Predictors of durable immune responses six months after the last vaccination in preventive HIV vaccine trials

Abstract

Background The evaluation of durable immune responses is important in HIV vaccine research and development. The efficiency of such evaluation could be increased by incorporating predictors of the responses in the statistical analysis. In this paper, we investigated whether and how baseline demographic variables and immune responses measured two weeks after vaccination predicted durable immune responses measured six months later. Methods We included data from seven preventive HIV vaccine regimens evaluated in three clinical trials: a Phase 1 study of four DNA, NYVAC and/or AIDSVAX vaccine regimens (HVTN096), a Phase 2 study of two DNA and/or MVA vaccine regimens (HVTN205), and a Phase 3 study of a single ALVAC/AIDSVAX regimen (RV144). Regularized random forests and linear regression models were used to identify and evaluate predictors of the positivity and magnitude of durable immune responses. Results We analyzed 201 vaccine recipients with data from 10 to 127 immune response biomarkers, and 3–5 demographic variables. The best prediction of participants’ durable response positivity based on twoweek responses rendered up to close-to-perfect accuracy; the best prediction of participants’ durable response magnitude rendered correlation coefficients between the observed and predicted responses ranging up to 0.91. Though prediction performances differed among biomarkers, durable immune responses were best predicted by the two-week response level of the same biomarker. Adding demographic information and two-week response levels of different biomarkers provided little or no improvement in the predictions. Conclusions For some biomarkers and for the vaccines we studied, two-week post-vaccination responses can well predict durable responses six months later. Therefore, if immune response durability is only assessed in a sub-sample of vaccine recipients, statistical analyses of durable responses will have increased efficiency by incorporating two-week response data. Further research is needed to generalize the findings to other vaccine regimens and biomarkers. Conclusions Clinicaltrials.gov identifiers: NCT01799954, NCT00820846, NCT00223080.

Safety and immune responses after a 12-month booster in healthy HIV-uninfected adults in HVTN 100 in South Africa: A randomized double-blind placebo-controlled trial of ALVAC-HIV (vCP2438) and bivalent subtype C gp120/MF59 vaccines

“…Additionally, durability of the immune response could be influenced by host-related factors such as antibody titers resulting from vaccination, host genetics (e.g., HLA type) [30], health history, and microbiome. For some biomarkers and for some vaccines, including those administered in the RV144 trial, 2-week post-vaccination responses predict durable responses 6 months later [31]. Our study of a heterologous prime-boost regimen demonstrates immune responses that vary considerably amongst individuals, suggesting that host factors contribute substantially to immune response durability.…”

Immune correlates of the Thai RV144 HIV vaccine regimen in South Africa

“…Env-specific CD8 +5 T cell response rates, though rarely detectable in both trials, when present, were significantly higher in HVTN 097 (P = 0.031) (table S1). HIV-1 Gag-specific CD4 + and CD8 + T cell response rates were very low and not statistically different between HVTN 097 (3.8%) and RV144 (2.5%), as demonstrated from samples derived from a cohort of uninfected RV144 vaccinees (n = 40) selected in 2010 (20). COMPASS analysis of the Env-specific CD4 + T cell single-cell functionality and polyfunctionality scores revealed that South African participants in HVTN 097 had a higher functionality score as compared to the Thai participants in RV144 (P = 0.038) (Fig.…”

“…By 6 months after second ALVAC/AIDSVAX vaccination (durability time point), the frequency of circulating 92TH023-Env specific CD4 + T cell responses among vaccine recipients in both studies had declined significantly when assessed by prevalence and magnitude; response rate dropped from 70.8 to 36.1% in HVTN 097 (P < 0.001, Table 2) and from 36.1 to 27.5% in the n = 40 uninfected vaccinees selected from RV144 samples in 2010 (P < 0.001) (20).…”

Human Immunodeficiency Virus C.1086 Envelope gp140 Protein Boosts following DNA/Modified Vaccinia Virus Ankara Vaccination Fail To Enhance Heterologous Anti-V1V2 Antibody Response and Protection against Clade C Simian-Human Immunodeficiency Virus Challenge

“…At the conclusion of the 3-year trial, the vaccine efficacy was 31.2% (2). Importantly, the RV144 trial identified multiple correlates for reduced risk of infection (3)(4)(5)(6). These include higher binding titers to an HIV envelope (Env) V1V2 scaffolded protein and antibody (Ab)dependent cellular cytotoxicity (ADCC) activity (3,4).…”