{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T20:54:12Z","timestamp":1770065652788,"version":"3.49.0"},"reference-count":35,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2021,6,30]],"date-time":"2021-06-30T00:00:00Z","timestamp":1625011200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI17321, AI134367, P30AI124414"],"award-info":[{"award-number":["R01AI17321, AI134367, P30AI124414"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Herpes simplex virus (HSV) prevention is a global health priority but, despite decades of research, there is no effective vaccine. Prior efforts focused on generating glycoprotein D (gD) neutralizing antibodies, but clinical trial outcomes were disappointing. The deletion of gD yields a single-cycle candidate vaccine (\u2206gD-2) that elicits high titer polyantigenic non-gD antibodies that exhibit little complement-independent neutralization but mediate antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP). Active or passive immunization with \u0394gD-2 completely protects mice from lethal disease and latency following challenge with clinical isolates of either serotype. The current studies evaluated the role of complement in vaccine-elicited protection. The immune serum from the \u0394gD-2 vaccinated mice exhibited significantly greater C1q binding compared to the serum from the gD protein vaccinated mice with infected cell lysates from either serotype as capture antigens. The C1q-binding antibodies recognized glycoprotein B. This resulted in significantly greater antibody-mediated complement-dependent cytolysis and neutralization. Notably, complete protection was preserved when the \u0394gD-2 immune serum was passively transferred into C1q knockout mice, suggesting that ADCC and ADCP are sufficient in mice. We speculate that the polyfunctional responses elicited by \u0394gD-2 may prove more effective in preventing HSV, compared to the more restrictive responses elicited by adjuvanted gD protein vaccines.<\/jats:p>","DOI":"10.3390\/v13071284","type":"journal-article","created":{"date-parts":[[2021,7,1]],"date-time":"2021-07-01T05:00:10Z","timestamp":1625115610000},"page":"1284","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Antibodies Elicited in Response to a Single Cycle Glycoprotein D Deletion Viral Vaccine Candidate Bind C1q and Activate Complement Mediated Neutralization and Cytolysis"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7112-7111","authenticated-orcid":false,"given":"Maria Luisa","family":"Visciano","sequence":"first","affiliation":[{"name":"Departments of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0530-122X","authenticated-orcid":false,"given":"Aakash Mahant","family":"Mahant","sequence":"additional","affiliation":[{"name":"Departments of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5041-1412","authenticated-orcid":false,"given":"Carl","family":"Pierce","sequence":"additional","affiliation":[{"name":"Departments of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard","family":"Hunte","sequence":"additional","affiliation":[{"name":"Departments of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Betsy C.","family":"Herold","sequence":"additional","affiliation":[{"name":"Departments of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA"},{"name":"Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY 10461, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Looker, K.J., Magaret, A.S., May, M.T., Turner, K.M.E., Vickerman, P., Gottlieb, S.L., and Newman, L.M. (2015). Global and Regional Estimates of Prevalent and Incident Herpes Simplex Virus Type 1 Infections in 2012. PLoS ONE., 10.","DOI":"10.1371\/journal.pone.0140765"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Looker, K.J., Magaret, A.S., Turner, K.M., Vickerman, P., Gottlieb, S.L., and Newman, L.M. (2015). Global estimates of prevalent and incident herpes simplex virus type 2 infections in 2012. PLoS ONE., 10.","DOI":"10.1371\/journal.pone.0128615"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1056\/NEJMe068302","article-title":"Synergistic copathogens--HIV-1 and HSV-2","volume":"356","author":"Corey","year":"2007","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Abu-Raddad, L.J., Magaret, A.S., Celum, C., Wald, A., Longini, I.M., Self, S.G., and Corey, L. (2008). Genital herpes has played a more important role than any other sexually transmitted infection in driving HIV prevalence in Africa. PLoS ONE, 3.","DOI":"10.1371\/journal.pone.0002230"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"7408","DOI":"10.1016\/j.vaccine.2017.10.084","article-title":"Meeting report: Initial World Health Organization consultation on herpes simplex virus (HSV) vaccine preferred product characteristics, March 2017","volume":"37","author":"Gottlieb","year":"2019","journal-title":"Vaccine"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"469","DOI":"10.21775\/cimb.041.469","article-title":"Alphaherpesvirus Vaccines","volume":"41","author":"Aschner","year":"2021","journal-title":"Curr. Issues Mol. