With this mail, I want to re-open the chapter of “cellular immunity “ in SARS-CoV-2. Now that we start to see problems with naturally acquired or vaccine-induced neutralizing antibodies, because they might not be active enough to counter the new variants, people tend to refer to T cells: they may do the job. Possibly, but what is known about the importance and protective efficacy of T cells in COVID? Today, I will introduce the issue by presenting two recent reviews on the topic. See below. In the coming days, I will elaborate it further by analyzing even more recent papers in detail
But first, let’s see what are the most recent evolutions in the ever-changing field of vaccines, variants etc….
- A very interesting study from Catalunya (Ep 109-1a), showing the importance of viral load as an important risk factor for: rate of transmission, risk of developing symptoms and the shortening of incubation time. These data nicely confirm our Medical Hypothesis paper (Ep 109-1b).
- A preprint from Israel (Ep 109-2) shows that in people who got infected between 12 and 28 days after the first dose of the Pfizer vaccine had clearly a lower viral load than matched infected subjects who were either unvaccinated or just 0-7 days after first dose. As can be seen on p. 12, they analyzed a large cohort with a large age distribution. It is a pity that they do not provide data on the relation of viral load with age….
- While the US has not developed it’s sequence capacity, the data on new variants are sparse (Ep 109-3), but Denmark is the sequence champion (Ep 109-4). There is a very sharp rise in the British variant and Denmark has tightened it’s control measures.
- The last introductory paper (Ep 109-5) is a conversation with Philip Dormitzer (Pfizer). He is very confident that his company can develop mRNA vaccines, adapted to new variants, since they have a large production capacity. The question will be what the regulatory requirements will be to allow the roll-out.
Yesterday, I attended the ISV conference on COVID vaccines, hoping that Gamaleya, Astra-Zeneca, Moderna or Pfizer would show new (unpublished) data, but they did not. You find some screen shots in attachment (Ep 109-6 to -9). The last presentation on side effects of Pfizer and Moderna in the US (26 million doses administered) contained some interesting new data:
- Overall 372 non-serious and 45 serious adverse events per million doses
- Anaphylaxis occurred in 5 and 2.8 per million doses of Pfizer and Moderna resp.
- Death amongst elderly in nursing homes was not increased.
A very didactic and “narrative” review in Cell by Allessandro Sette (Ep 109-10):
Fig 1 shows the immune elements of the adaptive immune system that will be considered: antibodies, B cells, CD4 T helper and CD8 T cytotoxic cells.
Fig 2 illustrates the model of the author (that I fully agree with): the determining factor is the early innate response, mainly the type I (and III) interferons: if these are defective because of genetic errors or by the various SARS-CoV-2 factors that inhibit this response, the “adaptive” immunity (which needs time to develop) will be too late to prevent various degrees of immune-pathology. Age and co-morbidities are important factors, because of “immunosenescence”, a state of exhaustion: background inflammation, too few naïve T cells.
Fig 3 indicates the important functions of CD4 T cells, recognizing mainly spike (S), nucleocapsid (N) and membrane (M) epitopes, have been associated with milder disease:
- T follicular helper function for stimulation of B cells
- Helper function towards cytolytic CD8 T cells
- Direct Cytolytic effect of CD4 T cells
- CCR6 (+) mucosal migration
- Cytokine profile: Th1 (IFN-gamma, IL-2); IL-21 (help for B and CD8 CTL) and IL-22 (tissue repair)
B cells and antibodies: mainly against S and N: a characteristic of neutralizing Ab is that they appear rather quickly and do not need extensive somatic mutations, which is positive. However, a high viral load also drives high neut Ab titers of poor “quality”. Other functions of Ab (including enhancing phagocytosis and other “Fc receptor” dependent activities) need more attention.
The authors argue that T cell responses are more closely associated with recovery than neutralizing antibodies. However, there are no data that confirm the original fear that SARS-CoV-2 antibodies could have a pathogenic role via antibody-dependent enhancement or auto-reactivity. The authors do not think that T cells have a pathogenic role.
Pre-existing immunity: a proportion of non-infected subjects show T cell responses to SARS-CoV-2 epitopes, which could have been induced by “common cold” coronaviruses. The question whether these “cross-reactive” T cells have any “protective” potential remains very controversial. The authors rather believe they do.
T and B cell memory: is also controversial, as some data argue that especially antibodies wane rather quickly, while others show rather robust B and especially T cell memory. The authors believe that protection against reinfection, also against mutants, may be mediated better by T cells than by antibodies.
A more systematic review by Madhumita Shrotri in PLoS One (Ep 109-11)
- Overall T cell depletion in moderate and severe cases, but not in asymptomatic and pediatric cases, with a selective depletion of “memory-effector” and “terminally differentiated” cells, which migrate to the lungs. Correlates with viral load and disease severity, even death.
Potentially due to redistribution, but also reduced recovery from broncho-alveolar lavage. Hence: apoptotic loss and reduced mobilization from bone marrow: the latter could be related to IL-6
- Breath and magnitude of CD4 T cells associated with recovery from severe disease. Robust cTFH (follicular T helper) cells activity to the SARS-CoV-2 S-protein was observed among the convalescent group. Role of CD8 T cells in protective immunity less clear. There is however a correlation between CD4 T, CD8 T and B cell responses (anti-receptor binding domain).
- Cytokine overproduction: source?
- Cross-reactivity of pre-pandemic T cells with HKU1 epitopes, more concentrated in S2 (fusion domain), but also N and non-structural proteins (NSP7, NSP13). Lower frequency and magnitude of T cell responses, and differential epitope dominance, in reactive controls relative to SARS-CoV-2 convalescents. Nevertheless some indirect indication of lower pre-existing cross-reactivity in hospitalized COVID-19 cases compared with mild cases.
I hope to be back soon with more news on T cells!
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9 April Episode 127 antibody persistent, risk on reinfection, cross-neutralization, disease and mortality risks
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20 March 2021 Episode 121 Present treatment strategies and perspectives on new therapeutics
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