ABSTRACT
Therapeutic vaccination has the potential to contribute to functional HIV cure strategies. However, to show functional HIV cure, study participants must be taken off combination antiretroviral therapy (cART). The availability of suitable biomarkers that can predict viral load (VL) or CD4 count outcomes following therapeutic HIV vaccination would reduce the risks associated with cART interruption in such studies. This report sought to determine baseline and postvaccination biomarker predictors of vaccine effect (VE) on VL and CD4 counts following cART interruption in a double-blind, randomized phase 2 study of the peptide-based therapeutic HIV vaccine, Vacc-4x (n = 93), versus placebo (n = 43). Antibody responses to a novel envelope glycoprotein antigen, C5/gp41732-744, and three safety marker measurements [C-reactive protein (CRP), white blood cell, and lactate dehydrogenase] were considered. Interaction tests in univariate and multivariate linear regression models were used to estimate the effect of biomarkers on VE, defined as the VL or CD4 count difference in Vacc-4x versus placebo groups. The reported q-values (considered significant for hypothesis-generating purposes if ≤0.2) accounted for multiple comparisons using the false discovery rate method. Data were analyzed from all available 58 Vacc-4x and 25 placebo recipients before cART resumption. Lower postvaccination fold-change over baseline of CRP concentration (interaction p- (q-) value = 0.005 (0.11) for VL) and higher fold-change of anti-C5/gp41732-744 antibody levels (0.005 (0.11) for VL and 0.009 (0.20) for CD4) were associated with Vacc-4x benefit. These findings suggest potential roles for inflammation and immune activation markers in predicting therapeutic HIV VE.
Subject(s)
AIDS Vaccines/immunology , AIDS Vaccines/pharmacology , C-Reactive Protein/drug effects , HIV Infections/immunology , HIV Infections/prevention & control , HIV-1/immunology , Adult , Antibody Formation/drug effects , C-Reactive Protein/metabolism , CD4 Lymphocyte Count , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Dose-Response Relationship, Immunologic , Double-Blind Method , Endpoint Determination , Female , Humans , Male , Middle Aged , Viral Load/drug effects , Viral Load/immunology , Young AdultABSTRACT
Current influenza vaccines mainly induce antibody responses to the variable hemagglutinin proteins of the virus strains included in the vaccine. Instead, a broadly protective influenza vaccine should aim at inducing antibody- and/or cell-mediated immunity against conserved viral proteins. Vacc-FLU is a peptide based vaccine combining conserved B and T cell epitopes. Peptide selection was done using a proprietary peptide design platform technology focusing on responses to human leukocyte antigen (HLA)-restricted epitopes. Immunization of wild-type mice and mice transgenic for HLA-A2.1 with the peptide mix successfully induced both humoral and cell mediated immune responses. Partial protection from severe weight loss upon challenge was observed in both mouse strains but was stronger and observed at lower vaccine doses in transgenic mice. Our results show that the Vacc-FLU peptide mix is capable of inducing IFNγ-producing T cells and antibody-producing B cells which can protect from severe disease symptoms upon infection.
Subject(s)
Immunity, Cellular , Immunity, Humoral , Influenza A virus/immunology , Influenza Vaccines/immunology , Influenza, Human/prevention & control , Peptides/immunology , Animals , Disease Models, Animal , Epitopes, T-Lymphocyte/immunology , Female , HLA-A2 Antigen , Humans , Immunization , Influenza, Human/virology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Random AllocationABSTRACT
Antibodies to the carboxy-terminal constant (C5) region 5 of the HIV-1 envelope glycoprotein gp120 have previously been associated with slow disease progression. This is one of the regions on gp120 that interact with the transmembrane glycoprotein, gp41, anchoring it to the viral and infected cell membrane. This study analyzed humoral responses to a novel heterodimeric peptide construct comprising the C5501-512 region and a compatible region on gp41732-744. Antibody levels to C5501-512/gp41732-744 were associated with slow disease progression in a treatment naive historical longitudinal cohort from Norway (n = 32; p = .00001). Elevated anti-C5501-512/gp41732-744 antibody levels correlated with moderate viral load (VL) (50-10,000 copies/ml) in a cohort, including natural viral suppressors (NVS) in the Unites States (n = 58; p = .002). Analysis of HIV-positive sera from treatment naive patients in Estonia (n = 300) showed an inverse correlation between anti-C5501-512/gp41732-744 antibodies and VL when comparing VL 2,000-10,000 copies/ml with VL >10,000 (p = .050). Further mapping using peptide inhibition of antibody binding revealed that responses to the C5501-506 subdomain correlated with preserved CD4 counts (n = 55; p = .0012) irrespective of VL in this cohort. The C5 region encompassing C5501-506 shows sequence similarity to the shared epitope (SE) of certain HLA-DR associated with immune dysfunction. Partial antigenic cross-reactivity between SE and C5 is indicated by partial inhibition of NVS antibody binding using SE 15-mer peptide (median 65% inhibition), the C5501-506 6-mer peptide (79% inhibition), and binding of rheumatoid arthritis patient sera to both SE and C5 peptide sequences. The potential influence of these observations on HIV-1 pathogenesis remains to be determined.
