Human Immunodeficiency Virus Vaccine Trials

U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910.
Cold Spring Harbor Perspectives in Medicine (Impact Factor: 7.56). 12/2012; 2(12). DOI: 10.1101/cshperspect.a007351
Source: PubMed

ABSTRACT More than 2 million AIDS-related deaths occurred globally in 2008, and more than 33 million people are living with HIV/AIDS. Despite promising advances in prevention, an estimated 2.7 million new HIV infections occurred in that year, so that for every two patients placed on combination antiretroviral treatment, five people became infected. The pandemic poses a formidable challenge to the development, progress, and stability of global society 30 years after it was recognized. Experimental preventive HIV-1 vaccines have been administered to more than 44,000 human volunteers in more than 187 separate trials since 1987. Only five candidate vaccine strategies have been advanced to efficacy testing. The recombinant glycoprotein (rgp)120 subunit vaccines, AIDSVAX B/B and AIDSVAX B/E, and the Merck Adenovirus serotype (Ad)5 viral-vector expressing HIV-1 Gag, Pol, and Nef failed to show a reduction in infection rate or lowering of postinfection viral set point. Most recently, a phase III trial that tested a heterologous prime-boost vaccine combination of ALVAC-HIV vCP1521 and bivalent rgp120 (AIDSVAX B/E) showed 31% efficacy in protection from infection among community-risk Thai participants. A fifth efficacy trial testing a DNA/recombinant(r) Ad5 prime-boost combination is currently under way. We review the clinical trials of HIV vaccines that have provided insight into human immunogenicity or efficacy in preventing HIV-1 infection.

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    • "Although five vaccine candidates were tested in phase IIb/III efficacy trials, only one demonstrated some level of protection [6]. The recent phase III clinical trial RV144 was the first to demonstrate a modest evidence of protection against acquisition of HIV-1 infection among vaccines in the absence of serum-neutralizing antibodies, with an estimated vaccine efficacy of 31.2% [7] [8]. "
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    ABSTRACT: The development of an effective HIV vaccine is still a major scientific challenge. HIV vaccine trials conducted until now were not able to induce broad neutralizing antibodies or effective cell mediated immune responses. More recently, CD4+ T cells have been shown to play an important role in viral control and better disease prognosis. We have recently developed a DNA vaccine encoding 18 conserved multiple HLA-DR-binding HIV-1 CD4 epitopes (HIVBr18), capable of eliciting broad CD4+ T cell responses in BALB/c and in multiple HLA class II transgenic mice. Despite the advantages of DNA vaccines and a large number of clinical trials, it has been a challenge to transfer the success of inducing potent immunity observed in animal models to humans. Here, we sought to evaluate the potential use of bupivacaine, a local anesthetic, as an adjuvant for HIVBr18. We observed that the concomitant administration of the local anesthetic bupivacaine with the DNA vaccine HIVBr18 increased the magnitude of CD4+ and CD8+ T cell responses and cytokine production without compromising their breadth. Furthermore, we demonstrate that coadministration of bupivacaine also impacted the longevity of specific immune responses. Since bupivacaine is used in clinical settings, we believe that this concept may contribute to overcome the limited immunogenicity of DNA vaccines in humans.
    01/2014; 3:95–101. DOI:10.1016/j.trivac.2014.05.001
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    ABSTRACT: Neutralizing antibodies (NAbs) typically play a key role in controlling viral infections and contribute to the protective effect of many successful vaccines. In the case of HIV-1 infection, there is compelling data in experimental animal models that NAbs can prevent HIV-1 acquisition, although there is no similar data in humans and their role in controlling established infection in humans is also limited. It is clear HIV-specific NAbs drive the evolution of the HIV-1 envelope glycoprotein within an infected individual. The virus's ability to evade immune selection may be the main reason HIV-1 NAbs exert limited control during infection. The extraordinary antigenic diversity of HIV-1 also presents formidable challenges to defining NAbs that could provide broad protection against diverse circulating HIV-1 strains. Several new potent monoclonal antibodies (MAbs) have been identified, and are beginning to yield important clues into the epitopes common to diverse HIV-1 strains. In addition, antibodies can also act in concert with effector cells to kill HIV-infected cells; this could provide another mechanism for antibody-mediated control of HIV-1 replication. Understanding the impact of antibodies on HIV-1 transmission and pathogenesis is critical to helping move forward with rational HIV-1 vaccine design.
    Cold Spring Harbor Perspectives in Medicine 01/2012; 2(1):a007039. DOI:10.1101/cshperspect.a007039 · 7.56 Impact Factor
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    ABSTRACT: INTRODUCTION: The development of an effective vaccine against HIV-1 has been challenging but recent advances in both the HIV prevention landscape and the partial efficacy of the recent RV144 vaccine efficacy trial in Thailand provide hope for an improved arsenal of approaches to prevent HIV-1 transmission. AREAS COVERED: This review describes recent advances in HIV-1 prevention such as circumcision, microbicides and pre-exposure prophylaxis with antiretroviral therapy, but focuses mainly on the current state of HIV-1 vaccine development in the post-RV144 era. EXPERT OPINION: The field of HIV-1 vaccine development has been plagued by the unprecedented challenges involved with designing a vaccine effective in preventing transmission of a retrovirus, due in part to sequence diversity, retroviral integration into host chromosomes, establishment of reservoir sites and glycosylation shielding of the HIV-1 envelope. The partial efficacy of the recent RV144 vaccine trial in Thailand may allow for better understanding of immune correlates of infection risk, which could enable iterative improvements to vaccine regimens in the development pipeline. In parallel, a number of promising vaccine strategies incorporating viral vectors, novel immunogens, delivery systems and adjuvants are advancing in clinical development. Vaccine development must occur in parallel with continued advances in HIV-1 prevention.
    Expert opinion on biological therapy 05/2012; 12(8):983-94. DOI:10.1517/14712598.2012.688020 · 3.65 Impact Factor
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