Safety and immunogenicity of an HIV adenoviral vector boost after DNA plasmid vaccine prime by route of administration: a randomized clinical trial

Abstract

Background: In the development of HIV vaccines, improving immunogenicity while maintaining safety is critical. Route of administration can be an important factor.

Methodology/principal findings: This multicenter, open-label, randomized trial, HVTN 069, compared routes of administration on safety and immunogenicity of a DNA vaccine prime given intramuscularly at 0, 1 and 2 months and a recombinant replication-defective adenovirus type 5 (rAd5) vaccine boost given at 6 months by intramuscular (IM), intradermal (ID), or subcutaneous (SC) route. Randomization was computer-generated by a central data management center; participants and staff were not blinded to group assignment. The outcomes were vaccine reactogenicity and humoral and cellular immunogenicity. Ninety healthy, HIV-1 uninfected adults in the US and Peru, aged 18-50 were enrolled and randomized. Due to the results of the Step Study, injections with rAd5 vaccine were halted; thus 61 received the booster dose of rAd5 vaccine (IM: 20; ID:21; SC:20). After the rAd5 boost, significant differences by study arm were found in severity of headache, pain and erythema/induration. Immune responses (binding and neutralizing antibodies, IFN-γ ELISpot HIV-specific responses and CD4+ and CD8+ T-cell responses by ICS) at four weeks after the rAd5 booster were not significantly different by administration route of the rAd5 vaccine boost (Binding antibody responses: IM: 66.7%; ID: 70.0%; SC: 77.8%; neutralizing antibody responses: IM: 11.1%; ID: 0.0%; SC 16.7%; ELISpot responses: IM: 46.7%; ID: 35.3%; SC: 44.4%; CD4+ T-cell responses: IM: 29.4%; ID: 20.0%; SC: 35.3%; CD8+ T-cell responses: IM: 29.4%; ID: 16.7%; SC: 50.0%.)

Conclusions/significance: This study was limited by the reduced sample size. The higher frequency of local reactions after ID and SC administration and the lack of sufficient evidence to show that there were any differences in immunogenicity by route of administration do not support changing route of administration for the rAd5 boost.

Trial registration: ClinicalTrials.gov NCT00384787.

Figure 1. Study flow diagram.

Figure 2. Anti-Env Binding antibody response by administration route at 4 weeks post Ad5 boost.

Anti-Env binding antibody levels and % response are shown per route of administration. Positive responses are in red and non-responders in blue.

Figure 3. Interferon-γ ELISpot response to Env, Gag, Nef, Pol global PTE peptide stimulation by administration route.

(A) At 2 weeks post last DNA prime and (B) 4 weeks post Ad5 boost. The scale indicates spot-forming cells per million peripheral blood mononuclear cells.

Figure 4. Percentage of CD4+ T cells producing interferon γ and/or Interleukine 2 by administration route.

(A) in response to any Env peptides (B) in response to any Gag peptides before (2 weeks post last DNA prime) and after the Ad5 boost (4 weeks post Ad5 boost).

Figure 5. Percentage of CD8+ T cells producing interferon γ and/or Interleukine 2 by administration route.

(A) in response to any Env peptides (B) in response to any Pol peptides before (2 weeks post last DNA prime) and after the Ad5 boost (4 weeks post Ad5 boost).