Leaders in Pharmaceutical Business Intelligence (LPBI) Group

A growing body of evidence indicates sex differences in the clinical outcomes of coronavirus disease 2019 (COVID-19)^1–5. However, whether immune responses against SARS-CoV-2 differ between sexes, and whether such differences explain male susceptibility to COVID-19, is currently unknown. In this study, we examined sex differences in

• viral loads,
• SARS-CoV-2-specific antibody titers,
• plasma cytokines, as well as
• blood cell phenotyping in COVID-19 patients.

By focusing our analysis on patients with moderate disease who had not received immunomodulatory medications, our results revealed that

• male patients had higher plasma levels of innate immune cytokines such as IL-8 and IL-18 along with more robust induction of non-classical monocytes. In contrast,
• female patients mounted significantly more robust T cell activation than male patients during SARS-CoV-2 infection, which was sustained in old age.
• Importantly, we found that a poor T cell response negatively correlated with patients’ age and was associated with worse disease outcome in male patients, but not in female patients.
• Conversely, higher innate immune cytokines in female patients associated with worse disease progression, but not in male patients.
• These findings reveal a possible explanation underlying observed sex biases in COVID-19, and provide an important basis for the development of
• a sex-based approach to the treatment and care of men and women with COVID-19.

1. These authors contributed equally: Takehiro Takahashi, Mallory K. Ellingson, Patrick Wong, Benjamin Israelow, Carolina Lucas, Jon Klein, Julio Silva, Tianyang Mao.

Affiliations

1. Department of Immunobiology, Yale University School of Medicine, New Haven, CT, 06520, USA

   Takehiro Takahashi, Patrick Wong, Benjamin Israelow, Carolina Lucas, Jon Klein, Julio Silva, Tianyang Mao, Ji Eun Oh, Maria Tokuyama, Peiwen Lu, Arvind Venkataraman, Annsea Park, Feimei Liu, Eric Y. Wang, Molly L. Bucklin, Yiyun Cao, William Khoury-Hanold, Daniel Kim, Eriko Kudo, Melissa Linehan, Alice Lu-Culligan, Anjelica Martin, Tyler Rice, Eric Song, Nicole Sonnert, Yexin Yang, Aaron M. Ring & Akiko Iwasaki

2. Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, 06520, USA

   Mallory K. Ellingson, Arnau Casanovas-Massana, Anne L. Wyllie, Chantal B.F. Vogels, Rebecca Earnest, Sarah Lapidus, Isabel M. Ott, Adam J. Moore, Kristina Brower, Chaney Kalinich, M. Catherine Muenker, Isabel Ott, Mary Petrone, Annie Watkins, Elizabeth B. White, Nathan D. Grubaugh, Albert I. Ko & Saad B. Omer

3. Department of Medicine, Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT, 06520, USA

   Benjamin Israelow, Melissa Campbell, Rupak Datta, Subhasis Mohanty, Haowei Wang, Albert Shaw, John B. Fournier, Camila D. Odio, Shelli Farhadian & Saad B. Omer

4. Department of Biomedical Engineering, Yale School of Engineering & Applied Science, New Haven, CT, 06511, USA

   Feimei Liu

5. Boyer Center for Molecular Medicine, Department of Microbial Pathogenesis, Yale University, New Haven, CT, 06510, USA

   Amit Meir

6. Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, 06520, USA

   Jonathan Sun

7. Department of Ecology and Evolutionary Biology, Yale University, New Haven, CT, 06520, USA

   Isabel M. Ott

8. Department of Medicine, Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, CT, 06520, USA

   Giuseppe DeIuliis, Lokesh Sharma & Charles Dela Cruz

9. Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT, 06520, USA

   Wade L. Schulz

10. Center for Outcomes Research and Evaluation, Yale-New Haven Hospital, New Haven, CT, 06520, USA

    Wade L. Schulz

11. Yale Institute for Global Health, Yale University, New Haven, CT, 06520, USA

    Amyn A. Malik & Saad B. Omer

12. Yale School of Nursing, Yale University, Orange, CT, 06477, USA

    Saad B. Omer

13. Howard Hughes Medical Institute, Chevy Chase, MD, 20815, USA

    Akiko Iwasaki

14. Yale Center for Clinical Investigation, Yale University School of Medicine, New Haven, CT, 06520, USA

    Kelly Anastasio, Staci Cahill & Maxine Kuang

15. Department of Neurology, Yale University School of Medicine, New Haven, CT, 06520, USA

    Michael H. Askenase & Sofia Velazquez

16. Yale School of Medicine, New Haven, CT, 06520, USA

    Maria Batsu, Hannah Beatty, Santos Bermejo, Bertie Geng, Laura Glick, Ryan Handoko, Lynda Knaggs, Irene Matos, David McDonald, Maksym Minasyan, Nida Naushad, Allison Nelson, Jessica Nouws, Abeer Obaid, Hong-Jai Park, Xiaohua Peng, Harold Rahming, Kadi-Ann Rose, Lorenzo Sewanan, Denise Shepard, Erin Silva, Michael Simonov, Mikhail Smolgovsky, Yvette Strong, Codruta Todeasa, Jordan Valdez & Pavithra Vijayakumar

17. Department of Biochemistry and of Molecular Biology, Yale University School of Medicine, New Haven, CT, 06520, USA

    Sean Bickerton & Edward Courchaine

18. Yale Viral Hepatitis Program, Yale University School of Medicine, New Haven, CT, 06520, USA

    Joseph Lim

19. Equity Research and Innovation Center, Yale University, New Haven, CT, 06520, USA

    Marcella Nunez-Smith

20. Department of Molecular, Cellular and Developmental Biology, Yale University School of Medicine, New Haven, CT, 06520, USA

    Sarah Prophet

Consortia

Corresponding author

Correspondence to Akiko Iwasaki.