Journal: Nature Communications

Article Title: High monoclonal neutralization titers reduced breakthrough HIV-1 viral loads in the Antibody Mediated Prevention trials

doi: 10.1038/s41467-023-43384-y

Figure Lengend Snippet: a Pre-ART viral loads pooled across trials and stratified by treatment arm -- placebo (gray; N = 62), 10 mg/kg VRC01 (light blue; N = 52), and 30 mg/kg VRC01 (green; N = 43). b VRC01 sensitivity of the acquired isolate for the placebo and VRC01 pooled treatment arms. Dashed vertical line indicates resistant and sensitive threshold for viruses, defined as IC80 ≥ 1 µg/ml and IC80 < 1 µg/ml, respectively. Black diamonds indicate group median for each of four treatment/sensitivity groups: placebo sensitive (navy; N = 17), placebo resistant (red; N = 45), VRC01 pooled sensitive (blue; N = 9), and VRC01 pooled resistant (orange; N = 87). c Pre-ART viral loads by treatment/sensitivity groups. In a , d , time values are presented relative to first positive viral loads such that negative days indicate the last negative viral load visit. Thick lines are geometric means binned by week. d Viral loads shown by treatment arm and VRC01 sensitive/resistant status grouped into first positive (placebo sensitive: navy, N = 17 placebo resistant: red, N = 45; VRC01 pooled sensitive: blue, N = 9; VRC01 pooled resistant: orange, N = 87), values after first but before 3 weeks (placebo sensitive: navy, N = 12; placebo resistant: red, N = 39; VRC01 pooled sensitive: blue, N = 5; VRC01 pooled resistant: orange, N = 64), and values after 3 weeks (placebo sensitive: navy, N = 23; placebo resistant: red, N = 53; VRC01 pooled sensitive: blue, N = 8; VRC01 pooled resistant: orange, N = 108). Filled circles indicate the placebo arm, and squares indicate VRC01 pooled. Dashed lines indicate non-significant comparisons, solid lines indicate p < 0.05, and bold lines indicate statistical significance after correcting for the 6 comparisons p < 0.008 (1-sided Mann–Whitney U test). e First positive viral loads grouped by geographic region -- South Africa ( N = 41), Not South Africa ( N = 31), US+Switzerland ( N = 22), and South America ( N = 68) -- and colored by HIV-1 subtype. Population distributions are not significantly different, p = 0.3 by Kruskal-Wallis H-test indicates no differences between groups so individual comparisons were not made. In all plots, box plots indicate median, IQR (box) and 1.5x IQR (fliers).

Article Snippet: The VRC01 drug product (Leidos Biomedical Research, Inc./VRC-HIVMAB060-00-AB, lot no. 16–524; stock concentrations prepared at Duke and sent to the The National Institute For Communicable Diseases) served as a positive control.

Techniques: MANN-WHITNEY

Journal: Nature Communications

Article Title: High monoclonal neutralization titers reduced breakthrough HIV-1 viral loads in the Antibody Mediated Prevention trials

doi: 10.1038/s41467-023-43384-y

Figure Lengend Snippet: Mean (dot) and 95% confidence interval (line) first positive viral loads for the following groups: placebo sensitive (navy; N = 17), placebo resistant (red; N = 45), VRC01 pooled sensitive (blue; N = 9), and VRC01 pooled resistant (orange; N = 87), calculated adjusting for protocol and study geographic location using a regression model (Methods).

Article Snippet: The VRC01 drug product (Leidos Biomedical Research, Inc./VRC-HIVMAB060-00-AB, lot no. 16–524; stock concentrations prepared at Duke and sent to the The National Institute For Communicable Diseases) served as a positive control.

Techniques:

Journal: Nature Communications

Article Title: High monoclonal neutralization titers reduced breakthrough HIV-1 viral loads in the Antibody Mediated Prevention trials

doi: 10.1038/s41467-023-43384-y

Figure Lengend Snippet: a A two-compartment pharmacokinetic (PK) model trained on the present data–model structure was previously designed for VRC01 PK using an AMP case-control cohort (Supplementary Table ) . b Observed (dots) and modeled (line) VRC01 concentrations over time in a representative participant. The horizontal lines illustrate VRC01 concentrations corresponding to PT80 titers of 10, 1, 1/10 and 1/100 against the participant’s acquired isolate. c–g PK and combined PKPD activity visualized as “dose-response relationships” for variables against first positive viral load. c Projected VRC01 concentration at first positive viral load. d Acquired virus sensitivity to VRC01 in VRC01 pooled group. e Predicted 80% titer (PT80) at first positive. f Instantaneous inhibitory potential (IIP). g Acquired virus sensitivity to VRC01 in placebo group. Squares and blue/orange colors indicate sensitive/resistant VRC01 pooled participant data, whereas dots and navy/red colors indicate sensitive/resistant placebo participant data. Black dashed line is a linear regression line (Pearson correlation coefficient r and p -value noted in panel title). In e , f two-segment dose-response models described data better than the linear model. In those cases, the segmented model is shown as a solid gray line with a blue shaded 95% confidence interval around the change point of the segments.

Article Snippet: The VRC01 drug product (Leidos Biomedical Research, Inc./VRC-HIVMAB060-00-AB, lot no. 16–524; stock concentrations prepared at Duke and sent to the The National Institute For Communicable Diseases) served as a positive control.

