TLR9-adjuvanted pneumococcal conjugate vaccine induces antibody-independent memory responses in HIV-infected adults

Offersen, Rasmus; Melchjorsen, Jesper; Paludan, Søren R.; Østergaard, Lars; Tolstrup, Martin; Søgaard, Ole Schmeltz

doi:10.4161/hv.20707

Cited by 17 publications

(16 citation statements)

References 19 publications

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“…In the same cohort of patients, increased Ab dependent cellular immunity was detected after the second vaccination accompanied by significantly higher PBMC cytokine responses involving IL-1 ( p = 0.0046), IL-6 ( p = 0.0051), IFN-α ( p = 0.0047), MIP-β ( p = 0.0086), and IL-2R ( p = 0.0062). PBMC from the CpG 7909 adjuvanted group responded to LPS stimulation by producing IL-1β ( p = 0.038) and IFN-α ( p = 0.019) at significantly higher levels when compared to non-CpG controls [94]. HIV pro-viral DNA levels fell by 12.6% in the CpG 7909 treated group versus a rise of 6.7% in the placebo group after the 3rd vaccination (at 10 months) ( p = 0.056).…”

Section: Cpg Odn As An Adjuvant In Hiv-infected Individualsmentioning

confidence: 99%

Clinical evaluation of CpG oligonucleotides as adjuvants for vaccines targeting infectious diseases and cancer

Scheiermann

Klinman

2014

Vaccine

281

255

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Synthetic oligonucleotides (ODN) that express unmethylated “CpG motifs” trigger cells that express Toll-like receptor 9. In humans this includes plasmacytoid dendritic cells and B cells. CpG ODN induce an innate immune response characterized by the production of Th1 and pro-inflammatory cytokines. Their utility as vaccine adjuvants was evaluated in a number of clinical trials. Results indicate that CpG ODN improve antigen presentation and the generation of vaccine-specific cellular and humoral responses. This work provides an up-to-date overview of the utility of CpG ODN as adjuvants for vaccines targeting infectious agents and cancer.

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Section: Cpg Odn As An Adjuvant In Hiv-infected Individualsmentioning

confidence: 99%

Clinical evaluation of CpG oligonucleotides as adjuvants for vaccines targeting infectious diseases and cancer

Scheiermann

Klinman

2014

Vaccine

281

255

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“…However, as we were unable to assess changes in residual viremia or viral transcription, it remains uncertain whether the decrease in proviral reservoir observed in this study can be attributed to induced virus production in latently infected cells, effects on HIV-specific T cell immunity, or non-specific effect on other immune effector cells, or a combination of the three. It has previously been shown that besides increasing antibody production, CPG 7909-adjuvanted pneumococcal vaccination also enhances antibody-independent cellular immunity [29]. In addition to B cells, TLR9 is also abundant in plasmacytoid dendritic cells (pDCs) [41].…”

Section: Discussionmentioning

confidence: 99%

“…Owing to their immune stimulatory properties via TLR9, synthetic CpG oligodeoxynucleotides (CpG ODNs) are used as vaccine adjuvants and have been shown to enhance vaccine immunogenicity in HIV-infected individuals and healthy adults with an acceptable safety profile [25]–[28]. Besides inducing humoral immunity, CPG-adjuvanted pneumococcal vaccine has been shown to enhance antibody-independent cellular immunity [29], [30]. In addition, CpG ODNs reactivate HIV-1 expression in latently infected cells by mechanisms that involve TLR9 signalling and eventually activation of NF-κB [31], [32], but the mechanistic details remain largely unresolved.…”

Section: Introductionmentioning

confidence: 99%

“…Given CpG's ability to reactivate HIV from latently infected cells in vitro [31], [32], we hypothesized that the observed systemic immunological events may have triggered the release of latent proviruses from long-lived cellular reservoirs. Hence, the CpG/pneumococcal vaccine trial provided a unique opportunity to evaluate the in vivo effect of a compound that in prior studies has been shown to enhance innate and cellular immunity[36] as well as to induce HIV-1 expression in latently infected cells [31], [32]. Therefore, we aimed to assess whether administration of CPG 7909 to HIV-infected individuals led to any changes in the size of the proviral reservoir.…”

Section: Introductionmentioning

confidence: 99%

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Administration of a Toll-Like Receptor 9 Agonist Decreases the Proviral Reservoir in Virologically Suppressed HIV-Infected Patients

et al. 2013

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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.

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“…In a post hoc analysis of a phase I study, ART suppressed HIV-infected individuals who received a pneumococcal vaccine regimen plus CPG 7909 had a reduction in proviral DNA compared to the group that received the vaccine with placebo. Reductions in proviral DNA was correlated with increasing levels of HIV specific CD8 cells [98, 99]. …”

Section: Intracellular Reservoir Targetsmentioning

confidence: 99%

Leveraging Cancer Therapeutics for the HIV Cure Agenda: Current Status and Future Directions

Polizzotto

Chen

Tressler

et al. 2015

Drugs

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Despite effective antiretroviral therapy (ART) and undetectable HIV RNA in the plasma, latent replication-competent HIV persists indefinitely in long-lived cells. Cessation of ART results in rebound of HIV from these persistent reservoirs. While this was thought to be an insurmountable obstacle to viral eradication, recent cases suggest otherwise. To date one patient has been “cured” of HIV and several others have been able to interrupt ART without viral rebound for prolonged periods. These events have sparked renewed interest in developing strategies that will allow eradication of HIV in infected individuals. We review the current knowledge of HIV latency and the viral reservoir, describe the potential utility of emerging cancer therapeutics in HIV cure research with an emphasis on pathways implicated in reservoir persistence, and outline opportunities and challenges in the context of the current clinical trial and regulatory environment.

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TLR9-adjuvanted pneumococcal conjugate vaccine induces antibody-independent memory responses in HIV-infected adults

Cited by 17 publications

References 19 publications

Clinical evaluation of CpG oligonucleotides as adjuvants for vaccines targeting infectious diseases and cancer

Clinical evaluation of CpG oligonucleotides as adjuvants for vaccines targeting infectious diseases and cancer

Administration of a Toll-Like Receptor 9 Agonist Decreases the Proviral Reservoir in Virologically Suppressed HIV-Infected Patients

Leveraging Cancer Therapeutics for the HIV Cure Agenda: Current Status and Future Directions

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