First Phase I human clinical trial of a killed whole-HIV-1 vaccine: demonstration of its safety and enhancement of anti-HIV antibody responses

Retrovirology. 2016 Nov 28;13(1):82. doi: 10.1186/s12977-016-0317-2.

Abstract

Background: Vaccination with inactivated (killed) whole-virus particles has been used to prevent a wide range of viral diseases. However, for an HIV vaccine this approach has been largely negated due to inherent safety concerns, despite the ability of killed whole-virus vaccines to generate a strong, predominantly antibody-mediated immune response in vivo. HIV-1 Clade B NL4-3 was genetically modified by deleting the nef and vpu genes and substituting the coding sequence for the Env signal peptide with that of honeybee melittin signal peptide to produce a less virulent and more replication efficient virus. This genetically modified virus (gmHIV-1NL4-3) was inactivated and formulated as a killed whole-HIV vaccine, and then used for a Phase I human clinical trial (Trial Registration: Clinical Trials NCT01546818). The gmHIV-1NL4-3 was propagated in the A3.01 human T cell line followed by virus purification and inactivation with aldrithiol-2 and γ-irradiation. Thirty-three HIV-1 positive volunteers receiving cART were recruited for this observer-blinded, placebo-controlled Phase I human clinical trial to assess the safety and immunogenicity.

Results: Genetically modified and killed whole-HIV-1 vaccine, SAV001, was well tolerated with no serious adverse events. HIV-1NL4-3-specific PCR showed neither evidence of vaccine virus replication in the vaccine virus-infected human T lymphocytes in vitro nor in the participating volunteers receiving SAV001 vaccine. Furthermore, SAV001 with adjuvant significantly increased the pre-existing antibody response to HIV-1 proteins. Antibodies in the plasma of vaccinees were also found to recognize HIV-1 envelope protein on the surface of infected cells as well as showing an enhancement of broadly neutralizing antibodies inhibiting tier I and II of HIV-1 B, D, and A subtypes.

Conclusion: The killed whole-HIV vaccine, SAV001, is safe and triggers anti-HIV immune responses. It remains to be determined through an appropriate trial whether this immune response prevents HIV infection.

Keywords: AIDS; Clinical trial; HIV; Immune responses; Killed whole-HIV vaccine; Neutralizing antibodies; Safety.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial

MeSH terms

  • AIDS Vaccines* / administration & dosage
  • AIDS Vaccines* / adverse effects
  • AIDS Vaccines* / immunology
  • Adult
  • Animals
  • Antibodies, Neutralizing / blood*
  • Antibodies, Neutralizing / immunology
  • Bees / genetics
  • Female
  • Gene Products, nef / genetics
  • HIV Antibodies / blood*
  • HIV Antibodies / immunology
  • HIV Infections / immunology
  • HIV Infections / prevention & control*
  • HIV-1 / genetics
  • HIV-1 / immunology*
  • Human Immunodeficiency Virus Proteins / genetics
  • Humans
  • Immunogenicity, Vaccine*
  • Male
  • Middle Aged
  • Protein Sorting Signals
  • Vaccines, Inactivated / administration & dosage
  • Vaccines, Inactivated / adverse effects
  • Vaccines, Inactivated / immunology
  • Viral Regulatory and Accessory Proteins / genetics
  • Young Adult

Substances

  • AIDS Vaccines
  • Antibodies, Neutralizing
  • Gene Products, nef
  • HIV Antibodies
  • Human Immunodeficiency Virus Proteins
  • Protein Sorting Signals
  • Vaccines, Inactivated
  • Viral Regulatory and Accessory Proteins
  • vpu protein, Human immunodeficiency virus 1