Application of the Polyvalent Approach to HIV-1 Vaccine Development

Abstract

One major obstacle to the design of a global HIV-1 vaccine is viral diversity. Presently, data suggest that a single antigen will not suffice to generate broadly reactive neutralizing antibodies to protect all individuals against all subtypes of HIV-1 infection. While some of the neutralizing epitopes are identified in the constant regions of the HIV-1 envelope (Env) glycoprotein, many are localized to variable regions and differ conformationally from one virus to the next. The successes of polyvalent vaccine approaches against other antigenically variable pathogens encourage adoption of the same approach for HIV-1 vaccine design. The critical question is which envelope antigens should be combined in a vaccine cocktail to provide maximum protection against HIV-1. A review of the existing human vaccines based on the polyvalent principle is included here to provide a historical perspective for the current effort of developing a polyvalent HIV-1 vaccine. Data generated from several groups actively working on candidate polyvalent HIV-1 vaccines are summarized. Information presented in this review highlights the potential and importance of the polyvalent vaccine approach for the future development of an effective HIV-1 vaccine.

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

“…Our studies included a demonstration that successive inoculations with envelope recombinant vaccines given in the order D, V and P elicited durable B-cell and T-cell responses [22;45-47]. We also showed that multi-envelope vaccines generated superior immune breadth compared to single-envelope vaccines (as has also been demonstrated by other groups [7;48-50]), that the inclusion of a minor component in a mixed vaccine was sufficient to elicit a type-specific immune response [51], and that the grouping of envelopes by subtype or origin did not always correlate with antigenicity (as also confirmed by work in other laboratories [52;53]). Finally, we demonstrated that a multi-envelope D-V-P vaccine could protect macaques from disease following challenge with a heterologous SHIV [54].…”

Infection by Discordant Strains of HIV-1 Markedly Enhances the Neutralizing Antibody Response against Heterologous Virus

“…These data support the use of vaccine constructs that carry epitopes of divergent HIV-1 variants rather than of single strains, and they imply that polyvalent vaccination schemes may be preferable to monovalent ones. Indeed, recent vaccine studies support this hypothesis, suggesting that vaccines based on multiple strains do induce superior nAbs (11,23,(28)(29)(30). Zolla-Pazner et al demonstrated that immunization of rabbits with V3 fusion proteins from HIV-1 clades A, B, and C induces anti-HIV-1 antibodies with better potency and breadth than immunization of rabbits with V3 fusion proteins from a single clade (30).…”

A Minimum CR2 Binding Domain of C3d Enhances Immunity Following Vaccination

“…The HIV-1 Env gp120 was conjugated to multimers of P28 and directly compared to elicitation of immune responses by Env gp120 conjugated to multimers of the full C3d protein. DNA vaccines expressing Env gp120 are poorly immunogenic when expressed from DNA, eliciting low anti-Env immunity ( Figures 3 and 4, as well as 11,12,17,20,[30][31][32] ); however, the HIV-1 envelope is highly immunogenic when presented to the immune system as a purified protein 30,[35][36][37][38][39][40][41][42][43][44][45][46][47][48] . Fusion of multimers of the whole C3d or the P28 peptide to Env gp120 enhanced the level of immunogenicity, regardless of the route of inoculation of DNA.…”