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1. mRNA COVID-19 vaccine elicits potent adaptive immune response without the acute inflammation of SARS-CoV-2 infection

Author

Ellie N. Ivanova, Jasmine Shwetar, Joseph C. Devlin, Terkild B. Buus, Sophie Gray-Gaillard, Akiko Koide, Amber Cornelius, Marie I. Samanovic, Alberto Herrera, Eleni P. Mimitou, Chenzhen Zhang, Trishala Karmacharya, Ludovic Desvignes, Niels Ødum, Peter Smibert, Robert J. Ulrich, Mark J. Mulligan, Shohei Koide, Kelly V. Ruggles, Ramin S. Herati, and Sergei B. Koralov

Subjects
Immunology, Immune response, Transcriptomics, Science
Abstract

Summary: SARS-CoV-2 infection and vaccination elicit potent immune responses. Our study presents a comprehensive multimodal single-cell analysis of blood from COVID-19 patients and healthy volunteers receiving the SARS-CoV-2 vaccine and booster. We profiled immune responses via transcriptional analysis and lymphocyte repertoire reconstruction. COVID-19 patients displayed an enhanced interferon signature and cytotoxic gene upregulation, absent in vaccine recipients. B and T cell repertoire analysis revealed clonal expansion among effector cells in COVID-19 patients and memory cells in vaccine recipients. Furthermore, while clonal αβ T cell responses were observed in both COVID-19 patients and vaccine recipients, expansion of clonal γδ T cells was found only in infected individuals. Our dataset enables side-by-side comparison of immune responses to infection versus vaccination, including clonal B and T cell responses. Our comparative analysis shows that vaccination induces a robust, durable clonal B and T cell responses, without the severe inflammation associated with infection.

Published
2023
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2. Risk of COVID-19 after natural infection or vaccinationResearch in context