Techniques: Control, Activity Assay, Concentration Assay, Virus

Journal: Nature Communications

Article Title: High monoclonal neutralization titers reduced breakthrough HIV-1 viral loads in the Antibody Mediated Prevention trials

doi: 10.1038/s41467-023-43384-y

Figure Lengend Snippet: a The viral dynamics and PKPD (PKPD-V) mathematical model used to impute viral load curves . Susceptible cells S are born and die in the absence of virus (rates \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${{{{{{\rm{\alpha }}}}}}}_{{{{{{\rm{S}}}}}}}$$\end{document} α S and \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${{{{{{\rm{\delta }}}}}}}_{{{{{{\rm{S}}}}}}}$$\end{document} δ S , respectively) and are infected upon exposure to virus V with infectivity rate \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${{{{{\rm{\beta }}}}}}$$\end{document} β , infected cells \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${{{{{\rm{I}}}}}}$$\end{document} I die nonlinearly with rate \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\delta }_{{{{{{\rm{I}}}}}}}\left({{{{{\rm{I}}}}}}\right)=\kappa {I}^{n}$$\end{document} δ I I = κ I n , virions are produced with rate \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${{{{{\rm{\pi }}}}}}$$\end{document} π and cleared with rate \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${{{{{\rm{\gamma }}}}}}$$\end{document} γ . VRC01 concentration is predicted by the same PK model as in Fig. and is connected into the viral dynamics through the PD model where VRC01 concentration reduces cell infection events, \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${{{{{\rm{\beta }}}}}}({{{{{{\rm{C}}}}}}}_{{{{{{\rm{t}}}}}}},{{{{{\rm{IC}}}}}}80,{{{{{\rm{\rho }}}}}})$$\end{document} β ( C t , IC 80 , ρ ) based on IC80 of acquired virus and in vivo potency reduction. The indirect effect implies viral production is lowered for more resistant isolates \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${{{{{\rm{\pi }}}}}}({{{{{\rm{IC}}}}}}80)$$\end{document} π ( IC 80 ) . b Eight examples of participants with simultaneous PK and viral load fits relative to first positive viral load (see all in Supplementary Data & ). Dots represent observed concentrations and viral loads, solid lines represent model output, and dashed lines represent counterfactual model simulations with no potency reduction. PK curve colors indicate treatment arm (light blue: 10 mg/kg; green: 30 mg/kg). Viral load curve colors indicate acquired virus sensitivity to VRC01 (blue: VRC01 sensitive; orange: VRC01 resistant). Annotations provide definitions for model-based metrics. Horizontal gray lines in PK plots contextualize serum concentrations relative to in vitro IC80s. c Predicted % of cellular infections blocked at a given titer estimated from in vivo viral load data (solid red) compared to in vitro predicted neutralization (dashed black). The pink shading around the solid red curve denotes 95% confidence intervals. The difference between the curves illustrates the 600-fold potency reduction in vivo.

Article Snippet: The VRC01 drug product (Leidos Biomedical Research, Inc./VRC-HIVMAB060-00-AB, lot no. 16–524; stock concentrations prepared at Duke and sent to the The National Institute For Communicable Diseases) served as a positive control.

Techniques: Virus, Infection, Produced, Concentration Assay, In Vivo, In Vitro, Neutralization

Journal: Nature Communications

Article Title: High monoclonal neutralization titers reduced breakthrough HIV-1 viral loads in the Antibody Mediated Prevention trials

doi: 10.1038/s41467-023-43384-y

Figure Lengend Snippet: a Predicted titer (PT80) at estimated date of infection using our model compared to a published infection timing approach ; orange and blue dots indicate resistant ( N = 84) and sensitive ( N = 11) isolates, respectively, from VRC01 recipients with available timing estimates. The maximum measured concentration divided by the minimum observed IC80 is shown as a dashed horizontal line to contextualize a theoretical upper bound on PT80s. b Model estimated metrics for the following treatment and resistance groupings: placebo sensitive (navy; N = 17), placebo resistant (red; N = 45), VRC01 pooled sensitive (blue; N = 9), and VRC01 pooled resistant (orange; N = 87). Each dot represents a participant model value and box plots indicate median, IQR (box) and 1.5x IQR (fliers) across participants. The p -values are two-sided and unadjusted for multiple comparisons, and were obtained from a linear regression model adjusting for protocol and study geographic location. Model peaks were not statistically compared. c Modeled longitudinal viral loads from all VRC01 recipients split by sensitive (blue lines) and resistant (orange lines) viruses. d Modeled longitudinal HIV “reservoir size” (assumed proportional to viral load area under the curve) from all VRC01 recipients split by sensitive (blue lines) and resistant (orange lines) viruses. In c , d from left to right panels indicate counterfactual of participants without VRC01, AMP participants as in the actual trial, and 3 different levels (10x, 100x, and 1000x) of higher-potency trials. There are fewer lines in some plots because the modeled higher potency scenarios sometimes completely suppress viremia below limit of detection. e Differences between AMP study and other modeled scenarios. Viral load difference is calculated by subtracting off (on log10 scale) the peak AMP study viral load from each theoretical scenario in c where viral load is calculated at the original time of peak relative to acquisition. Reservoir size difference is calculated by subtracting off the week 4 AMP study viral load from each theoretical scenario in c where viral load is also calculated at week 4 relative to acquisition. Each dot indicates a participant’s difference (on log10 scale) from each new scenario relative to their baseline (AMP study) value. Box plots indicate median, IQR (box) and 1.5x IQR (whiskers), calculated from VRC01 pooled sensitive (blue; N = 9), and VRC01 pooled resistant (orange; N = 87). In all panels, box plots indicate median, IQR (box) and 1.5x IQR (fliers).

Article Snippet: The VRC01 drug product (Leidos Biomedical Research, Inc./VRC-HIVMAB060-00-AB, lot no. 16–524; stock concentrations prepared at Duke and sent to the The National Institute For Communicable Diseases) served as a positive control.

Techniques: Infection, Concentration Assay