Cutting Edge: Novel Vaccination Modality Provides Significant Protection against Mucosal Infection by Highly Pathogenic Simian Immunodeficiency Virus

Vaccine induced protection against infection by HIV or highly pathogenic and virulent SIV-strains has been limited. Here, in a proof of concept study, we show that a novel vaccine approach significantly protects Rhesus macaques from mucosal infection by the highly pathogenic strain SIV(mac251). We vaccinated 3 cohorts of 12 macaques each with live, irradiated vaccine cells secreting the modified ER chaperone gp96(−)Ig. Cohort 1 was vaccinated with cells secreting gp96(SIV)Ig carrying SIV peptides. Cohort 2 in addition received recombinant envelope protein SIV-gp120. Cohort 3 was injected with cells secreting gp96-Ig (no SIV antigens) vaccines. Cohort 2 was protected from infection. After seven rectal challenges with highly pathogenic SIV(mac251) the hazard ratio was 0.27 corresponding to a highly significant, 73% reduced risk of viral acquisition. The apparent success of the novel vaccine modality recommends further study

Gp96SIVIg immunization induces potent polyepitope specific, multifunctional memory responses in rectal and vaginal mucosa

The ER-resident chaperone gp96, when released by cell lysis, induces an immunogenic chemokine signature and causes innate immune activation of DC and NK cells. Here we show that intraperitoneal immunization with a genetically engineered, secreted form of gp96, gp96-Ig chaperoning SIV antigens, induces high levels of antigen specific CD8 CTL in the rectal and vaginal mucosa of Rhesus macaques. The frequency of SIV Gag- and SIV Tat-tetramer positive CD8 CTL in the intestinal mucosa reached 30-50% after the third immunization. Tetramer positive CD8 CTL expressed appropriate functional (granzyme B) and migration markers (CD103). The polyepitope specificity of the mucosal CD8 and CD4 response is evident from a strong, multifunctional cytokine response upon stimulation with peptides covering the gag, tat and env proteins. Induction of powerful mucosal effector CD8 CTL responses by cell-based gp96(SIV)-Ig immunization may provide a pathway to the development of safe and effective SIV/HIV vaccines