Author

Anne-Marie Rick, Matthew B. Laurens, Ying Huang, Chenchen Yu, Thomas C.S. Martin, Carina A. Rodriguez, Christina A. Rostad, Rebone M. Maboa, Lindsey R. Baden, Hana M. El Sahly, Beatriz Grinsztejn, Glenda E. Gray, Cynthia L. Gay, Peter B. Gilbert, Holly E. Janes, James G. Kublin, Yunda Huang, Brett Leav, Ian Hirsch, Frank Struyf, Lisa M. Dunkle, Kathleen M. Neuzil, Lawrence Corey, Paul A. Goepfert, Stephen R. Walsh, Dean Follmann, Karen L. Kotloff, Atoya Adams, Eric Miller, Bruce G. Rankin, Steven Shinn, Marshall Nash, Sinikka L. Green, Colleen Jacobsen, Jayasree Krishnankutty, Sikhongi Phungwayo, Richard M. Glover, II, Stacy Slechta, Troy Holdeman, Robyn Hartvickson, Amber Grant, Terry L. Poling, Terry D. Klein, Thomas C. Klein, Tracy R. Klein, William B. Smith, Richard L. Gibson, Jennifer Winbigler, Elizabeth Parker, Priyantha N. Wijewardane, Eric Bravo, Jeffrey Thessing, Michelle Maxwell, Amanda Horn, Catherine Mary Healy, Christine Akamine, Laurence Chu, R. Michelle Chouteau, Michael J. Cotugno, George H. Bauer, Jr., Greg Hachigian, Masaru Oshita, Michael Cancilla, Kristen Kiersey, William Seger, Mohammed Antwi, Allison Green, Anthony Kim, Michael Desjardins, Jennifer A. Johnson, Amy Sherman, Judith Borger, Nafisa Saleem, Joel Solis, Martha Carmen Medina, Westly Keating, Edgar Garcia, Cynthia Bueno, Nathan Segall, Douglas S. Denham, Thomas Weiss, Ayoade Avworo, Parke Hedges, Cynthia Becher Strout, Rica Santiago, Yvonne Davis, Patty Howenstine, Alison Bondell, Kristin Marks, Tina Wang, Timothy Wilkin, Mary Vogler, Carrie Johnston, Michele P. Andrasik, Jessica G. Andriesen, Gail Broder, Niles Eaton, Huub G. Gelderblom, Rachael McClennen, Nelson Michael, Merlin Robb, Carrie Sopher, Vicki E. Miller, Fredric Santiago, Blanca Gomez, Insiya Valika, Amy Starr, Valeria D. Cantos, Sheetal Kandiah, Carlos del Rio, Nadine Rouphael, Srilatha Edupuganti, Evan J. Anderson, Andres Camacho-Gonzalez, Satoshi Kamidani, Meghan Teherani, David J. Diemert, Elissa Malkin, Marc Siegel, Afsoon Roberts, Gary Simon, Bindu Balani, Carolene Stephenson, Steven Sperber, Cristina Cicogna, Marcus J. Zervos, Paul Kilgore, Mayur Ramesh, Erica Herc, Kate Zenlea, Abram Burgher, Ann M. Milliken, Joseph D. Davis, Brendan Levy, Sandra Kelman, Matthew W. Doust, Denise Sample, Sandra Erickson, Shane G. Christensen, Christopher Matich, James Longe, John Witbeck, James T. Peterson, Alexander Clark, Gerald Kelty, Issac Pena-Renteria, Michael J. Koren, Darlene Bartilucci, Alpa Patel, Carolyn Tran, Christina Kennelly, Robert Brownlee, Jacob Coleman, Hala Webster, Carlos A. Fierro, Natalia Leistner, Amy Thompson, Celia Gonzalez, Lisa A. Jackson, Janice Suyehira, Milton Haber, Maria M. Regalado, Veronica Procasky, Alisha Lutat, Carl P. Griffin, Ripley R. Hollister, Jeremy Brown, Melody Ronk, Wayne L. Harper, Lisa Cohen, Lynn Eckert, Matthew Hong, Rambod Rouhbakhsh, Elizabeth Danford, John Johnson, Richard Calderone, Shishir K. Khetan, Oyebisi Olanrewaju, Nan Zhai, Kimberly Nieves, Allison O'Brien, Paul S. Bradley, Amanda Lilienthal, Jim Callis, Adam B. Brosz, Andrea Clement, Whitney West, Luke Friesen, Paul Cramer, Frank S. Eder, Ryan Little, Victoria Engler, Heather Rattenbury-Shaw, David J. Ensz, Allie Oplinger, Brandon J. Essink, Jay Meyer, Frederick Raiser, III, Kimberly Mueller, Keith W. Vrbicky, Charles Harper, Chelsie Nutsch, Wendell Lewis, III, Cathy Laflan, Jordan L. Whatley, Nicole Harrell, Amie Shannon, Crystal Rowell, Christopher Dedon, Mamodikoe Makhene, Gregory M. Gottschlich, Kate Harden, Melissa Gottschlich, Mary Smith, Richard Powell, Murray A. Kimmel, Simmy Pinto, Timothy P. Vachris, Mark Hutchens, Stephen Daniels, Margaret Wells, Mimi Van Der Leden, Peta-Gay Jackson-Booth, Mira Baron, Pamela Kane, Shannen Seversen, Mara Kryvicky, Julia Lord, Jamshid Saleh, Matthew Miles, Rafael Lupercio, John W. McGettigan, Jr., Walter Patton, Riemke Brakema, Karin Choquette, Jonlyn McGettigan, Judith L. Kirstein, Marcia Bernard, Mary Beth Manning, Joan Rothenberg, Toby Briskin, Denise Roadman, Sharita Tedder-Edwards, Howard I. Schwartz, Surisday Mederos, Shobha Swaminathan, Amesika Nyaku, Tilly Varughese, Michelle DallaPiazza, Sharon E. Frey, Irene Graham, Getahun Abate, Daniel Hoft, Leland N. Allen, III, Leslie A. Edwards, William S. Davis, Jr., Jessica M. Mena, Mark E. Kutner, Jorge Caso, Maria Hernandez Moran, Marianela Carvajal, Janet Mendez, Larkin T. Wadsworth, III, Michael R. Adams, Leslie Iverson, Joseph L. Newberg, Laura Pearlman, Paul J. Nugent, Michele D. Reynolds, Jennifer Bashour, Robert Schmidt, Neil P. Sheth, Kenneth Steil, Ramy J. Toma, William Kirby, Pink Folmar, Samantha Williams, Paul Pickrell, Stefanie Mott, Carol Ann Linebarger, Hussain Malbari, David Pampe, Veronica G. Fragoso, Lisa Holloway, Cecilia McKeown-Bragas, Teresa Becker, Barton G. Williams, William H. Jones, Jesse L. Clark, Steven Shoptaw, Michele Vertucci, Will Hernandez, Stephen A. Spector, Amaran Moodley, Jill Blumenthal, Lisa Stangl, Karen Deutsch, Kathleen M. Mullane, David Pitrak, Cheryl Nuss, Judy Pi, Carl Fichtenbaum, Margaret Powers-Fletcher, Michelle Saemann, Sharon Kohrs, Thomas B. Campbell, Andrew Lauria, Jose C. Mancilla, Hillary Dunlevy, Richard M. Novak, Andrea Wendrow, Scott Borgetti, Ben Ladner, Lisa Chrisley, Cheryl Young, Susanne Doblecki-Lewis, Maria L. Alcaide, Jose Gonzales-Zamora, Stephen Morris, David Wohl, Joseph Eron, Jr., Ian Frank, Debora Dunbar, David Metzger, Florence Momplaisir, Judith Martin, Alejandro Hoberman, Timothy Shope, Gysella Muniz, Richard Rupp, Amber Stanford, Megan Berman, Laura Porterfield, Michael Lewis, Elham Ghadishah, Joseph Yusin, Mai Pham, Clarence B. Creech, II, Shannon Walker, Stephanie Rolsma, Robert Samuels, Isaac Thomsen, Spyros A. Kalams, Greg Wilson, Gregg H. Lucksinger, Kevin Parks, Ryan Israelsen, Jaleh Ostovar, Kary Kelly, Jeffrey S. Overcash, Hanh Chu, Kia Lee, Luis I. De La Cruz, Steve Clemons, Elizabeth Everette, Suzanna Studdard, Gowdhami Mohan, Stefanie Tyson, Alyssa-Kay Peay, Danyel Johnson, Gregory J. Feldman, May-Yin Suen, Jacqueline Muenzner, Joseph Boscia, Farhan Siddiqui, John Sanders, James Peacock, Julio Nasim, Michael L. Levin, Julie Hussey, Marcy Kulic, Mark M. McKenzie, Teresa Deese, Erica Osmundsen, Christy Sweet, Valentine M. Ebuh, Elwaleed Elnagar, Georgette Ebuh, Genevieve Iwuala, Laurie J. Han-Conrad, Todd Simmons, Denis Tarakjian, Jeremy Ackermann, Mark S. Adams, José O. Alemán, Mohamed S. Al-Ibrahim, David R. Andes, Jeb Andrews, Roberto C. Arduino, Martín Bäcker, Diana Badillo, Emma Bainbridge, Teresa A. Batteiger, Jose A. Bazan, Roger J. Bedimo, Jorge A. Benitez, Annette R. Bennett, David I. Bernstein, Kristin Bialobok, Rebecca Boas, Judith Brady, Cynthia Brown, Catherine A. Bunce, Robert S. Call, Wesley Campbell, Ellie Carmody, Christopher Carpenter, Steven E. Carsons, Marvin Castellon, Mario Castro, Hannah Catan, Jennifer Chang, Mouna G. Chebib, Corey M. Chen, Margaret Cheng, Brian D.W. Chow, Annie Ciambruschini, Joseph P. Connor, James H. Conway, Maureen Cooney, Marcel Curlin, Claudia De La Matta Rodriguez, Jon F. Dedon, Emily Degan, Michelle Dickey, Craig Dietz, Jennifer L. Dong, Brenda Dorcely, Michael P. Dube, Carmel B. Dyer, Benjamin Eckhardt, Edward Ellerbeck, Evan C. Ewers, Amy Falk, Brittany Feijoo, Uriel R. Felsen, Tom Fiel, David Fitz-Patrick, Charles M. Fogarty, Stacy Ford, Lina M. Forero, Elizabeth Formentini, Doris Franco-Vitteri, Robert W. Frenck, Jr., Elie Gharib, Suzanne Gharib, Rola G. Rucker, James N. Goldenberg, Luis H. González, Brett Gray, Rusty Greene, Robert M. Grossberg, Juan V. Guanira-Carranza, Alfredo Gilberto Guerreros Benavides, Clint C. Guillory, Shauna H. Gunaratne, David Halpert, Holli Hamilton, William R. Hartman, Sheryl L. Henderson, Ramin Herati, Laura Hernandez Guarin, Robin Hilder, Ken Ho, Leila Hojat, Sybil G. Hosek, Jeffrey M. Jacobson, Melanie Jay, Diane H. Johnson, Kathleen S. Jones, Edward C. Jones-López, Jessica E. Justman, Scott Kahney, Lois Katz, Melinda Katz, Daniel Kaul, Michael C. Keefer, Ashley Kennedy, Jennifer Knishinsky, Laura Kogelman, Susan L. Koletar, Angelica Kottkamp, Maryrose Laguio-Vila, Raphael J. Landovitz, Jessica L. Lee, Albert Liu, Eneyda Giuvanela Llerena Zegarra, Anna S. Lok, James Lovell, Ronald Lubelchek, John Lucaj, Gary Luckasen, Annie Luetkemeyer, Njira Lucia Lugogo, Janine Maenza, Carlos Malvestutto, Monica Mauri, Ryan C. Maves, Kenneth H. Mayer, Michael J. McCartney, Margaret E. McCort, M. Juliana McElrath, Meredith McNairy, Fernando L. Merino, Eric A. Meyerowitz, Carol L. Mitchell, Cynthia L. Monaco, Sauda Muhammad, Sigridh Muñoz-Gómez, Sonal Munsiff, Paul Nee, Nicole L. Nollen, Asif Noor, Claudio Nuñez Lagos, Jason F. Okulicz, Patrick A. Oliver, Jessica Ortega, Steven Palmer, Lalitha Parameswaran, Purvi Parikh, Susan Parker, Reza Parungao, Juana R. Pavie, Rebecca P. Madan, Henry Peralta, Jennifer Petts, Kristen K. Pierce, E. Javier Pretell Alva, Lawrence J. Purpura, Vanessa Raabe, Sergio E. Recuenco, Tamara Richards, Sharon A. Riddler, Barbara Rizzardi, Rachel Rokser, Charlotte-Paige Rolle, Adam Rosen, Jeffrey Rosen, Lena R. Freese, María E. Santolaya, Linda M. Schipani, Adam Schwartz, Tiffany Schwasinger-Schmidt, Hyman Scott, Beverly E. Sha, Shivanjali Shankaran, Adrienne E. Shapiro, Stephan C. Sharp, Bo Shopsin, Matthew D. Sims, Stephanie Skipper, Derek M. Smith, Michael J. Smith, M. Mahdee Sobhanie, Brit Sovic, Stephanie Sterling, Robert Striker, Karla Beatriz Tafur Bances, Kawsar R. Talaat, Edward M. Tavel, Jr., Hong V. Tieu, Christian Tomaszewski, Ryan Tomlinson, Juan P. Torres, Julian A. Torres, John J. Treanor, Sade Tukuru, Robert J. Ulrich, Gregory C. Utz, Veronica Viar, Roberto A. Viau Colindres, Edward E. Walsh, Mary C. Walsh, Emmanuel B. Walter, Jessica L. Weidler, Yi H. Wu, Kinara