Poster abstracts

Poster number 102 submitted by Jianchao Zhang

In vivo Antibody Gene Transfer Provides Protective Immunity Against Virulent Challenge in a Rhesus Macaque Infection Model

Jianchao Zhang (Biophysics Program, The Ohio State University, Columbus, OH), Bruce Schnepp (Pediatrics, Childrens Hospital of Philadelphia, Philadelphia, PA), Ronald Desrosiers (Microbiology and Molecular Genetics, Harvard Medical School, Southborough, MA), Mary Connell (Pediatrics, Childrens Hospital of Philadelphia, Philadelphia, PA), Philip Johnson (Pediatrics, Childrens Hospital of Philadelphia, Philadelphia, PA), K. Reed Clark (Center for Gene Therapy, The Research Institute at Nationwide Childrens Hospital,Columbus, OH)

Abstract:
We are developing a novel HIV-1 vaccine approach utilizing antibody gene transfer to provide protective host humoral immune responses against HIV-1. “Reverse immunization” is predicated on the efficient delivery of antibody genes that encode broadly HIV-1 neutralizing antibodies (NAbs). Following in vivo gene transfer into skeletal muscle, the individual would be supplied with a constant source of potent anti-HIV-1 antibodies prior to pathogen exposure. Herein, we evaluated three different rAAV1 vaccine vectors each expressing rhesus derived, neutralizing fusion proteins (4L6, 5L7, and N4) for efficacy in a SIV/macaque challenge model. Following vector injection, six naïve monkeys and the 9 vaccinated ones were challenged with SIVmac316 4 weeks post-vaccination. The animals were bled bi-weekly.

Sustained serum levels of 4L6 and 5L7 in the range of 100-400 μg/ml were observed for all 6 vaccinated animals. The N4 group exhibited significantly lower levels (5-10 μg/ml), which may be related to the use of a single-strand rAAV1 compared to the self-complementary vectors for expression of 4L6 and 5L7. Significantly, SIV viremia was observed in all 6-control animals starting at 2 weeks post-challenge. In stark contrast, all 3 animals in the 4L6 group had undetectable levels of SIV in their sera up to 6 months post-challenge. Moreover, two animals in the N4 group and one in the 5L7 group also had undetectable levels of SIV. One animal in the 5L7 group displayed anti-antibody responses that appeared to neutralize 5L7 activity. Not unexpectedly, this animal became infected with similar kinetics as the control group. These data strongly suggest that sterilizing immunity was achieved in 6 of 9 vaccinated animals challenged with a virulent dose of primary-like isolated SIV. This study provides powerful proof-of-concept data demonstrating the feasibility of reverse immunization as a viable prophylactic HIV-1 vaccine approach.

References:
1. Lewis A, Chen R, Montefiori DC, Johnson PR, and Clark KR. (2002). Generation of serum neutralizing activity against HIV-1 by antibody gene transfer. Journal of Virology 76, 8769-8775.
2. Johnson W, Sanford H, Schwall L, Burton D, Parren P, Robinson J, Desrosiers R. (2003). Assorted Mutations in the Envelope Gene of Simian Immunodeficiency Virus Lead to Loss of Neutralization Resistance against Antibodies Representing a Broad Spectrum of Specificities. Journal of Virology 77, 9993-10003.

Keywords: HIV, SIV, Vaccine, rAAV