Deciphering the quality of SARS‐CoV‐2 specific T‐cell response associated with disease severity, immune memory and heterologous response

Pérez‐Gómez, Alberto; Gasca‐Capote, Carmen; Vitallé, Joana; Ostos, Francisco J.; Serna‐Gallego, Ana; Trujillo‐Rodríguez, María; Muñoz‐Muela, Esperanza; Giráldez‐Pérez, Teresa; Praena‐Segovia, Julia; Navarro‐Amuedo, María D.; Paniagua‐García, María; García‐Gutiérrez, Manuel; Aguilar‐Guisado, Manuela; Rivas‐Jeremías, Inmaculada; Jiménez‐León, María Reyes; Bachiller, Sara; Fernández‐Villar, Alberto; Pérez‐González, Alexandre; Gutiérrez‐Valencia, Alicia; Rafii‐El‐Idrissi Benhnia, Mohammed; Weiskopf, Daniela; Sette, Alessandro; López‐Cortés, Luis F.; Poveda, Eva; Ruiz‐Mateos, Ezequiel; ,

doi:10.1002/ctm2.802

Cited by 9 publications

(3 citation statements)

References 41 publications

(112 reference statements)

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“…Our results also showed that Clec9A-RBD single dose immunization induced a potent and sustained antigen-specific poly-functional T H 1 cellular response, consistent with our previous studies that targeted antigens to Clec9A-expressing cDC1 [16, 42]. Poly-functional T cells have been proposed to represent a correlate of protection in other infectious diseases such as dengue and this feature is applicable towards COVID-19 as well [43-45]. Furthermore, Clec9A-RBD was able to elicit robust RBD-specific T cell memory that could be recalled 6-12 months post-immunization.…”

Section: Discussionsupporting

confidence: 89%

Single shot dendritic cell targeting SARS-CoV-2 vaccine candidate induces broad and durable systemic and mucosal immune responses

Cheang

Tan

Purushotorman

et al. 2023

Preprint

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Current COVID-19 vaccines face certain limitations, which include waning immunity, immune escape by SARS-CoV-2 variants, limited CD8+ cellular response, and poor induction of mucosal immunity. Here, we engineered a Clec9A-RBD antibody construct that delivers the Receptor Binding Domain (RBD) from SARS-CoV-2 spike protein to conventional type 1 dendritic cells (cDC1). We showed that single dose immunization with Clec9A-RBD induced high RBD-specific antibody titers with a strong T-helper 1 (TH1) isotype profile and exceptional durability, whereby antibody titers were sustained for at least 21 months post-vaccination. Uniquely, affinity maturation of the antibody response was observed over time, as evidenced by enhanced neutralization potency and breadth across the sarbecovirus family. Consistently and remarkably, RBD-specific T-follicular helper cells and germinal center B cells were still detected at 12 months post-immunization. Increased antibody-dependent cell-mediated cytotoxicity (ADCC) activity of the immune sera was also measured over time with comparable efficacy against ancestral SARS-CoV-2 and variants, including Omicron. Furthermore, Clec9A-RBD immunization induced a durable poly-functional TH1-biased cellular response that was strongly cross-reactive against SARS-CoV-2 variants, including Omicron, and with robust CD8+ T cell signature. Lastly, Clec9A-RBD single dose systemic immunization primed effectively RBD-specific cellular and humoral mucosal immunity in lung. Taken together, Clec9A-RBD immunization has the potential to trigger robust and sustained, systemic and mucosal immune responses against rapidly evolving SARS-CoV2 variants.

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Section: Discussionsupporting

confidence: 89%

Single shot dendritic cell targeting SARS-CoV-2 vaccine candidate induces broad and durable systemic and mucosal immune responses

Cheang

Tan

Purushotorman

et al. 2023

Preprint

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“…These SARS‐CoV‐2 pools were made broadly available to the scientific community by distribution to over 110 laboratories in four different continents and were utilized in a large number of studies, resulting thus far in over 80 publications (Ansari et al., 2021; Ansari et al., 2022; Apostolidis et al., 2021; Arunachalam et al., 2022; Banki et al., 2022; Bhuiyan et al., 2022; Blixt et al., 2022; Boland et al., 2022; Bosteels et al., 2022; Bowen, Addetia, et al., 2022; Bowen, Park, et al., 2022; Brasu et al., 2022; Bueno et al., 2022; Cheon et al., 2021; Chiuppesi et al., 2022; Costa et al., 2022; da Silva Antunes, Pallikkuth, et al., 2021; Dan et al., 2021; Dentone et al., 2022; Galvez et al., 2022; Gao, Cai, Grifoni, et al., 2022; Gao, Cai, Wullimann, et al., 2022; Garcia‐Valtanen et al., 2022; Gazzinelli‐Guimaraes et al., 2022; Geers et al., 2023; GeurtsvanKessel et al., 2022; Goel et al., 2021; Grifoni et al., 2021; Grifoni, Sidney, et al., 2020; Grifoni, Weiskopf, et al., 2020; Hassan et al., 2020; He et al., 2022; Hsieh et al., 2022; Jin et al., 2021; Keeton et al., 2021; Keeton et al., 2022; Keeton et al., 2023; Lederer et al., 2022; Madelon, Heikkila, et al., 2022; Madelon, Lauper, et al., 2022; Mateus et al., 2021; Mateus, Grifoni, Tarke, et al., 2020; Meckiff et al., 2020; Mele et al., 2021; Melo‐Gonzalez et al., 2021; Murugesan et al., 2021; Nelson et al., 2022; Ogbe et al., 2021; Painter et al., 2021; Paul et al., 2022; Peluso et al., 2022; Perez‐Gomez et al., 2022...…”