S. Yang, Juan Luis Yrivarren Giorza, Arthur L. Zemanek, Kevin Zhang, Barry S. Zingman, Richard Gorman, Carmen A. Paez, Edith Swann, Simbarashe G. Takuva, Alex Greninger, Pavitra Roychoudhury, Robert W. Coombs, Keith R. Jerome, Flora Castellino, Xiaomi Tong, Corrina Pavetto, Teletha Gipson, Tina Tong, Marina Lee, James Zhou, Michael Fay, Kelly McQuarrie, Chimeremma Nnadi, Obiageli Sogbetun, Nina Ahmad, Ian De Proost, Cyrus Hoseyni, Paul Coplan, Najat Khan, Peter Ronco, Dawn Furey, Jodi Meck, Johan Vingerhoets, Boerries Brandenburg, Jerome Custers, Jenny Hendriks, Jarek Juraszek, Anne Marit de Groot, Griet Van Roey, Dirk Heerwegh, Ilse Van Dromme, Jorge F. Méndez Galván, Monica B. Carrascal, Adriana Sordo Duran, Laura Ruy Sanchez Guerrero, Martha Cecilia Gómora Madrid, Alejandro Quintín Barrat Hernández, Sharzhaad Molina Guizar, Denisse Alejandra González Estrada, Silvano Omar Martínez Pérez, Zindy Yazmín Zárate Hinojosa, Guillermo Miguel Ruiz-Palacios, Aurelio Cruz-Valdez, Janeth Pacheco-Flores, Anyela Lara, Secia Díaz-Miralrio, María José Reyes Fentanes, Jocelyn Zuleica Olmos Vega, Daniela Pineda Méndez, Karina Cano Martínez, Winniberg Stephany Alvarez León, Vida Veronica Ruiz Herrera, Eduardo Gabriel Vázquez Saldaña, Laura Julia Camacho Choza, Karen Sofia Vega Orozco, Sandra Janeth Ortega Domínguez, Jorge A. Chacón, Juan J. Rivera, Erika A. Cutz, Maricruz E. Ortegón, María I. Rivera, David Browder, Cortney Burch, Terri Moye, Paul Bondy, Lesley Browder, Rickey D. Manning, James W. Hurst, Rodney E. Sturgeon, Paul H. Wakefield, John A. Kirby, James Andersen, Szheckera Fearon, Rosa Negron, Amy Medina, John M. Hill, Vivek Rajasekhar, Hayes Williams, LaShondra Cade, Rhodna Fouts, Connie Moya, Corey G. Anderson, Naomi Devine, James Ramsey, Ashley Perez, David Tatelbaum, Michael Jacobs, Kathleen Menasche, Vincent Mirkil, Peter J. Winkle, Amina Z. Haggag, Michelle Haynes, Marysol Villegas, Sabina Raja, Robert Riesenberg, Stanford Plavin, Mark Lerman, Leana Woodside, Maria Johnson, C. Mary Healy, Jennifer A. Whitaker, Wendy A. Keitel, Robert L. Atmar, Gary Horwith, Robin Mason, Lisa Johnson, Tambra Dora, Deborah Murray, Logan Ledbetter, Beverly Ewing, Kathryn E. Stephenson, Chen S. Tan, Rebecca Zash, Jessica L. Ansel, Kate Jaegle, Caitlin J. Guiney, Jeffrey A. Henderson, Marcia O'Leary, Kendra Enright, Jill Kessler, Pete Ducheneaux, Asha Inniss, Donald M. Brandon, William B. Davis, Daniel T. Lawler, Yaa D. Oppong, Ryan P. Starr, Scott N. Syndergaard, Rozeli Shelly, Mashrur Islam Majumder, Danny Sugimoto, Jeffrey Dugas, Sr., Dolores Rijos, Sandra Shelton, Stephan Hong, Howard Schwartz, Nelia Sanchez-Crespo, Jennifer Schwartz, Terry Piedra, Barbara Corral, Carmen Medina, Michael E. Dever, Mitul Shah, Michael Delgado, Tameika Scott, Lisa S. Usdan, Lora J. McGill, Valerie K. Arnold, Carolyn Scatamacchia, Codi M. Anthony, Rajan Merchant, Anelgine C. Yoon, Janet Hill, Lucy Ng-Price, Teri Thompson-Seim, Ronald Ackerman, Jamie Ackerman, Florida Aristy, Nzeera Ketter, Jon Finley, Mildred Stull, Monica Murray, Zainab Rizvi, Sonia Guerrero, Yogesh K. Paliwal, Amit Paliwal, Sarah Gordon, Bryan Gordon, Cynthia Montano-Pereira, Christopher Galloway, Candice Montros, Lily Aleman, Samira Shairi, Wesley Van Ever, George H. Freeman, Esther L. Harmon, Marshall A. Cross, Kacie Sales, Catherine Q. Gular, Matthew Hepburn, Nathan Alderson, Shana Harshell, Siham Mahgoub, Celia Maxwell, Thomas Mellman, Karl M. Thompson, Glenn Wortman, Jeff Kingsley, April Pixler, LaKondria Curry, Sarah Afework, Austin Swanson, Jeffry Jacqmein, Maggie Bowers, Dawn Robison, Victoria Mosteller, Janet Garvey, Mary Easley, Rebecca J. Kurnat, Raymond Cornelison, Shanda Gower, William Schnitz, Destiny S. Heinzig-Cartwright, Derek Lewis, Fred E. Newton, Aeiress Duhart, Breanz Watkins, Brandy Ball, Jill York, Shelby Pickle, David B. Musante, William P. Silver, Linda R. Belhorn, Nicholas A. Viens, David Dellaero, Priti Patel, Kendra Lisec, Beth Safirstein, Luz Zapata, Lazaro Gonzalez, Evelyn Quevedo, Farah Irani, Joseph Grillo, Amy Potts, Julie White, Patrick Flume, Gary Headden, Brandie Taylor, Ashley Warden, Amy Chamberlain, Robert Jeanfreau, Susan Jeanfreau, Paul G. Matherne, Amy Caldwell, Jessica Stahl, Mandy Vowell, Lauren Newhouse, Vladimir Berthaud, Zudi-Mwak Takizala, Genevieve Beninati, Kimberly Snell, Sherrie Baker, James Walker, Tavane Harrison, Meagan Miller, Janet Otto, Roni Gray, Christine Wilson, Tiffany Nemecek, Hannah Harrington, Sally Eppenbach, Wendell Lewis, Tana Bourgeois, Lyndsea Folsom, Gregory Holt, Mehdi Mirsaeidi, Rafael Calderon, Paola Lichtenberger, Jalima Quintero, Becky Martinez, Lilly Immergluck, Erica Johnson, Austin Chan, Norberto Fas, LaTeshia Thomas-Seaton, Saadia Khizer, Jonathan Staben, Tatiana Beresnev, Maryam Jahromi, Mary A. Marovich, Julia Hutter, Martha Nason, Julie Ledgerwood, John Mascola, Mark Leibowitz, Fernanda Morales, Mike Delgado, Rosario Sanchez, Norma Vega, Germán Áñez, Gary Albert, Erin Coston, Chinar Desai, Haoua Dunbar, Mark Eickhoff, Jenina Garcia, Margaret Kautz, Angela Lee, Maggie Lewis, Alice McGarry, Irene McKnight, Joy Nelson, Patrick Newingham, Patty Price-Abbott, Patty Reed, Diana Vegas, Bethanie Wilkinson, Katherine Smith, Wayne Woo, Iksung Cho, Gregory M. Glenn, Filip Dubovsky, David L. Fried, Lynne A. Haughey, Ariana C. Stanton, Lisa Stevens Rameaka, David Rosenberg, Lee Tomatsu, Viviana Gonzalez, Millie Manalo, Bernard Grunstra, Donald Quinn, Phillip Claybrook, Shelby Olds, Amy Dye, Kevin D. Cannon, Mesha M. Chadwick, Bailey Jordan, Morgan Hussey, Hannah Nevarez, Colleen F. Kelley, Michael Chung, Caitlin Moran, Paulina Rebolledo, Christina Bacher, Elizabeth Barranco-Santana, Jessica Rodriguez, Rafael Mendoza, Karen Ruperto, Odette Olivieri, Enrique Ocaña, Paul E. Wylie, Renea Henderson, Natasa Jenson, Fan Yang, Amy Kelley, Kenneth Finkelstein, David Beckmann, Tanya Hutchins, Sebastian Garcia Escallon, Kristen Johnson, Teresa S. Sligh, Parul Desai, Vincent Huynh, Carlos Lopez, Erika Mendoza, Jeffrey Adelglass, Jerome G. Naifeh, Kristine J. Kucera, Waseem Chughtai, Shireen H. Jaffer, Matthew G. Davis, Jennifer Foley, Michelle L. Burgett, Tammi L. Shlotzhauer, Sarah M. Ingalsbe-Geno, Daniel Duncanson, Kelly Kush, Lori Nesbitt, Cora Sonnier, Jennifer McCarter, Michael B. Butcher, James Fry, Donna Percy, Karen Freudemann, Bruce C. Gebhardt, Padma N. Mangu, Debra B. Schroeck, Rajesh K. Davit, Gayle D. Hennekes, Benjamin J. Luft, Melissa Carr, Sharon Nachman, Alison Pellecchia, Candace Smith, Bruno Valenti, Maria I. Bermudez, Noris Peraita, Ernesto Delgado, Alicia Arrazcaeta, Natalie Ramirez, Carmen Amador, Horacio Marafioti, Lyly Dang, Lauren Clement, Jennifer Berry, Mohammed Allaw, Georgettea Geuss, Chelsea Miles, Zachary Bittner, Melody Werne, Cornell Calinescu, Shannon Rodman, Joshua Rindt, Erin Cooksey, Kristina Harrison, Deanna Cooper, Manisha Horton, Amanda Philyaw, William Jennings, Hilario Alvarado, Michele Baka, Malina Regalado, Linda Murray, Sherif Naguib, Justin Singletary, Sha-Wanda Richmond, Sarah Omodele, Emily Oppenheim, Reuben Martinez, Victoria Andriulis, Leonard Singer, Jeanne Blevins, Meagan Thomas, Christine Hull, Isabel Pereira, Gina Rivero, Tracy Okonya, Frances Downing, Paulina Miller, Margaret Rhee, Katherine Stapleton, Jeffrey Klein, Rosamond Hong, Suzanne Swan, Tami Wahlin, Elizabeth Bennett, Amy Salzl, Sharine Phan, Jewel J. White, Amanda Occhino, Ruth Paiano, Morgan McLaughlin, Elisa Swieboda, Veronica Garcia-Fragoso, Maria G. Becerra, Toni White, Christine B. Turley, Andrew McWilliams, Tiffany Esinhart, Natasha Montoya, Shamika Huskey, Leena Paul, Karen Tashima, Jennie Johnson, Marguerite Neill, Martha Sanchez, Natasha Rybak, Maria Mileno, Stuart H. Cohen, Monica Ruiz, Dean M. Boswell, Elizabeth E. Robison, Trina L. Reynolds, Sonja Neumeister, Carmen D. Zorrilla, Juana Rivera, Jessica Ibarra, Iris García, Dianca Sierra, Wanda Ramon, Suzanne Fiorillo, Rebecca Pitotti, Victoria R. Anderson, Jose Castillo Mancilla, Nga Le, Patricia L. Winokur, Dilek Ince, Theresa Hegmann, Jeffrey Meier, Jack Stapleton, Laura Stulken, Monica McArthur, Andrea Berry, Milagritos Tapia, Elizabeth Hammershaimb, Toni Robinson, Rosa MacBryde, Susan Kline, Joanne L. Billings, Winston Cavert, Les B. Forgosh, Timothy W. Schacker, Tyler D. Bold, Dima Dandachi, Taylor Nelson, Andres Bran, Grant Geiger, S. Hasan Naqvi, Diana F. Florescu, Richard Starlin, David Kline, Andrea Zimmer, Anum Abbas, Natasha Wilson, Joseph J. Eron, Michael Sciaudone, A. Lina Rosengren, John S. Kizer, Sarah E. Rutstein, Elizabeth Bruce, Claudia Espinosa, Lisa J. Sanders, Kami Kim, Denise Casey, Barbara S. Taylor, Thomas Patterson, Ruth S. Pinilla, Delia Bullock, Philip Ponce, Jan Patterson, R. Scott McClelland, Dakotah C. Lane, Anna Wald, Frank James, Elizabeth Duke, Kirsten Hauge, Jessica Heimonen, Erin A. Goecker, Youyi Fong, Carol Kauffman, Kathleen Linder, Kimberly Nofz, Andrew McConnell, Robert J. Buynak, Angella Webb, Taryn Petty, Stephanie Andree, Erica Sanchez, Nolan Mackey, Clarisse Baudelaire, Sarah Dzigiel, Adrienna Marquez, Kim Quillin, Michelle King, Vanessa Abad, Jennifer Knowles, Michael Waters, Karla Zepeda, Jordan Coslet, Dalia Tovar, Marian E. Shaw, Mark A. Turner, Cory J. Huffine, Esther S. Huffine, Julie A. Ake, Elizabeth Secord, Eric McGrath, Phillip Levy, Brittany Stewart, Charnell Cromer, Ayanna Walters, Grant Ellsworth, Caroline Greene, Sarah Galloway, Shashi Kapadia, Elliot DeHaan, Clint Wilson, Jason Milligan, Danielle Raley, Joseph Bocchini, Bruce McClenathan, Mary Hussain, Evelyn Lomasney, Evelyn Hall, Sherry Lamberth, Christy Schmeck, Vickie Leathers, Deborah A. Theodore, Angela R. Branche, Daniel S. Graciaa, Timothy J. Hatlen, Jacqueline Miller, Jerald Sadoff, Ann R. Falsey, and Magdalena E. Sobieszczyk

