A phase I randomized clinical trial of candidate human immunodeficiency virus type 1 vaccine MVA.HIVA administered to Gambian infants

Muhammed O Afolabi, Jorjoh Ndure, Abdoulie Drammeh, Fatoumatta Darboe, Shams-Rony Mehedi, Sarah L Rowland-Jones, Nicola Borthwick, Antony Black, Gwen Ambler, Grace C John-Stewart, Marie Reilly, Tomáš Hanke, Katie L Flanagan, Muhammed O Afolabi, Jorjoh Ndure, Abdoulie Drammeh, Fatoumatta Darboe, Shams-Rony Mehedi, Sarah L Rowland-Jones, Nicola Borthwick, Antony Black, Gwen Ambler, Grace C John-Stewart, Marie Reilly, Tomáš Hanke, Katie L Flanagan

Abstract

Background: A vaccine to decrease transmission of human immunodeficiency virus type 1 (HIV-1) during breast-feeding would complement efforts to eliminate infant HIV-1 infection by antiretroviral therapy. Relative to adults, infants have distinct immune development, potentially high-risk of transmission when exposed to HIV-1 and rapid progression to AIDS when infected. To date, there have been only three published HIV-1 vaccine trials in infants.

Trial design: We conducted a randomized phase I clinical trial PedVacc 001 assessing the feasibility, safety and immunogenicity of a single dose of candidate vaccine MVA.HIVA administered intramuscularly to 20-week-old infants born to HIV-1-negative mothers in The Gambia.

Methods: Infants were followed to 9 months of age with assessment of safety, immunogenicity and interference with Expanded Program on Immunization (EPI) vaccines. The trial is the first stage of developing more complex prime-boost vaccination strategies against breast milk transmission of HIV-1.

Results: From March to October 2010, 48 infants (24 vaccine and 24 no-treatment) were enrolled with 100% retention. The MVA.HIVA vaccine was safe with no difference in adverse events between vaccinees and untreated infants. Two vaccine recipients (9%) and no controls had positive ex vivo interferon-γ ELISPOT assay responses. Antibody levels elicited to the EPI vaccines, which included diphtheria, tetanus, whole-cell pertussis, hepatitis B virus, Haemophilus influenzae type b and oral poliovirus, reached protective levels for the vast majority and were similar between the two arms.

Conclusions: A single low-dose of MVA.HIVA administered to 20-week-old infants in The Gambia was found to be safe and without interference with the induction of protective antibody levels by EPI vaccines, but did not alone induce sufficient HIV-1-specific responses. These data support the use of MVA carrying other transgenes as a boosting vector within more complex prime-boost vaccine strategies against transmission of HIV-1 and/or other infections in this age group.

Trial registration: ClinicalTrials.gov NCT00982579. The Pan African Clinical Trials Registry PACTR2008120000904116.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. A schematic diagram of the…
Figure 1. A schematic diagram of the HIV-1 clade A (HIVA) immunogen.
The HIVA protein consists of consensus amino acid sequences of clade A p24 and p17 Gag and a string of partially overlapping CD8+ T-cell epitopes identified in chronically infected individuals [23]. Pool P90 of 15-mer peptides overlapping by 11 amino acids across the Gag portion is shown below the protein. Pool P9 consisted of known CD8+ T-cell epitope peptides derived from the polyepitope region.
Figure 2. Trial Profile.
Figure 2. Trial Profile.
Diagram indicating the numbers of infants screened and followed up throughout the study.
Figure 3. MVA.HIVA-elicited weak T-cell responses in…
Figure 3. MVA.HIVA-elicited weak T-cell responses in fresh IFN-γ ELISPOT assay.
The net fresh ex-vivo ELISPOT frequencies of IFN-γ-producing cells (mean of stimulated wells minus mean of negative control wells) to HIVA peptide pools P9 and P90 at all 4 bleed time points for the control (Con) and vaccinated (Vac) groups are shown. The p value for the only statistically significant difference between the two groups after Bonferroni correction is given. The median ‘mock’ no-peptide background response across all wells on plates that passed QC was 5 SFU/106 PBMC (IQ range 0-20), and median PHA response was 1,850 SFU/106 PBMC (IQ range 1,065- 2,960).

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