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2. Pro-inflammatory and pro-resolving lipid mediators of inflammation in HIV: effect of aspirin intervention

Author

Dalli, Jesmond, Kitch, Douglas, O'Brien, Meagan P, Hunt, Peter W, Funderburg, Nicholas, Moisi, Daniela, Gupta, Amita, Brown, Todd T, Tien, Phyllis C, Aberg, Judith A, and Shivakoti, Rupak

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Clinical Research, Cardiovascular, Heart Disease, Infectious Diseases, Prevention, HIV/AIDS, Good Health and Well Being, Humans, Aspirin, Cardiovascular Diseases, Eicosanoids, HIV Infections, Inflammation, Inflammation Mediators, HIV, SPMs, Clinical Sciences, Public Health and Health Services, Clinical sciences, Epidemiology
Abstract

BackgroundPersons with HIV (PWH) have an increased risk of cardiovascular disease (CVD) compared to HIV-seronegative individuals (SN). Inflammation contributes to this risk but the role of lipid mediators, with central roles in inflammation, in HIV infection remain to be established; further aspirin reduces CVD risk in the general population through production of some of these anti-inflammatory lipid mediators, but they have not been studied in PWH.MethodsWe evaluated the relationship between plasma lipid mediators (i.e. 50 lipid mediators including classic eicosanoids and specialized pro-resolving mediators (SPMs)) and HIV status; and the impact of aspirin in PWH on regulating these autacoids. Plasma samples were obtained from 110 PWH receiving antiretroviral therapy (ART) from a randomized trial of aspirin (ACTG-A5331) and 107 matched SN samples (MACS-WIHS Combined Cohort).FindingsPWH had lower levels of arachidonic acid-derived pro-inflammatory prostaglandins (PGs: PGE2 and PGD2) and thromboxanes (Tx: TxB2), and higher levels of select pro-resolving lipid mediators (e.g. RvD4 and MaR2n-3 DPA) compared to SN. At the interval tested, aspirin intervention was observed to reduced PGs and Tx, and while we did not observe an increase in aspirin triggered mediators, we observed the upregulation of other SPM in aspirin treated PWH, namely MaR2n-3 DPA.InterpretationTogether these observations demonstrate that plasma lipid mediators profiles, some with links to systemic inflammation and CVD risk, become altered in PWH. Furthermore, aspirin intervention did not increase levels of aspirin-triggered pro-resolving lipid mediators, consistent with other reports of an impaired aspirin response in PWH.FundingNIH.

Published
2023

3. Efficacy and safety of a single dose of casirivimab and imdevimab for the prevention of COVID-19 over an 8-month period: a randomised, double-blind, placebo-controlled trial

Author

Chani, Achint, Adepoju, Adebiyi, Mahmood, Adnan, Mortagy, Aisha, Dupljak, Ajla, Baum, Alina, Brown, Alison, Froment, Amy, Hooper, Andrea, Margiotta, Andrea, Bombardier, Andrew, Islam, Anita, Smith, Anne, Dhillon, Arvinder, McMillian, Audra, Breazna, Aurora, Aslam, Ayesha, Carpentino, Barabara, Kowal, Bari, Siliverstein, Barry, Horel, Benjamin, Zhu, Bo, Musser, Bret, Bush, Brian, Head, Brian, Snow, Brian, Zhu, Bryan, Debray, Camille, Phillips, Careta, Simiele, Carmella, Lee, Carol, Nienstedt, Carolyn, Trbovic, Caryn, Chan, Casey (Kuo-Chen), Elliott, Catherine, Fish, Chad, Ni, Charlie, Polidori, Christa, Enciso, Christine, Caira, Christopher, Powell, Christopher, Kyratsous, Christos A., Baum, Cliff, McDonald, Colin, Leigh, Cynthia, Pan, Cynthia, Wolken, Dana, Manganello, Danielle, Liu, David, Stein, David, Weinreich, David M., Hassan, Dawlat, Gulabani, Daya, Fix, Deborah, Leonard, Deborah, Sarda, Deepshree, Bonhomme, Denise, Kennedy, Denise, Darcy, Devin, Barron, Dhanalakshmi, Hughes, Diana, Rofail, Diana, Kaur, Dipinder, Ramesh, Divya, Bianco, Dona, Cohen, Donna, Forleo-Neto, Eduardo, Jean-Baptiste, Edward, Bukhari, Ehsan, Doyle, Eileen, Bucknam, Elizabeth, Labriola-Tomkins, Emily, Nanna, Emily, Huffman O'Keefe, Esther, Gasparino, Evelyn, Fung, Evonne, Isa, Flonza, To, Fung-Yee, Herman, Gary, Yancopoulos, George D., Bellingham, Georgia, Sumner, Giane, Moggan, Grainne, Power, Grainne, Zeng, Haixia, Mariveles, Hazel, Gonzalez, Heath, Kang, Helen, Noor, Hibo, Minns, Ian, Heirman, Ingeborg, Peszek, Izabella, Donohue, James, Rusconi, Jamie, Austin, Janice, Parrino, Janie, Yo, Jeannie, McDonnell, Jenna, Hamilton, Jennifer D., Boarder, Jessica, Wei, Jianguo, Yu, Jingchun, Malia, Joanne, Tucciarone, Joanne, Tyler-Gale, Jodie, Davis, John D., Strein, John, Cohen, Jonathan, Meyer, Jonathan, Ursino, Jordan, Im, Joseph, Tramaglini, Joseph, Wolken, Joseph, Potter, Kaitlyn, Scacalossi, Kaitlyn, Naidu, Kamala, Browning, Karen, Rutkowski, Karen, Yau, Karen, Woloshin, Katherine, Lewis-Amezcua, Kelly, Turner, Kenneth, Dornheim, Kimberly, Chiu, Kit, Mohan, Kosalai, McGuire, Kristina, Macci, Kristy, Ringleben, Kurt, Mohammadi, Kusha, Foster, Kyle, Knighton, Latora, Lipsich, Leah, Darling, Lindsay, Boersma, Lisa, Cowen, Lisa, Hersh, Lisa, Jackson, Lisa, Purcell, Lisa, Sherpinsky, Lisa, Lai, Livia, Faria, Lori, Geissler, Lori, Boppert, Louise, Fiske, Lyra, Dickens, Marc, Mancini, Marco, Leigh, Maria C., O'Brien, Meagan P., Batchelder, Michael, Klinger, Michael, Partridge, Michael, Tarabocchia, Michel, Wong, Michelle, Rodriguez, Mivianisse, Albizem, Moetaz, O'Byrne, Muriel, Braunstein, Ned, Sarkar, Neena, Stahl, Neil, Deitz, Nicole, Memblatt, Nicole, Shah, Nirav, Kumar, Nitin, Herrera, Olga, Adedoyin, Oluchi, Yellin, Ori, Snodgrass, Pamela, Floody, Patrick, D'Ambrosio, Paul, Gao, Paul (Xiaobang), Hou, Peijie, Hearld, Philippa, Li, Qin, Kitchenoff, Rachel, Ali, Rakiyya, Iyer, Ramya, Chava, Ravikanth, Alaj, Rinol, Pedraza, Rita, Hamlin, Robert, Hosain, Romana, Gorawala, Ruchin, White, Ryan, Yu, Ryan, Fogarty, Rylee, Dass, S. Balachandra, Bollini, Sagarika, Ganguly, Samit, DeCicco, Sandra, Patel, Sanket, Cassimaty, Sarah, Somersan-Karakaya, Selin, McCarthy, Shane, Henkel, Sharon, Ali, Shazia, Geila Shapiro, Shelley, Kim, Somang, Nossoughi, Soraya, Bisulco, Stephanie, Elkin, Steven, Long, Steven, Sivapalasingam, Sumathi, Irvin, Susan, Wilt, Susan, Min, Tami, Constant, Tatiana, Devins, Theresa, DiCioccio, Thomas, Norton, Thomas, Bernardo, Travis, Chuang, Tzu-Chien, Wei, Victor (Jianguo), Nuce, Vinh, Battini, Vishnu, Caldwell, Wilson, Gao, Xiaobang, Chen, Xin, Tian, Yanmei, Khan, Yasmin, Zhao, Yuming, Kim, Yunji, Dye, Bonnie, Hurt, Christopher B., Burwen, Dale R., Barouch, Dan H., Burns, David, Brown, Elizabeth, Bar, Katharine J., Marovich, Mary, Clement, Meredith, Cohen, Myron S., Sista, Nirupama, Barnabas, Ruanne V., Zwerski, Sheryl, Herman, Gary A, O'Brien, Meagan P, Chan, Kuo-Chen, Bar, Katharine J, Barnabas, Ruanne V, Barouch, Dan H, Cohen, Myron S, Hurt, Christopher B, Burwen, Dale R, Marovich, Mary A, Musser, Bret J, Davis, John D, Turner, Kenneth C, Hooper, Andrea T, Hamilton, Jennifer D, Subramaniam, Danise, Kyratsous, Christos A, DiCioccio, A Thomas, Yancopoulos, George D, and Weinreich, David M

