Characterization of a Potent HIV-specific CD4+ T Cell Response Induced by an Adjuvanted Protein HIV Vaccine in Seronegative Volunteers
L McNally1, E Van Braeckel2, P Bourguignon1, Marguerite Koutsoukos*1, F Clement2, M Janssens1, A Collard1, M-A Demoitié1, G Voss1, and G Leroux-Roels2
1GlaxoSmithKline Biologicals, Rixensart, Belgium and 2Ghent Univ and Hosp, Belgium
Background: Several lines of evidence indicate that
CD4+ T cells contribute to an efficient immune control of HIV
replication. However, most current candidate vaccines focus on the induction of
CD8+ T cells, while inducing only modest CD4+ T cell
responses. We present final results of the first prospective randomized
observer-blind clinical trial of a recombinant purified fusion protein (F4)
comprised of the 4 HIV antigens p17 and p24 Gag, reverse transcriptase, and
Nef, derived from clade B strains and formulated with GSK Biologicals proprietary
Adjuvant System AS01.
Methods: We vaccinated 180 subjects with escalating
doses of 10, 30, or 90 mg F4 adjuvanted
or not with AS01. Local and systemic reactogenicity as well as serious adverse
events were evaluated. Peripheral blood mononuclear cells were collected before
and after immunization and analyzed by flow cytometry for expression of CD40L
and production of interleukin-2 (IL-2), interferon-g (IFN-g), and tumor necrosis factor-a (TNF-a) using peptide pools from clade A, B, and C
HIV strains. Continuous measurements and percentages of responders were
summarized per study group for each relevant time point. Analyses of variance
were performed for each antigen to compare the 3 doses of F4 with or without
adjuvant two weeks after the second vaccination.
Results: There were no vaccine related serious
adverse events. Reactogenicity was not antigen dose level related but was
higher after the second than first dose of the F4/AS01 vaccine. Elevated
frequencies of persistent CD4+ T cells were detected in all F4/AS01
vaccinated volunteers. The highest frequencies and responder rates (100% to 3
HIV antigens and 80% to all 4, indicating broad reactivity) were observed in
the 10-mg F4/AS01 group. In this group,
the geometric mean frequency of F4-specific CD4+ T cells reached 1.2
%. The majority of specific CD4+ T cells expressed CD40L and
produced IL-2 alone or in combination with TNF-a
or IFN-g, indicating the polyfunctional
properties of these vaccine-induced specific CD4+ T cells. In
addition, these responses persisted up to the end of the study (month 12).
Conclusions: The reactogenicity profile of the
vaccine was acceptable and there were no safety concerns. The vaccine elicited
high levels of HIV-specific persistent polyfunctional CD4+ T cells.
Given the importance of a strong CD4+-mediated immune response, the
vaccine candidate will be further evaluated for safety, immunogenicity, and
efficacy in HIV-infected subjects.