Subjects
COVID-19, Natural infection, Hybrid immunity, Vaccination, Medicine, Medicine (General), R5-920
Abstract

Summary: Background: While vaccines have established utility against COVID-19, phase 3 efficacy studies have generally not comprehensively evaluated protection provided by previous infection or hybrid immunity (previous infection plus vaccination). Individual patient data from US government-supported harmonized vaccine trials provide an unprecedented sample population to address this issue. We characterized the protective efficacy of previous SARS-CoV-2 infection and hybrid immunity against COVID-19 early in the pandemic over three-to six-month follow-up and compared with vaccine-associated protection. Methods: In this post-hoc cross-protocol analysis of the Moderna, AstraZeneca, Janssen, and Novavax COVID-19 vaccine clinical trials, we allocated participants into four groups based on previous-infection status at enrolment and treatment: no previous infection/placebo; previous infection/placebo; no previous infection/vaccine; and previous infection/vaccine. The main outcome was RT-PCR-confirmed COVID-19 >7–15 days (per original protocols) after final study injection. We calculated crude and adjusted efficacy measures. Findings: Previous infection/placebo participants had a 92% decreased risk of future COVID-19 compared to no previous infection/placebo participants (overall hazard ratio [HR] ratio: 0.08; 95% CI: 0.05–0.13). Among single-dose Janssen participants, hybrid immunity conferred greater protection than vaccine alone (HR: 0.03; 95% CI: 0.01–0.10). Too few infections were observed to draw statistical inferences comparing hybrid immunity to vaccine alone for other trials. Vaccination, previous infection, and hybrid immunity all provided near-complete protection against severe disease. Interpretation: Previous infection, any hybrid immunity, and two-dose vaccination all provided substantial protection against symptomatic and severe COVID-19 through the early Delta period. Thus, as a surrogate for natural infection, vaccination remains the safest approach to protection. Funding: National Institutes of Health.

Published
2023
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3. Author Correction: Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials

Author

Cathrine Axfors, Andreas M. Schmitt, Perrine Janiaud, Janneke van’t Hooft, Sherief Abd-Elsalam, Ehab F. Abdo, Benjamin S. Abella, Javed Akram, Ravi K. Amaravadi, Derek C. Angus, Yaseen M. Arabi, Shehnoor Azhar, Lindsey R. Baden, Arthur W. Baker, Leila Belkhir, Thomas Benfield, Marvin A. H. Berrevoets, Cheng-Pin Chen, Tsung-Chia Chen, Shu-Hsing Cheng, Chien-Yu Cheng, Wei-Sheng Chung, Yehuda Z. Cohen, Lisa N. Cowan, Olav Dalgard, Fernando F. de Almeida e Val, Marcus V. G. de Lacerda, Gisely C. de Melo, Lennie Derde, Vincent Dubee, Anissa Elfakir, Anthony C. Gordon, Carmen M. Hernandez-Cardenas, Thomas Hills, Andy I. M. Hoepelman, Yi-Wen Huang, Bruno Igau, Ronghua Jin, Felipe Jurado-Camacho, Khalid S. Khan, Peter G. Kremsner, Benno Kreuels, Cheng-Yu Kuo, Thuy Le, Yi-Chun Lin, Wu-Pu Lin, Tse-Hung Lin, Magnus Nakrem Lyngbakken, Colin McArthur, Bryan J. McVerry, Patricia Meza-Meneses, Wuelton M. Monteiro, Susan C. Morpeth, Ahmad Mourad, Mark J. Mulligan, Srinivas Murthy, Susanna Naggie, Shanti Narayanasamy, Alistair Nichol, Lewis A. Novack, Sean M. O’Brien, Nwora Lance Okeke, Léna Perez, Rogelio Perez-Padilla, Laurent Perrin, Arantxa Remigio-Luna, Norma E. Rivera-Martinez, Frank W. Rockhold, Sebastian Rodriguez-Llamazares, Robert Rolfe, Rossana Rosa, Helge Røsjø, Vanderson S. Sampaio, Todd B. Seto, Muhammad Shahzad, Shaimaa Soliman, Jason E. Stout, Ireri Thirion-Romero, Andrea B. Troxel, Ting-Yu Tseng, Nicholas A. Turner, Robert J. Ulrich, Stephen R. Walsh, Steve A. Webb, Jesper M. Weehuizen, Maria Velinova, Hon-Lai Wong, Rebekah Wrenn, Fernando G. Zampieri, Wu Zhong, David Moher, Steven N. Goodman, John P. A. Ioannidis, and Lars G. Hemkens

Subjects
Science
Published
2024
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4. Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials

Author

Cathrine Axfors, Andreas M. Schmitt, Perrine Janiaud, Janneke van’t Hooft, Sherief Abd-Elsalam, Ehab F. Abdo, Benjamin S. Abella, Javed Akram, Ravi K. Amaravadi, Derek C. Angus, Yaseen M. Arabi, Shehnoor Azhar, Lindsey R. Baden, Arthur W. Baker, Leila Belkhir, Thomas Benfield, Marvin A. H. Berrevoets, Cheng-Pin Chen, Tsung-Chia Chen, Shu-Hsing Cheng, Chien-Yu Cheng, Wei-Sheng Chung, Yehuda Z. Cohen, Lisa N. Cowan, Olav Dalgard, Fernando F. de Almeida e Val, Marcus V. G. de Lacerda, Gisely C. de Melo, Lennie Derde, Vincent Dubee, Anissa Elfakir, Anthony C. Gordon, Carmen M. Hernandez-Cardenas, Thomas Hills, Andy I. M. Hoepelman, Yi-Wen Huang, Bruno Igau, Ronghua Jin, Felipe Jurado-Camacho, Khalid S. Khan, Peter G. Kremsner, Benno Kreuels, Cheng-Yu Kuo, Thuy Le, Yi-Chun Lin, Wu-Pu Lin, Tse-Hung Lin, Magnus Nakrem Lyngbakken, Colin McArthur, Bryan J. McVerry, Patricia Meza-Meneses, Wuelton M. Monteiro, Susan C. Morpeth, Ahmad Mourad, Mark J. Mulligan, Srinivas Murthy, Susanna Naggie, Shanti Narayanasamy, Alistair Nichol, Lewis A. Novack, Sean M. O’Brien, Nwora Lance Okeke, Léna Perez, Rogelio Perez-Padilla, Laurent Perrin, Arantxa Remigio-Luna, Norma E. Rivera-Martinez, Frank W. Rockhold, Sebastian Rodriguez-Llamazares, Robert Rolfe, Rossana Rosa, Helge Røsjø, Vanderson S. Sampaio, Todd B. Seto, Muhammad Shahzad, Shaimaa Soliman, Jason E. Stout, Ireri Thirion-Romero, Andrea B. Troxel, Ting-Yu Tseng, Nicholas A. Turner, Robert J. Ulrich, Stephen R. Walsh, Steve A. Webb, Jesper M. Weehuizen, Maria Velinova, Hon-Lai Wong, Rebekah Wrenn, Fernando G. Zampieri, Wu Zhong, David Moher, Steven N. Goodman, John P. A. Ioannidis, and Lars G. Hemkens

