First-in-human evaluation of a hexon chimeric adenovirus vector expressing HIV-1 Env (IPCAVD 002)

J Infect Dis. 2014 Oct 1;210(7):1052-61. doi: 10.1093/infdis/jiu217. Epub 2014 Apr 8.

Abstract

Background: We report the first-in-human safety and immunogenicity assessment of a prototype hexon chimeric adenovirus (Ad) serotype 5 (Ad5) vector containing the hexon hypervariable regions of Ad serotype 48 (Ad48) and expressing human immunodeficiency virus (HIV) type 1 EnvA.

Methods: Forty-eight Ad5 and Ad48 seronegative, HIV-uninfected subjects were enrolled in a randomized, double-blind, placebo-controlled, dose escalation phase 1 study. Four groups of 12 subjects received 10(9) to 10(11) viral particles (vp) of the Ad5HVR48.EnvA.01 vaccine (n = 10 per group) or placebo (n = 2 per group) at week 0 or weeks 0, 4, and 24. Safety and immunogenicity were assessed.

Results: Self-limited reactogenicity was observed after the initial immunization in the highest (10(11) vp) dose group. Responses in vaccinees included Ad48 neutralizing antibody (nAb) titers higher than Ad5 nAb titers, EnvA-specific enzyme-linked immunosorbent assay titers, and EnvA-specific enzyme-linked immunospot assay responses, and these responses generally persisted at week 52. At week 28 in the 10(9), 10(10), and 10(11) vp 3-dose groups, geometric mean EnvA enzyme-linked immunosorbent assay titers were 5721, 10 929, and 3420, respectively, and Ad48 nAb titers were a median of 1.7-fold higher than for Ad5.

Conclusions: Ad5HVR48.ENVA.01 was safe, well tolerated, and immunogenic at all doses tested. Vector-elicited nAb responses were greater for Ad48 than Ad5, confirming that Ad-specific nAbs in humans are primarily, but not exclusively, directed against the hexon hypervariable regions. Clinical Trials Registration. NCT00695877.

Keywords: HIV vaccine; adenovirus 5 HVR48; dose escalation; immunogenicity; safety.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • AIDS Vaccines / administration & dosage
  • AIDS Vaccines / adverse effects*
  • AIDS Vaccines / genetics
  • AIDS Vaccines / immunology*
  • Adenoviruses, Human / genetics*
  • Adolescent
  • Adult
  • Antibodies, Neutralizing / blood
  • Capsid Proteins / genetics*
  • Double-Blind Method
  • Drug Carriers
  • Drug-Related Side Effects and Adverse Reactions / epidemiology
  • Drug-Related Side Effects and Adverse Reactions / pathology
  • Enzyme-Linked Immunosorbent Assay
  • Enzyme-Linked Immunospot Assay
  • Female
  • Gene Expression*
  • Genetic Vectors
  • HIV Antibodies / blood
  • HIV-1 / genetics*
  • Humans
  • Leukocytes, Mononuclear / immunology
  • Male
  • Middle Aged
  • Placebos / administration & dosage
  • Vaccines, Synthetic / administration & dosage
  • Vaccines, Synthetic / adverse effects
  • Vaccines, Synthetic / genetics
  • Vaccines, Synthetic / immunology
  • Young Adult
  • env Gene Products, Human Immunodeficiency Virus / genetics*

Substances

  • AIDS Vaccines
  • Antibodies, Neutralizing
  • Capsid Proteins
  • Drug Carriers
  • HIV Antibodies
  • Placebos
  • Vaccines, Synthetic
  • env Gene Products, Human Immunodeficiency Virus
  • hexon capsid protein, Adenovirus

Associated data

  • ClinicalTrials.gov/NCT00695877