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1. Post-acute COVID-19 outcomes including participant-reported long COVID: amubarvimab/romlusevimab versus placebo in the ACTIV-2 trialResearch in context

Author

Teresa H. Evering, Carlee Moser, Nikolaus Jilg, Justin Ritz, David A. Wohl, Jonathan Z. Li, David Margolis, Arzhang Cyrus Javan, Joseph J. Eron, Judith S. Currier, Eric S. Daar, Davey M. Smith, Michael D. Hughes, Kara W. Chew, Kara Chew, David (Davey) Smith, Eric Daar, David Wohl, Judith Currier, Joseph Eron, Michael Hughes, Mark Giganti, Lara Hosey, Jhoanna Roa, Nilam Patel, Kelly Colsh, Irene Rwakazina, Justine Beck, Scott Sieg, Jonathan Li, Courtney Fletcher, William Fischer, Rachel Bender Ignacio, Sandra Cardoso, Katya Corado, Prasanna Jagannathan, Alan Perelson, Sandy Pillay, Cynthia Riviere, Upinder Singh, Babafemi Taiwo, Joan Gottesman, Matthew Newell, Susan Pedersen, Joan Dragavon, Cheryl Jennings, Brian Greenfelder, William Murtaugh, Jan Kosmyna, Morgan Gapara, Akbar Shahkolahi, Verónica Lacal, Diego Salusso, Sebastian Nuñez, Marcelo Rodrigo Rodriguez, Luciana Laborde, Marcelo Papasidero, Luis Wehbe, Mariana Gonzalez, Felicitas Fernandez Voena, Tomas Alvarez, Amaru Lopez, Virginia Huhn, Ulises D'Andrea Nores, Pablo Dieser, Fernando Bordese, Marisa Mussi, Rodrigo de Carvalho Santana, Adriana Aparecida Tiraboschi Bárbaro, Breno Santos, Rita de Cássia Alves Lira, Andre Luiz Machado da Silva, Sandra Wagner Cardoso, Maria Pia Diniz Ribeiro, Nathália Soliva, Eduardo Vasconcellos, Jorge Eurico Ribeiro, Miriam Amaral Enéas, Jorge Pinto, Julia Fonseca de Morais Caporali, Flávia Gomes Faleiro Ferreira, Norma Erendira Rivera Martinez, Victor Casildo Bohorquez Lopez, Melchor Victor Frias, Krystle Fetalvero, Alyxzza Maranan, Jennifer Rosa, Thomas Coetzer, Maureen Mohata, Sr., Umesh Lalloo, Penelope Madlala, Larisha Pillay-Ramaya, Jaclyn Ann Bennet, Noluthando Mwelase, Nokuphiwa Mbhele, Frederick Petrick, Leonard Joubert, Rose Mbali, Sr., Natasha Joseph, Mmatsie Manentsa, Eugene van der Walt, Mduduzi Sandile Lawrance Masilela, Zinhle Zwane, Tendai Chiperera, Lerato Mohapi, Suri Moonsamy, Usha Singh, Kirsten McHarry, Elizma Snyman, Pieter Lennox, James Craig Innes, Oteng Letlape, Olebogeng Jonkane, William Brumskine, Tania Adonis, Ni Ni Sein, Modulakgotla Sebe, Yacoob Vahed, Nazreen Jeewa Hussen, Ismail Mitha, Vasundhara Cheekati, Purna Cheekati, Christie Lummus, Samuel Idarraga, Andrew Kim, David N. Pham, Wei-Hsin Kao, Michael M. Pfeffer, Miriam Batule Dominguez, Anju Malik, Anna Bryan, Melanie Arnold, Idania Fernandez, Cinzia Karpf, Aniuska Ruiz, David Taylor, Eric Folkens, Jennifer Manne, Sigal Yawetz, Cheryl Keenan, Emeka Eziri, Carl Fichtenbaum, Jenifer Baer, Sarah Trentman, Robert Call, Leroy Vaughan, Aaron Milstone, Jamie Alex Slandzicki, Jessica Wallan, Clinton Guillory, Nancy Andrews, Leslie Hughes, Jonathan Berardi, Celine Arar, Randall Quinn, Jorge P. Amaya, Marissa Gomez-Martinez, Luis Cantu, Monica Betancourt-Garcia, Nwora Lance Okeke, Charles M. Burns, Fadi Haddad, Victoria Haddad, Augusto Focil, Griselda Rosas, Susana Moyano, Yaneicy Gonzalez Rojas, Ahmad Aswad, Yevgeniy Bukhman, Manish Jain, Eugene Bukhman, Humam Farah, Rebekah McClain, Sadia Shaik, Timothy Hatlen, Deepa Gotur, Joseph Surber, Jeffrey Kingsley, April Pixler, Alex Zopo, Jack Herman, Craig Herman, Ramon Leon, Boris Nikolov, Fernando Gonzalez Vergara, Ana I. Gonzalez, Noemi Gonzalez, Michael Gelman, Olga Andriunas, Zarema Jagizarov, Jan Westerman, David Davis, Donna Sherer, Kelly Dooley, Becky Becker, Adaliah Wilkins, Jose Pérez, Eloy Roman, Heriberto Fernández, Bharat Mocherla, Kelly Beck, Valarie Maldonado, Jennifer Veltman, Rajesh Gandhi, Katrina Shea, Matthew Planchon, Laura Bogan Herpel, Kaushlendra K. Tripathi, Donald C. Day, John Pullman, Sr., Erin Williams-Leber, Misty Johnson, Michelle Hecker, Ann Avery, Keila Hoover, George W. Monlux, Elizabeth Juneja, Jr., Arthur Wernick, Karelia Ruiz, Maureen Hernández, Yadilys Pérez, Babafemi O. Taiwo, Claudia Hawkins, Baiba Berzins, Carlos Malvestutto, Heather Harber, Robyn Cicarella, Edwin DeJesus, Charlotte-Paige Rolle, Almena L. Free, Sallie D. Pulliam, Debra Weinstein, Rosa M. Suarez, Ezequiel Socorro, Estefania Socorro, Gene Neytman, Raymond Easley, Mariam Aziz, Joan Swiatek, Avish Nagpal, Breanna Kompelien, Kathryn McEvoy, Susan E. Hoover, Allison Lutz, Jessica Just, Manuel Hernandez, Yanly B. Victoria, Gabriel Rodriguez, Divya Pathak, Joshua J. Ordway, Megan Heffner, Patrick Weston, Khalilah Weston, Madhu Choudhary, Jennifer Sullivano, Olayemi Osiyemi, Myriam Izquierdo, Odelsey Torna, Brian Clemency, Renoj Varughese, Joshua Lynch, Aleen Khodabakhshian, Samantha Fortier, Christopher Coyne, Alexandrea Cronin, Constance Benson, Steven Hendrickx, Rosemarie Ramirez, Anne Luetkemeyer, Suzanne Hendler, Dennis Dentoni-Lasofsky, Mobeen Rathore, Saniyyah Mahmoudi, Amna Riaz, Mario Castro, Leslie Spikes, Chase Hall, Jonathan Oakes, Amy James Loftis, Pablo Tebas, William Short, Michael P. Dube, Saahir Khan, Luis M. Mendez, Sarah McGuffin, Chris Jonsson, Mamta K. Jain, Smruthi Senthil, Kimberly Turner-Gray, Sanjay Mehta, Mary Lewinski, Masoud Azizad, Christopher Chow, Lisa Nakatani, Derrick Williamson, Hisham Atriss, Matthew Caloura, Midhun Malla, Hannah Hazard-Jenkins, Aimee Wilkin, Jamraus Fayssoux, Hannah Seagle, Rachel Presti, and Alem Haile

