6 March Episode 115 Variants vaccines immunology and treatment

Sat, 03/06/2021 - 12:34

Dear colleagues,

Thanks to all who sent me suggestions and questions. Stimulating….

Par 1 Variants and vaccines

Var 1: Davies on transmission : the Science paper based on previous preprint showing that the “British variant’ (B1.1.7) has a significantly (+ 60 %) higher transmissibility.  It has clearly inspired the British to keep restrictive measures for a long time and to speed up vaccination.

Var 2 Bager on hospitalization: As we know, Denmark is doing a fantastic job with regard to whole genome sequencing (they sequenced 23,000 of the 36,000 PCR positive cases of Jan) and had follow-up.  Thus they could establish that the “odds ratio” of hospitalization by the B.1.1.7 variant were 1.64 as compared to other SARS-CoV-2, which is in line with the similarly higher transmissibility.

Var 3:  Logically, the risk of death also increases by an estimated 35 %.  Davies makes it more explicit “In absolute terms, this increased hazard of death corresponds to the risk of death for a male aged 55–69 increasing from 0.56% to 0.73% over the 28 days following a positive SARS-CoV-2 test..”

 

Var 4: A plea in Nature to increase and coordinate the efforts on sequencing and especially on a much more streamlined workflow to categorize the data into phylogenetic trees in order to recognize newly spreading variants earlier….

Var 5 and 6 Several emerging variants in the US, of which the “New Yorker” (B 1.526) could be the most important, because carrying both N501Y (enhancing infectivity) and 484K (immune escape) mutations.

Var 7: The apparently reassuring message from Tarke et al from La Jolla: CD4 and CD8 T cell responses in either convalescent patients or Pfizer/Moderna vaccinees are equally potent against the variants (Brit, Br; SA, Cal) as compared to wild type.

Obviously, this shows that the virus escapes in the first place from the antibodies and those mutations do not affect the T cell epitopes.  The question is how to interpret these data:

  • Does it mean that T cells do not exert immune pressure on the virus and may be less important for protective immunity?
  • Or can (vaccine-induced) T cell responses be a “back-up” for  antibody responses that are less potent against some of the variants.  Thus T cells provide a “second line of protection”?
    •  In view of how T cells function (recognizing already infected cells), this could imply that, after vaccination with the present generation of vaccines, you could have a higher chance to get infected with a variant (as compared to wild type), but that the T cells protect you against uncontrolled viral replication, hence against disease?

 

Var 8 A similar message in a preprint from Oxford, but with also a more detailed analysis of the antibody responses, showing that after a prime only, the neutralizing capacity against variants is similarly affected as in WT convalescent sera, but after prime-boost, the neutralization against the variants is stronger and also broader responses are present: against other CoV and presumably against epitopes outside the ones affected by the variants.  Clearly an argument to stick  to prime-boost and not just rely on one shot.      

 

Par 2 More on antibodies

Ab 1 and Ab 2 are included as a reminder and were discussed in Episode 90 already.

Ab 3 Anderson et al. confirm cross-reactivity, but

  • Pre-pandemic SARS-CoV-2 reactive antibodies are not associated with protection upon infection.
  • Antibodies to a related betacoronavirus are boosted upon SARS-CoV-2 infection

 

Ab 4: Morgenlander in JCI reminds us that besides neutralzing activity, Ab can also act by other “functionalities”, such as antibody-dependent cytotoxicity, phagocytosis and complement activation, that could be important in anti-viral defense.  They perform a thorough analysis on the epitopes responsible for  those function.  As this is a purely in vitro and in silico exercise on convalescent plasma, the real “clinical” importance remains unclear. 

 

Ab 5 Becker in Nat Comm provides a multiplex assay to analyze antibodies to SARS-CoV-2 and other CoV more specifically and with higher sensitivity than the regular commercial assays. Some interesting observations:

  • Ab against S1 fewer false positives than to S2
  • Binding to N more sensitive, but also less specific
  • IgA earlier positive than IgG and maybe associated with severe disease
  • Still 10 % of SARS-CoV-2 patients fail to develop detectable Ig levels.

 

 

Par 3 More on T cells: the question if and how T cells contribute to protection or disease progression is far from resolved.  I add Allesandro Sette’s review again for those who need orientation.

 

T cell 1 Using relatively simple technology (IFN-g ELISPOT) Tan shows that early T cell responses against structural and non-structural epitopes are associated with mild disease.

 

T cell 2 A much more detailed but cross-sectional analysis by Neidleman argues that Spike-specific CD127+ Th1 cells are increased in survivors of severe COVID-19, while Spike-specific Tregs and IL6+ CD8+ T cells as well as activated lung-homing CXCR4+ T cells are increased in fatal COVID-19.  These data make sense as Th1 and CD127 (IL7-receptor) are associated with functional and proliferating anti-viral T cells, while Tregs are rather suppressive and IL-6 is supposed to activate inflammation. 

 

T cell 3 the data by Petra Bacher et al are very intriguing, because they associate low avidity and pre-existing SARS-CoV-2 specific T cells with worse prognosis.  This is consistent with the “immune aging” and “inflamm-aging” concepts. 

