pf-3512676 and HIV-Infections

Toll-like receptor (TLR) agonists can reactivate HIV from latently infected cells in vitro. We aimed to investigate the TLR-9 agonist, CPG 7909's in vivo effect on the proviral HIV reservoir and HIV-specific immunity. This was a post-hoc analysis of a double-blind randomized controlled vaccine trial. HIV-infected adults were randomized 1:1 to receive pneumococcal vaccines with or without 1 mg CPG 7909 as adjuvant at 0, 3 and 9 months. In patients on suppressive antiretroviral therapy we quantified proviral DNA at 0, 3, 4, 9, and 10 months (31 subjects in the CPG group and 37 in the placebo-adjuvant group). Furthermore, we measured HIV-specific antibodies, characterized T cell phenotypes and HIV-specific T cell immunity. We observed a mean reduction in proviral DNA in the CPG group of 12.6% (95% CI: -23.6-0.0) following each immunization whereas proviral DNA in the placebo-adjuvant group remained largely unchanged (6.7% increase; 95% CI: -4.2-19.0 after each immunization, p = 0.02). Among participants with additional cryo-preserved PBMCs, HIV-specific CD8+ T cell immunity as indicated by increased expression of degranulation marker CD107a and macrophage inflammatory protein 1β (MIP1β) tended to be up-regulated following immunization with CPG 7909 compared with placebo as adjuvant. Further, increasing proportion of HIV-specific CD107a and MIP1β-expressing CD8+ T cells were strongly correlated with decreasing proviral load. No changes were observed in T cell phenotype distribution, HIV-specific CD4+ T cell immunity, or HIV-specific antibodies. TLR9-adjuvanted pneumococcal vaccination decreased proviral load. Reductions in proviral load correlated with increasing levels of HIV specific CD8+ T cells. Further investigation into the potential effect of TLR9 agonists on HIV latency is warranted.

Topics: Adult; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Compartmentation; Disease Reservoirs; HIV Antibodies; HIV Infections; Humans; Immunity; Immunologic Memory; Middle Aged; Oligodeoxyribonucleotides; Phenotype; Proviruses; Species Specificity; Toll-Like Receptor 9; Viral Load

HIV-patients have excess of pneumococcal infection. We immunized 40 HIV-patients twice with pneumococcal conjugate vaccine (Prevnar, Pfizer) +/- a TLR9 agonist (CPG 7909). Peripheral blood mononuclear cells were stimulated with pneumococcal polysaccharides and cytokine concentrations measured. The CPG 7909 adjuvant group had significantly higher relative cytokine responses than the placebo group for IL-1β, IL-2R, IL-6, IFN-γ and MIP-β, which, did not correlate with IgG antibody responses. These findings suggests that CPG 7909 as adjuvant to pneumococcal conjugate vaccine induces cellular memory to pneumococcal polysaccharides in HIV-patients, independently of the humoral response.

Topics: Adjuvants, Immunologic; Adult; Antibodies, Bacterial; Cytokines; Double-Blind Method; Female; HIV Infections; Humans; Immunoglobulin G; Immunologic Memory; Leukocytes, Mononuclear; Male; Middle Aged; Oligodeoxyribonucleotides; Placebos; Pneumococcal Vaccines; Vaccines, Conjugate

Vaccination responses may be affected by concomitant use of highly active antiretroviral therapy (HAART). We aimed to determine HAART's impact on seven-valent pneumococcal conjugate (7vPnC) vaccine immunization with or without a Toll-like receptor 9 (TLR9) agonist adjuvant.. Observational cohort study.. Adults with HIV were immunized with double doses of 7vPnC +/-1 mg CPG 7909, a TLR9 agonist and vaccine adjuvant, at 0 and 3 months, and 23-valent pneumococcal polysaccharide vaccine at 9 months. We measured IgG levels (ELISA) and opsonophagocytic activity (OPA) at months 0, 3, 4, 9, and 10. Persistent 7vPnC vaccine responders were defined as individuals with two-fold IgG increases to 1 microg/ml or more for at least five of the 7vPnC serotypes at 9 months.. We included 75 participants on HAART and 20 HAART-naive. Forty-one received CPG 7909 and 48 received placebo adjuvant. More persistent 7vPnC vaccine responders were found among HAART-treated than among HAART-naive (42.3 vs. 15.0%, P = 0.03). Mean loss of vaccine-specific IgG from month 4 to 9 was greater among HAART-naive than among HAART-treated (54.8 vs. 38.1%, P = 0.001). Functional activity (OPA) was higher among HAART-treated than among HAART-naive at 4, 9, and 10 months. In a logistic regression analysis (adjusted for baseline CD4 cell count, CPG 7909, smoking status, BMI, AIDS diagnosis, and age), HAART use was significantly associated with being persistent 7vPnC vaccine responder at month 9 [odds ratio = 4.65, 95% confidence interval (CI) 1.07-20.2].. HIV-infected adults on HAART achieved a more durable antibody response of higher functional activity following pneumococcal conjugate vaccination than HAART-naive individuals, independently of baseline CD4 cell count.

