Modified Adenovirus Prime-Protein Boost Clade C HIV Vaccine Strategy Results in Reduced Viral DNA in Blood and Tissues Following Tier 2 SHIV Challenge.

Delphine C Malherbe,Samir K Lakhashe,Michael K Axthelm,Nancy L Haigwood,Jonah B Sacha,Shilpi Pandey,Jason Mendy,Lo Vang,D Noah Sather,Jeff Alexander,Deborah H Fuller,Ruth M Ruprecht,Penny L Moore,Ann J Hessell,Harlan Robins,Bettie W Kareko,David A Spencer ,Jason S Reed ,Philip Barnette ,Constantinos Kurt Wibmer ,Byung Park ,James M Wilson

doi:10.3389/fimmu.2020.626464

Abstract

Designing immunogens and improving delivery methods eliciting protective immunity is a paramount goal of HIV vaccine development. A comparative vaccine challenge study was performed in rhesus macaques using clade C HIV Envelope (Env) and SIV Gag antigens. One group was vaccinated using co-immunization with DNA Gag and Env expression plasmids cloned from a single timepoint and trimeric Env gp140 glycoprotein from one of these clones (DNA+Protein). The other group was a prime-boost regimen composed of two replicating simian (SAd7) adenovirus-vectored vaccines expressing Gag and one Env clone from the same timepoint as the DNA+Protein group paired with the same Env gp140 trimer (SAd7+Protein). The env genes were isolated from a single pre-peak neutralization timepoint approximately 1 year post infection in CAP257, an individual with a high degree of neutralization breadth. Both DNA+Protein and SAd7+Protein vaccine strategies elicited significant Env-specific T cell responses, lesser Gag-specific responses, and moderate frequencies of Env-specific TFH cells. Both vaccine modalities readily elicited systemic and mucosal Env-specific IgG but not IgA. There was a higher frequency and magnitude of ADCC activity in the SAd7+Protein than the DNA+Protein arm. All macaques developed moderate Tier 1 heterologous neutralizing antibodies, while neutralization of Tier 1B or Tier 2 viruses was sporadic and found primarily in macaques in the SAd7+Protein group. Neither vaccine approach provided significant protection from viral acquisition against repeated titered mucosal challenges with a heterologous Tier 2 clade C SHIV. However, lymphoid and gut tissues collected at necropsy showed that animals in both vaccine groups each had significantly lower copies of viral DNA in individual tissues compared to levels in controls. In the SAd7+Protein-vaccinated macaques, total and peak PBMC viral DNA were significantly lower compared with controls. Taken together, this heterologous Tier 2 SHIV challenge study shows that combination vaccination with SAd7+Protein was superior to combination DNA+Protein in reducing viral seeding in tissues in the absence of protection from infection, thus emphasizing the priming role of replication-competent SAd7 vector. Despite the absence of correlates of protection, because antibody responses were significantly higher in this vaccine group, we hypothesize that vaccine-elicited antibodies contribute to limiting tissue viral seeding.

Highlights

Despite the progress achieved in the last 30 years, immunogen design and optimization of delivery methods that elicit protective immunity remain vital goals of HIV vaccine development
CAP257 54wpi_D Env glycoprotein expressed on the surface of simian adenovirus 7 (SAd7)-infected cells was recognized by Env-specific broadly neutralizing antibodies (bNAbs) (Figure 1B) that neutralized CAP257 54wpi_D pseudoviruses [5], demonstrating the presence of these epitopes on the SAd7-expressed Env
The selected CAP257 full-length envs were motif optimized for expression in mammalian cells, and plasmid DNA vaccines expressing Env gp160 were tested as pseudoviruses for neutralization by bNAbs

Summary

Introduction

Despite the progress achieved in the last 30 years, immunogen design and optimization of delivery methods that elicit protective immunity remain vital goals of HIV vaccine development. The need is acute in sub-Saharan Africa, which bears the heaviest infection burden, where the dominant genotype is clade C. Many early vaccine efforts have focused on clade B viruses that are predominant in the USA, Europe, and Australia. The critical role for HIV Envelope (Env)-directed antibodies and neutralizing antibodies (NAbs) for protection from infection has been firmly established in passive antibody studies in nonhuman primates [reviewed in [1]] as well as in recent vaccine studies [2]. Effectiveness in blocking and controlling infection depends upon both the quality and the magnitude of the response, and many questions remain as to how to enhance vaccine-induced humoral and cellular immunity

Methods

Results

Conclusion