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Preventive Technologies, Immune-Based and Gene Therapies and Research Toward a Cure

September 2011

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Spurred by the borderline but statistically significant protection observed in the RV144 trial of ALVAC/AIDSVAX, HIV vaccine research continues to move ahead on multiple fronts.


Identifying Correlates of Protection in RV144

Many scientists are engaged in the search for immunological markers that might have been linked to protection against HIV in the RV144 trial. Identification of such "correlates of protection" is one of the Holy Grails of vaccine research and currently, according to Jerome Kim from the US HIV Military HIV Research Program, 35 investigators from 20 institutions are working on 32 different assays that could potentially be used to analyze RV144 samples (Kim 2011). Data from this work should start to become available toward the end of 2011. In the meantime, Kim and colleagues have unveiled some of their results hinting that CD4 T cells targeting the V2 region of the HIV envelope could have played a role in the trial outcome (Currier 2011).


Replicating and Extending the RV144 Results

While the vaccine field has been buoyed by RV144, there remains a deflating possibility that the observed evidence of protection was not a consequence of immunization, but simply a result of chance. A recently published statistical reevaluation of the efficacy result argues there is a 22% or greater probability it was spurious, which the authors note is "an inference that reflects greater uncertainty than has much of the discussion about this trial" (Gilbert 2011). This uncertainty emphasizes the importance of efforts to try and replicate and extend the RV144 findings.

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The HIV Vaccine Trials Network (HVTN) has published plans for adaptive trial designs (Corey 2011) which will be used to rapidly evaluate a variety of prime-boost vaccine regimens in the high prevalence setting of South Africa. The US HIV Military Research Program is also planning a new efficacy trial in men who have sex with men (MSM) in Thailand, using the same or a similar regimen to RV144 but with an additional booster immunization at the 12 month time point (the last shot in RV144 was at six months). This trial is slated to begin in 2014 (Kim 2011).

There is only one ongoing HIV vaccine efficacy trial, HVTN 505. It involves a prime-boost regimen comprising a DNA vaccine followed by an adenovirus serotype 5 (Ad5) vector. The target population is circumcised MSM and male-to-female (MTF) transgender persons who have sex with men. The design of the trial has gone through myriad iterations, and until recently the primary goal was to look at whether the vaccines reduced viral load in recipients who subsequently acquired HIV. In light of the RV144 results, consideration is now being given to expanding HVTN 505 in size so that the effect of vaccination on risk of HIV acquisition can also be evaluated.


Developing New Vectors, Immunogens and Adjuvants

As the term implies, vectors are delivery vehicles -- often weakened forms of viruses -- that carry vaccine ingredients into the body. Immunogens are the ingredients derived from HIV that the vaccine aims to induce immune responses against, and adjuvants are substances designed to enhance the magnitude and/or quality of those immune responses. The HIV vaccine pipeline contains a variety of vector/immunogen/adjuvant combinations, most commonly administered in prime-boost regimens. New vectors in human trials in 2011 include measles virus, vesicular stomatitis virus (VSV), and a chimpanzee adenovirus (Lorin 2004; Cooper 2008; Rosario 2010). Also in the mix are vaccines that deliver proteins or protein fragments directly, similar to the AIDSVAX envelope protein vaccine used as a booster shot in the RV144 trial.

A novel HIV vaccine vector that has received widespread media coverage due to promising results in macaques is cytomegalovirus (CMV). The vector is under development by the Vaccine and Gene Therapy Institute (VGTI) in collaboration with the International AIDS Vaccine Initiative (IAVI), but has not yet entered human testing. In a study published in the journal Nature, the use of CMV as an SIV vaccine vector led to an unprecedented degree of immunological control of a highly pathogenic challenge virus, SIVmac251 (Hansen 2011). Although large swathes of the human population are already infected with CMV, pre-existing immunity to the vector is not considered an issue because the virus has evolved immune evasion mechanisms that allow it to re-infect (Hansen 2010). There is, however, an important caveat about the use of CMV that was conspicuously absent from press reports about this study; over the last couple of decades, evidence has accumulated that CMV infection has an array of pernicious long-term effects on human health, contributing to cardiovascular disease (Stassen 2006), earlier mortality (Simanek 2011), and a type of immune system damage called immunosenescence that is associated with morbidity and mortality as people reach old age (Pawelec 2011). Although researchers are attempting to render CMV vectors safe for human use, it is currently unclear if -- and how -- safety can be sufficiently demonstrated to allow clinical trials.

New approaches to immunogen design attempt to improve the ability of vaccines to induce immune responses against a broad array of HIV targets. Oxford University and Tomas Hanke are testing HIVconsv, an immunogen incorporating fourteen parts of HIV that are highly conserved among multiple different clades (Létourneau 2007). Mosaic HIV immunogens represent another approach with the same goal; human testing is anticipated to start within the next year (Corey 2010).