Published
2022
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4. Repeat subcutaneous administration of casirivimab and imdevimab in adults is well-tolerated and prevents the occurrence of COVID-19

Author

Isa, Flonza, Forleo-Neto, Eduardo, Meyer, Jonathan, Zheng, Wenjun, Rasmussen, Scott, Armas, Danielle, Oshita, Masaru, Brinson, Cynthia, Folkerth, Steven, Faria, Lori, Heirman, Ingeborg, Sarkar, Neena, Musser, Bret J., Bansal, Shikha, O'Brien, Meagan P., Turner, Kenneth C., Ganguly, Samit, Mahmood, Adnan, Dupljak, Ajla, Hooper, Andrea T., Hamilton, Jennifer D., Kim, Yunji, Kowal, Bari, Soo, Yuhwen, Geba, Gregory P., Lipsich, Leah, Braunstein, Ned, Yancopoulos, George D., Weinreich, David M., and Herman, Gary A.

Published
2022
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7. A Randomized Placebo Controlled Trial of Aspirin Effects on Immune Activation in Chronically Human Immunodeficiency Virus-Infected Adults on Virologically Suppressive Antiretroviral Therapy.

Author

O'Brien, Meagan P, Hunt, Peter W, Kitch, Douglas W, Klingman, Karin, Stein, James H, Funderburg, Nicholas T, Berger, Jeffrey S, Tebas, Pablo, Clagett, Brian, Moisi, Daniela, Utay, Netanya S, Aweeka, Fran, and Aberg, Judith A

Subjects
CD14, HIV, aspirin, platelets
Abstract

BackgroundImmune activation persists despite suppressive antiretroviral therapy (ART) in human immunodeficiency virus (HIV) infection and predicts non-Acquired Immune Deficiency Syndrome (AIDS) comorbidities including cardiovascular disease. Activated platelets play a key role in atherothrombosis and inflammation, and platelets are hyperactivated in chronic HIV infection. Aspirin is a potent inhibitor of platelet activation through the cyclooxygenase-1 (COX-1) pathway. We hypothesized that platelet activation contributes to immune activation and that aspirin would reduce immune activation and improve endothelial function in ART-suppressed HIV-infected individuals.MethodsIn this prospective, double-blind, randomized, placebo-controlled 3-arm trial of 121 HIV-infected participants on suppressive ART for >48 weeks, we evaluated the effects of 12 weeks of daily aspirin 100 mg, aspirin 300 mg, or placebo on soluble and cellular immune activation markers, flow-mediated dilation (FMD) of the brachial artery, and serum thromboxane B2, a direct readout of platelet COX-1 inhibition.ResultsThe 300-mg and 100-mg aspirin arms did not differ from placebo in effects on soluble CD14, interleukin (IL)-6, soluble CD163, D-dimer, T-cell or monocyte activation, or the other immunologic endpoints measured. Endothelial function, as measured by FMD, also was not significantly changed when comparing the 300-mg and 100-mg aspirin arms to placebo.ConclusionsAspirin treatment for 12 weeks does not have a major impact on soluble CD14, IL-6, soluble CD163, D-dimer, T-cell or monocyte activation, or FMD, suggesting that inhibition of COX-1-mediated platelet activation does not significantly improve HIV-related immune activation and endothelial dysfunction. Although future studies are needed to further identify the causes and consequences of platelet activation in ART-treated HIV infection, interventions other than COX-1 inhibition will need to be explored to directly reduce immune activation in treated HIV infection.

Published
2017

8. Nasopharyngeal Viral Load Is the Major Driver of Incident Antibody Immune Response to SARS-CoV-2 Infection

Author

Xu, Meng, primary, O’Brien, Meagan P, additional, Hooper, Andrea T, additional, Forleo-Neto, Eduardo, additional, Isa, Flonza, additional, Hou, Peijie, additional, Chan, Kuo-Chen, additional, Cohen, Myron S, additional, Marovich, Mary A, additional, Hamilton, Jennifer D, additional, Hirshberg, Boaz, additional, Herman, Gary A, additional, and Musser, Bret J, additional

Published
2023
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9. Differential modulation of allergic rhinitis nasal transcriptome by dupilumab and allergy immunotherapy.

Author

Wipperman, Matthew F., Gayvert, Kaitlyn M., Atanasio, Amanda, Wang, Claire Q., Corren, Jonathan, Covarrubias, Angelica, Setliff, Ian, Chio, Erica, Laws, Elizabeth, Wolfe, Kelley, Harel, Sivan, Maloney, Jennifer, Herman, Gary, Orengo, Jamie M., Lim, Wei Keat, Hamon, Sara C., Hamilton, Jennifer D., and O'Brien, Meagan P.

Subjects
ALLERGIC rhinitis, DUPILUMAB, TRANSCRIPTOMES, IMMUNOTHERAPY, INFLAMMATORY mediators
Abstract

Background: Nasal epithelial cells are important regulators of barrier function and immune signaling; however, in allergic rhinitis (AR) these functions can be disrupted by inflammatory mediators. We aimed to better discern AR disease mechanisms using transcriptome data from nasal brushing samples from individuals with and without AR. Methods: Data were drawn from a feasibility study of individuals with and without AR to Timothy grass and from a clinical trial evaluating 16 weeks of treatment with the following: dupilumab, a monoclonal antibody that binds interleukin (IL)‐4Rα and inhibits type 2 inflammation by blocking signaling of both IL‐4/IL‐13; subcutaneous immunotherapy with Timothy grass (SCIT), which inhibits allergic responses through pleiotropic effects; SCIT + dupilumab; or placebo. Using nasal brushing samples from these studies, we defined distinct gene signatures in nasal tissue of AR disease and after nasal allergen challenge (NAC) and assessed how these signatures were modulated by study drug(s). Results: Treatment with dupilumab (normalized enrichment score [NES] = −1.73, p =.002) or SCIT + dupilumab (NES = −2.55, p <.001), but not SCIT alone (NES = +1.16, p =.107), significantly repressed the AR disease signature. Dupilumab (NES = −2.55, p <.001), SCIT (NES = −2.99, p <.001), and SCIT + dupilumab (NES = −3.15, p <.001) all repressed the NAC gene signature. Conclusion: These results demonstrate type 2 inflammation is an important contributor to the pathophysiology of AR disease and that inhibition of the type 2 pathway with dupilumab may normalize nasal tissue gene expression. [ABSTRACT FROM AUTHOR]

Published
2024
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11. Examining protective effects of SARS-CoV-2 neutralizing antibodies after vaccination or monoclonal antibody administration

Author

Follmann, Dean, primary, O’Brien, Meagan P., additional, Fintzi, Jonathan, additional, Fay, Michael P., additional, Montefiori, David, additional, Mateja, Allyson, additional, Herman, Gary A., additional, Hooper, Andrea T., additional, Turner, Kenneth C., additional, Chan, Kuo- Chen, additional, Forleo-Neto, Eduardo, additional, Isa, Flonza, additional, Baden, Lindsey R., additional, El Sahly, Hana M., additional, Janes, Holly, additional, Doria-Rose, Nicole, additional, Miller, Jacqueline, additional, Zhou, Honghong, additional, Dang, Weiping, additional, Benkeser, David, additional, Fong, Youyi, additional, Gilbert, Peter B., additional, Marovich, Mary, additional, and Cohen, Myron S., additional

Published
2023
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13. Effectiveness of Casirivimab and Imdevimab Antibody Combination in Immunocompromised Hospitalized Patients with COVID-19: A Post-Hoc Analysis in a Phase 1/2/3 Double-Blind Trial

