6 October Episode 76T cell immunity, evolution and reinfection

1. Progress un understanding role of T cells

• Weiskopf et al in Science Immunology show that during development of ARDS: viral load decreases,  but S-specific antibody and T cell responses increase, with production of multiple Th1/Th2/Th17 cytokines = part of cytokine storm?  But what about distinction between mild and severe cases?
• Peng et al in bioRxiv investigates this question retrospectively (in convalescent people). They show that severe disease is associated with higher T cell responses to spike, but also  to Membrane and ORF3a. However, the proportion of CD8/CD4 T cell responses  is higher in mild disease, especially to M, NP and E.  They tentatively conclude that protective immunity (by vaccination) should not only induce anti-S antibodies, but also preferentially CD8 T cell responses to other structural proteins (M, NP…)
• Anft et al perform a prospective study (at admission) and find that both CD4 and CD8 T cells of patients, who will become critical have higher expression of cytokines upon S antigen stimulation. Moreover there is a depletion in the periphery of T cells with activated cytotoxic and migratory phenotype (expressing HLA-DR, CD57, CD11a, most probably because of migration towards the tissues, since these phenotypes re-emerge upon recovery.  Clearly, these observation suggest a pathogenic role of activated T cells in the “cytokine storm” and tissue damage.
• Finally, Bacher et al in medRxiv investigate the role of pre-existing SARS-CoV-2 memory T cells.  They find these cells in all unexposed healthy individuals with the following characteristics:

• increase in the elderly,
• not primarily driven by CCCoVs.
•  only low TCR avidity, suggesting impaired functionailty.

In severe COVID-19 (in contrast to mild disease): functional impairment in COVID-reactive memory T cells  → they may originate from the pre-existing memory T cells. They speculate that a large number of suboptimal low avidity memory cells may compete and prevent naive T cell activation and high affinity selection and that immunological age =  potential risk factor for severe COVID-19

All in all, there is quite some evidence that T cells have an immunopathogenic role, but rather limited evidence of a protective role, during the course of natural infection.  That does not exclude that they can have a positive role in vaccination, but we would like to see some more evidence of that potential….

2. Viral evolution: the spike D614G mutation has “taken over” the pandemic (see Korber et al). Two independent groups    (Hou et al, North Carolina and Tokio; Plante in Texas) now convincingly show that the G variant is indeed fitter and more transmittable:

• a clearly higher “fitness” (in bona fide in vitro competition assays)
• in a hamster model, higher infectious virus titers that infects naïve animals more readily. 

3. Persistent infection, reactivation and reinfection:

• Two papers on immunocompromised patients.   
  • Moore et al : A 63-Year-Old Woman with a History of Non-Hodgkin Lymphoma with Persistent symptomatic SARS-CoV-2 Infection Who Was Seronegative and Treated with Convalescent Plasma 
  • Lacman et al descxribe Severe COVID‑19 virus reactivation following treatment for B cell acute lymphoblastic leukemia
• Reinfection
  • Likely (but not sequence proven) in an Italian HCW by Marco Bongiovanni
  • Sequence proven in a “sexagenarian” with serious co-morbidities (emphysema, hypertension): the authors also show that, up to now, this is a rare phenomenon and that all other of the 43 cases with 2 separate positive tests could be explained by other factors than reinfection.

Will the rate of reinfection in (highly exposed) HCW and (highly susceptible) patients with comorbidities increase, now that the second wave is hitting us badly?