Adjuvants that have ambled into clinical trials since the last TAG pipeline report include heat shock protein 70 (Hsp70), a naturally occurring protein under study as an enhancer of mucosal immune responses (Lehner 2004), and the cumbersomely-named cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF for short), which the company GeoVax is investigating as an adjuvant for its DNA/MVA vaccine after obtaining promising results in macaques (Lai 2011).

The multitude of candidates in the HIV vaccine pipeline prompts the question of how products will be selected for advancement into efficacy trials. At one time, the major criteria were the nature and magnitude of the anti-HIV immune responses invoked by the vaccines in early studies, along with evidence from pre-clinical research in the SIV/macaque model. However, one of the implications of the RV144 trial is that current immune response assays and animal models may not necessarily predict protective efficacy in humans (the ALVAC/AIDSVAX combination performed dismally by both criteria). It has also become clear that ostensibly similar regimens can induce immune responses that differ substantially in quality, with unclear implications for their effectiveness (Pillai 2011). The uncertainty regarding predictors of success is an additional motivation behind HVTN's adaptive efficacy trial design proposal, which allows for multiple parallel trials of different vaccine approaches with pre-planned interim analyses for the purpose of both rapidly discarding ineffective candidates and quickly identifying and advancing those showing promise (Corey 2011).


Inducing Neutralizing Antibodies

Scientists continue to wrestle with the spiky problem of inducing antibodies that can effectively inhibit HIV. As described in last year's report, several new broadly neutralizing antibodies have been isolated from HIV positive individuals and their structures and targets are now being characterized in detail (Davenport 2011; Pancera 2010; Pejchal 2010; Zhou 2010). There has also been potentially significant progress in understanding how these rare antibodies are generated by the immune system. The production of antibodies by B cells involves a complex process called somatic hypermutation. Essentially, a B cell that is stimulated to make antibodies undergoes several rounds of division during which the genetic code for producing the antibody is shuffled each time, leading to alterations in the antibody structure. If the B cell's genetic mutations produce an antibody with an improved ability to glom onto its target, the cell is selected to undergo more rounds of division. Repeated cycles of this mutation and selection process (referred to as "affinity maturation") lead to the generation of antibodies with a high affinity for their targets. Typically, affinity maturation takes an average of around 10-15 mutations. Remarkably, the broadly neutralizing antibodies against HIV that have been identified show evidence of a more arduous affinity maturation process involving more than 60 mutations. The next step for vaccine researchers is to figure out whether this complex pathway can be recapitulated with a vaccine, leading to the generation of similarly effective antibodies. Signs so far are encouraging, but considerable work remains (Kwong 2011).


Table 2. PrEP and Microbicides Pipeline 2011
ProductTypeManufacturer/SponsorStatus
Viread (tenofovir)Nucleotide reverse transcriptase inhibitorGilead Sciences/NIAID/CDCPhase III
Truvada (tenofovir/emtrictabine)Combined nucleoside and nucleotide reverse transcriptase inhibitorsGilead Sciences/NIAID/CDC/University of WashingtonPhase III
Truvada (tenofovir/emtrictabine)Combined nucleoside and nucleotide reverse transcriptase inhibitorsGilead Sciences/HIV Prevention Trials NetworkPhase II
TMC278LANon-nucleoside reverse transcriptase inhibitor, long-acting injectable formulationSt Stephens Aids TrustPhase I
Ibalizumab (formerly TNX-355)Monoclonal antibodyTaiMed Biologics Inc., Aaron Diamond AIDS Research Center, Bill and Melinda Gates FoundationPhase I
Tenofovir gelReverse transcriptase inhibitorCONRAD/CAPRISA/NIAIDPhase IIb
Dapivirine (TMC120) gelReverse transcriptase inhibitor nternational Partnership for MicrobicidesPhase I/II
Dapivirine (TMC120) vaginal ringReverse transcriptase inhibitorInternational Partnership for MicrobicidesPhase I/II
UC-781Dapivirine (TMC120) vaginal ringBioSynPhase I