Author

Somersan-Karakaya, Selin, primary, Mylonakis, Eleftherios, additional, Mou, Jenni, additional, Oviedo-Orta, Ernesto, additional, O’Brien, Meagan P, additional, Casullo, Veronica Mas, additional, Mahmood, Adnan, additional, Hooper, Andrea T, additional, Hussein, Mohamed, additional, Ali, Shazia, additional, Marty, Francisco M, additional, Forleo-Neto, Eduardo, additional, Bhore, Rafia, additional, Hamilton, Jennifer D, additional, Herman, Gary A, additional, Hirshberg, Boaz, additional, and Weinreich, David M, additional

Published
2023
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15. Efficacy and safety of a single dose of casirivimab and imdevimab for the prevention of COVID-19 over an 8-month period: a randomised, double-blind, placebo-controlled trial

Author

Herman, Gary A, primary, O'Brien, Meagan P, additional, Forleo-Neto, Eduardo, additional, Sarkar, Neena, additional, Isa, Flonza, additional, Hou, Peijie, additional, Chan, Kuo-Chen, additional, Bar, Katharine J, additional, Barnabas, Ruanne V, additional, Barouch, Dan H, additional, Cohen, Myron S, additional, Hurt, Christopher B, additional, Burwen, Dale R, additional, Marovich, Mary A, additional, Musser, Bret J, additional, Davis, John D, additional, Turner, Kenneth C, additional, Mahmood, Adnan, additional, Hooper, Andrea T, additional, Hamilton, Jennifer D, additional, Parrino, Janie, additional, Subramaniam, Danise, additional, Baum, Alina, additional, Kyratsous, Christos A, additional, DiCioccio, A Thomas, additional, Stahl, Neil, additional, Braunstein, Ned, additional, Yancopoulos, George D, additional, Weinreich, David M, additional, Chani, Achint, additional, Adepoju, Adebiyi, additional, Mortagy, Aisha, additional, Dupljak, Ajla, additional, Brown, Alison, additional, Froment, Amy, additional, Hooper, Andrea, additional, Margiotta, Andrea, additional, Bombardier, Andrew, additional, Islam, Anita, additional, Smith, Anne, additional, Dhillon, Arvinder, additional, McMillian, Audra, additional, Breazna, Aurora, additional, Aslam, Ayesha, additional, Carpentino, Barabara, additional, Kowal, Bari, additional, Siliverstein, Barry, additional, Horel, Benjamin, additional, Zhu, Bo, additional, Musser, Bret, additional, Bush, Brian, additional, Head, Brian, additional, Snow, Brian, additional, Zhu, Bryan, additional, Debray, Camille, additional, Phillips, Careta, additional, Simiele, Carmella, additional, Lee, Carol, additional, Nienstedt, Carolyn, additional, Trbovic, Caryn, additional, Chan, Casey (Kuo-Chen), additional, Elliott, Catherine, additional, Fish, Chad, additional, Ni, Charlie, additional, Polidori, Christa, additional, Enciso, Christine, additional, Caira, Christopher, additional, Powell, Christopher, additional, Kyratsous, Christos A., additional, Baum, Cliff, additional, McDonald, Colin, additional, Leigh, Cynthia, additional, Pan, Cynthia, additional, Wolken, Dana, additional, Manganello, Danielle, additional, Liu, David, additional, Stein, David, additional, Weinreich, David M., additional, Hassan, Dawlat, additional, Gulabani, Daya, additional, Fix, Deborah, additional, Leonard, Deborah, additional, Sarda, Deepshree, additional, Bonhomme, Denise, additional, Kennedy, Denise, additional, Darcy, Devin, additional, Barron, Dhanalakshmi, additional, Hughes, Diana, additional, Rofail, Diana, additional, Kaur, Dipinder, additional, Ramesh, Divya, additional, Bianco, Dona, additional, Cohen, Donna, additional, Jean-Baptiste, Edward, additional, Bukhari, Ehsan, additional, Doyle, Eileen, additional, Bucknam, Elizabeth, additional, Labriola-Tomkins, Emily, additional, Nanna, Emily, additional, Huffman O'Keefe, Esther, additional, Gasparino, Evelyn, additional, Fung, Evonne, additional, To, Fung-Yee, additional, Herman, Gary, additional, Yancopoulos, George D., additional, Bellingham, Georgia, additional, Sumner, Giane, additional, Moggan, Grainne, additional, Power, Grainne, additional, Zeng, Haixia, additional, Mariveles, Hazel, additional, Gonzalez, Heath, additional, Kang, Helen, additional, Noor, Hibo, additional, Minns, Ian, additional, Heirman, Ingeborg, additional, Peszek, Izabella, additional, Donohue, James, additional, Rusconi, Jamie, additional, Austin, Janice, additional, Yo, Jeannie, additional, McDonnell, Jenna, additional, Hamilton, Jennifer D., additional, Boarder, Jessica, additional, Wei, Jianguo, additional, Yu, Jingchun, additional, Malia, Joanne, additional, Tucciarone, Joanne, additional, Tyler-Gale, Jodie, additional, Davis, John D., additional, Strein, John, additional, Cohen, Jonathan, additional, Meyer, Jonathan, additional, Ursino, Jordan, additional, Im, Joseph, additional, Tramaglini, Joseph, additional, Wolken, Joseph, additional, Potter, Kaitlyn, additional, Scacalossi, Kaitlyn, additional, Naidu, Kamala, additional, Browning, Karen, additional, Rutkowski, Karen, additional, Yau, Karen, additional, Woloshin, Katherine, additional, Lewis-Amezcua, Kelly, additional, Turner, Kenneth, additional, Dornheim, Kimberly, additional, Chiu, Kit, additional, Mohan, Kosalai, additional, McGuire, Kristina, additional, Macci, Kristy, additional, Ringleben, Kurt, additional, Mohammadi, Kusha, additional, Foster, Kyle, additional, Knighton, Latora, additional, Lipsich, Leah, additional, Darling, Lindsay, additional, Boersma, Lisa, additional, Cowen, Lisa, additional, Hersh, Lisa, additional, Jackson, Lisa, additional, Purcell, Lisa, additional, Sherpinsky, Lisa, additional, Lai, Livia, additional, Faria, Lori, additional, Geissler, Lori, additional, Boppert, Louise, additional, Fiske, Lyra, additional, Dickens, Marc, additional, Mancini, Marco, additional, Leigh, Maria C., additional, O'Brien, Meagan P., additional, Batchelder, Michael, additional, Klinger, Michael, additional, Partridge, Michael, additional, Tarabocchia, Michel, additional, Wong, Michelle, additional, Rodriguez, Mivianisse, additional, Albizem, Moetaz, additional, O'Byrne, Muriel, additional, Deitz, Nicole, additional, Memblatt, Nicole, additional, Shah, Nirav, additional, Kumar, Nitin, additional, Herrera, Olga, additional, Adedoyin, Oluchi, additional, Yellin, Ori, additional, Snodgrass, Pamela, additional, Floody, Patrick, additional, D'Ambrosio, Paul, additional, Gao, Paul (Xiaobang), additional, Hearld, Philippa, additional, Li, Qin, additional, Kitchenoff, Rachel, additional, Ali, Rakiyya, additional, Iyer, Ramya, additional, Chava, Ravikanth, additional, Alaj, Rinol, additional, Pedraza, Rita, additional, Hamlin, Robert, additional, Hosain, Romana, additional, Gorawala, Ruchin, additional, White, Ryan, additional, Yu, Ryan, additional, Fogarty, Rylee, additional, Dass, S. Balachandra, additional, Bollini, Sagarika, additional, Ganguly, Samit, additional, DeCicco, Sandra, additional, Patel, Sanket, additional, Cassimaty, Sarah, additional, Somersan-Karakaya, Selin, additional, McCarthy, Shane, additional, Henkel, Sharon, additional, Ali, Shazia, additional, Geila Shapiro, Shelley, additional, Kim, Somang, additional, Nossoughi, Soraya, additional, Bisulco, Stephanie, additional, Elkin, Steven, additional, Long, Steven, additional, Sivapalasingam, Sumathi, additional, Irvin, Susan, additional, Wilt, Susan, additional, Min, Tami, additional, Constant, Tatiana, additional, Devins, Theresa, additional, DiCioccio, Thomas, additional, Norton, Thomas, additional, Bernardo, Travis, additional, Chuang, Tzu-Chien, additional, Wei, Victor (Jianguo), additional, Nuce, Vinh, additional, Battini, Vishnu, additional, Caldwell, Wilson, additional, Gao, Xiaobang, additional, Chen, Xin, additional, Tian, Yanmei, additional, Khan, Yasmin, additional, Zhao, Yuming, additional, Kim, Yunji, additional, Dye, Bonnie, additional, Hurt, Christopher B., additional, Burwen, Dale R., additional, Barouch, Dan H., additional, Burns, David, additional, Brown, Elizabeth, additional, Bar, Katharine J., additional, Marovich, Mary, additional, Clement, Meredith, additional, Cohen, Myron S., additional, Sista, Nirupama, additional, Barnabas, Ruanne V., additional, and Zwerski, Sheryl, additional

