Activation of Innate Immunity in Healthy
            <i>Macaca mulatta</i>
            Macaques by a Single Subcutaneous Dose of GMP CpG 7909: Safety Data and Interferon-Inducible Protein-10 Kinetics for Humans and Macaques

Stewart, V. Ann; McGrath, Shannon; Krieg, Arthur Μ.; Larson, Noelle; Angov, Evelina; Smith, Christopher L.; Brewer, Thomas G.; Heppner, D. Gray

doi:10.1128/cvi.00420-07

Cited by 17 publications

(13 citation statements)

References 12 publications

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“…In agreement with previous reports of SC administration of CPG 7909 [2;18;19] we found comparable response kinetics and magnitudes of IP-10 and IL-6 serum content after the vaccines were administered IM. These responses were transient and returned to baseline by day 7, indicating the potential to monitor repeated doses of CpG-adjuvanted vaccines for potentially unregulated activation of innate immunity by evaluating cytokine/chemokines or readily available CRP or ALC.…”

Section: Discussionsupporting

confidence: 93%

“…Human serum biomarkers affected by CpG adjuvants include increased IP-10 and IL-6 [2], IL-12, MCP-1 and IFN-α [3] as well as enhanced antibody responses [1;4;5]. Also reported were transiently decreased absolute lymphocyte counts (ALC) and C-reactive Protein (CRP) after subcutaneous (SC) administration [3;6;19], in vitro interferon-gamma (IFN-γ) production by peripheral blood mononuclear cells (PBMC) obtained after in vivo CpG treatment [4], increased T cell expansion [7], increased circulating T cells and NK cells after intra-venous (IV) administration [6] and increased CD8 + T cells.…”

Section: Introductionmentioning

confidence: 99%

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Enhanced early innate and T cell-mediated responses in subjects immunized with Anthrax Vaccine Adsorbed Plus CPG 7909 (AV7909)

Minang

Inglefield

Harris

et al. 2014

Vaccine

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NuThrax™ (Anthrax Vaccine Adsorbed with CPG 7909 Adjuvant) (AV7909) is in development. Samples obtained in a Phase Ib clinical trial were tested to confirm biomarkers of innate immunity and evaluate effects of CPG 7909 (PF-03512676) on adaptive immunity. Subjects received two intramuscular doses of commercial BioThrax® (Anthrax Vaccine Adsorbed, AVA), or two intramuscular doses of one of four formulations of AV7909. IP-10, IL-6, and C-reactive protein (CRP) levels were elevated 24 to 48 hours after administration of AV7909 formulations, returning to baseline by Day 7. AVA (no CPG 7909) resulted in elevated IL-6 and CRP, but not IP-10. Another marker of CpG, transiently decreased absolute lymphocyte counts (ALC), correlated with transiently increased IP-10. Cellular recall responses to anthrax Protective Antigen (PA) or PA peptides were assessed by IFN-gamma ELISpot assay performed on cryopreserved PBMCs obtained from subjects prior to immunization and 7 days following the second immunization (study day 21). One-half of subjects that received AV7909 with low-dose (0.25 mg/dose) CPG 7909 possessed positive Day 21 T cell responses to PA. In contrast, positive T cell responses occurred at an 11% average rate (1/9) for AVA-treated subjects. Differences in cellular responses due to dose level of CPG 7909 were not associated with differences in humoral anti-PA IgG responses, which were elevated for recipients of AV7909 compared to recipients of AVA. Serum markers at 24 or 48 hours (i.e. % ALC decrease, or increase in IL-6, IP-10, or CRP) correlated with the humoral (antibody) responses 1 month later, but did not correlate with cellular ELISpot responses. In summary, biomarkers of early responses to CPG 7909 were confirmed, and adding a CpG adjuvant to a vaccine administered twice resulted in increased T cell effects relative to vaccine alone. Changes in early biomarkers correlated with subsequent adaptive humoral immunity but not cellular immunity.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Enhanced early innate and T cell-mediated responses in subjects immunized with Anthrax Vaccine Adsorbed Plus CPG 7909 (AV7909)