Subjects
Science
Abstract

Abstract Substantial COVID-19 research investment has been allocated to randomized clinical trials (RCTs) on hydroxychloroquine/chloroquine, which currently face recruitment challenges or early discontinuation. We aim to estimate the effects of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished. We present a rapid meta-analysis of ongoing, completed, or discontinued RCTs on hydroxychloroquine or chloroquine treatment for any COVID-19 patients (protocol: https://osf.io/QESV4/ ). We systematically identified unpublished RCTs (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, Cochrane COVID-registry up to June 11, 2020), and published RCTs (PubMed, medRxiv and bioRxiv up to October 16, 2020). All-cause mortality has been extracted (publications/preprints) or requested from investigators and combined in random-effects meta-analyses, calculating odds ratios (ORs) with 95% confidence intervals (CIs), separately for hydroxychloroquine and chloroquine. Prespecified subgroup analyses include patient setting, diagnostic confirmation, control type, and publication status. Sixty-three trials were potentially eligible. We included 14 unpublished trials (1308 patients) and 14 publications/preprints (9011 patients). Results for hydroxychloroquine are dominated by RECOVERY and WHO SOLIDARITY, two highly pragmatic trials, which employed relatively high doses and included 4716 and 1853 patients, respectively (67% of the total sample size). The combined OR on all-cause mortality for hydroxychloroquine is 1.11 (95% CI: 1.02, 1.20; I² = 0%; 26 trials; 10,012 patients) and for chloroquine 1.77 (95%CI: 0.15, 21.13, I² = 0%; 4 trials; 307 patients). We identified no subgroup effects. We found that treatment with hydroxychloroquine is associated with increased mortality in COVID-19 patients, and there is no benefit of chloroquine. Findings have unclear generalizability to outpatients, children, pregnant women, and people with comorbidities.

Published
2021
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5. Hydroxychloroquine/chloroquine for the treatment of hospitalized patients with COVID-19: An individual participant data meta-analysis

Author

Leon Di Stefano, Elizabeth L. Ogburn, Malathi Ram, Daniel O. Scharfstein, Tianjing Li, Preeti Khanal, Sheriza N. Baksh, Nichol McBee, Joshua Gruber, Marianne R. Gildea, Megan R. Clark, Neil A. Goldenberg, Yussef Bennani, Samuel M. Brown, Whitney R. Buckel, Meredith E. Clement, Mark J. Mulligan, Jane A. O’Halloran, Adriana M. Rauseo, Wesley H. Self, Matthew W. Semler, Todd Seto, Jason E. Stout, Robert J. Ulrich, Jennifer Victory, Barbara E. Bierer, Daniel F. Hanley, and Daniel Freilich

Subjects
Medicine, Science
Abstract

Background Results from observational studies and randomized clinical trials (RCTs) have led to the consensus that hydroxychloroquine (HCQ) and chloroquine (CQ) are not effective for COVID-19 prevention or treatment. Pooling individual participant data, including unanalyzed data from trials terminated early, enables more detailed investigation of the efficacy and safety of HCQ/CQ among subgroups of hospitalized patients. Methods We searched ClinicalTrials.gov in May and June 2020 for US-based RCTs evaluating HCQ/CQ in hospitalized COVID-19 patients in which the outcomes defined in this study were recorded or could be extrapolated. The primary outcome was a 7-point ordinal scale measured between day 28 and 35 post enrollment; comparisons used proportional odds ratios. Harmonized de-identified data were collected via a common template spreadsheet sent to each principal investigator. The data were analyzed by fitting a prespecified Bayesian ordinal regression model and standardizing the resulting predictions. Results Eight of 19 trials met eligibility criteria and agreed to participate. Patient-level data were available from 770 participants (412 HCQ/CQ vs 358 control). Baseline characteristics were similar between groups. We did not find evidence of a difference in COVID-19 ordinal scores between days 28 and 35 post-enrollment in the pooled patient population (odds ratio, 0.97; 95% credible interval, 0.76–1.24; higher favors HCQ/CQ), and found no convincing evidence of meaningful treatment effect heterogeneity among prespecified subgroups. Adverse event and serious adverse event rates were numerically higher with HCQ/CQ vs control (0.39 vs 0.29 and 0.13 vs 0.09 per patient, respectively). Conclusions The findings of this individual participant data meta-analysis reinforce those of individual RCTs that HCQ/CQ is not efficacious for treatment of COVID-19 in hospitalized patients.

Published
2022

6. Author Correction: Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials

Author

Cathrine Axfors, Andreas M. Schmitt, Perrine Janiaud, Janneke van’t Hooft, Sherief Abd-Elsalam, Ehab F. Abdo, Benjamin S. Abella, Javed Akram, Ravi K. Amaravadi, Derek C. Angus, Yaseen M. Arabi, Shehnoor Azhar, Lindsey R. Baden, Arthur W. Baker, Leila Belkhir, Thomas Benfield, Marvin A. H. Berrevoets, Cheng-Pin Chen, Tsung-Chia Chen, Shu-Hsing Cheng, Chien-Yu Cheng, Wei-Sheng Chung, Yehuda Z. Cohen, Lisa N. Cowan, Olav Dalgard, Fernando F. de Almeida e Val, Marcus V. G. de Lacerda, Gisely C. de Melo, Lennie Derde, Vincent Dubee, Anissa Elfakir, Anthony C. Gordon, Carmen M. Hernandez-Cardenas, Thomas Hills, Andy I. M. Hoepelman, Yi-Wen Huang, Bruno Igau, Ronghua Jin, Felipe Jurado-Camacho, Khalid S. Khan, Peter G. Kremsner, Benno Kreuels, Cheng-Yu Kuo, Thuy Le, Yi-Chun Lin, Wu-Pu Lin, Tse-Hung Lin, Magnus Nakrem Lyngbakken, Colin McArthur, Bryan J. McVerry, Patricia Meza-Meneses, Wuelton M. Monteiro, Susan C. Morpeth, Ahmad Mourad, Mark J. Mulligan, Srinivas Murthy, Susanna Naggie, Shanti Narayanasamy, Alistair Nichol, Lewis A. Novack, Sean M. O’Brien, Nwora Lance Okeke, Léna Perez, Rogelio Perez-Padilla, Laurent Perrin, Arantxa Remigio-Luna, Norma E. Rivera-Martinez, Frank W. Rockhold, Sebastian Rodriguez-Llamazares, Robert Rolfe, Rossana Rosa, Helge Røsjø, Vanderson S. Sampaio, Todd B. Seto, Muhammad Shahzad, Shaimaa Soliman, Jason E. Stout, Ireri Thirion-Romero, Andrea B. Troxel, Ting-Yu Tseng, Nicholas A. Turner, Robert J. Ulrich, Stephen R. Walsh, Steve A. Webb, Jesper M. Weehuizen, Maria Velinova, Hon-Lai Wong, Rebekah Wrenn, Fernando G. Zampieri, Wu Zhong, David Moher, Steven N. Goodman, John P. A. Ioannidis, and Lars G. Hemkens

Subjects
Science
Published
2021
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7. Author Correction: Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials