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1093\/infdis\/jit651","article-title":"Correlate of immune protection against HSV-1 genital disease in vaccinated women","volume":"209","author":"Belshe","year":"2014","journal-title":"J. Infect. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1056\/NEJMoa1103151","article-title":"Efficacy results of a trial of a herpes simplex vaccine","volume":"366","author":"Belshe","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1086\/429240","article-title":"Safety and immunogenicity of glycoprotein D-adjuvant genital herpes vaccine","volume":"40","author":"Bernstein","year":"2005","journal-title":"Clin. Infect. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1652","DOI":"10.1056\/NEJMoa011915","article-title":"Glycoprotein-D-adjuvant vaccine to prevent genital herpes","volume":"347","author":"Stanberry","year":"2002","journal-title":"N. Engl. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1001\/jama.282.4.331","article-title":"Recombinant glycoprotein vaccine for the prevention of genital HSV-2 infection: Two randomized controlled trials. Chiron HSV Vaccine Study Group","volume":"282","author":"Corey","year":"1999","journal-title":"JAMA"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Aschner, C.B., Pierce, C., Knipe, D.M., and Herold, B.C. (2020). Vaccination Route as a Determinant of Protective Antibody Responses against Herpes Simplex Virus. Vaccines, 8.","DOI":"10.3390\/vaccines8020277"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e00335-20","DOI":"10.1128\/JVI.00335-20","article-title":"A Single-Cycle Glycoprotein D Deletion Viral Vaccine Candidate, DeltagD-2, Elicits Polyfunctional Antibodies That Protect against Ocular Herpes Simplex Virus","volume":"94","author":"Ramsey","year":"2020","journal-title":"J. Virol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1093\/infdis\/jiz521","article-title":"Murine Model of Maternal Immunization Demonstrates Protective Role for Antibodies That Mediate Antibody-Dependent Cellular Cytotoxicity in Protecting Neonates From Herpes Simplex Virus Type 1 and Type 2","volume":"221","author":"Kao","year":"2020","journal-title":"J. Infect. Dis."},{"key":"ref_15","first-page":"754","article-title":"A Herpes Simplex Virus (HSV)-2 Single-Cycle Candidate Vaccine Deleted in Glycoprotein D Protects Male Mice from Lethal Skin Challenge with Clinical Isolates of HSV-1 and HSV-2","volume":"217","author":"Burn","year":"2018","journal-title":"J. Infect. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e88529","DOI":"10.1172\/jci.insight.88529","article-title":"HSV-2 DeltagD elicits FcgammaR-effector antibodies that protect against clinical isolates","volume":"1","author":"Petro","year":"2016","journal-title":"JCI Insight."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e06054","DOI":"10.7554\/eLife.06054","article-title":"Herpes simplex type 2 virus deleted in glycoprotein D protects against vaginal, skin and neural disease","volume":"4","author":"Petro","year":"2015","journal-title":"eLife"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Burn Aschner, C., Loh, L.N., Galen, B., Delwel, I., Jangra, R.K., Garforth, S.J., Chandran, K., Almo, S., Jacobs, W.R., and Ware, C.F. (2020). HVEM signaling promotes protective antibody-dependent cellular cytotoxicity (ADCC) vaccine responses to herpes simplex viruses. Sci. Immunol., 5.","DOI":"10.1126\/sciimmunol.aax2454"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/j.chom.2009.09.003","article-title":"Complement protein C1q reduces the stoichiometric threshold for antibody-mediated neutralization of West Nile virus","volume":"6","author":"Mehlhop","year":"2009","journal-title":"Cell Host Microbe"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1486","DOI":"10.1128\/jvi.62.5.1486-1494.1988","article-title":"A herpes simplex virus mutant in which glycoprotein D sequences are replaced by beta-galactosidase sequences binds to but is unable to penetrate into cells","volume":"62","author":"Ligas","year":"1988","journal-title":"J. Virol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2584","DOI":"10.1096\/fj.12-220285","article-title":"HSV activates Akt to trigger calcium release and promote viral entry: Novel candidate target for treatment and suppression","volume":"27","author":"Cheshenko","year":"2013","journal-title":"FASEB