High titre neutralizing antibodies in response to SARS–CoV–2 infection require RBD–specific CD4 T cells that include proliferative memory cells
Year: 2022
Type: article
Abstract: 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 Summary Individuals 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.
Source: Frontiers in Immunology
Authors: Chansavath Phetsouphanh, Weng Hua Khoo, Katherine Jackson, Vera Klemm, Annett Howe, Anupriya Aggarwal, Anouschka Akerman, Vanessa Milogiannakis, Alberto Ospina Stella, Romain Rouet, Peter Schofield, Megan L. Faulks, Hannah Law, Thidarat Danwilai, Mitchell Starr, C. Mee Ling Munier, Daniel Christ, Mandeep Singh, Peter I Croucher, Fabienne Brilot-Turville, Stuart Turville, Tri Giang Phan, Gregory J Dore, David Darley, Philip Cunningham, Gail V Matthews, Anthony D Kelleher, John J Zaunders
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,950
OpenAlex ID: W4311545700