Comparison of Vaccine Strategies Using Recombinant env–gag–pol MVA with or without an Oligomeric Env Protein Boost in the SHIV Rhesus Macaque Model

Abstract

Rhesus macaques were immunized with a replication-deficient vaccinia virus (MVA) expressing human immunodeficiency virus type 1 89.6 envelope (env) and SIV gagpol (MVA/SHIV89.6) with or without a protein boost consisting of soluble 89.6 env (gp140). Immunization with MVA/SHIV89.6 alone elicited binding antibodies in all animals and neutralizing antibodies in 5 of 15 animals. Both types of antibodies were enhanced by protein boosting. In addition, CD8 cells exhibiting CM9 tetramer binding were detected in the subset of animals that were Mamu-A*01 positive. Animals were challenged intravenously with either SHIV-89.6 (Study 1) or the more pathogenic derivative SHIV-89.6P (Study 2). In Study 1, all control and vaccinated animals except one became infected. However, the levels of viremia were as follows: controls > rMVA alone > rMVA + protein. The differences were statistically significant between immunized and control groups but not between the two immunized groups. In Study 2, all animals became infected; however, the vaccinated group exhibited a 5-fold reduction in peak viremia and a 10-fold reduction in the postacute phase viremia in comparison to the controls. All of the controls required euthanasia by 10 months after challenge. A relationship between vaccine-induced antibody titers and reduction in virus burden was observed in both studies. Thus, immunization with MVA/SHIV89.6 alone or with a protein boost stimulated both arms of the immune system and resulted in significant control of viremia and delayed progression to disease after challenge with SHIV-89.6P.

Potent, Persistent Induction and Modulation of Cellular Immune Responses in Rhesus Macaques Primed with Ad5hr-Simian Immunodeficiency Virus (SIV) env/rev , gag , and/or nef Vaccines and Boosted with SIV gp120

“…The peak percentage of unstimulated CD8 ϩ T cells able to bind p11C tetramer postAd5hr-SIV gag immunization ranged from 0.5 to 1.6%. This is comparable to some DNA-cytokine approaches (6) and greater than some alternate vector approaches (21,53), but less than that achieved by two high-dose replication-defective Ad5-SIV gag immunizations (57) and by a DNA/MVA approach (2). In contrast, IFN-␥ secretion in response to the p11C peptide was higher in our study following the two replicating Ad5hr-SIV gag immunizations (mean of 1,600 SFC/10 6 PBMC) than responses following two or three replicationdefective Ad5-SIV gag immunizations (reference 57 and supplemental information).…”

A Single Injection of Recombinant Measles Virus Vaccines Expressing Human Immunodeficiency Virus (HIV) Type 1 Clade B Envelope Glycoproteins Induces Neutralizing Antibodies and Cellular Immune Responses to HIV

“…Actually, different HIV-1 strains were used in the different studies cited above. Third, different vaccination methods can induce different patterns of immune responses (12), especially regarding the induction of neutralizing antibodies (20). Good immunogenicity in our system is likely due to good levels of expression and maturation of HIV Env in cells infected by live recombinant MV, resulting to an efficient presentation to the immune system.…”

Protection of Rhesus Monkeys against Infection with Minimally Pathogenic Simian-Human Immunodeficiency Virus: Correlations with Neutralizing Antibodies and Cytotoxic T Cells

“…Recent efforts to use synthetic peptides or recombinant proteins in creative ways that may induce effective neutralizing antibody responses have not substantially improved on the disappointing results obtained with similar approaches used in early HIV vaccine studies (9,23,25,28,38,41,68,69). Neither has the use of a virus-like particle vaccine or in vivo expression systems achieved potent primary virus-neutralizing antibody responses (2,4,16,24,37,49,50,58,59,72). The outcome obtained in such studies always included one of the following: no neutralizing antibodies were detected, neutralizing antibodies were obtained that were specific for the homologous immunizing strain or cross-reacted with only T-cell line-adapted strains, or neutralizing antibodies were not observed until after the monkeys were challenged with SHIV.…”