Improved Protection of Rhesus Macaques against Intrarectal Simian Immunodeficiency Virus SIV_mac251Challenge by a Replication-Competent Ad5hr-SIVenv/revand Ad5hr-SIVgagRecombinant Priming/gp120 Boosting Regimen

Abstract

In this study we investigated the ability of a replication-competent Ad5hr-SIVenv/rev and Ad5hr-SIVgag recombinant priming/gp120 boosting regimen to induce protective immunity in rhesus macaques against pathogenic simian immunodeficiency virus mac251 . Immunization of macaques by two sequential administrations of the same recombinants by the same route resulted in boosting and persistence of SIV-specific cellular immune responses for 42 weeks past the initial immunization. Anti-SIV gp120 immunoglobulin G (IgG) and IgA antibodies were induced in secretory fluids, and all macaques exhibited serum neutralizing antibody activity. After intrarectal SIV mac251 challenge, all of the macaques became infected. However, relative protection, as assessed by statistically significant lower SIV viral loads in plasma at both acute infection and set point, was observed in 8 out of 12 immunized non-Mamu-A‫10ء‬ animals. Elevated mean cellular immune responses to Gag and Env, neutralizing antibody activity, and IgG and IgA binding antibody levels were observed in the eight protected macaques. Statistically significant correlations with protective outcome were observed for cellular immune responses to SIV Env and Gag and for SIV gp120-specific IgG antibodies in nasal and vaginal fluids. Two macaques that exhibited the greatest and most persistent viremia control also exhibited strong CD8؉ T-cell antiviral activity. The results suggest that a spectrum of immune responses may be necessary for adequate control of viral replication and disease progression and highlight a potential role for nonneutralizing antibodies at mucosal sites.

Vaccine-Elicited Antibodies Mediate Antibody-Dependent Cellular Cytotoxicity Correlated with Significantly Reduced Acute Viremia in Rhesus Macaques Challenged with SIVmac251

“…challenge with HIV (18). Protective efficacy has also been observed in rhesus macaques that have been challenged vaginally or rectally with pathogenic SIV (19,20,22,25). In our most recent Ad-SIV/gp120 vaccine efficacy study, a strong level of protection against an intrarectal SIV mac251 challenge was achieved (24,25).…”

Replicating adenovirus vector prime/protein boost strategies for HIV vaccine development

“…During this same time period, others using primarily Gag-based vaccines to induce cellular immunity were achieving dramatic reduction of SHIV 89.6P viral loads following challenge of rhesus macaques [10,11,84]. Due to the high variation among HIV-1 env sequences, the isolatespecific env-only vaccine might have been too narrow in scope.…”

“…Subsequent SIV gp120 protein boosts concomitantly elevated cellular, mucosal and humoral immune responses, with detection of anti-SIV gp120 IgA and IgG antibodies in serum, nasal and vaginal secretions, and saliva. Following intrarectal challenge with SIV mac251 , protection was maintained into the chronic phase of infection [89]. Cellular immunity to SIV Gag and Env post and pre-challenge, respectively, as well as Env-specific IgG binding antibodies in nasal and vaginal secretions observed at the time of challenge correlated with significant reduction of acute phase viremia by 1 log, and of set point viremia by 1-1.5 logs among Mamu A*01 (−) immunized and control macaques.…”

Evaluation of Passively Transferred, Nonneutralizing Antibody-Dependent Cellular Cytotoxicity-Mediating IgG in Protection of Neonatal Rhesus Macaques against Oral SIVmac251 Challenge

“…Sera and plasma from mock-immunized control macaques from the same study (after monophosphoryl lipid A-stable emulsion immunizations, wk 26, 30, 34, 38, and 42) were also thawed and combined as pool B. To obtain sufficient control sera and plasma, samples obtained following the last mock-booster immunization (wk 38 and 42) were added from a previous study in which macaques received two intranasal administrations of empty Ad5hr vector and two immunizations with QS-21 adjuvant only (19). The final volume of pool A was 135 ml, whereas pool B contained 109 ml.…”