Subjects
COVID-19, Monoclonal antibodies, Outpatient treatment, Clinical trial, Post COVID conditions, Long COVID, Medicine (General), R5-920
Abstract

Summary: Background: It is unknown if early COVID-19 monoclonal antibody (mAb) therapy can reduce risk of Long COVID. The mAbs amubarvimab/romlusevimab were previously demonstrated to reduce risk of hospitalization/death by 79%. This study assessed the impact of amubarvimab/romlusevimab on late outcomes, including Long COVID. Methods: Non-hospitalized high-risk adults within 10 days of COVID-19 symptom onset enrolled in a randomized, double-blind, placebo-controlled phase 2/3 trial of amubarvimab/romlusevimab for COVID-19 treatment. Late symptoms, assessed using a participant-completed symptom diary, were a pre-specified exploratory endpoint. The primary outcome for this analysis was the composite of Long COVID by participant self-report (presence of COVID-19 symptoms as recorded in the diary at week 36) or hospitalization or death by week 36. Inverse probability weighting (IPW) was used to address incomplete outcome ascertainment, giving weighted risk ratios (wRR) comparing amubarvimab/romlusevimab to placebo. Findings: Participants received amubarvimab/romlusevimab (n = 390) or placebo (n = 390) between January and July 2021. Median age was 49 years, 52% were female, 18% Black/African American, 49% Hispanic/Latino, and 9% COVID-19-vaccinated at entry. At week 36, 103 (13%) had incomplete outcome ascertainment, and 66 (17%) on amubarvimab/romlusevimab and 92 (24%) on placebo met the primary outcome (wRR = 0.70, 95% confidence interval (CI) 0.53–0.93). The difference was driven by fewer hospitalizations/deaths with amubarvimab/romlusevimab (4%) than placebo (13%). Among 652 participants with available diary responses, 53 (16%) on amubarvimab/romlusevimab and 44 (14%) on placebo reported presence of Long COVID. Interpretation: Amubarvimab/romlusevimab treatment, while highly effective in preventing hospitalizations/deaths, did not reduce risk of Long COVID. Additional interventions are needed to prevent Long COVID. Funding: National Institute of Allergy and Infectious Diseases of the National Institutes of Health. Amubarvimab and romlusevimab supplied by Brii Biosciences.

