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The HSV-2 gC2 and gD2 proteins were expressed in baculovirus, while the U<jats:sub>L<\/jats:sub>19 and U<jats:sub>L<\/jats:sub>47 genes were expressed from replication-defective adenovirus vectors. Adenovirus vectors containing U<jats:sub>L<\/jats:sub>19 and U<jats:sub>L<\/jats:sub>47 stimulated human and murine CD4<jats:sup>+<\/jats:sup>and CD8<jats:sup>+<\/jats:sup>T cell responses. Guinea pigs were either (i) mock immunized; (ii) immunized with gC2\/gD2, with CpG and alum as adjuvants; (iii) immunized with the U<jats:sub>L<\/jats:sub>19\/U<jats:sub>L<\/jats:sub>47 adenovirus vectors; or (iv) immunized with the combination of gC2\/gD2-CpG\/alum and the U<jats:sub>L<\/jats:sub>19\/U<jats:sub>L<\/jats:sub>47 adenovirus vectors. Immunization with gC2\/gD2 produced potent neutralizing antibodies, while U<jats:sub>L<\/jats:sub>19 and U<jats:sub>L<\/jats:sub>47 also stimulated antibody responses. After intravaginal HSV-2 challenge, the mock and U<jats:sub>L<\/jats:sub>19\/U<jats:sub>L<\/jats:sub>47 adenovirus groups developed severe acute disease, while 2\/8 animals in the gC2\/gD2-only group and none in the combined group developed acute disease. No animals in the gC2\/gD2 or combined group developed recurrent disease; however, 5\/8 animals in each group had subclinical shedding of HSV-2 DNA, on 15\/168 days for the gC2\/gD2 group and 13\/168 days for the combined group. Lumbosacral dorsal root ganglia were positive for HSV-2 DNA and latency-associated transcripts for 5\/8 animals in the gC2\/gD2 group and 2\/8 animals in the combined group. None of the differences comparing the gC2\/gD2-only group and the combined group were statistically significant. Therefore, adding the T cell immunogens U<jats:sub>L<\/jats:sub>19 and U<jats:sub>L<\/jats:sub>47 to the gC2\/gD2 vaccine did not significantly reduce genital disease and vaginal HSV-2 DNA shedding compared with the excellent protection provided by gC2\/gD2 in the guinea pig model.<\/jats:p><jats:p><jats:bold>IMPORTANCE<\/jats:bold>HSV-2 infection is a common cause of genital ulcer disease and a significant public health concern. Genital herpes increases the risk of transmission and acquisition of HIV-1 infection 3- to 4-fold. A herpes vaccine that prevents genital lesions and asymptomatic genital shedding will have a substantial impact on two epidemics, i.e., both the HSV-2 and HIV-1 epidemics. We previously reported that a vaccine containing HSV-2 glycoprotein C (gC2) and glycoprotein D (gD2) reduced genital lesions and asymptomatic HSV-2 genital shedding in guinea pigs, yet the protection was not complete. We evaluated whether adding the T cell immunogens U<jats:sub>L<\/jats:sub>19 (capsid protein VP5) and U<jats:sub>L<\/jats:sub>47 (tegument protein VP13\/14) would enhance the protection provided by the gC2\/gD2 vaccine, which produces potent antibody responses. Here we report the efficacy of a combination vaccine containing gC2\/gD2 and U<jats:sub>L<\/jats:sub>19\/U<jats:sub>L<\/jats:sub>47 for prevention of genital disease, vaginal shedding of HSV-2 DNA, and latent infection of dorsal root ganglia in guinea pigs.<\/jats:p>","DOI":"10.1128\/jvi.01089-15","type":"journal-article","created":{"date-parts":[[2015,6,4]],"date-time":"2015-06-04T11:25:31Z","timestamp":1433417131000},"page":"8497-8509","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":20,"title":["A Dual-Modality Herpes Simplex Virus 2 Vaccine for Preventing Genital Herpes by Using Glycoprotein C and D Subunit Antigens To Induce Potent Antibody Responses and Adenovirus Vectors Containing Capsid and Tegument Proteins as T Cell Immunogens"],"prefix":"10.1128","volume":"89","author":[{"given":"Sita","family":"Awasthi","sequence":"first","affiliation":[{"name":"Infectious Disease Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gregory G.","family":"Mahairas","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, School of Medicine, University of Washington, Seattle, Washington, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carolyn E.","family":"Shaw","sequence":"additional","affiliation":[{"name":"Infectious Disease Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meei-Li","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, School of Medicine, University of Washington, Seattle, Washington, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David M.","family":"Koelle","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, School of Medicine, University of Washington, Seattle, Washington, USA"},{"name":"Department of Medicine, School of Medicine, University of Washington, Seattle, Washington, USA"},{"name":"Fred Hutchinson Cancer Research Center, Seattle, Washington, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christine","family":"Posavad","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, School of Medicine, University of Washington, Seattle, Washington, USA"},{"name":"Fred Hutchinson Cancer Research Center, Seattle, Washington, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lawrence","family":"Corey","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, School of Medicine, University of Washington, Seattle, Washington, USA"},{"name":"Department of Medicine, School of Medicine, University of Washington, Seattle, Washington, USA"},{"name":"Fred Hutchinson Cancer Research Center, Seattle, Washington, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Harvey M.","family":"Friedman","sequence":"additional","affiliation":[{"name":"Infectious Disease Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.2471\/BLT.07.046128"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-98-6-958"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-116-3-197"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199206043262305"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198711123172002"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199708213370801"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1542\/peds.108.2.230"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1086\/368357"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1086\/345867"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1086\/338231"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1086\/314486"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa035144"},{"key":"e_1_3_2_14_2","first-page":"916","article-title":"Treatment of first episodes of genital herpes simplex virus infection with oral acyclovir","volume":"308","author":"Bryson YJ","year":"1983","unstructured":"Bryson YJ, Dillon M, Lovett M, Acuna G, Taylor S, Cherry JD, Johnson BL, Wiesmeier E, Growdon W, Creagh-Kirk T, Keeney R. 1983. 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