Published
2022
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16. REGN1908/1909 prevented cat allergen–induced early asthmatic responses in an environmental exposure unit

Author

de Blay, Frederic J., primary, Gherasim, Alina, additional, Domis, Nathalie, additional, Meier, Pretty, additional, Shawki, Furat, additional, Wang, Claire Q., additional, Orengo, Jamie M., additional, DeVeaux, Michelle, additional, Ramesh, Divya, additional, Jalbert, Jessica J., additional, Kamal, Mohamed A., additional, Abdallah, Hisham, additional, Dingman, Robert, additional, Perlee, Lorah, additional, Weinreich, David.M., additional, Herman, Gary, additional, Yancopoulos, George D., additional, and O’Brien, Meagan P., additional

Published
2022
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17. 1079. Casirivimab and Imdevimab (CAS + IMD) Antibody Combination for the Treatment of Immunocomprised Hospitalized Patients with COVID-19

Author

Somersan-Karakaya, Selin, primary, Mylonakis, Eleftherios, additional, Oviedo-Orta, Ernesto, additional, O’Brien, Meagan P, additional, Casullo, Veronica Mas, additional, Mou, Jenni, additional, Xiao, Jing, additional, Bhore, Rafia, additional, Mahmood, Adnan, additional, Hooper, Andrea T, additional, Hussein, Mohamed, additional, Ali, Shazia, additional, Forleo-Neto, Eduardo, additional, Herman, Gary A, additional, Hirshberg, Boaz, additional, and Weinreich, David M, additional

Published
2022
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18. Assessing the Combined Public Health Impact of Pharmaceutical Interventions on Pandemic Transmission and Mortality: An Example in SARS CoV ‐2

Author

Kamal, Mohamed A., primary, Kuznik, Andreas, additional, Qi, Luyuan, additional, Więcek, Witold, additional, Hussein, Mohamed, additional, Hassan, Hazem E., additional, Patel, Kashyap, additional, Obadia, Thomas, additional, Toroghi, Masood Khaksar, additional, Conrado, Daniela J., additional, Al‐Huniti, Nidal, additional, Casciano, Roman, additional, O'Brien, Meagan P., additional, Barnabas, Ruanne V., additional, Cohen, Myron S., additional, and Smith, Patrick F., additional

Published
2022
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20. Effectiveness of Casirivimab and Imdevimab Antibody Combination in Immunocompromised Hospitalized Patients With Coronavirus Disease 2019: A Post Hoc Analysis in a Phase 1/2/3 Double–Blind Trial.

Author

Somersan-Karakaya, Selin, Mylonakis, Eleftherios, Mou, Jenni, Oviedo-Orta, Ernesto, O'Brien, Meagan P, Casullo, Veronica Mas, Mahmood, Adnan, Hooper, Andrea T, Hussein, Mohamed, Ali, Shazia, Marty, Francisco M, Forleo-Neto, Eduardo, Bhore, Rafia, Hamilton, Jennifer D, Herman, Gary A, Hirshberg, Boaz, and Weinreich, David M

Abstract

Background Individuals who are immunocompromised (IC) are at high risk for severe coronavirus disease 2019 (COVID-19). Methods Post hoc analyses of a double-blind trial conducted prior to Omicron (June 2020–April 2021), in hospitalized patients with COVID-19 assessed viral load, clinical outcomes, and safety of casirivimab plus imdevimab (CAS + IMD) versus placebo in IC versus overall study patients. Results Ninety-nine of 1940 (5.1%) patients were IC. IC versus overall patients were more frequently seronegative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies (68.7% vs 41.2%) and had higher median baseline viral loads (7.21 vs 6.32 log10 copies/mL). On placebo, IC versus overall patients had slower viral load declines. CAS + IMD reduced viral load in IC and overall patients; least-squares mean difference versus placebo in time-weighted average change from baseline viral load at day 7 was −0.69 (95% confidence interval [CI], −1.25 to −.14) log10 copies/mL for IC patients and −0.31 (95% CI, −.42 to −.20) log10 copies/mL for overall patients. For IC patients, the cumulative incidence of death or mechanical ventilation at day 29 was lower with CAS + IMD (11.0%) versus placebo (17.2%), consistent with overall patients (15.7% CAS + IMD vs 18.3% placebo). IC and overall patients receiving CAS + IMD exhibited similar rates of treatment-emergent adverse events (30.4% and 26.6%, respectively), grade ≥2 hypersensitivity or infusion-related reactions (1.4% and 2.5%), and deaths (8.7% and 12.2%). Conclusions IC patients were more likely to exhibit high viral loads and be seronegative at baseline. For susceptible SARS-CoV-2 variants, CAS + IMD reduced viral load and resulted in fewer death or mechanical ventilation events in IC and overall study patients. There were no new safety findings among IC patients. Clinical Trials Registration. NCT04426695. [ABSTRACT FROM AUTHOR]

Published
2023
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21. Efficacy and Safety of Sarilumab in Hospitalized Patients With Coronavirus Disease 2019: A Randomized Clinical Trial

Author

Sivapalasingam, Sumathi, primary, Lederer, David J, additional, Bhore, Rafia, additional, Hajizadeh, Negin, additional, Criner, Gerard, additional, Hosain, Romana, additional, Mahmood, Adnan, additional, Giannelou, Angeliki, additional, Somersan-Karakaya, Selin, additional, O’Brien, Meagan P, additional, Boyapati, Anita, additional, Parrino, Janie, additional, Musser, Bret J, additional, Labriola-Tompkins, Emily, additional, Ramesh, Divya, additional, Purcell, Lisa A, additional, Gulabani, Daya, additional, Kampman, Wendy, additional, Waldron, Alpana, additional, Ng Gong, Michelle, additional, Saggar, Suraj, additional, Sperber, Steven J, additional, Menon, Vidya, additional, Stein, David K, additional, Sobieszczyk, Magdalena E, additional, Park, William, additional, Aberg, Judith A, additional, Brown, Samuel M, additional, Kosmicki, Jack A, additional, Horowitz, Julie E, additional, Ferreira, Manuel A, additional, Baras, Aris, additional, Kowal, Bari, additional, Thomas DiCioccio, A, additional, Akinlade, Bolanle, additional, Nivens, Michael C, additional, Braunstein, Ned, additional, Herman, Gary A, additional, Yancopoulos, George D, additional, and Weinreich, David M, additional

Published
2022
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23. Novel antibody cocktail targeting Bet v 1 rapidly and sustainably treats birch allergy symptoms in a phase 1 study

Author

Gevaert, Philippe, primary, De Craemer, Jarno, additional, De Ruyck, Natalie, additional, Rottey, Sylvie, additional, de Hoon, Jan, additional, Hellings, Peter W., additional, Volckaert, Bram, additional, Lesneuck, Kristof, additional, Orengo, Jamie M., additional, Atanasio, Amanda, additional, Kamal, Mohamed A., additional, Abdallah, Hisham, additional, Kamat, Vishal, additional, Dingman, Robert, additional, DeVeaux, Michelle, additional, Ramesh, Divya, additional, Perlee, Lorah, additional, Wang, Claire Q., additional, Weinreich, David M., additional, Herman, Gary, additional, Yancopoulos, George D., additional, and O’Brien, Meagan P., additional

Published
2022
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24. Cat allergen exposure in a naturalistic exposure chamber: a prospective observational study in cat‐allergic subjects

Author

Yang, William H., primary, Kelly, Suzanne, additional, Haya, Laura, additional, Mehri, Rym, additional, Ramesh, Divya, additional, DeVeaux, Michelle, additional, Wang, Claire Q., additional, Meier, Pretty, additional, Narula, Sumit, additional, Shawki, Furat, additional, Pennington, Ryan, additional, Perlee, Lorah, additional, and O’Brien, Meagan P., additional

Published
2021
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25. COVID-19 prevention with subcutaneous administration of the monoclonal antibodies casirivimab and imdevimab: Subgroup analysis in participants with cardiovascular disease and diabetes

