The views expressed are those of the authors and should not be construed to represent the positions of the US Army or the Department of Defense

The views expressed are those of the authors and should not be construed to represent the positions of the US Army or the Department of Defense. Data Availability The data underlying the findings of this manuscript can be accessed via the public-facing HVTN website at the following link: https://atlas.scharp.org/cpas/project/HVTN%20Public%20Data/Cross-Protocol%20HVTN%20Manuscripts/begin.view? and are also Phenformin hydrochloride publicly available at figshare (https://doi.org/10.6084/m9.figshare.11664042).. link: https://atlas.scharp.org/cpas/project/HVTN%20Public%20Data/Cross-Protocol%20HVTN%20Manuscripts/begin.view? and are also publicly available at figshare (https://doi.org/10.6084/m9.figshare.11664042). Abstract Background HIV vaccine trials routinely measure multiple vaccine-elicited immune responses to compare regimens and study their potential associations with protection. Here we employ unsupervised learning tools facilitated by a bidirectional power transformation to explore the multivariate binding antibody and T-cell response patterns of immune responses elicited by two pox-protein HIV vaccine regimens. Both regimens utilized a recombinant canarypox vector (ALVAC-HIV) primary and a bivalent recombinant HIV-1 Envelope glycoprotein 120 subunit boost. We hypothesized that within each trial, Rabbit Polyclonal to CKI-gamma1 there were participant subgroups sharing similar Phenformin hydrochloride immune responses and that their frequencies differed across trials. Methods and findings We analyzed data from three trialsCRV144 (NCT00223080), HVTN 097 (NCT02109354), and HVTN 100 (NCT02404311), the latter of which was pivotal in advancing the tested pox-protein HIV vaccine regimen to the HVTN 702 Phase 2b/3 efficacy trial. We found that bivariate CD4+ T-cell and anti-V1V2 IgG/IgG3 antibody response patterns were similar by age, sex-at-birth, and body mass index, but differed for the pox-protein clade AE/B alum-adjuvanted regimen analyzed in RV144 and HVTN 097 (PAE/B/alum) compared to the pox-protein clade C/C MF59-adjuvanted regimen analyzed in HVTN 100 (PC/MF59). Specifically, more PAE/B/alum recipients experienced low CD4+ T-cell and high anti-V1V2 IgG/IgG3 responses, and more PC/MF59 recipients experienced broad responses of both types. Analyses limited to vaccine-matched antigens suggested that some of the differences in responses between the regimens could have been due to antigens in the assays that did not match the vaccine immunogens. Our approach was also useful in identifying subgroups with unusually absent or high co-responses across assay types, flagging individuals for further characterization by functional assays. We also found that co-responses of anti-V1V2 IgG/IgG3 and CD4+ T cells experienced broad variability. As additional immune response assays are standardized and validated, we anticipate our framework will be progressively useful for multivariate analysis. Conclusions Our approach can be used to advance vaccine development objectives, including the characterization and comparison of candidate vaccine multivariate immune responses and improved design of studies to identify correlates of protection. For instance, results suggested that HVTN 702 will have adequate power to interrogate immune correlates including anti-V1V2 IgG/IgG3 and CD4+ T-cell co-readouts, but will have lower power Phenformin hydrochloride to study anti-gp120/gp140 IgG/IgG3 due to their lower dynamic ranges. The findings also generate hypotheses for future screening in experimental and computational analyses aimed at achieving a mechanistic understanding of vaccine-elicited immune response heterogeneity. Introduction The current global HIV incidence-to-prevalence ratio of 0.05 indicates that without more effective prevention tools the total number of people living with HIV globally will continue to increase [1]. The mission to design a safe and effective preventative HIV vaccine, which is believed to be a critical tool for controlling the current HIV pandemic [2, 3], has been hindered by pathogen variability and immune escape, a lack of knowledge of immune correlates of protection, and an incomplete understanding of the variance in vaccine-induced immune responses [4]. New quantitative methods may help to tackle these pressing problems. Out of the six phase 3 preventative HIV vaccine efficacy trials that have been performed to date [5C10], only the RV144 trial of a recombinant canarypox vector vaccine (ALVAC-HIV of clade AE) and a bivalent recombinant HIV-1 Envelope (Env) glycoprotein 120 (gp120) subunit vaccine (AIDSVAX B/E) prime-boost regimen (hereafter referred to as the PAE/B/alum regimen, where P stands for pox-protein), conducted in an HIV-seronegative populace in Thailand where HIV subtype CRF01_AE B/E is usually.