) targeting glycoprotein D (gD), failed to provide durable protection. We adopted a different strategy and evaluated a single-cycle virus deleted in gD (ΔgD-2). ΔgD-2elicits antibodies that primarily mediate antibody-dependent cell mediated cytolysis (ADCC) and provides complete protection against clinical isolates of HSV in multiple lethal mouse models. To assess durability, we vaccinated mice (2 doses administered intramuscularly) with ΔgD-2, adjuvanted recombinant gD-2 (rgD-2/Alum-MPL), or uninfected cells as a control, and quantified antibody responses over one year. Mice (n = 5/group) were lethally challenged at 2, 4, 6, 8, and 10-months post-boost. ΔgD-2-vaccinated mice elicited a durable ADCC-mediating response, which provided complete protection against challenge at all timepoints. In contrast, rgD-2/Alum-MPL elicited only nAbs, which declined significantly within 6 months, provided only partial protection at early timepoints, and no protection after 6 months. Serum sampling after viral challenge showed that infection elicited low levels of ADCC-mediating antibodies in rgD-2/Alum-MPL-vaccinated mice and boosted the nAb response, but only after 6 months. Conversely, infection significantly and consistently boosted both the ADCC and nAbs responses in ΔgD-2-vaccinated mice. Results recapitulate clinical trial outcomes with gD vaccines, highlight the importance of ADCC, and predict that ΔgD-2 will elicit durable responses in humans. |
| first_indexed | 2024-03-10T23:32:06Z |
| format | Article |
| id | doaj.art-e2a638bd645d4d09bc9ba285320ba755 |
| institution | Directory Open Access Journal |
| issn | 2076-393X |
| language | English |
| last_indexed | 2024-03-10T23:32:06Z |
| publishDate | 2023-08-01 |
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| record_format | Article |
| series | Vaccines |
| spelling | doaj.art-e2a638bd645d4d09bc9ba285320ba7552023-11-19T03:18:07ZengMDPI AGVaccines2076-393X2023-08-01118136210.3390/vaccines11081362Greater Durability and Protection against Herpes Simplex Viral Disease following Immunization of Mice with Single-Cycle ΔgD-2 Compared to an Adjuvanted Glycoprotein D Protein VaccineAakash Mahant Mahant0Matthew S. Gromisch1Leah Kravets2Clare Burn Aschner3Betsy C. Herold4Department of Microbiology-Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USADepartment of Microbiology-Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USADepartment of Microbiology-Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USADepartment of Microbiology-Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USADepartment of Microbiology-Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USAHerpes simplex viruses (HSV) cause chronic infections with significant morbidity. Prior vaccines, designed to generate neutralizing antibodies (nAbs) targeting glycoprotein D (gD), failed to provide durable protection. We adopted a different strategy and evaluated a single-cycle virus deleted in gD (ΔgD-2). ΔgD-2elicits antibodies that primarily mediate antibody-dependent cell mediated cytolysis (ADCC) and provides complete protection against clinical isolates of HSV in multiple lethal mouse models. To assess durability, we vaccinated mice (2 doses administered intramuscularly) with ΔgD-2, adjuvanted recombinant gD-2 (rgD-2/Alum-MPL), or uninfected cells as a control, and quantified antibody responses over one year. Mice (n = 5/group) were lethally challenged at 2, 4, 6, 8, and 10-months post-boost. ΔgD-2-vaccinated mice elicited a durable ADCC-mediating response, which provided complete protection against challenge at all timepoints. In contrast, rgD-2/Alum-MPL elicited only nAbs, which declined significantly within 6 months, provided only partial protection at early timepoints, and no protection after 6 months. Serum sampling after viral challenge showed that infection elicited low levels of ADCC-mediating antibodies in rgD-2/Alum-MPL-vaccinated mice and boosted the nAb response, but only after 6 months. Conversely, infection significantly and consistently boosted both the ADCC and nAbs responses in ΔgD-2-vaccinated mice. Results recapitulate clinical trial outcomes with gD vaccines, highlight the importance of ADCC, and predict that ΔgD-2 will elicit durable responses in humans.https://www.mdpi.com/2076-393X/11/8/1362herpes simplex virusvaccine durabilityantibody-dependent cellular cytotoxicitysingle-cycle DgD-2 vaccineglycoprotein D subunit vaccine |
| spellingShingle | Aakash Mahant Mahant Matthew S. Gromisch Leah Kravets Clare Burn Aschner Betsy C. Herold Greater Durability and Protection against Herpes Simplex Viral Disease following Immunization of Mice with Single-Cycle ΔgD-2 Compared to an Adjuvanted Glycoprotein D Protein Vaccine Vaccines herpes simplex virus vaccine durability antibody-dependent cellular cytotoxicity single-cycle DgD-2 vaccine glycoprotein D subunit vaccine |
| title | Greater Durability and Protection against Herpes Simplex Viral Disease following Immunization of Mice with Single-Cycle ΔgD-2 Compared to an Adjuvanted Glycoprotein D Protein Vaccine |
| title_full | Greater Durability and Protection against Herpes Simplex Viral Disease following Immunization of Mice with Single-Cycle ΔgD-2 Compared to an Adjuvanted Glycoprotein D Protein Vaccine |
| title_fullStr | Greater Durability and Protection against Herpes Simplex Viral Disease following Immunization of Mice with Single-Cycle ΔgD-2 Compared to an Adjuvanted Glycoprotein D Protein Vaccine |
| title_full_unstemmed | Greater Durability and Protection against Herpes Simplex Viral Disease following Immunization of Mice with Single-Cycle ΔgD-2 Compared to an Adjuvanted Glycoprotein D Protein Vaccine |
| title_short | Greater Durability and Protection against Herpes Simplex Viral Disease following Immunization of Mice with Single-Cycle ΔgD-2 Compared to an Adjuvanted Glycoprotein D Protein Vaccine |
| title_sort | greater durability and protection against herpes simplex viral disease following immunization of mice with single cycle δgd 2 compared to an adjuvanted glycoprotein d protein vaccine |
| topic | herpes simplex virus vaccine durability antibody-dependent cellular cytotoxicity single-cycle DgD-2 vaccine glycoprotein D subunit vaccine |
| url | https://www.mdpi.com/2076-393X/11/8/1362 |
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