Abstract
BackgroundWe conducted a Phase I randomized, dose-escalation, route-comparison trial of MVA-CMDR, a candidate HIV-1 vaccine based on a recombinant modified vaccinia Ankara viral vector expressing HIV-1 genes env/gag/pol. The HIV sequences were derived from circulating recombinant form CRF01_AE, which predominates in Thailand. The objective was to evaluate safety and immunogenicity of MVA-CMDR in human volunteers in the US and Thailand.Methodology/Principal FindingsMVA-CMDR or placebo was administered intra-muscularly (IM; 107 or 108 pfu) or intradermally (ID; 106 or 107 pfu) at months 0, 1 and 3, to 48 healthy volunteers at low risk for HIV-1 infection. Twelve volunteers in each dosage group were randomized to receive MVA-CMDR or placebo (10∶2). Volunteers were actively monitored for local and systemic reactogenicity and adverse events post vaccination. Cellular immunogenicity was assessed by a validated IFNγ Elispot assay, an intracellular cytokine staining assay, lymphocyte proliferation and a 51Cr-release assay. Humoral immunogenicity was assessed by ADCC for gp120 and binding antibody ELISAs for gp120 and p24. MVA-CMDR was safe and well tolerated with no vaccine related serious adverse events. Cell-mediated immune responses were: (i) moderate in magnitude (median IFNγ Elispot of 78 SFC/106 PBMC at 108 pfu IM), but high in response rate (70% 51Cr-release positive; 90% Elispot positive; 100% ICS positive, at 108 pfu IM); (ii) predominantly HIV Env-specific CD4+ T cells, with a high proliferative capacity and durable for at least 6 months (100% LPA response rate by the IM route); (iv) dose- and route-dependent with 108 pfu IM being the most immunogenic treatment. Binding antibodies against gp120 and p24 were detectable in all vaccination groups with ADCC capacity detectable at the highest dose (40% positive at 108 pfu IM).Conclusions/SignificanceMVA-CMDR delivered both intramuscularly and intradermally was safe, well-tolerated and elicited durable cell-mediated and humoral immune responses.Trial RegistrationClinicalTrials.gov NCT00376090
Highlights
An estimated 33.4 million people currently live with HIV/AIDS and in 2008 alone, an estimated 2.7 million new infections occurred [1]
We report here a phase I safety and immunogenicity study with a recombinant modified vaccinia Ankara (MVA)-HIV vaccine expressing env/gag/pol inserts derived from a CRF01_AE HIV-1 isolate from Chiang Mai, Thailand, referred to here as MVA-CMDR (Chiang Mai Double Recombinant)
Study vaccine candidate The MVA-CMDR was developed through collaboration between the Laboratory of Viral Diseases (LVD)/National Institute of Allergy and Infectious Diseases (NIAID) and the Walter Reed Army Instiutite of Research (WRAIR)/US Military HIV Research Program (MHRP) [8]
Summary
An estimated 33.4 million people currently live with HIV/AIDS and in 2008 alone, an estimated 2.7 million new infections occurred [1]. HIV vaccine development was invigorated recently by the modest level of protective efficacy observed in the low incident Thai heterosexual population in the ALVAC-HIV/AIDSVAX B/E Phase III trial (RV144) [5]. In the absence of an immune correlate, HIV vaccine development is currently directed towards the quantitative and qualitative improvement of vaccine-induced responses through the use of novel vectors alone, or in prime-boost configurations [2,4]. The inclusion of ALVAC, a poxvirus-based vector, as a component of the Thai Phase III trial suggests that improved poxvirus vectors may be effective components of a realistic strategy for vaccination against HIV infection. We conducted a Phase I randomized, dose-escalation, route-comparison trial of MVA-CMDR, a candidate HIV-1 vaccine based on a recombinant modified vaccinia Ankara viral vector expressing HIV-1 genes env/gag/pol.
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