Cross-subtype antibody and cellular immune responses induced by a polyvalent DNA prime–protein boost HIV-1 vaccine in healthy human volunteers
Introduction
Development of an effective HIV vaccine is critical to control the worldwide AIDS pandemic, which has caused 25 million deaths in the last 25 years and is the cause for more than 40 million people living with HIV/AIDS today [1]. Early efforts in HIV vaccine development focused on the induction of humoral responses by using recombinant Env glycoproteins [2], [3], [4], [5]. The immunogenicity of recombinant Env protein-based vaccines was poor in humans, as shown by overall low-level binding antibodies measured by solid phase assays [6] and by the narrow spectrum of neutralizing activities mainly against T cell line adapted (TCLA) viral isolates [7], [8], [9]. Ultimately, recombinant protein-based HIV-1 vaccines failed to show protection efficacy in Phase III clinical trials [10], [11]. In contrast, recent progress with gene-based vaccination approaches, which have used either DNA or viral vectors as delivery systems, have been effective in eliciting cell-mediated immune (CMI) responses in early phase human studies. However, these studies either did not put forth an effort to elicit protective antibody responses [12], [13] or were not effective, when used alone, in eliciting neutralizing antibodies (NAbs) against even relatively sensitive viral isolates [14], [15].
Recently, we demonstrated that a DNA prime–protein boost immunization strategy was effective in eliciting humoral and CMI responses in both small animals and non-human primates, including sterilizing immunity in a non-pathogenic SHIV model [16], [17], [18]. Our preclinical study results also indicated that this combination vaccination approach, but not recombinant protein alone, was effective in eliciting NAbs against primary HIV isolates [19], a finding that has since been confirmed by other independent studies [20], [21], [22], [23], [24], [25], [26]. Furthermore, when polyvalent primary Env antigen formulations were used, the DNA prime–protein boost approach was more effective than the monovalent primary Env antigen in eliciting rabbit NAbs against a wide range of selected primary viral isolates across subtypes A–E [27]. In the current study, a multi-gene, polyvalent DNA prime–protein boost HIV-1 vaccine was formulated based on the above preclinical study findings, and its immunogenicity was tested in healthy adults in a Phase I clinical trial. These results demonstrate that this formulation was able to induce balanced cell-mediated and antibody immune responses against HIV-1 antigens, including low but positive neutralizing activities against selected primary HIV-1 isolates across different subtypes.
Section snippets
DNA vaccines
The DP6-001 vaccine contains equal amounts of six individual DNA plasmid components utilizing the same vector pSW3891 [17]: five plasmids each encoding a codon-optimized gp120 gene sequence from the following primary HIV-1 envelope proteins: subtypes A (92UG037.8), B (92US715.6 and Bal), C (96ZM651) and E (93TH976.17) and the sixth plasmid encoding a codon-optimized gag gene from subtype C (96ZM651) as previously described [28]. The cGMP plasmid DNA for this Phase I clinical trial was produced
Design of the Phase I clinical trial in healthy adult volunteers
The multi-gene, polyvalent primary Env DNA prime–protein boost HIV vaccine, DP6-001, included 6 DNA plasmids (one expressing a subtype C full length Gag antigen and the other five each expressing one of the five primary gp120 antigens from subtypes A, B, C or E) as the prime and five recombinant gp120 proteins matching the Env DNA prime as the boost (Table 1). The study was a 3-group trial that tested two dosing levels of DNA administered either intradermally (ID) or intramuscularly (IM) and
Discussion
Induction of anti-Env antibody responses in small animals was one of the first pieces of evidence that established DNA immunization as a novel approach for vaccination [35]. Although significant progress has been made using DNA immunization to elicit HIV-1-specific CMI in small animals, non-human primates and humans over the past 15 years [12], [13], [14], [15], [16], [18], [36], [37], [38], [39], there has been no report of using Env DNA immunization to elicit broadly cross-reactive antibodies
Acknowledgements
This work was supported in part by the HIV Vaccine Design and Development Teams contract N01AI05394, and grants R29AI40337, R21AI46294 and R01AI65250 from the National Institute of Allergy and Infectious Diseases to S.L. and AI46705 and AI30034 to D.C.M. The PhenoSense neutralization assay was conducted at the Mongram, Inc. and funded by the International AIDS Vaccine Initiative. The project also used core facility resources at the University of Massachusetts Medical School supported by NIH
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These authors contributed equally to this work.