Author

O'Brien, Meagan P., primary, Forleo-Neto, Eduardo, additional, Musser, Bret J., additional, Isa, Flonza, additional, Chan, Kuo-Chen, additional, Sarkar, Neena, additional, Bar, Katharine J., additional, Barnabas, Ruanne V., additional, Barouch, Dan H., additional, Cohen, Myron S., additional, Marovich, Mary A., additional, Hou, Peijie, additional, Heirman, Ingeborg, additional, Davis, John D., additional, Turner, Kenneth C., additional, Ramesh, Divya, additional, Mahmood, Adnan, additional, Purcell, Lisa, additional, Hooper, Andrea T., additional, Hamilton, Jennifer D., additional, Kim, Yunji, additional, Baum, Alina, additional, Kyratsous, Christos A., additional, Krainson, James, additional, Perez-Perez, Richard, additional, Mohseni, Rizwana, additional, Kowal, Bari, additional, DiCioccio, A. Thomas, additional, Stahl, Neil, additional, Lipsich, Leah, additional, Braunstein, Ned, additional, Herman, Gary, additional, Yancopoulos, George D., additional, and Weinreich, David M., additional

Published
2021
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26. Monoclonal Antibodies to Reduce SARS CoV-2 Transmission and Mortality

Author

Kamal, Mohamed, Kuznik, Andreas, Qi, Luyuan, Wiecek, Witold, Hussein, Mohamed, Hassan, Hazem E, Patel, Kashyap, Obadia, Thomas, Khaksar Toroghi, Masood, Conrado, Daniela J, Al-Huniti, Nidal, Casciano, Roman, O'Brien, Meagan P, Barnabas, Ruanne V, Cohen, Myron S, and Smith, Patrick F

Subjects
SARS-CoV-2, vaccine, viral transmission, post-exposure prophylaxis, COVID-19, monoclonal antibodies, treatment as prevention, agent-based model
Abstract

To evaluate the role of anti-viral monoclonal antibodies (mAbs) in reducing SARS-CoV-2 transmission and mortality, an agent-based model was developed that accounted for social contacts, movement/travel, disease progression, and viral shedding. The model was calibrated to mortality from October 2020 and April 2021 (aggressive pandemic phase). The model also projected an extended outlook to estimate mortality during a less aggressive phase (April to August 2021). Simulated scenarios evaluated mAbs for averting infections and deaths on top of vaccine and aggregated non-pharmaceutical interventions. mAbs were used as active treatment and as passive immunity for post-exposure prophylaxis (PEP). Rapid diagnostic testing paired with mAbs was evaluated as early Treatment-as-Prevention strategy. Sensitivity analyses determined impact of increasing mAb supply and vaccine rollout. Allocation of mAbs as PEP or targeting those ≥65 years provided the greatest incremental benefits, averting up to 17% and 41% more infections and deaths, respectively, than vaccine alone. Rapid testing for earlier diagnosis and mAb use amplified these benefits. The model was sensitive to mAb supply; doubling supply further reduced infections and mortality. mAbs continued to provide incremental benefits even as the proportion of the vaccinated population increased. Model projections estimated that ~42% of the expected deaths between April and August 2021 could be averted. Use of mAbs as early treatment and PEP on top of a vaccination program would substantially reduce SARS-CoV-2 transmission and mortality even as vaccination increases and overall mortality decreases. These results provide a template for informing public health policy for current and future pandemic preparedness.

Published
2021
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27. Subcutaneous REGEN-COV Antibody Combination in Early SARS-CoV-2 Infection

Author

O’Brien, Meagan P., Forleo-Neto, Eduardo, Sarkar, Neena, Isa, Flonza, Hou, Peijie, Chan, Kuo-Chen, Musser, Bret J., Bar, Katharine J., Barnabas, Ruanne V., Barouch, Dan H., Cohen, Myron S., Hurt, Christopher B., Burwen, Dale R., Marovich, Mary A., Heirman, Ingeborg, Davis, John D., Turner, Kenneth C., Ramesh, Divya, Mahmood, Adnan, Hooper, Andrea T., Hamilton, Jennifer D., Kim, Yunji, Purcell, Lisa A., Baum, Alina, Kyratsous, Christos A., Krainson, James, Perez-Perez, Richard, Mohseni, Rizwana, Kowal, Bari, DiCioccio, A. Thomas, Stahl, Neil, Lipsich, Leah, Braunstein, Ned, Herman, Gary, Yancopoulos, George D., and Weinreich, David M.

Subjects
Article
Abstract

Background: Casirivimab and imdevimab administered together (REGEN-COV™) markedly reduces the risk of hospitalization or death in high-risk, symptomatic individuals with COVID-19. Here, we report phase 3 results of early treatment of asymptomatic, SARS-CoV-2–positive adults and adolescents with subcutaneous REGEN-COV. Methods: Individuals ≥12 years of age were eligible if identified within 96 hours of a household contact being diagnosed as SARS-CoV-2-positive; 314 were randomized 1:1 to receive subcutaneous REGEN-COV 1200mg or placebo. The primary endpoint was the proportion of infected participants without evidence of prior immunity (i.e., SARS-CoV-2-RT-qPCR–positive/seronegative) who subsequently developed symptomatic Covid-19 during a 28-day efficacy assessment period. Results: Subcutaneous REGEN-COV 1200mg significantly prevented progression from asymptomatic to symptomatic disease compared with placebo (31.5% relative risk reduction; 29/100 [29.0%] vs. 44/104 [42.3%], respectively; P=0.0380). REGEN-COV also reduced the overall population burden of high viral load weeks (39.7% reduction vs. placebo; 48 vs. 82 total weeks; P=0.0010) and of symptomatic weeks (45.3% reduction vs. placebo; 89.6 vs. 170.3 total weeks; P=0.0273), the latter corresponding to an approximately 5.6-day reduction per symptomatic participant. Six placebo-treated participants had a Covid-19-related hospitalization or ER visit versus none for those receiving REGEN-COV. The proportion of participants receiving placebo who had ≥1 treatment-emergent adverse events was 48.1% compared to 33.5% for those receiving REGEN-COV, including Covid-19-related (39.7% vs. 25.8%, respectively) or non-Covid-19-related (16.0% vs. 11.0%, respectively) events. Conclusions: Subcutaneous REGEN-COV 1200mg prevented progression from asymptomatic to symptomatic infection, reduced the duration of high viral load and symptoms, and was well tolerated. (ClinicalTrials.gov number, NCT04452318.)

Published
2021

28. Anti-SARS-CoV-2 IgA Identifies Asymptomatic Infection in First Responders

Author

Montague, Brian T, primary, Wipperman, Matthew F, additional, Hooper, Andrea T, additional, Hamon, Sara C, additional, Crow, Rowena, additional, Elemo, Femi, additional, Hersh, Lisa, additional, Langdon, Shaun, additional, Hamilton, Jennifer D, additional, O’Brien, Meagan P, additional, and Simões, Eric A F, additional

Published
2021
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29. Subcutaneous REGEN-COV Antibody Combination to Prevent Covid-19

Author

O’Brien, Meagan P., primary, Forleo-Neto, Eduardo, additional, Musser, Bret J., additional, Isa, Flonza, additional, Chan, Kuo-Chen, additional, Sarkar, Neena, additional, Bar, Katharine J., additional, Barnabas, Ruanne V., additional, Barouch, Dan H., additional, Cohen, Myron S., additional, Hurt, Christopher B., additional, Burwen, Dale R., additional, Marovich, Mary A., additional, Hou, Peijie, additional, Heirman, Ingeborg, additional, Davis, John D., additional, Turner, Kenneth C., additional, Ramesh, Divya, additional, Mahmood, Adnan, additional, Hooper, Andrea T., additional, Hamilton, Jennifer D., additional, Kim, Yunji, additional, Purcell, Lisa A., additional, Baum, Alina, additional, Kyratsous, Christos A., additional, Krainson, James, additional, Perez-Perez, Richard, additional, Mohseni, Rizwana, additional, Kowal, Bari, additional, DiCioccio, A. Thomas, additional, Stahl, Neil, additional, Lipsich, Leah, additional, Braunstein, Ned, additional, Herman, Gary, additional, Yancopoulos, George D., additional, and Weinreich, David M., additional

Published
2021
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31. Short-Term Subcutaneous Allergy Immunotherapy and Dupilumab are Well Tolerated in Allergic Rhinitis: A Randomized Trial