Author

Steven N. Goodman, Norma E. Rivera-Martinez, Magnus Nakrem Lyngbakken, David Moher, John P. A. Ioannidis, Frank W. Rockhold, Todd B. Seto, Helge Røsjø, Vincent Dubée, Ahmad Mourad, Andrea B. Troxel, Carmen M. Hernández-Cárdenas, Vanderson de Souza Sampaio, Thuy Le, Andy I. M. Hoepelman, Fernando Val, Sean M. O'Brien, Ting Yu Tseng, Leila Belkhir, Susanna Naggie, Patricia Meza-Meneses, Marvin A.H. Berrevoets, Javed Akram, Alistair Nichol, Léna Perez, Rebekah Wrenn, Susan C. Morpeth, Laurent Perrin, Felipe Jurado-Camacho, Lindsey R. Baden, Shehnoor Azhar, Bryan J. McVerry, Cheng-Yu Kuo, Arantxa Remigio-Luna, Thomas Hills, Cathrine Axfors, Ireri Thirion-Romero, Steve Webb, Wuelton Marcelo Monteiro, Jason E. Stout, Jesper M. Weehuizen, Peter G. Kremsner, Shanti Narayanasamy, Derek C. Angus, Yehuda Z. Cohen, Shu Hsing Cheng, Gisely Cardoso de Melo, Rossana Rosa, Nwora Lance Okeke, Stephen R. Walsh, Srinivas Murthy, Anissa Elfakir, Mark J. Mulligan, Olav Dalgard, Cheng-Pin Chen, Tse Hung Lin, Fernando G. Zampieri, Khalid S. Khan, Yi-Wen Huang, Anthony C. Gordon, Yaseen M. Arabi, Wu Zhong, Hon Lai Wong, Wei Sheng Chung, Bruno Igau, Andreas M. Schmitt, Maria Velinova, Robert J. Ulrich, Nicholas A Turner, Wu Pu Lin, Janneke van’t Hooft, Shaimaa Soliman, Lennie P. G. Derde, Colin McArthur, Arthur W. Baker, Benno Kreuels, Ravi K. Amaravadi, Ronghua Jin, Benjamin S. Abella, Sherief Abd-Elsalam, Thomas Benfield, Lewis A. Novack, Lars G. Hemkens, Ehab F. Abdo, Perrine Janiaud, Sebastian Rodriguez-Llamazares, Chien Yu Cheng, Muhammad Shahzad, Robert Rolfe, Tsung Chia Chen, Yi-Chun Lin, Rogelio Perez-Padilla, Marcus V. G. Lacerda, and Lisa N. Cowan

Subjects
Adult, medicine.medical_specialty, 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), Epidemiology, International Cooperation, Science, MEDLINE, General Physics and Astronomy, Comorbidity, General Biochemistry, Genetics and Molecular Biology, law.invention, Randomized controlled trial, Pregnancy, law, Chloroquine, Internal medicine, Odds Ratio, medicine, Humans, Pregnancy Complications, Infectious, Author Correction, Child, Randomized Controlled Trials as Topic, Multidisciplinary, SARS-CoV-2, business.industry, COVID-19, Hydroxychloroquine, General Chemistry, Combined Modality Therapy, COVID-19 Drug Treatment, Viral infection, Meta-analysis, Female, Patient Participation, business, medicine.drug
Abstract

Substantial COVID-19 research investment has been allocated to randomized clinical trials (RCTs) on hydroxychloroquine/chloroquine, which currently face recruitment challenges or early discontinuation. We aim to estimate the effects of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished. We present a rapid meta-analysis of ongoing, completed, or discontinued RCTs on hydroxychloroquine or chloroquine treatment for any COVID-19 patients (protocol: https://osf.io/QESV4/ ). We systematically identified unpublished RCTs (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, Cochrane COVID-registry up to June 11, 2020), and published RCTs (PubMed, medRxiv and bioRxiv up to October 16, 2020). All-cause mortality has been extracted (publications/preprints) or requested from investigators and combined in random-effects meta-analyses, calculating odds ratios (ORs) with 95% confidence intervals (CIs), separately for hydroxychloroquine and chloroquine. Prespecified subgroup analyses include patient setting, diagnostic confirmation, control type, and publication status. Sixty-three trials were potentially eligible. We included 14 unpublished trials (1308 patients) and 14 publications/preprints (9011 patients). Results for hydroxychloroquine are dominated by RECOVERY and WHO SOLIDARITY, two highly pragmatic trials, which employed relatively high doses and included 4716 and 1853 patients, respectively (67% of the total sample size). The combined OR on all-cause mortality for hydroxychloroquine is 1.11 (95% CI: 1.02, 1.20; I² = 0%; 26 trials; 10,012 patients) and for chloroquine 1.77 (95%CI: 0.15, 21.13, I² = 0%; 4 trials; 307 patients). We identified no subgroup effects. We found that treatment with hydroxychloroquine is associated with increased mortality in COVID-19 patients, and there is no benefit of chloroquine. Findings have unclear generalizability to outpatients, children, pregnant women, and people with comorbidities.

Published
2021

8. SARS-CoV-2 mRNA vaccine elicits a potent adaptive immune response in the absence of IFN-mediated inflammation observed in COVID-19

Author

Amber Cornelius, Chenzhen Zhang, Mark J. Mulligan, Niels Ødum, Akiko Koide, Jasmine Shwetar, Alberto Herrera, Terkild B. Buus, Marie I. Samanovic, Joseph C. Devlin, Robert J. Ulrich, Ludovic Desvignes, Kelly V. Ruggles, Sergei B. Koralov, Ellie Ivanova, Eleni P. Mimitou, Shohei Koide, Peter Smibert, and Ramin S. Herati

Subjects
T cell, chemical and pharmacologic phenomena, Inflammation, biochemical phenomena, metabolism, and nutrition, Biology, Acquired immune system, Article, Virus, Vaccination, medicine.anatomical_structure, Immune system, Interferon, Immunology, medicine, bacteria, Cytotoxic T cell, medicine.symptom, medicine.drug
Abstract

Both SARS-CoV-2 infection and vaccination elicit potent immune responses. A number of studies have described immune responses to SARS-CoV-2 infection. However, beyond antibody production, immune responses to COVID-19 vaccines remain largely uncharacterized. Here, we performed multimodal single-cell sequencing on peripheral blood of patients with acute COVID-19 and healthy volunteers before and after receiving the SARS-CoV-2 BNT162b2 mRNA vaccine to compare the immune responses elicited by the virus and by this vaccine. Phenotypic and transcriptional profiling of immune cells, coupled with reconstruction of the B and T cell antigen receptor rearrangement of individual lymphocytes, enabled us to characterize and compare the host responses to the virus and to defined viral antigens. While both infection and vaccination induced robust innate and adaptive immune responses, our analysis revealed significant qualitative differences between the two types of immune challenges. In COVID-19 patients, immune responses were characterized by a highly augmented interferon response which was largely absent in vaccine recipients. Increased interferon signaling likely contributed to the observed dramatic upregulation of cytotoxic genes in the peripheral T cells and innate-like lymphocytes in patients but not in immunized subjects. Analysis of B and T cell receptor repertoires revealed that while the majority of clonal B and T cells in COVID-19 patients were effector cells, in vaccine recipients clonally expanded cells were primarily circulating memory cells. Importantly, the divergence in immune subsets engaged, the transcriptional differences in key immune populations, and the differences in maturation of adaptive immune cells revealed by our analysis have far-ranging implications for immunity to this novel pathogen.

Published
2021
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9. Discrete Immune Response Signature to SARS-CoV-2 mRNA Vaccination Versus Infection

Author

Amber Cornelius, Robert J. Ulrich, Marie I. Samanovic, Chenzhen Zhang, Ellie Ivanova, Ludovic Desvignes, Sergei B. Koralov, Alberto Herrera, Peter Smibert, Eleni P Mimitou, Terild B Buus, Ramin S. Herati, Joseph C. Devlin, Shohei Koide, Mark J. Mulligan, Akiko Koide, Kelly V. Ruggles, and Niels Ødum

Subjects
T-cell receptor, chemical and pharmacologic phenomena, biochemical phenomena, metabolism, and nutrition, Biology, Virus, Vaccination, Immune system, Immunity, Interferon, Immunology, medicine, bacteria, Cytotoxic T cell, Receptor, medicine.drug
Abstract

Both SARS-CoV-2 infection and vaccination elicit potent immune responses. A number of studies have described immune responses to SARS-CoV-2 infection. However, beyond antibody production, immune responses to COVID-19 vaccines remain largely uncharacterized. Here, we performed multimodal single-cell sequencing on peripheral blood of patients with acute COVID-19 and healthy volunteers before and after receiving the SARS-CoV-2 BNT162b2 mRNA vaccine to compare the immune responses elicited by the virus and by this vaccine. Phenotypic and transcriptional profiling of immune cells, coupled with reconstruction of the B and T cell antigen receptor rearrangement of individual lymphocytes, enabled us to characterize and compare the host responses to the virus and to defined viral antigens. While both infection and vaccination induced robust innate and adaptive immune responses, our analysis revealed significant qualitative differences between the two types of immune challenges. In COVID-19 patients, immune responses were characterized by a highly augmented interferon response which was largely absent in vaccine recipients. Increased interferon signaling likely contributed to the observed dramatic upregulation of cytotoxic genes in the peripheral T cells and innate-like lymphocytes in patients but not in immunized subjects. Analysis of B and T cell receptor repertoires revealed that while the majority of clonal B and T cells in COVID-19 patients were effector cells, in vaccine recipients clonally expanded cells were primarily circulating memory cells. Importantly, the divergence in immune subsets engaged, the transcriptional differences in key immune populations, and the differences in maturation of adaptive immune cells revealed by our analysis have far-ranging implications for immunity to this novel pathogen.

