HIV-1MN Recombinant Glycoprotein 160 Vaccine-Induced Cellular and Humoral Immunity Boosted by HIV-1MN Recombinant Glycoprotein 120 Vaccine

Abstract

We evaluated prime-boost immunization with two recombinant envelope glycoprotein subunit vaccines (HIV-1MN recombinant gp160 vaccine in alum adjuvant [MN rgp160] and HIV-1MN recombinant gp120 vaccine in alum adjuvant [MN rgp120]) for safety and immunogenicity in healthy, HIV-1-uninfected adults. The rationale was to combine the helper T cell memory and binding antibody responses typically induced by rgp160 vaccines with the superior neutralizing antibody responses induced by rgp120 vaccines. In a double-blinded, controlled trial, volunteers were randomly assigned to receive MN rgp160 or adjuvant placebo, and a subset later received MN rgp120. The two vaccines were safe, but reactions to MN rgp160 and its adjuvant placebo exceeded those to MN rgp120. MN rgp160 induced IgG binding antibodies, including all IgG subclasses, to MN rgp160 in all vaccine recipients. HIV-1MN-neutralizing and anti-V3 MN peptide-binding antibodies were observed in a majority of volunteers after the fourth MN rgp160 immunization, but at lower levels compared with immunization with MN rgp120 in historical controls. HIV-1-binding, neutralizing, and fusion inhibition antibodies were boosted to the highest levels among MN rgp160 recipients after MN rgp120 booster injections. MN rgp120 boosting appeared to alter the distribution of MN rgp160 vaccine-induced, anti-MN rgp160 IgG subclass antibodies. MN rgp160 induced helper T cell memory, measured by lymphocyte proliferation, Thl and Th2 cytokine production, and skin testing. Strategies including both subunit vaccines may help maximize antibody and helper T cell memory responses to HIV-1 envelope glycoprotein.

Cross-subtype antibody and cellular immune responses induced by a polyvalent DNA prime–protein boost HIV-1 vaccine in healthy human volunteers

“…Levels of anti-Env antibodies elicited in previous DNA vaccine clinical trials were either low or undetectable [42,43], nor was there a clear induction of NAbs against even sensitive viruses [14]. In the current study, one Env protein immunization following DNA prime was able to elicit human anti-Env antibody responses to a level that has proven difficult to achieve in previous studies that employed multiple injections of recombinant HIV-1 Env proteins [2,3,6]. Therefore, data from this study provides evidence that DNA vaccination can effectively prime the induction of high-level anti-Env antibody responses in humans.…”

“…Serum and PBMC samples were collected at Study Weeks 0, 2,4,6,12,14,16,20,22,24,28,30,32,36 and 52 to measure antibody and CMI responses. All volunteers were recruited and enrolled in the Clinical Vaccine Research Unit, UMMS.…”

“…Early efforts in HIV vaccine development focused on the induction of humoral responses by using recombinant Env glycoproteins [2][3][4][5]. The immunogenicity of recombinant Env protein-based vaccines was poor in humans, as shown by overall low-level binding antibodies measured by solid phase assays [6] and by the narrow spectrum of neutralizing activities mainly against T-cell line adapted (TCLA) viral isolates [7][8][9].…”

Toward Effective HIV Vaccination

“…Site-directed mutagenesis and crystallography studies indicate the crucial role of this region in maintaining the integrity of the CD4BS (3-6) (supplemental Table S2). However, experimental vaccination efforts have failed to document the synthesis of neutralizing Abs to the 421-433 region (77)(78)(79). Our studies indicate that a substantial proportion of mAbs (7/17) induced by covalent immunization neutralized HIV strains genetically heterologous to the E-gp120 immunogen.…”

Engineering, Expression, Purification, and Characterization of Stable Clade A/B Recombinant Soluble Heterotrimeric gp140 Proteins

“…The earliest soluble forms of Env tested preclinically and clinically as immunogens were based on the monomeric gp120 subunit (6,33,36,43,59,82). These constructs were shown to elicit neutralizing antibody responses of very narrow breadth; i.e., they elicited antibodies that primarily targeted the homologous virus and a few "easy-to-neutralize" viruses (tier 1 viruses) but not primary viruses (tier 2 and 3 viruses) (30,57,59).…”