Long-lasting memory responses and rapid recall of immune responses induced by the HIV-1 Conserved Element DNA Vaccine in rhesus macaques

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Authors

• Y Cai
• V Kulkarni
• A Valentin
• E Ramirez
• C Alicea
• X Hu
• M Rosati
• GN Pavlakis
• BK Felber

Abstract

Background: To overcome HIV sequence diversity and to address potential competition with “decoy” epitopes, we have designed a DNA vaccine focusing on conserved elements (CE) of HIV p24gag. All CE DNA-vaccinated macaques developed robust CE–specific memory responses with cytotoxic potential. Subsequent vaccination of these macaques with DNA expressing complete Gag, significantly boosted the magnitude and breadth of pre-existing CE responses. This concept is currently developed for a clinical trial supported by NIAID/HVTN. Methods: The longevity of CE-specific cellular immunity induced by plasmid DNA vaccination was monitored in macaques two years after immunization. PBMC samples were stimulated with peptide pools covering 7 CE and the antigen-specific responses were measured combining surface and intracellular cytokine staining followed by flow cytometry. Plasma samples were analyzed for humoral responses by p24gag ELISA. Results: We found persistent levels of CE-specific T cells in the blood of all 15 immunized animals even at ~2 years after the last vaccination. A single booster vaccination with p24CE DNA resulted in a significant and rapid (~6-22-fold) increase of the pre-existing responses reaching levels up to ~7% of total T cells. These levels were higher than the prior peak levels. The boosted memory responses were mediated by CD4+ and CD8+ T cells and have cytotoxic potential (Granzyme B+). Booster vaccination induced new CE responses in 3 of 15 animals. Conclusions: Priming with CE DNA and boosting with p55gag DNA is an effective vaccine strategy to maximize Gag responses, resulting in long-lasting CE-specific cytotoxic memory that can be rapidly activated.

Scientific Focus Area: Immunology

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