Multigene DNA prime‐boost vaccines for SHIV89.6P

Abstract

We assessed four prime-boost vaccine regimens with a Gene Gun component for SHIV89.6P in Macaca nemestrina. A dosing experiment using beta-galactosidase plasmid showed that 30 or 45 shots per dose elicited higher titer antibody than smaller doses. For SHIV89.6P, we administered a six-plasmid vaccine capable of producing non-infectious virions in vivo in combination with either vaccinia recombinants or inactivated virus. DNA prime/vaccinia boost, or the reverse, elicited strong immune responses. The SHIV89.6P challenge virus was grown in M. nemestrina peripheral blood mononuclear cells and titered in vivo intrarectally. As has been observed for SHIV89.6P in M. mulatta, the infected M. nemestrina experienced rapid and severe loss of circulating CD4+ T cells. Vaccinated macaques were challenged three weeks after the last boost. DNA prime/vaccina boost or vaccina prime/DNA boost protected 11/12 animals from acute CD4+ T cell depletion and disease, while other regimens were not effective.

Preclinical and clinical progress of particle-mediated DNA vaccines for infectious diseases

“…Recent studies have shown that the delivery device employed can inXuence the immunogenicity of PMED in nonhuman primates. The Bio-Rad Helios device has been used in nonhuman primates and shown to require 45-60 g of DNA administered over 45+ sites to induce a signiWcant response in 100% of the immunized animals [41,42]. This result may be due to diVerences in the delivery footprint of the two devices.…”

Sequential Immunization with a Subtype B HIV-1 Envelope Quasispecies Partially Mimics the In Vivo Development of Neutralizing Antibodies

“…In addition, this strategy partially reelicited a similar NAb response profile and the same epitope targeting as those obtained from macaque A141, from which the env sequences were cloned. The three immunization strategies induced gp120-specific BAbs in all rabbits, and as previously demonstrated (18,19), several DNA primes were required to mount a measurable immune response. In addition, BAb titers were improved by the protein boosts, which is consistent with the published literature (51).…”

“…Several studies have shown that weak autologous and heterologous NAbs can be elicited by a combination of DNA prime/ protein boost immunization (9,29,34,51,56), thereby suggesting that structures in the native Env are important for eliciting NAbs (50). Our prior studies exploring the use of ancestral DNA vaccines delivered intradermally by a Gene Gun showed that binding antibodies (BAbs) were elicited in a DNA dose-dependent manner (19) and that DNA vaccination followed by a boost with monomeric gp120 protein elicited weak NAb responses (17) that were poorly cross-reactive. We sought to improve upon these results by exploring a novel idea for env-based vaccines.…”

Consistent Patterns of Change during the Divergence of Human Immunodeficiency Virus Type 1 Envelope from That of the Inoculated Virus in Simian/Human Immunodeficiency Virus-Infected Macaques

“…A SHIV-89.6P bulk culture was kindly provided by Norm Letvin. The virus was passaged twice through Macaca nemestrina peripheral blood mononuclear cells (PBMCs), titrated in vivo, and then used to challenge M. nemestrina intrarectally with 50 50% macaque infectious doses (24). Sequencing of proviral gp120 from the PBMCs used to grow the virus revealed that the consensus sequence was identical to the published sequence KB9 (accession no.…”