Topics: Adult; AIDS-Related Opportunistic Infections; Antibody Formation; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Denmark; Double-Blind Method; Enzyme-Linked Immunosorbent Assay; Female; HIV Infections; Humans; Immunoglobulin G; Male; Middle Aged; Oligodeoxyribonucleotides; Pneumococcal Vaccines; RNA, Viral; Toll-Like Receptor 9; Vaccines, Conjugate

Human immunodeficiency virus (HIV)-infected persons are hyporesponsive to hepatitis B virus (HBV) vaccination. CPG 7909 is an oligodeoxynucleotide containing immunostimulatory CpG motifs that activate human B and plasmacytoid dendritic cells via Toll-like receptor 9. We previously reported that addition of CPG 7909 to a commercial HBV vaccine enhanced the kinetics, magnitude, and longevity of the seroprotective response over 48 weeks. We now report data for the 5-year period following vaccination.. A randomized, double-blind, controlled trial was conducted to determine clinical safety and immunogenicity of HBV vaccine in adult HIV-infected subjects receiving effective antiretroviral therapy. HBV-susceptible subjects, one-half of whom had experienced previous vaccination failure, were vaccinated at 0, 1, and 2 months with a double adult dose of recombinant HBV vaccine, with or without 1 mg of CPG 7909 (19 subjects per arm). Titers of antibody to HBV surface antigen (anti-HBs) were measured at 6-month intervals for up to 60 months.. The proportion of participants achieving and retaining seroprotection (surface antibody titers, > or =10 mIU/mL) was greater in CPG 7909 recipients (P < .05 at all time points). Geometric mean anti-HBs titers were higher in the CPG 7909 group than in the control group (without CPG 7909 adjuvant) at all measured time points.. The immunostimulatory properties of CPG 7909 present an important strategy in achieving long-term protection in HIV-infected patients and other HBV vaccine-hyporesponsive populations.

Topics: Adolescent; Adult; Double-Blind Method; Female; Hepatitis B Vaccines; HIV Infections; Humans; Male; Middle Aged; Oligodeoxyribonucleotides; Time Factors; Treatment Outcome; Vaccination

HIV patients are vaccine hyporesponsive.. We evaluated CPG 7909, a synthetic oligodeoxynucleotide containing immunostimulatory CpG motifs, as an adjuvant to Engerix-B. A randomized, double-blind controlled trial was conducted to determine safety and hepatitis B virus (HBV) immunogenicity in adult HIV subjects on effective antiretroviral therapy. HBV-susceptible subjects, half of whom had failed previous vaccination, were vaccinated at 0, 1 and 2 months with a double dose of Engerix-B with/without (+/-) 1 mg CPG 7909. HBV immune subjects (anti-HBsAg titres > or = 10 mIU/l) received either CPG 7909 alone or saline. Safety, anti-HBs titres and lymphocyte proliferation response (LPR) to HBsAg were assessed over 12 months.. Vaccinations with Engerix B +/- CPG 7909 were well tolerated locally and systemically. HIV suppression and CD4 cell counts were maintained. Anti-HBs titers were significantly higher in vaccinees receiving CPG 7909, for all time points after the second dose. Seroprotective titres (> or = 10 mIU/ml) by 6 and 8 weeks, and 12 months were found in 89, 89, and 100% of subjects receiving CPG 7909 compared to 53, 42, and 63% of controls respectively (P = 0.029, 0.005, and 0.008). HBsAg LPR was increased at all time-points up to 12 months after vaccination with addition of CPG 7909 (P < 0.05).. Addition of CPG 7909 achieves rapid, higher, and sustained HBV seroprotection and increases HBV-specific T helper cell response to HBV vaccine in HIV subjects. These results confirm a potential adjuvant role for CPG 7909 in vaccine hyporesponsive populations including those living with HIV.

Topics: Adjuvants, Immunologic; Adolescent; Adult; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Double-Blind Method; Female; Hepatitis B; Hepatitis B Surface Antigens; Hepatitis B Vaccines; HIV Infections; Humans; Lymphocyte Activation; Male; Middle Aged; Oligodeoxyribonucleotides; RNA, Viral; Vaccines, Synthetic