 

T cell 4: Nussenzweig’s group, who performed the ground-breaking studies on B cell memory (see Ab1), here shows that polyfunctional T cell responses are also maintained at 3 and 6 months after rather mild COVID infection.  The significancy for protection is unclear.

 

T cell 5 The observations by Peng et al are on more patients, with both mild and severe cases represented, but limited to IFN-g responses to selected peptides. While, overall, breath and magnitude of memory T cell responses after recovery (defined as ‘at least 28 days after symptoms onset”) were higher in severe cases and correlated with antibody responses, there was a clear trend for higher CD8 T cell responses to six immunodominant regions to be higher in mild versus severe cases.  It is not very clear whether the timing was comparable, but this study confirms that both overall B and T cell responses  are higher in severe cases. The trend of higher CD8 T cells to particular epitopes in mild cases may hint towards a mechanism of protection. 

 

Par 4 More on Treatment

 

Tr1  This review by Feuillet in Trends in Immunology is very didactic and gives critical insights in why some “repurposing” may work and other attempts have failed.  Based on these suggestions, I looked further in the even more recent literature for new results on some “repurposed” drugs.   

 

  1. Favipiravir:
  • Fav 1: An Egyptian open label study comparing chloroquine and Favipiravir in rather young mild to moderate COVID found no difference in outcome.
  • Fav 2: A similar study in India (but no chloroquine as control) showed some slight, but non-significant advantages: less need for mechanical ventilation; shorter time to PCR negative and discharge.  In a comment (Fav 4), this study is heavily criticized.
  • Fav 4: Similarly, an open label trial comparing Favipiravir + interferon-beta aerosol with HCQ in “moderate to severe” patients in Oman found no difference

 

Clearly, these preliminary, rather small open label studies in rather young patients provide little evidence in favor of Favipiravir.

 

  1. Colchicine: a meta-analysis of 8 studies with over 5000 patients included showed a seemingly clear benefit in mortality (3.2 % vs 8.3 %) and a trend to lower need for mechanical ventilation. However, these were purely observational studies and the inclusion criteria were different.

 

  1. Baricinitb: It is an orally administered, selective inhibitor of Janus kinase (JAK) 1 and 2 with the following characteristics:
  • inhibits the intracellular signaling pathway of cytokines known to be elevated in severe Covid-19, including interleukin-2, interleukin-6, interleukin-10, interferon-γ, and granulocyte–macrophage colony-stimulating factor;
  • acts against SARS-CoV-2 through the impairment of AP2-associated protein kinase 1 and the prevention of SARS-CoV-2 cellular entry and infectivity

 

Bar 1 is a full-scale phase 3 study with over 1000 patients comparing baricintib + remdesivir (polymerase inhibitor) with remdesivir only.  There was a slight overall benefit from the combination on recovery time, but in fact the benefit was mainly clear in a subgroup: patients receiving high-flow oxygen or noninvasive ventilation at enrollment had a time to recovery of 10 days with combination treatment and 18 days with control (rate ratio for recovery, 1.51). The 28-day mortality was 5.1% in the combination group and 7.8% in the control group (hazard ratio for death, 0.65).

 

These results are further discussed in an editorial by Goletti et al.  They argue that the place of both baricinitb and dexamethasone could indeed be useful to combine with remdesivir, especially in patients with severe disease, i.e. those needing either supplemental oxygen, non-invasive or  invasive mechanical ventilation.  The question is then whether baricitinib has any advantage over or synergy with dexamethasone.  

 

  1. Azithromycin: Clearly, Az is another “old workhorse that is taken from the stable”, when people don’t know how to get the job done and several colleagues asked me about it over the last year…. To be honest: I have no clear opinion on it and therefore I was happy to read the very nice review by Iwein Gyselinck.  Az is an antibiotic with “pleiotropic” immunomodulatory and potentially some anti-viral effects, which apparently have been successfully exploited already in the past in conditions such as chronic obstructive pulmonary disease, bronchiectasis, asthma and lung transplantation, but also in influenza.  In the meantime a large number of studies in COVID-19 has been published, but unfortunately of low quality and with equivocal results (see Table 1). And it Az has some cardial risk (Q-T), which in the most vulnerable COVID patients may limit its use.   So, once again, we need good quality phase 3 studies, before we can judge….

 

 Par 5: Various documentation

 

  1. A very interesting study from Spain, confirming once again that asymptomatic children have an equal viral load than asymptomatic adults
  2. First evidence of SARS-CoV-2 in wild animals and potential for “animal reservoir”?  

 

  1. Some interesting websites that colleagues sent me

FAQs on Protecting Yourself from Aerosol Transmission (google.com)

 

https://www.virology.ws/

http://www.microbe.tv/twiv/

 

  1. Some didactic slides
  • From Patrick Smits on transmission
  • My presentation for African NGO/self-organizations in Brussels (in French)

 

Need some time to prepare upcoming lectures now….

 

Best wishes,

 

Guido

 

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