Preclinical and Clinical Development of a Multi-Envelope, DNA-Virus-Protein (D-V-P) HIV-1 Vaccine

Abstract

The human immune system has evolved to recognize antigenic diversity, a strength that has been harnessed by vaccine developers to combat numerous pathogens (e.g. pneumococcus, influenza virus, rotavirus). In each case, vaccine cocktails were formulated to include antigenic variants of the target. To combat HIV-1 diversity, we assembled a cocktail vaccine comprising dozens of envelopes, delivered as recombinant DNA, vaccinia virus and protein for testing in a clinical trial. One vaccinee has now completed vaccinations with no serious adverse events. Preliminary analyses demonstrate early proof-of-principle that a multi-envelope vaccine can elicit neutralizing antibody responses toward heterologous HIV-1 in humans.

Murine Monoclonal Antibodies for Antigenic Discrimination of HIV-1 Envelope Proteins

“…As with other chronic infections (e.g., varicella zoster virus), a protective immune response may prevent exogenous virus infection, but may fail to clear endogenous virus, highlighting the importance of vaccinating individuals before a pathogen exposure has occurred. A multienvelope HIV vaccine approach, using dozens of envelopes, has proven protective against disease caused by a heterologous SHIV challenge in macaques (26,58) and has proven safe and immunogenic in an abbreviated clinical trial (8,25,45). Taken together, these results encourage continued testing of the strategy and simplification of cocktails to support advanced clinical studies.…”

SHIV Infection Protects Against Heterologous Pathogenic SHIV Challenge in Macaques: A Gold-Standard for HIV-1 Vaccine Development?

“…polio, VZV, papilloma virus, influenza virus). Perhaps a cocktail vaccine designed to harness the ‘gold-standard’ activity typifying SIV/SHIV-infected primates will ultimately protect humans from infections with HIV-1 [2;3;54-57]. …”

UV-inactivated vaccinia virus (VV) in a multi-envelope DNA-VV-protein (DVP) HIV-1 vaccine protects macaques from lethal challenge with heterologous SHIV

“…This vaccine was previously shown to control viral load and disease in macaques following a heterologous SHIV 89.6P challenge, even though no 89.6P envelope or any SIV component was represented by sequence in the vaccine [13–19]. A multi-envelope DVP vaccine was also tested in a brief clinical study in which it was both immunogenic and well-tolerated [16;20]. Cocktail vaccines have been successfully designed in other fields to combine mutually-exclusive membrane antigens and thereby recruit different populations of lymphocytes to function in unison to provide immune breadth.…”

“…Cocktail vaccines have been successfully designed in other fields to combine mutually-exclusive membrane antigens and thereby recruit different populations of lymphocytes to function in unison to provide immune breadth. The study described here tested the UV-inactivation strategy in the context of DVP [14–16;19;21–23] as a means to improve safety and advance an attractive HIV-1 multi-envelope vaccine approach.…”