Vaccination Route as a Determinant of Protective Antibody Responses against Herpes Simplex Virus
Herpes simplex viruses (HSV) are significant global health problems associated with mucosal and neurologic disease. Prior experimental vaccines primarily elicited neutralizing antibodies targeting glycoprotein D (gD), but those that advanced to clinical efficacy trials have failed. Preclinical studi...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-06-01
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| Series: | Vaccines |
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| Online Access: | https://www.mdpi.com/2076-393X/8/2/277 |
| _version_ | 1797566099670171648 |
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| author | Clare Burn Aschner Carl Pierce David M. Knipe Betsy C. Herold |
| author_facet | Clare Burn Aschner Carl Pierce David M. Knipe Betsy C. Herold |
| author_sort | Clare Burn Aschner |
| collection | DOAJ |
| description | Herpes simplex viruses (HSV) are significant global health problems associated with mucosal and neurologic disease. Prior experimental vaccines primarily elicited neutralizing antibodies targeting glycoprotein D (gD), but those that advanced to clinical efficacy trials have failed. Preclinical studies with an HSV-2 strain deleted in gD (ΔgD-2) administered subcutaneously demonstrated that it elicited a high titer, weakly neutralizing antibodies that activated Fcγ receptors to mediate antibody-dependent cellular cytotoxicity (ADCC), and completely protected mice against lethal disease and latency following vaginal or skin challenge with HSV-1 or HSV-2. Vaccine efficacy, however, may be impacted by dose and route of immunization. Thus, the current studies were designed to compare immunogenicity and efficacy following different routes of vaccination with escalating doses of ΔgD-2. We compared ΔgD-2 with two other candidates: recombinant gD protein combined with aluminum hydroxide and monophosphoryl lipid A adjuvants and a replication-defective virus deleted in two proteins involved in viral replication, <i>dl</i>5-29. Compared to the subcutaneous route, intramuscular and/or intradermal immunization resulted in increased total HSV antibody responses for all three vaccines and boosted the ADCC, but not the neutralizing response to ΔgD and <i>dl</i>5-29. The adjuvanted gD protein vaccine provided only partial protection and failed to elicit ADCC independent of route of administration. In contrast, the increased ADCC following intramuscular or intradermal administration of ΔgD-2 or <i>dl</i>5-29 translated into significantly increased protection. The ΔgD-2 vaccine provided 100% protection at doses as low as 5 × 10<sup>4</sup> pfu when administered intramuscularly or intradermally, but not subcutaneously. However, administration of a combination of low dose subcutaneous ΔgD-2 and adjuvanted gD protein resulted in greater protection than low dose ΔgD-2 alone indicating that gD neutralizing antibodies may contribute to protection. Taken together, these results demonstrate that ADCC provides a more predictive correlate of protection against HSV challenge in mice and support intramuscular or intradermal routes of vaccination. |
| first_indexed | 2024-03-10T19:21:55Z |
| format | Article |
| id | doaj.art-8b6dc9146af24307b2472351b0034a5f |
| institution | Directory Open Access Journal |
| issn | 2076-393X |
| language | English |
| last_indexed | 2024-03-10T19:21:55Z |
| publishDate | 2020-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Vaccines |
| spelling | doaj.art-8b6dc9146af24307b2472351b0034a5f2023-11-20T02:56:21ZengMDPI AGVaccines2076-393X2020-06-018227710.3390/vaccines8020277Vaccination Route as a Determinant of Protective Antibody Responses against Herpes Simplex VirusClare Burn Aschner0Carl Pierce1David M. Knipe2Betsy C. Herold3Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USADepartment of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USADepartment of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USADepartment of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USAHerpes simplex viruses (HSV) are significant global health problems associated with mucosal and neurologic disease. Prior experimental vaccines primarily elicited neutralizing antibodies targeting glycoprotein D (gD), but those that advanced to clinical efficacy trials have failed. Preclinical studies with an HSV-2 strain deleted in gD (ΔgD-2) administered subcutaneously demonstrated that it elicited a high titer, weakly neutralizing antibodies that activated Fcγ receptors to mediate antibody-dependent cellular cytotoxicity (ADCC), and completely protected mice against lethal disease and latency following vaginal or skin challenge with HSV-1 or HSV-2. Vaccine efficacy, however, may be impacted by dose and route of immunization. Thus, the current studies were designed to compare immunogenicity and efficacy following different routes of vaccination with escalating doses of ΔgD-2. We compared ΔgD-2 with two other candidates: recombinant gD protein combined with aluminum hydroxide and monophosphoryl lipid A adjuvants and a replication-defective virus deleted in two proteins involved in viral replication, <i>dl</i>5-29. Compared to the subcutaneous route, intramuscular and/or intradermal immunization resulted in increased total HSV antibody responses for all three vaccines and boosted the ADCC, but not the neutralizing response to ΔgD and <i>dl</i>5-29. The adjuvanted gD protein vaccine provided only partial protection and failed to elicit ADCC independent of route of administration. In contrast, the increased ADCC following intramuscular or intradermal administration of ΔgD-2 or <i>dl</i>5-29 translated into significantly increased protection. The ΔgD-2 vaccine provided 100% protection at doses as low as 5 × 10<sup>4</sup> pfu when administered intramuscularly or intradermally, but not subcutaneously. However, administration of a combination of low dose subcutaneous ΔgD-2 and adjuvanted gD protein resulted in greater protection than low dose ΔgD-2 alone indicating that gD neutralizing antibodies may contribute to protection. Taken together, these results demonstrate that ADCC provides a more predictive correlate of protection against HSV challenge in mice and support intramuscular or intradermal routes of vaccination.https://www.mdpi.com/2076-393X/8/2/277HSV vaccinesintradermalintramuscularADCC |
| spellingShingle | Clare Burn Aschner Carl Pierce David M. Knipe Betsy C. Herold Vaccination Route as a Determinant of Protective Antibody Responses against Herpes Simplex Virus Vaccines HSV vaccines intradermal intramuscular ADCC |
| title | Vaccination Route as a Determinant of Protective Antibody Responses against Herpes Simplex Virus |
| title_full | Vaccination Route as a Determinant of Protective Antibody Responses against Herpes Simplex Virus |
| title_fullStr | Vaccination Route as a Determinant of Protective Antibody Responses against Herpes Simplex Virus |
| title_full_unstemmed | Vaccination Route as a Determinant of Protective Antibody Responses against Herpes Simplex Virus |
| title_short | Vaccination Route as a Determinant of Protective Antibody Responses against Herpes Simplex Virus |
| title_sort | vaccination route as a determinant of protective antibody responses against herpes simplex virus |
| topic | HSV vaccines intradermal intramuscular ADCC |
| url | https://www.mdpi.com/2076-393X/8/2/277 |
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