Functional Glycomics in HIV Vaccine Design

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Functional Glycomics in HIV Vaccine Design
10 April 2012

http://www.vaccineorb.com/funding-opportunities/functional-glycomics-in-hiv-vaccine-design/

Halting the spread of HIV infection remains one of the highest research priorities of NIAID. Success in this effort will depend primarily on the identification and development of a safe and effective vaccine that prevents HIV transmission. Several vaccine candidates have been tested in human clinical studies, with one Phase III trial, RV144, showing modest efficacy in a community-based, randomized, multicenter, double-blind, placebo-controlled trial in Thailand. Additional analysis of this study identified six primary immune response variables. One variable, antibody binding levels to the HIV envelope (Env) glycoprotein first and second variable regions (V1V2), inversely correlated with HIV infection risk. While this study is encouraging, the need to identify new vaccine candidates with greater breadth, durability and efficacy remains a critical priority.

Approximately half of the molecular mass of HIV gp120 is comprised of N-linked glycans that shield the protein backbone. Several of these carbohydrate structures are critical for envelope folding, antigenicity, and immunogenicity. Determination of the identity and heterogeneity of glycans expressed on native gp120 trimers may be crucial for the development of new HIV vaccine candidates. Moreover, significant knowledge gaps remain in our understanding of broadly neutralizing antibody epitopes on the envelope spike that may serve as new targets for vaccination, as well as features that initiate broadly neutralizing antibody responses against the virus envelope glycoprotein.

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Lancet Article Explores Efficacy Variable in RV144MHRP researchers detail risk correlation and early effect 5/31/2012 In the 30 May issue of The Lancet Infectious Diseases, MHRP researchers and collaborators provide important insights on behavioral and time variables that may have influenced the efficacy seen in the RV144 HIV vaccine study. In an accompanying editorial, José Esparza of the Bill and Melinda Gates Foundation notes that “The article by Robb et al is important, not only because it adds confidence to the original findings from the RV144 trial, but also because it identifies important variables to be considered when planning for and conducting additional trials to confirm and extend the results from RV144.”  In their post-hoc analysis, MHRP researchers correlate self-reported risk factors with vaccine efficacy at six month intervals. The RV144 trial enrolled mainly heterosexual people from a population with low prevalence of HIV. Participants classified as high or increasing risk at least once during follow-up were compared with those who maintained low-risk or medium-risk behavior. Interaction of risk status and acquisition efficacy was significant (p=0.01), with greater efficacy in low-risk individuals. In addition, researchers report that vaccine efficacy seemed to peak early—cumulative vaccine efficacy was estimated to be 60.5% (95% CI 22–80)—through the 12 months after initial vaccination, after which it declined quickly. This early, high protective immune response suggests an additional boost or other augmentation of immune response would improve efficacy for all risk categories. Smaller clinical studies are starting in Thailand this year that will add a second boost to the RV144 vaccine regimen in an effort to increase the duration of the early protective effect. In addition, results gleaned from a recent study published in the New England journal of Medicine on the case controlled correlates analysis provide new clues about the immune responses that may have played a role in protection. This information can be used to improve the RV144 vaccine regimen and also to help inform future clinical trial designs.  MHRP researcher Dr. Merlin Robb said that “although the RV144 trial did not produce a vaccine for public health today, the results provide an opportunity to understand the variables that can lead to better vaccines and how vaccines may target different populations.”
 http://www.hivresearch.org/news.php?NewsID=241