This paper by Lin et al. has uncovered and displayed the importance of polyfunctional immune responses to HIV vaccination. The wealth of information stemming from follow-up studies on RV144 motivated scientists to develop better statistical and high throughput tools for interpreting the data. The sheer volume of data, the complexity of it and need to ‘catch’ antigen responses that may be at very low numbers within a patient’s total immune response are all factors. In the total T-cell population from PBMC isolated from any trial subject only a small fraction will be HIV specific. Within this rare group are T cells that target different viral epitopes, express different cytokine combinations, and have different immune function. Therefore, the numbers become very small and thus a need to find the proverbial needle in the haystack is crucial to determine important COP, not just for HIV but any important clinical endpoint. COMPASS can be used to compute the functionality score for each individual, defined as the proportion of vaccine-mediated antigen-specific T-cell subsets detected among all possible cytokine producing subsets. This statistical tool has uncovered differences in T-cell polyfunctionality in response to multiple antigens in TB and HIV disease, the latter of which has now been determined as a separate COP. Importantly, COMPASS provides meaning to complex multidimensional immunological readouts that allow one to actually now define polyfunctionality. This is critical as all T cells and all cytokines are not created equal. This tool to allow both rational description and analytical evaluation of antigen specific T cells is a major breakthrough for the field.
This Bayesian analysis methodology has already been applied to multiple other studies, highlighting the impact has and will have on clinical trial COP analysis, which is necessary for designing effective immunotherapies and vaccines.
VIDD scientists who co-authored the paper are Lin Lin, Greg Finak, Kevin Ushey, Nicole Frahm, Peter Gilbert, Stephen De Rosa, Julie McElrath, and Raphael Gottardo.
Lin L, Finak G, Ushey K, Seshadri C, Hawn TR, Frahm N, Scriba TJ, Mahomed H, Hanekom W, Bart PA, Pantaleo G, Tomaras GD, Rerks-Ngarm S, Kaewkungwal J, Nitayaphan S, Pitisuttithum P, Michael NL, Kim JH, Robb ML, O'Connell RJ, Karasavvas N, Gilbert P, C De Rosa S, McElrath MJ, Gottardo R. COMPASS identifies T-cell subsets correlated with clinical outcomes. Nat Biotechnol. 2015 Jun;33(6):610-6.