A Phase I Double Blind, Placebo-Controlled, Randomized Study of the Safety and Immunogenicity of Electroporated HIV DNA with or without Interleukin 12 in Prime-Boost Combinations with an Ad35 HIV Vaccine in Healthy HIV-Seronegative African Adults

PLoS One. 2015 Aug 7;10(8):e0134287. doi: 10.1371/journal.pone.0134287. eCollection 2015.

Abstract

Background: Strategies to enhance the immunogenicity of DNA vaccines in humans include i) co-administration of molecular adjuvants, ii) intramuscular administration followed by in vivo electroporation (IM/EP) and/or iii) boosting with a different vaccine. Combining these strategies provided protection of macaques challenged with SIV; this clinical trial was designed to mimic the vaccine regimen in the SIV study.

Methods: Seventy five healthy, HIV-seronegative adults were enrolled into a phase 1, randomized, double-blind, placebo-controlled trial. Multi-antigenic HIV (HIVMAG) plasmid DNA (pDNA) vaccine alone or co-administered with pDNA encoding human Interleukin 12 (IL-12) (GENEVAX IL-12) given by IM/EP using the TriGrid Delivery System was tested in different prime-boost regimens with recombinant Ad35 HIV vaccine given IM.

Results: All local reactions but one were mild or moderate. Systemic reactions and unsolicited adverse events including laboratory abnormalities did not differ between vaccine and placebo recipients. No serious adverse events (SAEs) were reported. T cell and antibody response rates after HIVMAG (x3) prime-Ad35 (x1) boost were independent of IL-12, while the magnitude of interferon gamma (IFN-γ) ELISPOT responses was highest after HIVMAG (x3) without IL-12. The quality and phenotype of T cell responses shown by intracellular cytokine staining (ICS) were similar between groups. Inhibition of HIV replication by autologous T cells was demonstrated after HIVMAG (x3) prime and was boosted after Ad35. HIV specific antibodies were detected only after Ad35 boost, although there was a priming effect with 3 doses of HIVMAG with or without IL-12. No anti-IL-12 antibodies were detected.

Conclusion: The vaccines were safe, well tolerated and moderately immunogenic. Repeated administration IM/EP was well accepted. An adjuvant effect of co-administered plasmid IL-12 was not detected.

Trial registration: ClinicalTrials.gov NCT01496989.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AIDS Vaccines / adverse effects*
  • AIDS Vaccines / immunology
  • Adenoviridae / metabolism
  • Adult
  • CD8-Positive T-Lymphocytes / immunology
  • DNA, Viral / adverse effects*
  • DNA, Viral / immunology*
  • Demography
  • Double-Blind Method
  • Electroporation*
  • Enzyme-Linked Immunospot Assay
  • Female
  • Flow Cytometry
  • HIV Antibodies / immunology
  • HIV Infections / immunology*
  • Humans
  • Immunity, Cellular
  • Immunity, Humoral
  • Immunization
  • Immunization, Secondary*
  • Interferon-gamma / metabolism
  • Interleukin-12 / immunology*
  • Male
  • Middle Aged
  • Placebos
  • Young Adult

Substances

  • AIDS Vaccines
  • DNA, Viral
  • HIV Antibodies
  • Placebos
  • Interleukin-12
  • Interferon-gamma

Associated data

  • ClinicalTrials.gov/NCT01496989

Grant support

IAVI’s work is made possible by generous support from many donors including: the Bill & Melinda Gates Foundation; the Ministry of Foreign Affairs of Denmark; Irish Aid; the Ministry of Finance of Japan in partnership with the World Bank; the Ministry of Foreign Affairs of the Netherlands; the Norwegian Agency for Development Cooperation (NORAD); the United Kingdom Department for International Development (DFID), and the United States Agency for International Development (USAID). The full list of IAVI donors is available at www.iavi.org. This study is made possible by the generous support of the American people through USAID. The contents are the responsibility of the International AIDS Vaccine Initiative and do not necessarily reflect the views of USAID or the United States Government. Profectus BioSciences, Inc. and ICHOR Medical Systems collaborated on the study, they reviewed the study design and have reviewed and approved the submitted manuscript. The salaries of co-authors ME and JE were supported by Profectus BioSciences likewise the salary of co-author DH was supported by ICHOR Medical Systems. Co-author LD is employed by The EMMES Corporation. EMMES supported the salaries for LD and other EMMES employees involved in the study design, sample size calculation and randomization, web-based data collection, statistics, data analysis and reporting, and preparation of the manuscript. The specific role of the author LD is articulated in the ‘author contributions’ section. The EMMES Corporation otherwise did not have any additional role in the study conduct, decision to publish, or preparation of the manuscript.