Published
2024
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2. Safety and efficacy of inhaled interferon-β1a (SNG001) in adults with mild-to-moderate COVID-19: a randomized, controlled, phase II trialResearch in context

Author

Prasanna Jagannathan, Kara W. Chew, Mark J. Giganti, Michael D. Hughes, Carlee Moser, Mark J. Main, Phillip D. Monk, Arzhang Cyrus Javan, Jonathan Z. Li, Courtney V. Fletcher, Caitlyn McCarthy, David A. Wohl, Eric S. Daar, Joseph J. Eron, Judith S. Currier, Upinder Singh, Davey M. Smith, William Fischer, Kara Chew, David (Davey) Smith, Eric Daar, David Wohl, Judith Currier, Joseph Eron, Michael Hughes, Mark Giganti, Justin Ritz, Lara Hosey, Jhoanna Roa, Nilam Patel, Kelly Colsh, Irene Rwakazina, Justine Beck, Scott Sieg, Jonathan Li, Courtney Fletcher, Teresa Evering, Rachel Bender Ignacio, Sandra Cardoso, Katya Corado, Nikolaus Jilg, Alan Perelson, Sandy Pillay, Cynthia Riviere, Babafemi Taiwo, Joan Gottesman, Matthew Newell, Susan Pedersen, Joan Dragavon, Cheryl Jennings, Brian Greenfelder, William Murtaugh, Jan Kosmyna, Morgan Gapara, Akbar Shahkolahi, Gerald Pierone, Juliana Elliott, Jeffrey Jacobson, Leila Hojat, Julie Pasternak, Jonathan Berardi, Celine Arar, Yevgeniy Bukhman, Manish Jain, Eugene Bukhman, Sadia Shaik, Timothy Hatlen, Kelly Dooley, Becky Becker, Adaliah Wilkins, Jose Pérez, Eloy Roman, Heriberto Fernández, Keila Hoover, James Renfroe, Mauney Weldon, Genei Bougher, Carlos Malvestutto, Heather Harber, Robyn Cicarella, Gene Neytman, Jack Herman, Craig Herman, Mariam Aziz, Joan Swiatek, Divya Pathak, Madhu Choudhary, Jennifer Sullivano, Olayemi Osiyemi, Myriam Izquierdo, Odelsey Torna, Aleen Khodabakhshian, Samantha Fortier, Constance Benson, Steven Hendrickx, Rosemarie Ramirez, Anne Luetkemeyer, Suzanne Hendler, Dennis Dentoni-Lasofsky, Mario Castro, Leslie Spikes, Chase Hall, Jonathan Oakes, Amy James Loftis, Pablo Tebas, William Short, Sarah McGuffin, Chris Jonsson, Rachel Presti, and Alem Haile

Subjects
Inhaled interferon, SARS-CoV-2, COVID-19, ACTIV-2, Randomized clinical trial, Medicine (General), R5-920
Abstract