Published
2021
Full Text
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10. Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19: an international collaborative meta-analysis of randomized trials

Author

Thomas Hills, Cathrine Axfors, Yehuda Z. Cohen, Nwora Lance Okeke, Fernando G. Zampieri, Lindsey R. Baden, Ting-Yu Tseng, Derek C. Angus, Vanderson de Souza Sampaio, Thuy Le, Bruno Igau, Fernando Almeida Val, Shanti Narayanasamy, Tsung-Chia Chen, Shaimaa Soliman, Srinivas Murthy, Nicholas A Turner, Lennie P. G. Derde, Sean M. O'Brien, Cheng-Pin Chen, Todd B. Seto, Benjamin S. Abella, Ireri Thirion-Romero, Stephen R. Walsh, Muhammad Shehzad, Wu Zhong, Yaseen M. Arabi, Sherief Abd-Elsalam, Anissa Elfakir, Javed Akram, Léna Perez, Mark J. Mulligan, Wei-Sheng Chung, John P. A. Ioannidis, Khalid S. Khan, Yi-Wen Huang, Felipe Jurado-Camacho, Thomas Benfield, Wuelton Marcelo Monteiro, Jason E. Stout, Anthony C. Gordon, Bryan J. McVerry, Lars G. Hemkens, Robert J. Ulrich, Colin McArthur, Sebastian Rodriguez-Llamazares, Hon-Lai Wong, Norma E. Rivera-Martinez, Leila Belkhir, Magnus Nakrem Lyngbakken, Andy I. M. Hoepelman, Ehab F. Abdo, David Moher, Maria Velinova, Benno Kreuels, Arthur W. Baker, Ravi K. Amaravadi, Ahmad Mourad, Ronghua Jin, Perrine Janiaud, Shehnoor Azhar, Marvin A.H. Berrevoets, Chien-Yu Cheng, Arantxa Remigio-Luna, Shu-Hsing Cheng, Lewis A. Novack, Steve Webb, Steven N. Goodman, Helge Røsjø, Tse-Hung Lin, Vincent Dubée, Andrea B. Troxel, Frank W. Rockhold, Rossana Rosa, Peter G. Kremsner, Rebekah Wrenn, Susan C. Morpeth, Laurent Perrin, Andreas M. Schmitt, Robert Rolfe, Alistair Nichol, Carmen M. Hernández-Cárdenas, Janneke van 't Hooft, Olav Dalgard, Susanna Naggie, Yi-Chun Lin, Jesper M. Weehuizen, Gisely Cardoso de Melo, Wu-Pu Lin, Patricia Meza-Meneses, Cheng-Yu Kuo, Lisa N. Cowan, Rogelio Perez-Padilla, and Marcus V. G. Lacerda

Subjects
medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), business.industry, Hydroxychloroquine, Odds ratio, Confidence interval, law.invention, Clinical trial, Randomized controlled trial, law, Chloroquine, Meta-analysis, Internal medicine, Medicine, business, medicine.drug
Abstract

BackgroundSubstantial COVID-19 research investment has been allocated to randomized clinical trials (RCTs) on hydroxychloroquine/chloroquine, which currently face recruitment challenges or early discontinuation. We aimed to estimate the effects of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished. Methods: Rapid meta-analysis of ongoing, completed, or discontinued RCTs on hydroxychloroquine or chloroquine treatment for any COVID-19 patients (protocol: https://osf.io/QESV4/). We systematically identified published and unpublished RCTs by September 14, 2020 (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, PubMed, Cochrane COVID-19 registry). All-cause mortality was extracted (publications/preprints) or requested from investigators and combined in random-effects meta-analyses, calculating odds ratios (ORs) with 95% confidence intervals (CIs), separately for hydroxychloroquine/chloroquine. Prespecified subgroup analyses included patient setting, diagnostic confirmation, control type, and publication status.ResultsSixty-two trials were potentially eligible. We included 16 unpublished trials (1596 patients) and 10 publications/preprints (6317 patients). The combined summary OR on all-cause mortality for hydroxychloroquine was 1.08 (95%CI: 0.99, 1.18; I2=0%; 24 trials; 7659 patients) and for chloroquine 1.77 (95%CI: 0.15, 21.13, I2=0%; 4 trials; 307 patients). We identified no subgroup effects.ConclusionsWe found no benefit of hydroxychloroquine or chloroquine on the survival of COVID-19 patients. For hydroxychloroquine, the confidence interval is compatible with increased mortality (OR 1.18) or negligibly reduced mortality (OR 0.99). Findings have unclear generalizability to outpatients, children, pregnant women, and people with comorbidities.

Published
2020
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11. Treating Covid-19 With Hydroxychloroquine (TEACH): A Multicenter, Double-Blind, Randomized Controlled Trial in Hospitalized Patients

Author

Mark J. Mulligan, Gabriel A. Robbins, Ellie Carmody, Jaishvi Eapen, Yi Li, Alexander Hrycko, Vanessa Raabe, Brooklyn Henderson, Dinuli Delpachitra, Yanina Dubrovskaya, Jonathan S. Austrian, Morris Jrada, Martin Backer, Prithiv J. Prasad, Jack DeHovitz, Camila Delgado, Andrea B. Troxel, and Robert J. Ulrich

Subjects
medicine.medical_specialty, hydroxychloroquine, medicine.medical_treatment, 030204 cardiovascular system & hematology, Placebo, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Statistical significance, Internal medicine, medicine, Extracorporeal membrane oxygenation, Major Article, 030212 general & internal medicine, Adverse effect, Mechanical ventilation, business.industry, SARS-CoV-2, COVID-19, Hydroxychloroquine, Intensive care unit, Editor's Choice, Infectious Diseases, AcademicSubjects/MED00290, Oncology, randomized controlled trial, business, medicine.drug
Abstract

Background Effective therapies to combat coronavirus 2019 (COVID-19) are urgently needed. Hydroxychloroquine (HCQ) has in vitro antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but the clinical benefit of HCQ in treating COVID-19 is unclear. Randomized controlled trials are needed to determine the safety and efficacy of HCQ for the treatment of hospitalized patients with COVID-19. Methods We conducted a multicenter, double-blind randomized clinical trial of HCQ among patients hospitalized with laboratory-confirmed COVID-19. Subjects were randomized in a 1:1 ratio to HCQ or placebo for 5 days and followed for 30 days. The primary efficacy outcome was a severe disease progression composite end point (death, intensive care unit admission, mechanical ventilation, extracorporeal membrane oxygenation, and/or vasopressor use) at day 14. Results A total of 128 patients were included in the intention-to-treat analysis. Baseline demographic, clinical, and laboratory characteristics were similar between the HCQ (n = 67) and placebo (n = 61) arms. At day 14, 11 (16.4%) subjects assigned to HCQ and 6 (9.8%) subjects assigned to placebo met the severe disease progression end point, but this did not achieve statistical significance (P = .350). There were no significant differences in COVID-19 clinical scores, number of oxygen-free days, SARS-CoV-2 clearance, or adverse events between HCQ and placebo. HCQ was associated with a slight increase in mean corrected QT interval, an increased D-dimer, and a trend toward an increased length of stay. Conclusions In hospitalized patients with COVID-19, our data suggest that HCQ does not prevent severe outcomes or improve clinical scores. However, our conclusions are limited by a relatively small sample size, and larger randomized controlled trials or pooled analyses are needed.

Published
2020

12. Clostridioides difficile Enteritis in Patients Following Total Colectomy—a Rare but Genuine Clinical Entity

Author

Jonathan Bott, Kerri Lopez, Robert J. Ulrich, Hannah Imlay, Krishna Rao, and Sandro Cinti

Subjects
0301 basic medicine, medicine.medical_specialty, medicine.drug_class, proton pump inhibitor, medicine.medical_treatment, 030106 microbiology, Proton-pump inhibitor, Gastroenterology, Inflammatory bowel disease, Enteritis, 03 medical and health sciences, 0302 clinical medicine, inflammatory bowel disease, Internal medicine, Major Article, Medicine, Colitis, enteritis, Colectomy, business.industry, Hazard ratio, Immunosuppression, Perioperative, medicine.disease, colectomy, 3. Good health, Editor's Choice, Infectious Diseases, Oncology, 030211 gastroenterology & hepatology, C. difficile, business
Abstract

Clostridioides difficile enteritis (CDE) after colectomy is an understudied infectious syndrome. We reviewed 20 years of post-colectomy data and found CDE in 44/855 (5.1%) patients, usually within one year of surgery. Risk factors include acid suppression, inflammatory bowel disease, and antibiotics with enteral feeds. Clostridioides difficile enteritis often presents with severe disease requiring hospitalization., Objective Clostridioides difficile infection (CDI) frequently causes colitis following antibiotic exposure and is a leading cause of gastrointestinal infectious mortality. Infection in the small bowel, C. difficile enteritis (CDE), was previously thought impossible, but case series have challenged this dogma. Clostridioides difficile enteritis prevalence, severity, and potential risk factors are unknown. Methods We retrospectively analyzed all total colectomy patients over a 20-year period at our institution. C. difficile enteritis was defined by clinical symptoms and positive C. difficile stool testing after colectomy. We compared CDE cases to controls using multivariable analysis to identify potential CDE risk factors. Results C. difficile enteritis occurred in 44 of 855 (5.1%) patients, a median of 130 days after colectomy. Compared to controls, CDE patients were similar in age, gender, and presence of immunosuppression. The majority (64%) had antibiotics

