Effect of the strength of adsorption of HIV 1 SF162dV2gp140 to aluminum-containing adjuvants on the immune response.

The importance of the strength of antigen adsorption by aluminum-containing adjuvants on immunopotentiation was studied using HIV 1 SF162dV2gp140 (gp140), a potential HIV/AIDS antigen. The strengths of adsorption by aluminum hydroxide (AH) adjuvant and aluminum phosphate adjuvant, as measured by the Langmuir adsorptive coefficient, were 1900 and 400 mL/mg, respectively. The strength of adsorption by AH was modified by pretreatment of AH with two different concentrations of potassium dihydrogen phosphate to produce phosphate-treated aluminum hydroxide adjuvants having adsorptive coefficients of 1200 and 800 mL/mg. The four adjuvants were used to prepare vaccines containing either 1 or 10 µg of gp140 per dose. Antibody studies in mice revealed that the presence of an adjuvant increased the immune response in comparison with a solution of gp140 when the dose was 1 µg. Furthermore, the immune response was inversely related to the adsorptive coefficient. In contrast, no significant difference in immunopotentiation was observed between treatments in the presence or absence of an adjuvant when the dose of gp140 was 10 µg. Analysis of the binding of gp140 to CD4 and anti-gp140 monoclonal antibodies by surface plasmon resonance suggests that tight binding induced structural changes in the antigen.

Neutralizing antibody responses to subtype B and C adjuvanted HIV envelope protein vaccination in rabbits.

Improving the potency, breadth, and durability of neutralizing antibody responses to HIV are major challenges for HIV vaccine development. To address these challenges, the studies described evaluate in rabbits the titers, breadth, and epitope specificities of antibody responses elicited by HIV envelope subunit vaccines adjuvanted with MF59 with or without CpG oligodeoxynucleotide (ODN). Animals were immunized with trimeric o-gp140DeltaV2 derived from subtype B HIV-1(SF162) or subtype C HIV-1(TV1), or proteins from both strains. Immunization with SF162 or TV1 with MF59/CpG elicited higher titers of binding and neutralizing antibodies to SF162 than monovalent immunization with MF59 alone (P<0.01). Bivalent immunization increased binding and neutralizing antibody titers over single envelope immunization in MF59 (P<0.01). Bivalent immunization also improved neutralization breadth. Epitope mapping indicated neutralizing activity in rabbits was directed to V3 and V4. Overall, our data suggests that a multivalent vaccination approach with MF59 and CpG can enhance humoral responses to HIV-1.

Evaluation of envelope vaccines derived from the South African subtype C human immunodeficiency virus type 1 TV1 strain.

Human immunodeficiency virus type 1 (HIV-1) subtype C infections are on the rise in Sub-Saharan Africa and Asia. Therefore, there is a need to develop an HIV vaccine capable of eliciting broadly reactive immune responses against members of this subtype. We show here that modified HIV envelope (env) DNA vaccines derived from the South African subtype C TV1 strain are able to prime for humoral responses in rabbits and rhesus macaques. Priming rabbits with DNA plasmids encoding V2-deleted TV1 gp140 (gp140TV1DeltaV2), followed by boosting with oligomeric protein (o-gp140TV1DeltaV2) in MF59 adjuvant, elicited higher titers of env-binding and autologous neutralizing antibodies than priming with DNA vaccines encoding the full-length TV1 env (gp160) or the intact TV1 gp140. Immunization with V2-deleted subtype B SF162 env and V2-deleted TV1 env together using a multivalent vaccine approach induced high titers of oligomeric env-binding antibodies and autologous neutralizing antibodies against both the subtypes B and C vaccine strains, HIV-1 SF162 and TV1, respectively. Low-level neutralizing activity against the heterologous South African subtype C TV2 strain, as well as a small subset of viruses in a panel of 13 heterologous primary isolates, was observed in some rabbits immunized with the V2-deleted vaccines. Immunization of rhesus macaques with the V2-deleted TV1 DNA prime/protein boost also elicited high titers of env-binding antibodies and moderate titers of autologous TV1 neutralizing antibodies. The pilot-scale production of the various TV1 DNA vaccine constructs and env proteins described here should provide an initial platform upon which to improve the immunogenicity of these subtype C HIV envelope vaccines.