Minang

Inglefield

Harris

et al. 2014

Vaccine

View full text Add to dashboard Cite

show abstract

“…Safety studies conducted in animals with CpG ODNs found them to be less reactogenic than other adjuvants [42–44] and has led to the use and testing of CpG ODN 7909 in human clinical trials [45, 46]. Of particular relevance to our study, a mouse study assessing safety of CpG ODNs administered IM reported minimal to no tissue damage in the injected tissue [42].…”

Section: 0 Discussionmentioning

confidence: 86%

Comparison of the immunological responses and efficacy of gamma-irradiated V3526 vaccine formulations against subcutaneous and aerosol challenge with Venezuelan equine encephalitis virus subtype IAB

Martin¹,

Bakken

Lind

et al. 2010

Vaccine

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We recently developed a gamma-irradiation method to inactivate V3526, a live-attenuated Venezuelan equine encephalitis virus (VEEV) vaccine candidate. Dosage and schedule studies were conducted to evaluate the immunogenicity and efficacy of gamma-irradiated V3526 (gV3526). Subcutaneous (SC) and low dosage intramuscular (IM) administration of gV3526 were highly effective in protecting mice against a SC challenge with VEEV IA/B Trinidad Donkey strain, but not against an equivalent aerosol challenge. More robust immune responses and increased protective efficacy were noted when the IM dosage of gV3526 was increased. IM administration of gV3526 formulated with either CpG or CpG plus Alhydrogel further augmented the immune response in mice and resulted in 100% protection against aerosol challenge.

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“…inoculations with intra-nasal (i.n.) immunization with the gp41t-Fc construct that could potentially induce antibodies localized to the FRT; use a TLR9 agonist and CpG adjuvant, with the rationale that TLR9 agonists have been shown to induce strong B cell responses in other settings [29] and have been used safely in rhesus macaques [30]. …”

Section: Resultsmentioning

confidence: 99%

Reproducing SIVΔnef vaccine correlates of protection

Voss

Macauley²,

Rogers³

et al. 2016

Aids

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Vaccination with SIVmac239Δnef provides robust protection against subsequent challenge with wild type SIV, but safety issues have precluded designing an HIV-1 vaccine based on a live attenuated virus concept. Safe immunogens and adjuvants that could reproduce identified immune correlates of SIVmac239Δnef protection therefore offer an alternative path for development of an HIV vaccine. Here we describe SIV envelope trimeric gp41 (gp41t) immunogens based on a protective correlate of antibodies to gp41t concentrated on the path of virus entry by the neonatal Fc receptor (FcRn) in cervical vaginal epithelium. We developed a gp41t immunogen-MPLA adjuvant liposomal nanoparticle for intra-muscular immunization and a gp41t-Fc immunogen for intranasal immunization for pilot studies in mice, rabbits, and rhesus macaques. Repeated immunizations to mimic persistent antigen exposure in infection elicited gp41t antibodies in rhesus macaques that were detectable in FcRn+ cervical vaginal epithelium, thus recapitulating one key feature of SIVmac239Δnef vaccinated and protected animals. While this strategy did not reproduce the system of local production of antibody in SIVmac239Δnef-vaccinated animals, passive immunization experiments supported the concept that sufficiently high levels of antibody can be concentrated by the FcRn at mucosal frontlines, thus setting the stage for assessing protection against vaginal challenge by gp41t immunization.

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Activation of Innate Immunity in Healthy Macaca mulatta Macaques by a Single Subcutaneous Dose of GMP CpG 7909: Safety Data and Interferon-Inducible Protein-10 Kinetics for Humans and Macaques

Cited by 17 publications

References 12 publications

Enhanced early innate and T cell-mediated responses in subjects immunized with Anthrax Vaccine Adsorbed Plus CPG 7909 (AV7909)

Enhanced early innate and T cell-mediated responses in subjects immunized with Anthrax Vaccine Adsorbed Plus CPG 7909 (AV7909)

Comparison of the immunological responses and efficacy of gamma-irradiated V3526 vaccine formulations against subcutaneous and aerosol challenge with Venezuelan equine encephalitis virus subtype IAB

Reproducing SIVΔnef vaccine correlates of protection

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