Published
2019

13. Introduction of Procalcitonin Testing and Antibiotic Utilization for Acute Exacerbations of Chronic Obstructive Pulmonary Disease

Author

Daniel Mcclung, Robert J. Ulrich, Bonnie R Wang, Spencer Winters, Krishna Rao, and Scott A. Flanders

Subjects
medicine.medical_specialty, medicine.drug_class, Antibiotics, Pulmonary disease, Procalcitonin, antibiotics, lcsh:Infectious and parasitic diseases, 03 medical and health sciences, COPD exacerbation, 0302 clinical medicine, respiratory infection, Internal medicine, parasitic diseases, medicine, lcsh:RC109-216, 030212 general & internal medicine, Original Research, business.industry, Respiratory infection, bacterial infections and mycoses, 3. Good health, 030228 respiratory system, Copd exacerbation, business, hormones, hormone substitutes, and hormone antagonists, procalcitonin
Abstract

Background: The majority of acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are triggered by nonbacterial causes, yet most patients receive antibiotics. Treatment guided by procalcitonin (PCT), a sensitive biomarker of bacterial infection, safely decreases antibiotic use in many controlled trials. We evaluated PCT implementation for inpatients with AECOPD at a large academic hospital. Methods: All patients admitted for AECOPD during the first 6 months of PCT-guided therapy were eligible for inclusion in this retrospective cohort study. Patients with PCT performed were compared with those without PCT. The primary outcome was antibiotic days of therapy (DOT). Secondary outcomes included 30-day readmission and mortality. Results: Of the 238 AECOPD admissions, 73 (31%) had PCT performed. Procalcitonin-tested patients were more likely to meet systemic inflammatory response syndrome (SIRS) criteria, require intensive care unit (ICU)-level care, and have a longer length of stay (LOS) compared with those without PCT. Even after adjustment for these factors, PCT-tested patients received more inpatient DOT and there was no difference in total DOT. However, a low PCT value (Conclusions: In this real-world analysis of inpatients with AECOPD, PCT-guided therapy was poorly adopted by providers and was not associated with a decrease in total antibiotic DOT. However, a low PCT level was associated with a 25.5% decrease in IV antibiotic DOT, suggesting increased comfort stepping down from IV to PO therapy.

Published
2019

14. Outcomes of Patients Undergoing Percutaneous Biliary Drainage to Reduce Bilirubin for Administration of Chemotherapy

Author

Lynn A. Brody, Raymond H. Thornton, Constantinos T. Sofocleous, Diane Reidy-Lagunes, Robert J. Ulrich, Chaya S. Moskowitz, Karen T. Brown, Meier Hsu, George I. Getrajdman, Anne M. Covey, P.M. Robson, and Stephen B. Solomon

Subjects
Adult, Male, medicine.medical_specialty, Percutaneous, Adolescent, Bilirubin, Population, Gastroenterology, Cholangiocarcinoma, chemistry.chemical_compound, Hepatic arterial infusion, Internal medicine, Humans, Medicine, Radiology, Nuclear Medicine and imaging, Gallbladder cancer, Child, education, Survival rate, Aged, Retrospective Studies, Aged, 80 and over, education.field_of_study, business.industry, Patient Selection, Hazard ratio, Retrospective cohort study, Middle Aged, medicine.disease, Surgery, Pancreatic Neoplasms, Survival Rate, Treatment Outcome, chemistry, Drainage, Female, Gallbladder Neoplasms, Cardiology and Cardiovascular Medicine, business
Abstract

To describe outcomes in patients undergoing percutaneous biliary drainage to reduce total serum bilirubin level for administration of chemotherapy.A total of 647 consecutive patients underwent percutaneous biliary drainage between September 2001 and December 2008. In 168, the indication for biliary drainage was to decrease total serum bilirubin level to permit administration of chemotherapy. Of these, 20 were excluded because they had hepatic arterial infusion pumps, leaving 148 patients as the study group. The primary diagnoses for these patients were gallbladder cancer (n = 23), cholangiocarcinoma (n = 21), pancreatic cancer (n = 36), and other metastatic cancers (n = 68). Medical records and imaging studies were reviewed for demographic data, procedural information, pre- and postdrainage total serum bilirubin level levels, 30-day complications, and subsequent biliary procedures.The probability of attaining a total serum bilirubin level of 1 mg/dL or lower by 100 days was 31% (95% CI, 23%-39%). Predrainage total serum bilirubin level of 9 mg/dL or lower (hazard ratio [HR], 3.27; 95% CI, 1.86-5.75; P.001), 100% liver drainage (HR 2.73, 95% CI, 1.56-4.78; P.001), and lower predrainage International Normalized Ratio (INR; HR, 0.80; 95% CI, 0.70-0.92; P = .002) were associated with an increased likelihood of attaining a total serum bilirubin level of 1 mg/dL or lower. The most common indication for follow-up was pericatheter leakage, which occurred in nearly one third of cases. During follow-up, patients required three visits per 100 catheter-days, or approximately one per month. Median overall survival in this population was approximately 3.5 months.Only 31% of patients attained a normal serum bilirubin level by 100 days, and median overall survival was 107 days. Careful patient selection is warranted before biliary drainage for this indication. Maximal biliary drainage, a preprocedure total serum bilirubin of less than 9 mg/dL, and a lower INR were factors associated with serum bilirubin normalization in this cohort.

Published
2012
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16. Abstract No. 340: Outcomes of patients undergoing percutaneous biliary drainage to reduce bilirubin for administration of chemotherapy

Author

Stephen B. Solomon, Constantinos T. Sofocleous, Raymond H. Thornton, P.M. Robson, Karen T. Brown, Robert J. Ulrich, Lynn A. Brody, and George I. Getrajdman

Subjects
medicine.medical_specialty, Chemotherapy, Biliary drainage, Percutaneous, business.industry, Bilirubin, medicine.medical_treatment, Surgery, chemistry.chemical_compound, chemistry, medicine, Radiology, Nuclear Medicine and imaging, Cardiology and Cardiovascular Medicine, business, Administration (government)
Published
2010
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17. Quorum-sensing agr system of Staphylococcus aureus primes gene expression for protection from lethal oxidative stress

Author

Magdalena Podkowik, Andrew I Perault, Gregory Putzel, Andrew Pountain, Jisun Kim, Ashley L DuMont, Erin E Zwack, Robert J Ulrich, Theodora K Karagounis, Chunyi Zhou, Andreas F Haag, Julia Shenderovich, Gregory A Wasserman, Junbeom Kwon, John Chen, Anthony R Richardson, Jeffrey N Weiser, Carla R Nowosad, Desmond S Lun, Dane Parker, Alejandro Pironti, Xilin Zhao, Karl Drlica, Itai Yanai, Victor J Torres, and Bo Shopsin

Subjects
agr, Staphylococcus aureus, quorum-sensing, reactive oxygen species (ROS), peroxide (H2O2), Medicine, Science, Biology (General), QH301-705.5
Abstract

The agr quorum-sensing system links Staphylococcus aureus metabolism to virulence, in part by increasing bacterial survival during exposure to lethal concentrations of H2O2, a crucial host defense against S. aureus. We now report that protection by agr surprisingly extends beyond post-exponential growth to the exit from stationary phase when the agr system is no longer turned on. Thus, agr can be considered a constitutive protective factor. Deletion of agr resulted in decreased ATP levels and growth, despite increased rates of respiration or fermentation at appropriate oxygen tensions, suggesting that Δagr cells undergo a shift towards a hyperactive metabolic state in response to diminished metabolic efficiency. As expected from increased respiratory gene expression, reactive oxygen species (ROS) accumulated more in the agr mutant than in wild-type cells, thereby explaining elevated susceptibility of Δagr strains to lethal H2O2 doses. Increased survival of wild-type agr cells during H2O2 exposure required sodA, which detoxifies superoxide. Additionally, pretreatment of S. aureus with respiration-reducing menadione protected Δagr cells from killing by H2O2. Thus, genetic deletion and pharmacologic experiments indicate that agr helps control endogenous ROS, thereby providing resilience against exogenous ROS. The long-lived ‘memory’ of agr-mediated protection, which is uncoupled from agr activation kinetics, increased hematogenous dissemination to certain tissues during sepsis in ROS-producing, wild-type mice but not ROS-deficient (Cybb−/−) mice. These results demonstrate the importance of protection that anticipates impending ROS-mediated immune attack. The ubiquity of quorum sensing suggests that it protects many bacterial species from oxidative damage.

Published
2024
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