J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1099\/0022-1317-2-3-357","article-title":"Characterization of herpes simplex virus strains differing in their effects on social behaviour of infected cells","volume":"2","author":"Ejercito","year":"1968","journal-title":"J. Gen. Virol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"6257","DOI":"10.1128\/JVI.00012-13","article-title":"Griffithsin Protects Mice from Genital Herpes by Preventing Cell-to-Cell Spread","volume":"87","author":"Nixon","year":"2013","journal-title":"J. Virol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Segarra, T.J., Fakioglu, E., Cheshenko, N., Wilson, S.S., Mesquita, P.M.M., Doncel, G.F., and Herold, B.C. (2011). Bridging the gap between preclinical and clinical microbicide trials: Blind evaluation of candidate gels in murine models of efficacy and safety. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0027675"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1172\/JCI110696","article-title":"Neutralization of Epstein-Barr virus by nonimmune human serum. Role of cross-reacting antibody to herpes simplex virus and complement","volume":"70","author":"Nemerow","year":"1982","journal-title":"J. Clin. Investig."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"9213","DOI":"10.1128\/JVI.01213-15","article-title":"Patient-Specific Neutralizing Antibody Responses to Herpes Simplex Virus Are Attributed to Epitopes on gD, gB, or Both and Can Be Type Specific","volume":"89","author":"Cairns","year":"2015","journal-title":"J. Virol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41541-017-0038-0","article-title":"Complement enhances in vitro neutralizing potency of antibodies to human cytomegalovirus glycoprotein B (gB) and immune sera induced by gB\/MF59 vaccination","volume":"2","author":"Li","year":"2017","journal-title":"NPJ Vaccines"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1006\/viro.1995.9957","article-title":"Differences in the role of glycoprotein C of HSV-1 and HSV-2 in viral binding may contribute to serotype differences in cell tropism","volume":"214","author":"Gerber","year":"1995","journal-title":"Virology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e01852-19","DOI":"10.1128\/JVI.01852-19","article-title":"Glycoprotein C of Herpes Simplex Virus 1 Shields Glycoprotein B from Antibody Neutralization","volume":"94","author":"Gianopulos","year":"2020","journal-title":"J. Virol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"8421","DOI":"10.1128\/JVI.01130-14","article-title":"Blocking herpes simplex virus 2 glycoprotein E immune evasion as an approach to enhance efficacy of a trivalent subunit antigen vaccine for genital herpes","volume":"88","author":"Awasthi","year":"2014","journal-title":"J. Virol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Awasthi, S., Hook, L.M., Pardi, N., Wang, F., Myles, A., Cancro, M.P., Cohen, G.H., Weissman, D., and Friedman, H.M. (2019). Nucleoside-modified mRNA encoding HSV-2 glycoproteins C, D, and E prevents clinical and subclinical genital herpes. Sci. Immunol., 4.","DOI":"10.1126\/sciimmunol.aaw7083"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1007\/s002620000120","article-title":"Comparison of in vitro antibody-targeted cytotoxicity using mouse, rat and human effectors","volume":"49","author":"Bergman","year":"2000","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1093\/infdis\/jiz364","article-title":"Survivors of Ebola Virus Disease Develop Polyfunctional Antibody Responses","volume":"221","author":"Gunn","year":"2020","journal-title":"J. Infect. Dis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e00765-21","DOI":"10.1128\/mBio.00765-21","article-title":"Markers of Polyfunctional SARS-CoV-2 Antibodies in Convalescent Plasma","volume":"12","author":"Natarajan","year":"2021","journal-title":"mBio"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Ackerman, M.E., Mikhailova, A., Brown, E.P., Dowell, K.G., Walker, B.D., Bailey-Kellogg, C., Suscovich, T.J., and Alter, G. (2016). Polyfunctional HIV-Specific Antibody Responses Are Associated with Spontaneous HIV Control. PLoS Pathog., 12.","DOI":"10.1371\/journal.ppat.1005315"}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/7\/1284\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:24:17Z","timestamp":1760163857000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/7\/1284"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,30]]},"references-count":35,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2021,7]]}},"alternative-id":["v13071284"],"URL":"https:\/\/doi.org\/10.3390\/v13071284","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,30]]}}}