Article

Polyvalent HIV-1 Env vaccine formulations delivered by the DNA priming plus protein boosting approach are effective in generating neutralizing antibodies against primary human immunodeficiency virus type 1 isolates from subtypes A, B, C, D and E

Laboratory of Nucleic Acid Vaccines, Department of Medicine, University of Massachusetts Medical School, 364 Plantation Street, Lazare Research Building, Worcester, MA 01605, USA.
Virology (Impact Factor: 3.32). 07/2006; 350(1):34-47. DOI: 10.1016/j.virol.2006.02.032
Source: PubMed

ABSTRACT

A major challenge in developing an HIV-1 vaccine is to identify immunogens and their delivery methods that can elicit broad neutralizing antibodies against primary isolates of different genetic subtypes. Recently, we demonstrated that priming with DNA vaccines expressing primary HIV-1 envelope glycoprotein (Env) followed by recombinant Env protein boosting was successful in generating positive neutralizing antibody responses against a clade B primary HIV-1 isolate, JR-FL, that was not easily neutralized. In the current study, we examined whether the DNA priming plus recombinant protein boosting approach delivering a polyvalent primary Env formulation was able to generate neutralizing antibodies against primary HIV-1 viral isolates from various genetic subtypes. New Zealand White rabbits were first immunized with DNA vaccines expressing one, three or eight primary HIV-1 gp120 antigens delivered by a gene gun followed by recombinant gp120 protein boosting. Neutralizing antibody responses were examined by two independently executed neutralization assays: the first one was a single round infection neutralization assay against a panel of 10 primary HIV-1 isolates of subtypes A, B, C and E and the second one used the PhenoSense assay against a panel of 12 pseudovirues expressing primary HIV-1 Env antigens from subtypes A, B, C, D and E as well as 2 pseudoviruses expressing the Env antigens from MN and NL4-3 viruses. Rabbit sera immunized with the DNA priming plus protein boosting approach, but not DNA vaccine alone or Env protein alone, were capable of neutralizing 7 of 10 viruses in the first assay and 12 of 14 viruses in the second assay. More importantly, sera immunized with the polyvalent Env antigens were able to neutralize a significantly higher percentage of viruses than the sera immunized with the monovalent antigens. Our results suggest that DNA priming followed by recombinant Env protein boosting can be used to deliver polyvalent Env-antigen-based HIV-1 vaccines to elicit neutralizing antibody responses against viruses with diverse genetic sequence variations.

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    • "The difficulty of applying this strategy to HIV vaccine development is the fact that there are no clear serotypes or immunotypes based on HIV-1 Env immunogen. However, a pilot study using the DNA prime-protein boost approach in rabbits to compare the immunogenicity between monovalent and polyvalent gp120 formulations expressing primary Env antigens from several major subtypes of circulating HIV-1 viral isolates provided promising data to support the use of polyvalent Env formulations as part of the overall HIV vaccine development effort [53]. At the peak level of post final boost immunization, rabbit immune sera elicited by the polyvalent gp120 formulation neutralized 67.86% of a multiclade panel of tested viruses, while the monovalent vaccine elicited sera neutralized only 38.39% viruses. "
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    • "Furthermore, ease of DNA manipulation provides a platform to deliver polyvalent or multi-gene vaccine components which can increase the breadth and depth of vaccine-induced immunity to reduce immune escape. This strategy showed remarkable success in rabbit experiments where a polyvalent gp120 vaccine induced broadly neutralizing antibody responses as opposed to the monovalent vaccine (Wang et al., 2006b). Similarly, polyvalent mosaic plasmid DNA vaccines have demonstrated enhanced immunogenicity in mice (Kong et al., 2009) and rhesus monkeys (Santra et al., 2010). "
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    • "The second aspect considered the possibility to broaden the neutralizing response by simultaneous immunization with three different env genes. A polyvalent approach of administering multiple Env proteins as opposed to a monovalent Env has proven effective to broaden the Ab response in several studies including rabbits and macaques4849505158,59]. Nevertheless, the antigens need to be selected carefully to maximize the generated immunity. "
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