3 Dec 2021 Episode 196 : More on omicron, molnupiravir and first part of T cells in disease and vaccination

Fri, 12/03/2021 - 17:35

Dear colleagues,

As promised, finally some info on emerging data on role of T cells below.

But first: rather cumbersome data on omicron and molunpiravir

Omicron (thanks to Patrick Smits)

Ep 196-1: Official communication from ECDC:

  • The impact of the further introduction and spread of the Omicron VOC could be VERY HIGH,
  • Clinic:
    • Among the cases reported in the EU/EEA for which there is available information on disease severity, half of the cases were asymptomatic and the other half presented with mild symptoms
    • Data from South Africa indicate an increase of hospital admissions of COVID-19 cases  
  • Options for response
    • Non-pharmacological interventions proven efficacy
    • Booster vaccine indicated
    • Travel restrictions of questionable value, since omicron is already “in”.
  • Immunity: highly mutated Spike may lead to escape, but immune escape potential from non-neutralizing antibodies and memory T cells directed at non-surface proteins is more difficult to determine (Read: immunity to conserved parts may save us…)
  • Protective efficacy og monoclonal antibodies (Regeneron etc) to be evaluated.

Ep 196-2: Summary of press conference by MOH SA this morning is rather worrying:

  • Rapid increase in hospitalizations in Gauteng
  • Increase in children, moving to older people.

But not yet 100 % sure it is all omicron?

Ep 196-3:   Omicron cluster in Australia

 

Molunpiravir :

Ep 196-4 : Rather sobering note in Science:

  • Risk of hospitalization or death in placebo = 9.7 % vs Molnupiravir = 6.8 %
  • Thus risk reduction  is now about 30 % , down from 50 % in the “interim analysis” (released earlier in the press)  

Clearly, after tempered enthusiasm about Remdesivir, now also sobering data on Molnupiravir. There is not yet a firm and safe polymerase inhibitor for SARS-CoV-2 !!!!

 

T cells

Ep 196-5:  A very nice and didactic introductory overview of studies in patients until March 2021. Some highlights:

  • Over 1400 unique epitopes characterized of which 1052 for CD8 T cells (HLA class I) and 382 for CD4 T cells (class II). Epitopes dominantly in the structural proteins Spike, Nuclecapsid and Membrane, but also in parts of the polymerase (nsp3 and nsp12, which are big proteins) and ORF3a (viroporin, inserted in cell membrane to promote viral release from cells) as well as ORF8a (a viral protein that downregulates HLA class I molecules, thus avoiding recognition of infected cells by CD8 T cells).
  • Each human individual has a specific set of polymorphic HLA molecules.  Hence large heterogeneity in recognition of viral peptides. Each individual is estimated to recognize, on average, 19 different CD4 and 17 different CD8 epitopes.    HLA-restricted epitopes were identified for 30 class I and 45 class II molecules, which provides good coverage of a number of different loci and alleles.
  • Cross-reactivity with “common cold coronaviruses” (CCCoV):
    • 50% of the epitopes defined in unexposed donors (presumably based on CCCoV immunity)were also recognized in SARS-CoV-2-infected subjects.
    • 80% of the epitopes defined in SARS-CoV-2-infected subjects were not recognized in unexposed donors
    • This seeming discrepancy is because most of the T cell responses against SARS-CoV-2 are NOT based on cross-reactivity , but activation of novel naïve T cells.
    • More extensive cross-reactivity with SARS-CoV-1 and MERS
    • Significance of cross-reactivity for contribution to protective versus pathogenic immunity unclear.  
  • Potential for immune escape is limited:
    • The vast majority of defined epitopes are conserved in SARS-CoV-2 variants (investigation till March limited to alpha, beta, gamma)
    • SARSCoV-2 is acute infection with rapid passage between individuals with a large heterogeneity

Ep 196-6: Comment in Nat Rev Imm (Nov 2021) on the potential importance of T cell immunity for vaccination:

  • Protection against disease has been seen in animal models and in human patients, lacking B cell (e.g. B cell depleting anti-CD20 therapy)
  • T cell memory against Coronaviruses last longer and the epitopes are more conserved  than for B cells (antibodies)
  • Many vaccine trials with different platform underway to specifically enhance T cell immunity (see highlighted text).

It is not likely to be possible to achieve herd immunity against the current COVID-19 pandemic owing to the decay of nAb titres and the continuing emergence of escape variants.

A practical goal may therefore be to reduce damage to public health by making COVID-19 a controllable disease, similar to influenza or the commoncold, although the elderly and immunocompromisedpatients would still be at risk of severe disease.

We therefore need to continue work on such vaccines that induce durable and broad protective T cell- mediated immunity against COVID-19.

Ep 196-7: Another interesting review by Julie Niessl in Sem Immunol (Aug 2021)

  • In acute phase
    • Strong CD4 and CD8 T cell responses against Spike and Nucleocapsid with Th1 and cytotoxic profile.
    • Cytokine storm not by T cells, but myeloid cells.
  • Correlates of disease severity:
    • Early CD4+ T cell response show a stronger correlation to less severe COVID-19 than antibody and CD8+ T cell responses.
    • Very rapid induction of CD8+ T cells could also be a cause of asymptomatic disease
    • Poor polyfunctionality and proliferative capacity in more severe disease
  • Mouse and macaque studies: CD8 T cells fundamental adaptive component of early SARS-CoV-2 control and clearance, while CD4+ T cells are necessary to induce antibody responses
  • In convalescent phase
    • Both CD4+ and CD8+ T cells retain their polyfunctional characteristics for >180 days.
    • CD4+ T cells exhibit responses against both structural and accessory SARS-CoV-2 proteins, CD8+ T cells show a preference for the nucleocapsid protein
  • Cross-reactivity: a lot of debate on beneficial vs deleterious effects
    • Highly-exposed seronegative individuals show a readily detectable T cell response against SARS-CoV-2 peptides that is significantly stronger than in healthy and unexposed donors.
    • CD8+ T cell responses directed against a highly conserved (cross-reactive) region () of coronavirus polymerase can be detected in uninfected individuals and are expanded in SARS-CoV-2-exposed health care workers that did not subsequently become infected
  • Tissue-resident memory T cells (TRMs) in respiratory mucosa crucial mediators of protection from secondary viral exposure.
    • Could be more and better induced by intranasal vaccination than intramuscular
  • Role of T cells in vaccination
    • BNT162b2, mRNA-1273, ChAdOx1 and Ad26.COV2.S vaccination induces
    • CD4+ and CD8+ T cell responses prior to neutralizing antibodies.
    • Combined spike and nucleocapsid-adenoviral vaccines furthermore decreased SARS-CoV-2 replication not only in lung, but also brain of challenged mice

Tomorrow I’ll back with more news.

Have a nice WE

Guido