Section: Introductionmentioning

confidence: 99%

The MegaPool Approach to Characterize Adaptive CD4+ and CD8+ T Cell Responses

da Silva Antunes,

Weiskopf,

Sidney

et al. 2023

Current Protocols

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Epitopes recognized by T cells are a collection of short peptide fragments derived from specific antigens or proteins. Immunological research to study T cell responses is hindered by the extreme degree of heterogeneity of epitope targets, which are usually derived from multiple antigens; within a given antigen, hundreds of different T cell epitopes can be recognized, differing from one individual to the next because T cell epitope recognition is restricted by the epitopes’ ability to bind to MHC molecules, which are extremely polymorphic in different individuals. Testing large pools encompassing hundreds of peptides is technically challenging because of logistical considerations regarding solvent‐induced toxicity. To address this issue, we developed the MegaPool (MP) approach based on sequential lyophilization of large numbers of peptides that can be used in a variety of assays to measure T cell responses, including ELISPOT, intracellular cytokine staining, and activation‐induced marker assays, and that has been validated in the study of infectious diseases, allergies, and autoimmunity. Here, we describe the procedures for generating and testing MPs, starting with peptide synthesis and lyophilization, as well as a step‐by‐step guide and recommendations for their handling and experimental usage. Overall, the MP approach is a powerful strategy for studying T cell responses and understanding the immune system's role in health and disease. © 2023 Wiley Periodicals LLC.Basic Protocol 1: Generation of peptide pools (“MegaPools”)Basic Protocol 2: MegaPool testing and quantitation of antigen‐specific T cell responses

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“…When blood samples from 37 patients who were hospitalized in the acute phase of COVID-19 were analyzed around 2 weeks after symptoms onset, the number of both spike (S) protein- and nucleocapsid (N)-specific CD4 + T cells with polyfunctionality (IL-2 + TNF-α + and IL-2 + IFN-γ + ) in patients with mild disease was higher than that in patients with severe infection. S-specific polyfunctional CD8 + T cells were also higher in patients with mild disease than in those with severe disease [ 24 ], whereas there is an apparent difference in the expression of coinhibitory molecules between patients with mild and severe diseases. S-specific CD8 + and CD4 + T cells in patients with severe disease express PD-1, TIM-3, CD39, VISTA, and Galectin-9 compared to those in patients with mild disease [ 25 ].…”

Section: Introductionmentioning

confidence: 99%

Association of cellular immunity with severity of COVID-19 from the perspective of antigen-specific memory T cell responses and cross-reactivity

et al. 2022

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Coronaviruses regularly cause outbreaks of zoonotic diseases characterized by severe pneumonia. The new coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused the global pandemic disease COVID-19 that began at the end of 2019 and spread rapidly owing to its infectious nature and rapidly progressing pneumonia. Although the infectivity of SARS-CoV-2 is high, indicated by the worldwide spread of the disease in a very short period, many individuals displayed only subclinical infection, and some of them transmitted the disease to individuals who then developed a severe symptomatic infection. Furthermore, there are differences in the severity of infection across countries, which can be attributed to factors such as the emergence of viral mutations in a short period of time as well as to the immune responses to viral factors. Anti-viral immunity generally consists of neutralizing antibodies that block viral infection and cytotoxic CD8+ T cells that eliminate the virus-infected cells. There is compelling evidence for the role of neutralizing antibodies in protective immunity in SARS-CoV-2 infection. However, the role of CD4+ and CD8+ T cells after the viral entry is complex and warrants a comprehensive discussion. Here, we discuss the protection afforded by cellular immunity against initial infection and development of severe disease. The initial failure of cellular immunity to control the infection worsens the clinical outcomes and functional profiles that inflict tissue damage without effectively eliminating viral reservoirs, while robust T cell responses are associated with mild outcomes. We also discuss persistent long-lasting memory T cell-mediated protection after infection or vaccination, which is rather complicated as it may involve SARS-CoV-2-specific cytotoxic T lymphocytes or cross-reactivity with previously infected seasonal coronaviruses, which are largely related to HLA genotypes. In addition, cross-reactivity with mutant strains is also discussed. Lastly, we discuss appropriate measures to be taken against the disease for immunocompromised patients. In conclusion, we provide evidence and discuss the causal relationship between natural infection- or vaccine-mediated memory T cell immunity and severity of COVID-19. This review is expected to provide a basis to develop strategies for the next generation of T cell-focused vaccines and aid in ending the current pandemic.

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Deciphering the quality of SARS‐CoV‐2 specific T‐cell response associated with disease severity, immune memory and heterologous response

Cited by 9 publications

References 41 publications

Single shot dendritic cell targeting SARS-CoV-2 vaccine candidate induces broad and durable systemic and mucosal immune responses

Single shot dendritic cell targeting SARS-CoV-2 vaccine candidate induces broad and durable systemic and mucosal immune responses

The MegaPool Approach to Characterize Adaptive CD4+ and CD8+ T Cell Responses

Association of cellular immunity with severity of COVID-19 from the perspective of antigen-specific memory T cell responses and cross-reactivity

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