Author

Corren, Jonathan, primary, Saini, Sarbjit S, additional, Gagnon, Remi, additional, Moss, Mark H, additional, Sussman, Gordon, additional, Jacobs, Joshua, additional, Laws, Elizabeth, additional, Chung, Elinore S, additional, Constant, Tatiana, additional, Sun, Yiping, additional, Maloney, Jennifer, additional, Hamilton, Jennifer D, additional, Ruddy, Marcella, additional, Wang, Claire Q, additional, and O’Brien, Meagan P, additional

Published
2021
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33. Monoclonal Antibody Treatment, Prophylaxis and Vaccines Combined to Reduce SARS CoV-2 Spread

Author

Kamal, Mohamed A., primary, Kuznik, Andreas, additional, Qi, Luyuan, additional, Więcek, Witold, additional, Hussein, Mohamed, additional, Hassan, Hazem E., additional, Patel, Kashyap, additional, Obadia, Thomas, additional, Toroghi, Masood Khaksar, additional, Conrado, Daniela J., additional, Al-Huniti, Nidal, additional, Casciano, Roman, additional, O’Brien, Meagan P., additional, Barnabas, Ruanne V., additional, Cohen, Myron S., additional, and Smith, Patrick F., additional

Published
2021
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34. Monoclonal antibodies against the spike protein alter the endogenous humoral response to SARS-CoV-2 vaccination and infection

Author

Petro, Christopher D., Hooper, Andrea T., Peace, Avery, Mohammadi, Kusha, Eagan, Will, Elbashir, Sayda M., DiPiazza, Anthony, Makrinos, Daniel, Pascal, Kristen, Bandawane, Pooja, Durand, Mauricio, Basu, Ranu, Coppi, Alida, Wang, Bei, Golubov, Jacquelynn, Asrat, Seblewongel, Ganguly, Samit, Koehler-Stec, Ellen-Marie, Wipperman, Matthew F., Ehrlich, George, Gonzalez Ortiz, Ana M., Isa, Flonza, Lewis, Mark G., Andersen, Hanne, Musser, Bret J., Torres, Marcela, Lee, Wen-Yi, Edwards, Darin, Skokos, Dimitris, Orengo, Jamie, Sleeman, Matthew, Norton, Thomas, O’Brien, Meagan, Forleo-Neto, Eduardo, Herman, Gary A., Hamilton, Jennifer D., Murphy, Andrew J., Kyratsous, Christos A., and Baum, Alina

Published
2024
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35. Anti-SARS-CoV-2 IgA Identifies Asymptomatic Infection in First Responders.

Author

Montague, Brian T, Wipperman, Matthew F, Hooper, Andrea T, Hamon, Sara C, Crow, Rowena, Elemo, Femi, Hersh, Lisa, Langdon, Shaun, Hamilton, Jennifer D, O'Brien, Meagan P, and Simões, Eric A F

Subjects
FIRST responders, FIRE fighters, SERODIAGNOSIS, EMERGENCY medical services, IMMUNE response, EMERGENCY medical personnel, IGA glomerulonephritis, INFECTION
Abstract

Background: Immunoglobulin A (IgA) is an important component of the early immune response to SARS-CoV-2. Prior serosurveys in high-risk groups employing IgG testing alone have provided discordant estimates. The potential added benefit of IgA in serosurveys has not been established.Methods: Longitudinal serosurvey of first responders (police, emergency medical service providers, fire fighters, and other staff) employing 3 serologic tests (anti-spike IgA, anti-spike IgG, and anti-nucleocapsid IgG) correlated with surveys assessing occupational and nonoccupational risk, exposure to COVID-19, and illnesses consistent with COVID-19.Results: Twelve percent of first responders in Colorado at baseline and 22% at follow-up were assessed as having SARS-CoV-2 infection. Five percent at baseline and 6% at follow-up were seropositive only for IgA. Among those IgA positive only at baseline, the majority (69%) had a positive antibody at follow-up; 45% of those infected at baseline and 33% at follow-up were asymptomatic. At all time points, the estimated cumulative incidence in our study was higher than that in the general population.Conclusions: First responders are at high risk of infection with SARS-CoV-2. IgA testing identified a significant portion of cases missed by IgG testing and its use as part of serologic surveys may improve retrospective identification of asymptomatic infection. [ABSTRACT FROM AUTHOR]

Published
2022
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36. Effect of Subcutaneous Casirivimab and Imdevimab Antibody Combination vs Placebo on Development of Symptomatic COVID-19 in Early Asymptomatic SARS-CoV-2 Infection: A Randomized Clinical Trial.

Author

O'Brien, Meagan P., Forleo-Neto, Eduardo, Sarkar, Neena, Isa, Flonza, Hou, Peijie, Chan, Kuo-Chen, Musser, Bret J., Bar, Katharine J., Barnabas, Ruanne V., Barouch, Dan H., Cohen, Myron S., Hurt, Christopher B., Burwen, Dale R., Marovich, Mary A., Brown, Elizabeth R., Heirman, Ingeborg, Davis, John D., Turner, Kenneth C., Ramesh, Divya, and Mahmood, Adnan

Abstract

Importance: Easy-to-administer anti-SARS-CoV-2 treatments may be used to prevent progression from asymptomatic infection to symptomatic disease and to reduce viral carriage.Objective: To evaluate the effect of combination subcutaneous casirivimab and imdevimab on progression from early asymptomatic SARS-CoV-2 infection to symptomatic COVID-19.Design, Setting, and Participants: Randomized, double-blind, placebo-controlled, phase 3 trial of close household contacts of a SARS-CoV-2-infected index case at 112 sites in the US, Romania, and Moldova enrolled July 13, 2020-January 28, 2021; follow-up ended March 11, 2021. Asymptomatic individuals (aged ≥12 years) were eligible if identified within 96 hours of index case positive test collection. Results from 314 individuals positive on SARS-CoV-2 reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) testing are reported.Interventions: Individuals were randomized 1:1 to receive 1 dose of subcutaneous casirivimab and imdevimab, 1200 mg (600 mg of each; n = 158), or placebo (n = 156).Main Outcomes and Measures: The primary end point was the proportion of seronegative participants who developed symptomatic COVID-19 during the 28-day efficacy assessment period. The key secondary efficacy end points were the number of weeks of symptomatic SARS-CoV-2 infection and the number of weeks of high viral load (>4 log10 copies/mL).Results: Among 314 randomized participants (mean age, 41.0 years; 51.6% women), 310 (99.7%) completed the efficacy assessment period; 204 were asymptomatic and seronegative at baseline and included in the primary efficacy analysis. Subcutaneous casirivimab and imdevimab, 1200 mg, significantly prevented progression to symptomatic disease (29/100 [29.0%] vs 44/104 [42.3%] with placebo; odds ratio, 0.54 [95% CI, 0.30-0.97]; P = .04; absolute risk difference, -13.3% [95% CI, -26.3% to -0.3%]). Casirivimab and imdevimab reduced the number of symptomatic weeks per 1000 participants (895.7 weeks vs 1637.4 weeks with placebo; P = .03), an approximately 5.6-day reduction in symptom duration per symptomatic participant. Treatment with casirivimab and imdevimab also reduced the number of high viral load weeks per 1000 participants (489.8 weeks vs 811.9 weeks with placebo; P = .001). The proportion of participants receiving casirivimab and imdevimab who had 1 or more treatment-emergent adverse event was 33.5% vs 48.1% for placebo, including events related (25.8% vs 39.7%) or not related (11.0% vs 16.0%) to COVID-19.Conclusions and Relevance: Among asymptomatic SARS-CoV-2 RT-qPCR-positive individuals living with an infected household contact, treatment with subcutaneous casirivimab and imdevimab antibody combination vs placebo significantly reduced the incidence of symptomatic COVID-19 over 28 days.Trial Registration: ClinicalTrials.gov Identifier: NCT04452318. [ABSTRACT FROM AUTHOR]

Published
2022
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37. Cat allergen exposure in a naturalistic exposure chamber: A prospective observational study in cat‐allergic subjects.

Author

Yang, William H., Kelly, Suzanne, Haya, Laura, Mehri, Rym, Ramesh, Divya, DeVeaux, Michelle, Wang, Claire Q., Meier, Pretty, Narula, Sumit, Shawki, Furat, Pennington, Ryan, Perlee, Lorah, and O'Brien, Meagan P.

