The polarity and specificity of SARS-CoV2 -specific T lymphocyte responses determine disease susceptibility (preprint)

Optimal vaccination and immunotherapy against coronavirus disease COVID-19 relies on the in-depth comprehension of immune responses determining the individual susceptibility to be infected by SARS-CoV-2 and to develop severe disease. We characterized the polarity and specificity of circulating SARS-CoV-2-specific T cell responses against whole virus lysates or 186 unique peptides derived from the SARS-CoV-2 or SARS-CoV-1 ORFeome on 296 cancer-bearing and 86 cancer-free individuals who were either from the pre-COVID-19 era (67 individuals) or contemporary COVID-19-free (237 individuals) or who developed COVID-19 (78 individuals) in 2020/21. The ratio between the prototypic T helper 1 (TH1) cytokine, interleukin-2, and the prototypic T helper 2 (TH2) cytokine, interleukin-5 (IL-5), released from SARS-CoV-2-specific memory T cells measured in early 2020, among SARS-CoV-2-negative persons, was associated with the susceptibility of these individuals to develop PCR-detectable SARS-CoV-2 infection in late 2020 or 2021. Of note, T cells from individuals who recovered after SARS-CoV-2 re-infection spontaneously produced elevated levels of IL-5 and secreted the immunosuppressive TH2 cytokine interleukin-10 in response to SARS-CoV-2 lysate, suggesting that TH2 responses to SARS-CoV-2 are inadequate. Moreover, individuals susceptible to SARS-CoV-2 infection exhibited a deficit in the TH1 peptide repertoire affecting the highly mutated receptor binding domain (RBD) amino acids (331-525) of the spike protein. Finally, current vaccines successfully triggered anti-RBD specific TH1 responses in 88% healthy subjects that were negative prior to immunization. These findings indicate that COVID-19 protection relies on TH1 cell immunity against SARS-CoV-2 S1-RBD which in turn likely drives the phylogenetic escape of the virus. The next generation of COVID-19 vaccines should elicit high-avidity TH1 (rather than TH2)-like T cell responses against the RBD domain of current and emerging viral variants.

Prolonged SARS-CoV-2 RNA virus shedding and lymphopenia are hallmarks of COVID-19 in cancer patients with poor prognosis (preprint)

Patients with cancer are at higher risk of severe coronavirus infectious disease 2019 (COVID-19), but the mechanisms underlying virus-host interactions during cancer therapies remain elusive. When comparing nasopharyngeal swabs from cancer and non-cancer patients for RT-qPCR cycle thresholds measuring acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in 1063 patients (58% with cancer, 89% COVID-19+), we found that malignant disease favors the magnitude and duration of viral RNA shedding concomitant with prolonged serum elevations of type 1 IFN that anticorrelated with anti-RBD IgG antibodies. Chronic viral RNA carriers exhibited the typical immunopathology of severe COVID-19 at the early phase of infection including circulation of immature neutrophils, depletion of non-conventional monocytes and a general lymphopenia that, however, was accompanied by a rise in plasmablasts, activated follicular T helper cells, and non-naive Granzyme B+FasL+, EomeshighTCF7high, PD-1+CD8+ Tc1 cells. Virus-induced lymphopenia worsened cancer-associated lymphocyte loss, and low lymphocyte counts correlated with chronic SARS-CoV-2 RNA shedding, COVID-19 severity and a higher risk of cancer-related death in the first and second surge of the pandemic. Lymphocyte loss correlated with significant changes in metabolites from the polyamine and biliary salt pathways as well as increased blood DNA from Enterobacteriaceae and Micrococcaceae gut family members in long term viral carriers. We surmise that cancer therapies may exacerbate the paradoxical association between lymphopenia and COVID-19-related immunopathology, and that the prevention of COVID-19-induced lymphocyte loss may reduce cancer-associated death.

Mortality of Patients with Cancer Presenting with Symptoms of COVID-19 With vs Without Detectable SARS-CoV-2: A Nationwide Prospective Cohort Study (preprint)

Background: This nationwide prospective cohort reports on the outcome of patients with cancer presenting COVID-19 symptoms with or without detectable SARS-COV2 on RT-PCR and/or specific CT-scan imaging.Methods: This prospective study was conducted in 23 Cancer Centers and hospitals. Inclusion criteria were :1) confirmed diagnosis of solid or hematologic cancer in treatment and 2) clinical symptoms of COVID-19. COVID-19 infection was defined as: 1) detectable SARS-CoV2 on RT-PCR (repeated twice if negative first) and/or specific CT-scan imaging if undocumented SARS-COV-2 on RT-PCR. The primary endpoint was death at day-28 after COVID-19 test, in patients with (COVID-19 positive group) or without (COVID-19 negative group) documented COVID-19.Findings: From March 1st 2020 to May 21st 2020, 1230 cancer patients with suspicion of COVID-19, including 1162 (94·5%) matching inclusion criteria were included. 425 (36·6%) [including 155 [13·3%] with diagnosis on CT-scan only], and 737 (63·4%) were in the COVID-19+ and COVID-19- groups respectively. Deaths within 28 days after COVID-19 diagnosis occurred in 116/425 (27·8%) of COVID-19+ patients, and in 118/737 (16·3%) of COVID-19 negative patients (p<0·001). With a follow-up of 2.1 (1·6-2·4) months, 143/425 (33·6%) deaths were reported in the COVID-19+ population: deaths were attributed to COVID-19 (N=73, 51·0%), cancer (N=50, 34·9%) or other causes (N=20, 13·9%). In the COVID-19 negative group, 167 deaths (22·7%) deaths were reported: 138 (82·7%) and 29 (17·3%) were attribued to cancer and other causes respectively. Male gender, age, metastatic disease, immunosuppressive treatments, lymphopenia, COVID-19 diagnosis and diabete were independent risk factors for death. In the COVID-19 positive subgroup with measured CRP at baseline, 65/122 (53·7%) of patients with CRP >100 mg/L vs 35/203 (17·4%) of other patients died before day 28 (p<0·001).Interpretation: Patients with cancer presenting COVID-19 symptoms with or without detectable SARS-COV-2 by RT-PCR are both at high risk of early mortality. COVID-19 is reported as the cause of death in 50% of the COVID-19 positive patients with cancer.Trial Registration: This trial is registered with ClinicalTrials.gov, number NCT04363632Funding Statement: This work was supported by LYRICAN (INCA-DGOS-INSERM-12563), the French National Research Agency [LabEx DEvweCAN (ANR-10-LABX0061)], RHU4-DEPGYN (ANR-18-RHUS-0009), INCA&DGOS (NetSARC, RREPS, RESOS), INCA (InterSARC), European commission (EURACAN-EC739521), Fondation ARC, PIA Institut Convergence François Rabelais PLAsCAN (17-CONV-0002), La Ligue contre le Cancer, La Ligue de L’Ain contre le Cancer. This work was partly supported by an unrestricted grant from Astra Zeneca. Declaration of Interests: The authors have declared no potential conflicts of interest.Ethics Approval Statement: Local approval of the Data Protection Officer of Centre Léon Bérard, the sponsoring center, was obtained in accordance with French national and European laws and directives. The coordinating center complies with the MR-004 French data protection authority (CNIL) requirements (project reference: R201-004-040).