A phase 1/2 study of a multiclade HIV-1 DNA plasmid prime and recombinant adenovirus serotype 5 boost vaccine in HIV-Uninfected East Africans (RV 172)

Abstract

Background: Human immunodeficiency virus (HIV) vaccine development remains a global priority. We describe the safety and immunogenicity of a multiclade DNA vaccine prime with a replication-defective recombinant adenovirus serotype 5 (rAd5) boost.

Methods: The vaccine is a 6-plasmid mixture encoding HIV envelope (env) subtypes A, B, and C and subtype B gag, pol, and nef, and an rAd5 expressing identical genes, with the exception of nef. Three hundred and twenty-four participants were randomized to receive placebo (n=138), a single dose of rAd5 at 10(10) (n = 24) or 10(11) particle units (n = 24), or DNA at 0, 1, and 2 months, followed by rAd5 at either 10(10) (n= 114) or 10(11) particle units (n = 24) boosting at 6 months. Participants were followed up for 24 weeks after the final vaccination.

Results: The vaccine was safe and well tolerated. HIV-specific T cell responses were detected in 63% of vaccinees. Titers of preexisting Ad5 neutralizing antibody did not affect the frequency and magnitude of T cell responses in prime-boost recipients but did affect the response rates in participants that received rAd5 alone (P = .037).

Conclusion: The DNA/rAd5 vaccination regimen was safe and induced HIV type 1 multi-clade T cell responses, which were not significantly affected by titers of preexisting rAd5 neutralizing antibody. Trial Registration. ClinicalTrials.gov identifier: NCT00123968 .

Figure 1

The maximum magnitude of T cell responses measured by interferon-γ ELISpot expressed as spot forming units (SFU) per one million peripheral blood mononuclear cells (PBMC) in vaccinees to either Env, Pol or Gag by immunization regimen 6 weeks after immunization. Open circles represent positive responses and black circles represent negative responses. A positive response was defined as at least 55 spot forming cells/10⁶PBMC in peptide pools and 4 X background number of spot forming cells/10⁶PBMC (media only). The box plots indicate the median, 25th and 75th percentile for each group and the error bars show the 5th and 95th percentiles. Placebo and baseline responses are not shown.

Figure 2

Breadth of T cell responses to HIV antigens. Frequencies of vaccinated subjects with detectable T cell responses to HIV antigens 6 weeks after immunization. Responses were measured by the interferon (IFN)-γ ELISpot assay. A positive response was defined as at least 55 spot forming cells/10⁶PBMC in peptide pools and 4 X background number of spot forming cells/10⁶PBMC (media only). The columns represent the percent volunteers with a positive IFN-γ ELISpot response for each study group represented by different colored bars for Env Gag or Pol peptides alone, Env alone, either Gag or Pol peptide pools, and for response rates to single, any two or three HIV antigens.

Figure 3

The maximum magnitude of IFN-γ ELISpot responses stratified by baseline Adenovirus type 5 neutralizing antibody titer of <12, 12–1000, 1000–5000 and > 5000. Results are expressed as spot forming units (SFU) per one million peripheral blood mononuclear cells (PBMC), for groups 1 and 2 combined and groups 3–5. Open circles represent positive responses and black circles represent negative responses. A positive response was defined as at least 55 spot forming cells/10⁶PBMC in peptide pools and 4 X background number of spot forming cells/10⁶PBMC (media only). The box plots indicate the median, 25th and 75th percentile for each group and the error bars show the 5th and 95th percentiles. Placebo and baseline responses are not shown.