Subjects
ALLERGENS, FORCED expiratory volume, LONGITUDINAL method, SCIENTIFIC observation, WHEEZE
Abstract

Background: To determine the proportion and reproducibility of cat‐allergic mild asthmatics with early asthmatic response (EAR) during cat allergen exposure in a naturalistic exposure chamber (NEC). Methods: This was a prospective, observational study in 30 cat‐allergic mild asthmatics who received two 180‐min cat‐allergen (Felis domesticus allergen 1 [Fel d 1]) challenges 27 days apart in an NEC. Results: An EAR (≥20% reduction from baseline in forced expiratory volume in 1 s [FEV1]) was observed in 67% and 52% of subjects at first and second NEC exposure, respectively, with similar median time to EAR; 44% of subjects had an EAR on days 1 and 28. Late asthmatic response (≥15% reduction in FEV1 within 24 h of NEC exit) was observed in 33% of subjects following either exposure. Average FEV1 and total nasal symptom score during NEC exposure were highly correlated within subjects between NEC exposures (r = 0.91, p < 0.0001; r = 0.73, p < 0.001), but total ocular symptom score was not. Time to EAR, but not average FEV1, was significantly associated with NEC Fel d 1 concentration, which was variable. There were no serious adverse events; 12/30 subjects experienced 20 adverse events (including asthma, 10%; headache, 10%). Conclusions: The NEC model demonstrates that average FEV1 change is highly reproducible and has a low correlation with cat allergen levels. However, time to EAR and incidence of EAR are less reproducible and are highly correlated with NEC allergen levels. Average FEV1, rather than incidence of EAR or time to EAR, could be considered as an endpoint for interventional trials testing cat‐specific anti‐allergy therapies using an NEC. [ABSTRACT FROM AUTHOR]

Published
2022
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38. Targeting thrombogenicity and inflammation in chronic HIV infection

Author

O’Brien, Meagan P., primary, Zafar, M. Urooj, additional, Rodriguez, Jose C., additional, Okoroafor, Ibeawuchi, additional, Heyison, Alex, additional, Cavanagh, Karen, additional, Rodriguez-Caprio, Gabriela, additional, Weinberg, Alan, additional, Escolar, Gines, additional, Aberg, Judith A., additional, and Badimon, Juan J., additional

Published
2019
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40. Attenuated Listeria monocytogenes Vectors Overcome Suppressive Plasma Factors During HIV Infection to Stimulate Myeloid Dendritic Cells to Promote Adaptive Immunity and Reactivation of Latent Virus.

Author

Miller, Elizabeth A., Spadaccia, Meredith R., Norton, Thomas, Demmler, Morgan, Gopal, Ramya, O'Brien, Meagan, Landau, Nathaniel, Dubensky, Thomas W., Lauer, Peter, Brockstedt, Dirk G., and Bhardwaj, Nina

Abstract

HIV-1 infection is characterized by myeloid dendritic cell (DC) dysfunction, which blunts the responsiveness to vaccine adjuvants. We previously showed that nonviral factors in HIV-seropositive plasma are partially responsible for mediating this immune suppression. In this study we investigated recombinant Listeria monocytogenes (Lm) vectors, which naturally infect and potently activate DCs from seronegative donors, as a means to overcome DC dysfunction associated with HIV infection. Monocyte-derived DCs were cocultured with plasma from HIV-infected donors (HIV-moDCs) to induce a dysregulated state and infected with an attenuated, nonreplicative vaccine strain of Lm expressing full length clade B consensus gag (KBMA Lm-gag). Lm infection stimulated cytokine secretion [interleukin (IL)-12p70, tumor necrosis factor (TNF)-α, and IL-6] and Th-1 skewing of allogeneic naive CD4 T cells by HIV-moDCs, in contrast to the suppressive effects observed by HIV plasma on moDCs on toll-like receptor ligand stimulation. Upon coculture of 'killed' but metabolically active (KBMA) Lm-gag-infected moDCs from HIV-infected donors with autologous cells, expansion of polyfunctional, gag-specific CD8+ T cells was observed. Reactivation of latent proviruses by moDCs following Lm infection was also observed in models of HIV latency in a TNF-α-dependent manner. These findings reveal the unique ability of Lm vectors to contend with dysregulation of HIV-moDCs, while simultaneously possessing the capacity to activate latent virus. Concurrent stimulation of innate and adaptive immunity and disruption of latency may be an approach to reduce the pool of latently infected cells during HIV infection. Further study of Lm vectors as part of therapeutic vaccination and eradication strategies may advance this evolving field. [ABSTRACT FROM AUTHOR]

Published
2015
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41. HIV Type 1 Infection of Plasmacytoid and Myeloid Dendritic Cells Is Restricted by High Levels of SAMHD1 and Cannot be Counteracted by Vpx.

Author

Bloch, Nicolin, O'Brien, Meagan, Norton, Thomas D., Polsky, Sylvie B., Bhardwaj, Nina, and Landau, Nathaniel R.

Abstract

Dendritic cells are professional antigen-presenting cells of the immune system and are major producers of type-I interferon. Their role in HIV-1 infection is not well understood. They express CD4 and CCR5 yet appear to be resistant to infection. In culture, infection of the cells with HIV-1 is inhibited by the host cell restriction factor SAMHD1. Lentiviruses such as HIV-2/SIVmac counteract the restriction by encoding Vpx, a virion-packaged accessory protein that induces the proteasomal degradation of SAMHD1. In this study we investigated SAMHD1-mediated restriction in the two major dendritic cell subsets: plasmacytoid dendritic cells (pDC) and myeloid dendritic cells (mDC). The cells were highly resistant to HIV-1 and expressed high levels of SAMHD1. SAMHD1 amino acid residue T592, a target of CDK1 phosphorylation, was unphosphorylated, corresponding to the antiviral form of the enzyme. The resistance to infection was not counteracted by Vpx and SAMHD1 was not degraded in these cells. Treatment of pDCs with a cocktail of antibodies that blocked type-I interferon signaling partially restored the ability of Vpx to induce SAMHD1 degradation and caused the cells to become partially permissive to infection. pDCs and mDCs responded to HIV-1 virions by inducing an innate immune response but did not appear to sense newly produced Gag protein. The findings suggest that in vivo, dendritic cells serve as sentinels to alert the immune system to the virus but do not themselves become infected by virtue of high levels of SAMHD1. [ABSTRACT FROM AUTHOR]

Published
2014
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44. Evidence of dysregulation of dendritic cells in primary HIV infection

Author

Sabado, Rachel Lubong, O'Brien, Meagan, Subedi, Abhignya, Qin, Li, Hu, Nan, Taylor, Elizabeth, Dibben, Oliver, Stacey, Andrea, Fellay, Jacques, Shianna, Kevin V., Siegal, Frederick, Shodell, Michael, Shah, Kokila, Larsson, Marie, Lifson, Jeffrey, Nadas, Arthur, Marmor, Michael, Hutt, Richard, Margolis, David, Garmon, Donald, Markowitz, Martin, Valentine, Fred, Borrow, Persephone, and Bhardwaj, Nina

Abstract

Myeloid and plasmacytoid dendritic cells (DCs) are important mediators of both innate and adaptive immunity against pathogens such as HIV. During the course of HIV infection, blood DC numbers fall substantially. In the present study, we sought to determine how early in HIV infection the reduction occurs and whether the remaining DC subsets maintain functional capacity. We find that both myeloid DC and plasmacytoid DC levels decline very early during acute HIV in-fection. Despite the initial reduction in numbers, those DCs that remain in circulation retain their function and are able to stimulate allogeneic T-cell responses, and up-regulate maturation markers plus produce cytokines/chemokines in response to stimulation with TLR7/8 agonists. Notably, DCs from HIV-infected subjects produced significantly higher levels of cytokines/chemokines in response to stimulation with TLR7/8 agonists than DCs from uninfected controls. Further examination of gene expression profiles indicated in vivo activation, either directly or indirectly, of DCs during HIV infection. Taken together, our data demonstrate that despite the reduction in circulating DC numbers, those that remain in the blood display hyperfunctionality and implicates a possible role for DCs in promoting chronic immune activation.

Published
2010
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47. Subcutaneous REGEN-COV Antibody Combination in Early Asymptomatic SARS-CoV-2 Infection: A Randomized Clinical Trial.

