Cellular immune response to SARS CoV 2 infection in humans: a systematic review

Introduction Understanding the cellular immune response to SARS-CoV-2 is critical to vaccine development, epidemiological surveillance and control strategies. This systematic review critically evaluates and synthesises the relevant peer-reviewed and pre-print literature published in recent months. Methods For this systematic review, independent keyword-structured literature searches were carried out in MEDLINE, Embase and COVID-19 Primer for studies published from 01/01/2020-26/06/2020. Papers were independently screened by two researchers, with arbitration of disagreements by a third researcher. Data were independently extracted into a pre-designed Excel template and studies critically appraised using a modified version of the MetaQAT tool, with resolution of disagreements by consensus. Findings were narratively synthesised. Results 61 articles were included. Almost all studies used observational designs, were hospital-based, and the majority had important limitations. Symptomatic adult COVID-19 cases consistently show peripheral T cell lymphopenia, which positively correlates with increased disease severity, duration of RNA positivity, and non-survival; while asymptomatic and paediatric cases display preserved counts. People with severe or critical disease generally develop more robust, virus-specific T cell responses. T cell memory and effector function has been demonstrated against multiple viral epitopes, and, cross-reactive T cell responses have been demonstrated in unexposed and uninfected adults, but the significance for protection and susceptibility, respectively, remains unclear. Interpretation A complex pattern of T cell response to SARS-CoV-2 infection has been demonstrated, but inferences regarding population level immunity are hampered by significant methodological limitations and heterogeneity between studies. In contrast to antibody responses, population-level surveillance of the cellular response is unlikely to be feasible in the near term. Focused evaluation in specific sub-groups, including vaccine recipients, should be prioritised. ### Competing Interest Statement JM is chief scientific officer, shareholder and scientific founder of Leucid Bio, a spinout company focused on development of cellular therapeutic agents. The authors report no other competing financial interests or conflicts of interest. ### Clinical Protocols ### Funding Statement This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors. MCIvS is funded by a NIHR Doctoral Fellowship (Ref NIHR300156). SAI is supported by a Wellcome Trust Clinical Research Training Fellowship (Ref No 215654/Z/19/Z). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Not applicable. All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes This was a systematic review based on analysis of openly published secondary data. * ARDS : Acute respiratory distress syndrome COVID-19 : Coronavirus disease (2019) CRS : Cytokine release syndrome ELISpot : Enzyme-linked immune absorbent spot (assay) HCoV : Human Coronavirus (HKU1, 229E, OC43, NL63) IFN-γ : Interferon gamma M : Membrane (protein) MEDLINE : Medical Literature Analysis and Retrieval System Online MERS : Middle East Respiratory Syndrome MetaQAT : Meta Quality Appraisal Tool NP : Nucleocapsid protein NSP7; NSP13 : Non-structural protein 7; non-structural protein 13 PBMC : Peripheral blood mononuclear cells PCR; RT-PCR : Polymerase chain reaction; reverse transcription polymerase chain reaction PRISMA : Preferred Reporting Items for Systematic Reviews and Meta-Analyses SARS-CoV-1 : Severe Acute Respiratory Syndrome Coronavirus-1 SARS-CoV-2 : Severe Acute Respiratory Syndrome Coronavirus-2 RBD : Receptor binding domain RNA : Ribonucleic acid TEMRA : T effector memory cells re-expressing CD45RA TFH; cTFH : T follicular helper cells; circulating T follicular helper cells Th : T helper cells WHO : World Health Organization