Summary: Background: With the emergence of SARS-CoV-2 variants resistant to monoclonal antibody therapies and limited global access to therapeutics, the evaluation of novel therapeutics to prevent progression to severe COVID-19 remains a critical need. Methods: Safety, clinical and antiviral efficacy of inhaled interferon-β1a (SNG001) were evaluated in a phase II randomized controlled trial on the ACTIV-2/A5401 platform (ClinicalTrials.gov NCT04518410). Adult outpatients with confirmed SARS-CoV-2 infection within 10 days of symptom onset were randomized and initiated either orally inhaled nebulized SNG001 given once daily for 14 days (n = 110) or blinded pooled placebo (n = 110) between February 10 and August 18, 2021. Findings: The proportion of participants reporting premature treatment discontinuation was 9% among SNG001 and 13% among placebo participants. There were no differences between participants who received SNG001 or placebo in the primary outcomes of treatment emergent Grade 3 or higher adverse events (3.6% and 8.2%, respectively), time to symptom improvement (median 13 and 9 days, respectively), or proportion with unquantifiable nasopharyngeal SARS-CoV-2 RNA at days 3 (28% [26/93] vs. 39% [37/94], respectively), 7 (65% [60/93] vs. 66% [62/94]) and 14 (91% [86/95] vs. 91% [83/81]). There were fewer hospitalizations with SNG001 (n = 1; 1%) compared with placebo (n = 7; 6%), representing an 86% relative risk reduction (p = 0.07). There were no deaths in either arm. Interpretation: In this trial, SNG001 was safe and associated with a non-statistically significant decrease in hospitalization for COVID-19 pneumonia. Funding: The ACTIV-2 platform study is funded by the NIH. Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number UM1 AI068634, UM1 AI068636 and UM1 AI106701. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Published
2023
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3. Challenges in Cybersecurity: Lessons from Biological Defense Systems

Author

Edward Schrom, Ann P. Kinzig, Stephanie Forrest, Andrea Graham, Simon Levin, Carl Bergstrom, Carlos Castillo-Chavez, James Collins, Rob J. de Boer, Adam Doupe, Roya Ensafi, Stuart Feldman, Bryan Grenfell, J. Alex Halderman, Silvie Huijben, Carlo Maley, Melanie Moses, Alan Perelson, Charles Perrings, Joshua Plotkin, Jennifer Rexford, and Mohit Tiwari

Published
2023
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7. Fitness costs and diversity of CTL response determine the rate of CTL escape during the acute and chronic phases of HIV infection (105.23)

Author

Vitaly Ganusov, Nilu Goonetilleke, Michael Liu, Guido Ferrari, George Shaw, Andrew McMichael, Persephone Borrow, Bette Korber, and Alan Perelson

Subjects
Immunology, Immunology and Allergy
Abstract

Human immunodeficiency virus type 1 (HIV-1, or HIV) often evades cytotoxic T cell (CTL) responses by generating variants that are not recognized by CTLs. We used single genome amplification and sequencing of complete HIV genomes to identify longitudinal changes in the transmitted/founder virus from the establishment of infection to the viral set-point at 1 year after the infection. We found that the rate of viral escape from CTL responses in a given patient decreases dramatically from the acute infection to the viral set point. Using a novel mathematical model that tracks the dynamics of viral escape at multiple epitopes we show that a number of factors could potentially contribute to a slower escape in the chronic phase of infection, such as a decreased magnitude of epitope-specific CTL responses, an increased fitness cost of escape mutations, or an increased diversity of the CTL response. In the model, increasing the diversity of the CTL response over time can reduce the rate of viral escape from a given CTL response, particularly if CD8+ T cells compete for killing of infected cells or control virus replication non-lytically. Our mathematical framework of viral escape from multiple CTL responses can be used to predict the breadth and magnitude of HIV-specific CTL response that needs to be induced by vaccination to prevent (or reduce) viral escape following HIV infection.

Published
2011
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9. Preface

Author

Hans Frauenfelder, Alan R. Bishop, Angel Garcia, Alan Perelson, Peter Schuster, David Sherrington, and Pieter J. Swart

Subjects
Statistical and Nonlinear Physics, Condensed Matter Physics
Published
1997
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10. Pharmacodynamics of Antiretroviral Agents in HIV-1 Infected Patients: Using Viral Dynamic Models that Incorporate Drug Susceptibility and Adherence.

Author

Hulin Wu, Yangxin Huang, Edward Acosta, Jeong Park, Song Yu, Susan Rosenkranz, Daniel Kuritzkes, Joseph Eron, Alan Perelson, and John Gerber