Author

O'Brien MP, Forleo-Neto E, Sarkar N, Isa F, Hou P, Chan KC, Musser BJ, Bar KJ, Barnabas RV, Barouch DH, Cohen MS, Hurt CB, Burwen DR, Marovich MA, Brown ER, Heirman I, Davis JD, Turner KC, Ramesh D, Mahmood A, Hooper AT, Hamilton JD, Kim Y, Purcell LA, Baum A, Kyratsous CA, Krainson J, Perez-Perez R, Mohseni R, Kowal B, DiCioccio AT, Stahl N, Lipsich L, Braunstein N, Herman G, Yancopoulos GD, and Weinreich DM

Abstract

Importance: Easy-to-administer antiviral treatments may be used to prevent progression from asymptomatic infection to COVID-19 and to reduce viral carriage., Objective: Evaluate the efficacy and safety of subcutaneous casirivimab and imdevimab antibody combination (REGEN-COV) to prevent progression from early asymptomatic SARS-CoV-2 infection to COVID-19., Design: Randomized, double-blind, placebo-controlled, phase 3 study that enrolled asymptomatic close contacts living with a SARS-CoV-2-infected household member (index case). Participants who were SARS-CoV-2 RT-qPCR-positive at baseline were included in the analysis reported here., Setting: Multicenter trial conducted at 112 sites in the United States, Romania, and Moldova., Participants: Asymptomatic individuals ≥12 years of age were eligible if identified within 96 hours of collection of the index case's positive SARS-CoV-2 test sample., Interventions: A total of 314 asymptomatic, SARS-CoV-2 RT-qPCR-positive individuals living with an infected household contact were randomized 1:1 to receive a single dose of subcutaneous REGEN-COV 1200mg (n=158) or placebo (n=156)., Main Outcomes and Measures: The primary endpoint was the proportion of participants who developed symptomatic COVID-19 during the 28-day efficacy assessment period. The key secondary efficacy endpoints were the number of weeks of symptomatic SARS-CoV-2 infection and the number of weeks of high viral load (>4 log 10 copies/mL). Safety was assessed in all treated participants., Results: Subcutaneous REGEN-COV 1200mg significantly prevented progression from asymptomatic to symptomatic disease compared with placebo (31.5% relative risk reduction; 29/100 [29.0%] vs 44/104 [42.3%], respectively; P =.0380). REGEN-COV reduced the overall population burden of high-viral load weeks (39.7% reduction vs placebo; 48 vs 82 total weeks; P =.0010) and of symptomatic weeks (45.3% reduction vs placebo; 89.6 vs 170.3 total weeks; P =.0273), the latter corresponding to an approximately 5.6-day reduction in symptom duration per symptomatic participant. Six placebo-treated participants had a COVID-19-related hospitalization or ER visit versus none for those receiving REGEN-COV. The proportion of participants receiving placebo who had ≥1 treatment-emergent adverse events was 48.1% compared with 33.5% for those receiving REGEN-COV, including events related (39.7% vs 25.8%, respectively) or not related (16.0% vs 11.0%, respectively) to COVID-19., Conclusions and Relevance: Subcutaneous REGEN-COV 1200mg prevented progression from asymptomatic SARS-CoV-2 infection to COVID-19, reduced the duration of high viral load and symptoms, and was well tolerated., Trial Registration: ClinicalTrials.gov Identifier, NCT04452318.

Published
2021
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48. Subcutaneous REGEN-COV Antibody Combination for Covid-19 Prevention.

Author

O'Brien MP, Forleo-Neto E, Musser BJ, Isa F, Chan KC, Sarkar N, Bar KJ, Barnabas RV, Barouch DH, Cohen MS, Hurt CB, Burwen DR, Marovich MA, Hou P, Heirman I, Davis JD, Turner KC, Ramesh D, Mahmood A, Hooper AT, Hamilton JD, Kim Y, Purcell LA, Baum A, Kyratsous CA, Krainson J, Perez-Perez R, Mohseni R, Kowal B, DiCioccio AT, Stahl N, Lipsich L, Braunstein N, Herman G, Yancopoulos GD, and Weinreich DM

Abstract

Background: Casirivimab and imdevimab (REGEN-COV™) markedly reduces risk of hospitalization or death in high-risk individuals with Covid-19. Here we explore the possibility that subcutaneous REGEN-COV prevents SARS-CoV-2 infection and subsequent Covid-19 in individuals at high risk of contracting SARS-CoV-2 by close exposure in a household with a documented SARS-CoV-2-infected individual., Methods: Individuals ≥12 years were enrolled within 96 hours of a household contact being diagnosed with SARS-CoV-2 and randomized 1:1 to receive 1200 mg REGEN-COV or placebo via subcutaneous injection. The primary efficacy endpoint was the proportion of participants without evidence of infection (SARS-CoV-2 RT-qPCR-negative) or prior immunity (seronegative) who subsequently developed symptomatic SARS-CoV-2 infection during a 28-day efficacy assessment period., Results: Subcutaneous REGEN-COV significantly prevented symptomatic SARS-CoV-2 infection compared with placebo (81.4% risk reduction; 11/753 [1.5%] vs. 59/752 [7.8%], respectively; P<0.0001), with 92.6% risk reduction after the first week (2/753 [0.3%] vs. 27/752 [3.6%], respectively). REGEN-COV also prevented overall infections, either symptomatic or asymptomatic (66.4% risk reduction). Among infected participants, the median time to resolution of symptoms was 2 weeks shorter with REGEN-COV vs. placebo (1.2 vs. 3.2 weeks, respectively), and the duration of time with high viral load (>10 4 copies/mL) was lower (0.4 vs. 1.3 weeks, respectively). REGEN-COV was generally well tolerated., Conclusions: Administration of subcutaneous REGEN-COV prevented symptomatic Covid-19 and asymptomatic SARS-CoV-2 infection in uninfected household contacts of infected individuals. Among individuals who became infected, REGEN-COV reduced the duration of symptomatic disease, decreased maximal viral load, and reduced the duration of detectable virus.(ClinicalTrials.gov number, NCT04452318.).

Published
2021
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49. Targeting thrombogenicity and inflammation in chronic HIV infection.

Author

O'Brien MP, Zafar MU, Rodriguez JC, Okoroafor I, Heyison A, Cavanagh K, Rodriguez-Caprio G, Weinberg A, Escolar G, Aberg JA, and Badimon JJ

Subjects
Adult, Antiretroviral Therapy, Highly Active methods, Biomarkers blood, Blood Platelets immunology, Blood Platelets virology, Coronary Thrombosis complications, Coronary Thrombosis immunology, Coronary Thrombosis virology, Cross-Sectional Studies, Female, Fibrin Fibrinogen Degradation Products genetics, Fibrin Fibrinogen Degradation Products immunology, Gene Expression, HIV Infections complications, HIV Infections immunology, HIV Infections virology, Humans, Immunity, Innate, Inflammation, Lipopolysaccharide Receptors genetics, Lipopolysaccharide Receptors immunology, Male, Middle Aged, Monocytes drug effects, Monocytes immunology, Monocytes virology, Platelet Aggregation drug effects, Receptors, Tumor Necrosis Factor, Type I genetics, Receptors, Tumor Necrosis Factor, Type I immunology, Receptors, Tumor Necrosis Factor, Type II genetics, Receptors, Tumor Necrosis Factor, Type II immunology, Anti-Inflammatory Agents therapeutic use, Aspirin therapeutic use, Blood Platelets drug effects, Clopidogrel therapeutic use, Coronary Thrombosis drug therapy, HIV Infections drug therapy, Platelet Aggregation Inhibitors therapeutic use
Abstract

Persons with HIV infection (PWH) have increased risk for cardiovascular disease (CVD), but the underlying mechanisms remain unclear. Coronary thrombosis is known to provoke myocardial infarctions, but whether PWH have elevated thrombotic propensity is unknown. We compared thrombogenicity of PWH on antiretroviral therapy versus matched controls using the Badimon chamber. Measures of inflammation, platelet reactivity, and innate immune activation were simultaneously performed. Enrolled PWH were then randomized to placebo, aspirin (81 mg), or clopidogrel (75 mg) for 24 weeks to assess treatment effects on study parameters. Thrombogenicity was significantly higher in PWH and correlated strongly with plasma levels of D-dimer, soluble TNF receptors 1 and 2, and circulating classical and nonclassical monocytes in PWH. Clopidogrel significantly reduced thrombogenicity and sCD14. Our data suggest that higher thrombogenicity, interacting with inflammatory and immune activation markers, contributes to the increased CVD risk observed in PWH. Clopidogrel exhibits an anti-inflammatory activity in addition to its antithrombotic effect in PWH.

Published
2019
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