Novel vaccination protocol with two live mucosal vectors elicits strong cell-mediated immunity in the vagina and protects against vaginal virus challenge.
Most HIV infections result from heterosexual transmission to women. Because cellular immunity plays a key role in the control of the infection, we sought to strengthen cellular immune responses in vaginal tissue. We explored a novel prime-boost protocol that used two live mucosal agents that trigger different pathways of innate immunity and induce strong cellular immunity. Adenovirus serotype 5 (Ad5) has frequently been used as a boost for DNA vaccines. In this study we used attenuated, recombinant L. monocytogenes-gag (rLm-gag) to prime mice by various mucosal routes-oral, intrarectal, and intravaginally (ivag)-followed by a systemic or mucosal boost with replication-defective rAd5-gag. Mice primed with a single administration of rLm-gag by any route and then boosted with rAd5-gag intramuscularly exhibited abundant Gag-specific CD8 T cells in spleen and vaginal lamina propria. Conversely, when boosted with rAd5-gag ivag, the immune response was reoriented toward the vagina with strikingly higher CD8 T cell responses in that tissue, particularly after ivag immunization by both vectors (ivag/ivag). Five weeks to 5 mo later, ivag/ivag-immunized mice continued to show high levels of effector memory CD8 T cells in vagina, while the pool of memory T cells in spleen assumed a progressively more central memory T cell phenotype. The memory mice showed high in vivo CTL activity in vagina, a strong recall response, and robust protection after ivag vaccinia-gag challenge, suggesting that this prime-boost strategy can induce strong cellular immunity, especially in vaginal tissues, and might be able to block the heterosexual transmission of HIV-1 at the vaginal mucosa.
Li
Zhongxia
Z
Department of Microbiology, University of Pennsylvania School of Medicine, 3610 Hamilton Walk, Philadelphia, PA 19104, USA.
Zhang
Manxin
M
Zhou
Chenghui
C
Zhao
Xinyan
X
Iijima
Norifumi
N
Frankel
Fred R
FR
D016915:AIDS Vaccines / Q000008:administration & dosage* / Q000276:immunology*; D000284:Administration, Oral; D000818:Animals; D001412:Bacillus subtilis / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D005260:Female; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000276:immunology*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology; D007111:Immunity, Cellular / Q000235:genetics; D007117:Immunization, Secondary; D007274:Injections, Intraperitoneal; D008089:Listeria monocytogenes / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009092:Mucous Membrane / Q000276:immunology / Q000821:virology; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000276:immunology; D014623:Vaginal Diseases / Q000276:immunology* / Q000517:prevention & control* / Q000821:virology; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology
D016915:AIDS Vaccines; D014613:Vaccines, Attenuated; D054301:gag Gene Products, Human Immunodeficiency Virus