Abstract

We developed a novel HIV-1 dynamic model with consideration of pharmacokinetics, drug adherence and drug susceptibility to link plasma drug concentration to the long-term changes in HIV-1 RNA observation after initiation of therapy. A Bayesian approach is proposed to fit this model to clinical data from ACTG A5055, a study of two dosage regimens of indinavir (IDV) with ritonavir (RTV) in subjects failing their first protease inhibitor treatment. The HIV RNA testing was completed at days 0, 7, 14, 28, 56, 84, 112, 140, and 168. An intensive pharmacokinetic (PK) evaluation was performed on day 14 and multiple trough concentrations were subsequently collected. Pill counts were used to monitor adherence. IC50 for IDV and RTV were determined at baseline and at virologic failure. Viral dynamic model fitting residuals were used to assess the significance of covariate effects on long-term virologic response. As univariate predictors, none of the four PK parameters Ctrough, C12 hour, Cmax, and AUC was significantly related to virologic response (p>0.05). By including drug susceptibility (IC50), or IC50 and adherence measured by pill counts together, Ctrough, C12 hour, Cmax and AUC were each significantly correlated to long-term virologic response (p=0.0055,0.0002,0.0136,0.0002 with IC50 and adherence measured by pill counts considered). The IC50 and adherence measured by pill counts alone were not related to the virologic response. In predicting virologic response adherence measured by pill counts did not provide any additional information to PK parameters (p=0.064), to drug susceptibility IC50 (p=0.086), and to their combination (p=0.22). Simple regression approaches did not detect any significant pharmacodynamic (PD) relationships. Any single factor of PK, adherence measured by pill counts and drug susceptibility did not contribute to long-term virologic response. But their combinations in viral dynamic modeling significantly predicted virologic response. The HIV dynamic modeling can appropriately capture complicated nonlinear relationships and interactions among multiple covariates. [ABSTRACT FROM AUTHOR]

Published
2006

11. Modeling SIV kinetics supports that cytotoxic response drives natural control and unravels heterogeneous populations of infected cells

Author

Christine Rouzioux, Asier Sáez-Cirión, Jeremie Guedj, Véronique Avettand-Fenoel, N Dereuddre-Bosquet, Antoine Millet, Caroline Peireira Bittencourt Passaes, Ramsès Djidjou-Demasse, Vincent Madelain, Bruno Vaslin, R Le Grand, Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, HIV, Inflammation et persistance - HIV, Inflammation and Persistence, Institut Pasteur [Paris] (IP), Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Infection à VIH, réservoirs, diversité génétique et résistance aux antirétroviraux (ARV) (EA 7327), Université Paris Descartes - Paris 5 (UPD5), Santé et agroécologie du vignoble (UMR SAVE), Université de Bordeaux (UB)-Institut des Sciences de la Vigne et du Vin (ISVV)-Ecole Nationale Supérieure des Sciences Agronomiques de Bordeaux-Aquitaine (Bordeaux Sciences Agro)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), We thank Alan Perelson, Ruy Ribeiro and Rodolphe Thiébaut for their helpful comments and suggestions on this work., Passaes, Caroline, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Université Sorbonne Paris Nord, HIV, Inflammation et persistance, and Institut Pasteur [Paris]

Subjects
0303 health sciences, Natural control, [SDV.IMM] Life Sciences [q-bio]/Immunology, animal diseases, viruses, Kinetics, Human immunodeficiency virus (HIV), Biology, Major histocompatibility complex, medicine.disease_cause, Virology, 03 medical and health sciences, 0302 clinical medicine, Immune system, biology.protein, medicine, Cytotoxic T cell, [SDV.IMM]Life Sciences [q-bio]/Immunology, 030217 neurology & neurosurgery, Ex vivo, CD8, 030304 developmental biology
Abstract

SIVmac251-infected Mauritius cynomolgus macaques presenting a M6 MHC haplotype or challenged with a low inoculum dose by mucosal route are models for natural HIV control. Here we characterized by modeling the dynamics of plasma SIV-RNA and of SIV-DNA in blood cells of 16 macaques of the ANRS SIC study.SIV-RNA kinetics was best fitted using a model where the cytotoxic immune response progressively mounted up and reduced actively infected cells half-life (t1/2) from 5.5 days early on to about 0.3 days. The model predicted that the control was achieved in animals able to mount an effective immune response within three months, and this was corroborated by the longitudinal analysis of the CD8+ T-cell antiviral activity measured ex vivo. The control of SIV-RNA was accompanied in parallel by a slow and biphasic decline of SIV-DNA. This unravels the presence of at least two compartments of non-actively infected cells that are not rapidly eliminated by the immune system, one with a rapid turnover rate (t1/2=5.1 days) and predominant as long as SIV-RNA levels are still large, and one with a slow turnover (t1/2=118 days) consistent with the half-life of memory T-cells, and only visible when control is achieved,.In summary, our analysis suggests that the establishment of an efficient CD8+ T-cell response in the first three months of the infection, and that progressively increases overtime is key to achieve SIV-RNA control in this model. Frequent SIV-DNA quantifications allowed identifying that most cells infected after viral peak have a short t1/2 but do not contribute significantly to viral production.One sentence summaryModeling viral dynamics in SIV natural controller macaques predicts that viral control is primarily driven by the capability to establish an efficient cytotoxic response and the viral decline during control unravels distinct compartments of infected cells.

Published
2020

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