A Phase I Randomized Clinical Trial of Candidate Human Immunodeficiency Virus type 1 Vaccine MVA.HIVA Administered to Gambian Infants

Abstract

BackgroundA 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 DesignWe 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.MethodsInfants 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.ResultsFrom 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.ConclusionsA 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 RegistrationClinicalTrials.gov NCT00982579 The Pan African Clinical Trials Registry PACTR2008120000904116

Characterization of T-Cell Responses to Conserved Regions of the HIV-1 Proteome in BALB/c Mice

“…Given the differences between the H-2 d and HLA major histocompatibility complex molecules, only some peptides immunogenic in the BALB/c mouse are also presented by the human HLAs. Thus, peptide H is unusual in that it has four anchor residues for H-2D d ( 30 , 31 ) and displays “promiscuous” binding to four different H-2D d , H-2D p , H-2 u , and H-2 q murine determinants ( 32 ) as well as human HLA-A2 ( 33 ), although in our hands, in human volunteers ( 16 , 34 – 43 ) or HLA-A2-transgenic HHD mice (unpublished data), such responses were never detected for either the HIVA ( 20 ) or the HIVconsv ( 9 ) immunogens. No responses were detected in 23 human recipients of the HIVconsv vaccine to peptide 42 or 112, while T cells were induced to peptides 151 and 164 ( 16 ).…”

PedVacc 002: A phase I/II randomized clinical trial of MVA.HIVA vaccine administered to infants born to human immunodeficiency virus type 1-positive mothers in Nairobi

“…HIV-1 testing was performed using HIV-1 DNA PCR at birth, 6, 10, 14 and 20 weeks; HIV-1 viral load at 19, 28, 36 and 48 weeks and HIV-ELISA at 48 weeks. Peripheral blood mononuclear cells (PBMC) were isolated and used for interferon (IFN)-γ ELISPOT assays or frozen [23] .…”

“…Fresh ex vivo and cultured IFN-γ ELISPOT assays were carried out as previously described [23] . An assay failed quality control if the mean background was >20 spot-forming units (SFU)/well (>100 SFU/10 6 PBMC) or mean phytohemagglutinine response was <30 SFU/well (<150 SFU/10 6 PBMC).…”

“…The tested ALVAC and protein vaccines caused no increase in serious adverse events (SAE) and elicited promising immune responses similar to those observed in adults. We recently reported that the PedVacc 001 trial had excellent safety and marginal immunogenicity among 20-week-old Gambian infants born to HIV-1-negative mothers [23] . Here, we report on the administration of MVA.HIVA to infants born to HIV-1-positive mothers in Kenya (PedVacc 002) with the primary aim to assess its safety.…”

Prevention of mother-to-child transmission of HIV Type 1: the role of neonatal and infant prophylaxis

“…No severe adverse events occurred during the trial, and the vaccine did not interfere with antibody induction to the standard childhood vaccines. However, only 9% of vaccinated infants demonstrated an HIV-1-specific T cell response [65]. The most promising vaccine study so far, a trial of ALVAC-HIV vCP 1521 among adults in Thailand that incorporated boosting with 2 recombinant envelope proteins, found that the vaccine had 31% efficacy (95% CI: 1.1–51.1%; P = .04) [66].…”