Preexposure Prophylaxis

Preexposure prophylaxis (PrEP) is the prophylactic use of antiretroviral drugs to prevent HIV infection. In late 2010, the long-awaited first human PrEP efficacy results were announced and published in the New England Journal of Medicine (Grant 2010). The trial, named iPrEx, recruited 2,470 MSM and 29 transgender women at high risk of HIV infection, assigning them to receive daily Truvada (a combination pill containing the antiretrovirals tenofovir and emtrictabine) or placebo. Trial sites were located in Brazil, Ecuador, Peru, South Africa, Thailand, and the United States. Over an average of 1.2 years of follow up, the risk of acquiring HIV infection was reduced by 43.8% among participants in the Truvada arm compared to the placebo arm, a highly statistically significant result. There were a total of 36 infections in Truvada recipients compared to 64 in those on placebo. Additional follow up from May through August 2010 was reported in February of this year: the number of HIV infection endpoints increased to 48 vs. 83 for a final efficacy estimate of 42% (with a 95% confidence interval of 18-60%) (Grant 2011). Importantly, there was a strong correlation between adherence to the PrEP regimen and protection; a subset analysis of the Truvada arm comparing individuals with detectable drug levels to those without found that the presence of drug was associated with a greater than 90% reduction in HIV acquisition risk. However, this analysis also revealed that drug levels were undetectable in around half the participants assigned to Truvada, providing an indication that adhering to daily PrEP was problematic for a large proportion of the trial population.

In terms of tolerability, relatively few side effects were reported. Only nausea and unintentional weight loss of 5% or more were reported more frequently in the Truvada arm compared to placebo (in both cases, these side effects were noted by around 2% of Truvada recipients vs. 1% placebo). There were a total of five confirmed cases of elevated creatinine, a potential marker for kidney toxicity, all in the Truvada group. Four out of five of these individuals stopped and then restarted the drug without a recurrence of the problem. No other abnormal laboratory values were reported. No cases of drug resistance were observed in the participants who became HIV infected during the trial. However, there were three instances of resistance to emtrictabine documented among 10 people who were found to have had undetected, pre-seroconversion HIV infection at the time of study enrollment.

The iPrEx research team, led by Robert Grant at UCSF, now has funding from NIAID to conduct an open label evaluation (dubbed iPrEx OLÉ) of Truvada as PrEP; all participants from the original randomized trial are being invited to participate. The goals for the study are to assess whether knowledge regarding Truvada's efficacy has any effect on adherence and/or sex practices, and also to gather more safety data over a longer period of follow up.

The iPrEx data has generated considerable excitement in the PrEP field, but results are pending from trials being conducted in other populations. In a sobering development announced earlier this year, a trial of Truvada as PrEP at sites in Kenya, Malawi, South Africa, and Tanzania (the FEM-PrEP trial, sponsored by Family Health International) was stopped midstream after a review by the Data and Safety Monitoring Board (DSMB) found that it would not be able to show efficacy even if carried to completion. The DSMB decision was based on the observation that 56 HIV infections had occurred, evenly divided between the placebo and Truvada arms. The explanation for the FEM-PrEP outcome is as yet unclear.

The US Centers for Disease Control and Prevention (CDC) is sponsoring two ongoing PrEP efficacy trials: one is evaluating tenofovir (Viread) compared to placebo in 2,400 injection drug users in Thailand, the other is looking at Truvada in a population of 2,000 heterosexual men and women in Botswana. The University of Washington is comparing tenofovir to Truvada as PrEP in a trial involving 3,900 serodiscordant couples in Kenya and Uganda. The Microbicide Trial Network's VOICE study has successfully completed enrolment of 5,000 African women and will compare three strategies: oral PrEP using tenofovir or Truvada and a tenofovir-containing vaginal microbicide gel. A recent DSMB review of VOICE gave it the green light to continue; follow up is due to end in June 2012 with results becoming available in early 2013.

The evidence from iPrEx regarding the difficulty of adhering to daily PrEP has renewed interest in intermittent dosing strategies. The HIV Prevention Trials Network (HPTN) is launching the "ADAPT" study (Alternate Dosing to Augment PrEP Tablet-taking, also known as HPTN 067) which plans to compare different Truvada dosing schemes in 180 MSM and 180 heterosexual women at high-risk of acquiring HIV infection. The trial is not of sufficient size to evaluate efficacy but will compare tolerance, acceptability and drug levels.

Since the 2010 TAG pipeline report two novel PrEP agents have entered phase I trials:

  • TMC278LA is a long-acting, injectable formulation of the approved antiretroviral drug rilpivirine that is being studied at four sites in the UK under the sponsorship of the St Stephens Aids Trust.
  • Ibalizumab is a monoclonal antibody delivered via intermittent injection; it interferes with the interaction between HIV and the CD4 molecule, thereby inhibiting infection. Studies in people with HIV have documented significant viral load reductions (Bruno 2010). The phase I trial of ibalizumab as PrEP is unusual in that it is recruiting HIV negative volunteers at risk for HIV infection; normally, early-phase studies are restricted to participants with low or no risk of exposure to the virus.
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This article was provided by Treatment Action Group and HIV i-Base. It is a part of the publication 2011 Pipeline Report.
 
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