Cross-subtype antibody and cellular immune responses induced by a polyvalent DNA prime–protein boost HIV-1 vaccine in healthy human volunteers

Abstract

An optimally effective AIDS vaccine would likely require the induction of both neutralizing antibody and cell-mediated immune responses, which has proven difficult to obtain in previous clinical trials. Here we report on the induction of human immunodeficiency virus type-1 (HIV-1)-specific immune responses in healthy adult volunteers that received the multi-gene, polyvalent, DNA prime–protein boost HIV-1 vaccine formulation, DP6-001, in a Phase I clinical trial. Robust cross-subtype HIV-1-specific T cell responses were detected in IFN-γ ELISPOT assays. Furthermore, we detected high titer serum antibody responses that recognized a wide range of primary HIV-1 Env antigens and also neutralized pseudotyped viruses that express the primary Env antigens from multiple HIV-1 subtypes. These findings demonstrate that the DNA prime–protein boost approach is an effective immunization method to elicit both humoral and cell-mediated immune responses in humans, and that a polyvalent Env formulation could generate broad immune responses against HIV-1 viruses with diverse genetic backgrounds.

The safety and tolerability of an HIV-1 DNA prime–protein boost vaccine (DP6-001) in healthy adult volunteers

“…However, the majority have not reproduced, in humans, the high immunogenicity seen in preclinical testing. Recently, we reported that a novel multi-gene, polyvalent DNA prime-recombinant protein boost HIV vaccine formulation, DP6-001, elicited strong and balanced humoral and cell-mediated immunity in healthy, HIV-1-negative adult subjects [1]. Preclinical testing of DP6-001 demonstrated no significant adverse reactions in either rabbits or non-human primates despite the induction of robust immunity [2,3].…”

“…The clinical trial was an open-label, 3-arm design requiring each subject to receive two vaccine components; three sequential inoculations using a DNA plasmid vaccine administered either intradermally (ID) or intramuscularly (IM) followed by two sequential inoculations using a protein vaccine as shown in Table 1. Healthy HIV-negative adults (aged 18-50) were enrolled under informed consent as previously described [1]. This study involved 2 dose levels of DNA vaccines (1.2mg (Groups A and B); 7.2mg (Group C)) expressing five gp120 Env antigens (HIV-1 clades A, B, C and E) and one Gag antigen (HIV-1 clade C), and a single dose level of the same five recombinant expressed gp120 protein vaccines, produced and purified from CHO cells, and mixed with QS21 adjuvant at the time of injection.…”

“…Healthy HIV-negative adults (aged 18-50) were enrolled under informed consent as previously described [1]. This study involved 2 dose levels of DNA vaccines (1.2mg (Groups A and B); 7.2mg (Group C)) expressing five gp120 Env antigens (HIV-1 clades A, B, C and E) and one Gag antigen (HIV-1 clade C), and a single dose level of the same five recombinant expressed gp120 protein vaccines, produced and purified from CHO cells, and mixed with QS21 adjuvant at the time of injection.…”

“…One major difference between the current trial and previous QS21-adjuvanted recombinant Env protein-based HIV vaccine trials [10,15] is that the current trial included a series of three DNA priming inoculations. The high titer and quick rise of antibody responses after only one protein boost [1] indicated a strong induction of immune priming by the DNA vaccine. The different sites used for the sequential DNA priming, as well as two sequential protein boost inoculations, enabled the clinical separation of DTH-like reactions from local reactions induced by QS21 as reported in a previous HIV Env-QS21 vaccine study [10].…”

DNA Vaccines: How Much Have We Accomplished In The Last 25 Years?

“…In this approach, the immune system is primed by administering the antigen of interest by one method (e.g DNA vaccine) and then boosted by a different one that delivers the same antigen (e.g recombinant protein, recombinant virus). A vast number of experiments have been performed in mice and non-human primates [139] and these strategies are already into clinical trials [140]. Detailed reviews on heterologous prime-boost strategies have been published elsewhere [3,[141][142][143].…”