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126 Combination of Monophosphoryl Lipid A and GM-CSF Adjuvant with an HIV Envelope Immunogen Coupled to a2-Macroglobulin Dramatically Increases HIV Envelope Subunit Immunogenicity
H.-X. Liao*, G. J. Ciancioloý, H. F. Staats, R. M. Scearce, D. M. Lapple, S. Stauffer, J. R. Thomasch, S. V. Pizzoý, D. C. Montefiori, and B. F. Haynes
Duke Univ. Med. Ctr., Durham, NC, USA
Critical to the success of HIV-1 subunit vaccines is the development of strategies to augment vaccine immunogenicity. Successful adjuvants must not only improve immunogenicity but must also decrease the dose of immunogen. We have evaluated a2-macroglobulin (a2M) and a squalene-based stable emulsion containing monophosphoryl lipid A (MPL-SE) and granulocyte-macrophage colony-stimulating factor (GM-CSF) as adjuvants to enhance the immunogenicity of vaccine candidate immunogens. Balb/c mice were subcutaneously immunized on day 0, 14, and 28 with doses ranging from 100 to 0.1 mg of HIV-1 envelope gp120 C4-V3 immunogens from either HIVIIIB (C4-V3IIIB) or SHIV89.6P (C4-V389.6P). Immunogens were covalently coupled to a2M, formulated with MPL-SE/GM-CSF or used as combinations of both. Using CFA/IFA, only 50- and 100-mg doses of C4-V3IIIB peptides induced antibody responses. In contrast, maximum antibody responses were detected in mice immunized with only 10 mg of C4-V3 peptide coupled to a2M (a2M*-peptide). Similar to CFA/IFA, MPL-SE/GM-CSF only significantly enhanced antibody responses at 50 and 100 mg of C4-V3 immunogen. However, the combination of MPL-SE/GM-CSF with a2M*-C4-V3 peptide decreased the dose of C4-V3 required for optimal antibody responses from 100 to 5 mg for C4-V3IIIB and from 100 to 1 mg for C4-V389.6P peptides. The combination of a2M*-peptide with MPL-SE/GM-CSF induced cytotoxic T lymphocyte (CTL) responses comparable to those induced by CFA/IFA or MPL-SE/GM-CSF alone. Taken together, HIV envelope gp120 C4-V3 peptides coupled to a2M* and formulated with MPL-SE/GM-CSF resulted in a subunit HIV immunogen capable of induction of high titers of anti-HIV envelope antibody responses at immunogen doses up to 100-fold less than needed with CFA/IFA.
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