High titre neutralizing antibodies in response to SARS-CoV-2 infection require RBD-specific CD4 T cells that include proliferative memory cells
High titre neutralizing antibodies in response to SARS-CoV-2 infection require RBD-specific CD4 T cells that include proliferative memory cells
ABSTRACT Long-term immunity to SARS-CoV-2 infection, including neutralizing antibodies and T cell-mediated immunity, is required in a very large majority of the population in order to reduce ongoing disease burden. We have investigated the association between memory CD4 and CD8 T cells and levels of neutralizing antibodies in convalescent COVID-19 subjects. Higher titres of convalescent neutralizing antibodies were associated with significantly higher levels of RBD-specific CD4 T cells, including specific memory cells that proliferated vigorously in vitro. Conversely, up to half of convalescent individuals had low neutralizing antibody titres together with a lack of receptor binding domain (RBD)- specific memory CD4 T cells. These low antibody subjects had other, non-RBD, spike-specific CD4 T cells, but with more of an inhibitory Foxp3+ and CTLA-4+ cell phenotype, rather than the effector T- bet+, cytotoxic granzymes+ and perforin+ cells seen in high antibody subjects. Single cell transcriptomics of antigen-specific CD4+ T cells from high antibody subjects revealed heterogenous RBD-specific CD4+ T cells that comprised central memory, transitional memory and Tregs, as well as cytotoxic clusters containing diverse TCR repertoires, that were absent in individuals with low antibody levels. However, vaccination in low antibody convalescent individuals led to a slight but significant improvement in RBD-specific memory CD4 T cells and increased neutralizing antibody titres. Our results suggest that targeting CD4 T cell epitopes proximal to and within the RBD- region should be prioritized in booster vaccines. One Sentence SummaryIndividuals with low neutralising antibody titres may be at risk of SARS-CoV-2 re-infection due to a failure to generate a high quality CD4 T cell response specific for receptor binding domain (RBD), including memory CD4 T cells that proliferate in vitro in response to RBD, and which are also therefore an important target for vaccine design.
Phan Tri Giang、Darley David、Cunningham Philip、Zaunders John J、Milogiannakis Vanessa、Stella Alberto Ospina、Munier C. Mee Ling、Turville Stuart、Brilot-Turville Fabienne、Singh Mandeep、Howe Annett、Kelleher Anthony D、Rouet Romain、Aggarwal Anupriya、Dore Gregory J、Danwilai Thidarat、Faulks Megan L.、Jackson Katherine、Christ Daniel、Akerman Anouschka、Khoo Weng Hua、Matthews Gail V、Law Hannah、Phetsouphanh Chansavath、Klemm Vera、Croucher Peter I、Schofield Peter、Starr Mitchell
Garvan Institute of Medical Research||St Vincent?ˉs Clinical School, Faculty of MedicineSt Vincent?ˉs Hospital SydneyNSW State Reference Laboratory for HIV, St Vincent?ˉs Centre for Applied Medical ResearchNSW State Reference Laboratory for HIV, St Vincent?ˉs Centre for Applied Medical ResearchKirby InstituteKirby InstituteKirby InstituteKirby InstituteBrain and Mind Centre, Children?ˉs Hospital at Westmead, University of Sydney||Sydney Institute for Infectious Diseases, The University of SydneyGarvan Institute of Medical Research||St Vincent?ˉs Clinical School, Faculty of MedicineKirby InstituteKirby Institute||St Vincent?ˉs Hospital SydneyGarvan Institute of Medical ResearchKirby InstituteKirby Institute||St Vincent?ˉs Hospital SydneyNSW State Reference Laboratory for HIV, St Vincent?ˉs Centre for Applied Medical ResearchGarvan Institute of Medical ResearchGarvan Institute of Medical ResearchGarvan Institute of Medical ResearchKirby InstituteGarvan Institute of Medical Research||St Vincent?ˉs Clinical School, Faculty of MedicineKirby Institute||St Vincent?ˉs Hospital SydneyKirby InstituteKirby InstituteKirby InstituteGarvan Institute of Medical ResearchGarvan Institute of Medical ResearchNSW State Reference Laboratory for HIV, St Vincent?ˉs Centre for Applied Medical Research
医药卫生理论医学研究方法基础医学
Phan Tri Giang,Darley David,Cunningham Philip,Zaunders John J,Milogiannakis Vanessa,Stella Alberto Ospina,Munier C. Mee Ling,Turville Stuart,Brilot-Turville Fabienne,Singh Mandeep,Howe Annett,Kelleher Anthony D,Rouet Romain,Aggarwal Anupriya,Dore Gregory J,Danwilai Thidarat,Faulks Megan L.,Jackson Katherine,Christ Daniel,Akerman Anouschka,Khoo Weng Hua,Matthews Gail V,Law Hannah,Phetsouphanh Chansavath,Klemm Vera,Croucher Peter I,Schofield Peter,Starr Mitchell.High titre neutralizing antibodies in response to SARS-CoV-2 infection require RBD-specific CD4 T cells that include proliferative memory cells[EB/OL].(2025-03-28)[2025-06-19].https://www.medrxiv.org/content/10.1101/2022.07.22.22277947.点此复制
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