12 December 2021 Episode 201: Omicron and also your feedback + my reflections on other topics

Sun, 12/12/2021 - 14:50

Dear colleagues,

An update on the latest on omicron remains worrying.

Lately, I received some structured feedback and suggestions from several of you.  I’m happy to share those in the second part (there is more coming in a next Episode. 

Clearly, this “blog” is not meant as an “open discussion forum” (there are plenty of those on social media), but as a source of synoptic information.  It is very useful and stimulating to receive your feedback and, as those who sent comments know, I’m usually taking them into account in some form in one of the next Episodes.  But if your comment is substantial, very stimulating or even provocative, I’m happy to share it with all of you.  However, I’m often not sure whether the author wishes to share his/her name as well.  Therefore please let me know if you prefer that I treat your comment anonymously or with your name and e-mail.  

       

OMICRON (Thanks once more to Patrick and Hans for contributing)

Ep 201-1 : Oleg Volkov medRxiv 11 Dec models the expected vaccine effectiveness of Pfizer against symptomatic COVID, taking into account the observed decrease of neutralization efficacy of serum from vaccinated people in vitro (see Ep 200).  You can see the tables with various scenario’s

VE against COVID would still remain about 60 % for 5 months after the 2 dose vaccination.

  • Obviously, a booster will significantly increase VE
  • Unfortunately, high transmissibility will still increase symptomatic cases in both unvaccinated, waned and recently vaccinated subjects.
  • This is a model, with many assumptions that will need correction, once more solid real-world data are available.   

Ep 201-2: Barnard from LSTMH in a non-peer reviewed paper clearly state: Omicron has the potential to cause substantial surges in cases, hospital admissions and deaths in populations with high levels of immunity. Table 1 shows that in both low and high escape conditions, the protection against hospitalization and death is much lower than for delta.  Clearly, the assumption here is that omicron has a similar pathogenic capacity as delta.

 

Even with the present NPI in place and in the most pessimistic scenario, the hospital admissions in England would be double those of January 2021 (which was a disaster with ambulances lining up at the hospital gates, as you might remember).  Clearly, strengthening of the NPI is needed.

Ep 201-3:  Tom Ambrose in The Guardian of 11 Dec calculates, based on the modeling of LSTMH that Omicron could cause an additional 175,000 hospitalizations and 25,000 deaths between now and end of April.  (In the worst case it could be 75,000 deaths).

Ep 201-4: The “Indian Express” claims that several medical sources in South-Africa found that the omicron variant is less pathogenic. (Sorry for the bad quality of the pdf).

Ep 201-5:   Description of first 43 cases in USA in MMWR 10 Dec.  As can be seen in the Table: most were below 60 yrs.;  34 had been vaccinated (14 even with a booster), but only 1 ended in hospital.

Ep 201-6:  UK Health Security Agency Technical Report 31 of 10 Dec:  260 Omicron cases.

  • None has been hospitalized.  However, it should be noted that most of the cases have a specimen date that is very recent and that there is a lag between onset of infection and hospitalisation and death (p. 37)
  • Increased transmission (at least 2 X more  than Delta) has been documented in households not adjusted for previous infection or vaccination (p. 4).
  • Approximately 3-8 fold increased risk of reinfection (p.22).    

Ep 201-7:   While waiting for solid data about pathogenicity in South-Africa, can we deduce anything from the statistics in the Worldometer https://www.worldometers.info/coronavirus/country/south-africa/ ?

 

Comparison of deaths in 4 waves at a time with similar level of cases:

Date (variant)

Cases

Deaths

9 July 2020 (Wuhan)

13,757

196

1 Jan 2021 (Beta)

16,827

481

30 June 2021 (Delta)

19,624

383

11 Dec 2021 (Omicron)

17,153

  36

 

So, at first view, it seems that the omicron wave is much less “deadly” than the previous ones.  However, the omicron infection curve is much steeper and mortality is known to lag several weeks after cases are identified.  Hence?  

Ep 201-7: News site AOL at 12PM on Sunday 12 Dec.

Things are evolving quickly in the UK:

  • According to overall UK Omicron case numbers, Saturday’s figure of 1,898 confirmed cases was up 50% on Friday’s figure when the total was 1,265.
  • Dr. Susan Hopkins: We’re also seeing hospitals diagnose more and more people coming through their emergency departments, and we expect to see increases in that number. I have not had a report of death yet

 

Provisional conclusions

  1. It is too early to decide on whether omicron is more “mild” than previous variants.
  2. Although previous infection or vaccination fails fully protect against omicron, vaccination and a third booster remain very important to mitigate the spread of this virus.
  3. Strengthening of NPI is also urgently needed, but will be very difficult to be accepted….

 

FEEDBACK AND REFLECTIONS

  1. What can we learn from the recent past? (Prof Geert Molenberghs)

Narrative: this is the 14-day incidence from September 1, 2020 to April 30, 2021 (four months before and four months after New Years).

 

* Belgium and Austria have a similar evolution: strong autumn peak, reduced around New Year, no effect from New Year, with an increasing plateau and a third wave around Easter.

(Note: if we were to replace the Belgian curve by the Flemish one, then the height of the second wave for Belgium is not 1800 but 1000, and shifted a little to the right; then the Belgium - Austria resemblance is even more striking). A legacy of Maria Theresa?

 

* UK, IRL, PT: especially in IE and PT, the autumn wave has remained reasonably under control; a bit brighter in the UK. But then there is a relaxation for Christmas and New Years, *and* the spread of alpha begins, resulting in very strong increases. Erika, Niel and I impressed Ben Weyts in that period with the "Irish curve". The relaxations were far-reaching, and then you get an unheard of rapid increase in the spread of a new, more contagious variant, because everything is aligned with the previous variant. The larger the country, the slower the rise, because a wave must also spread out over the territory in space. That can happen quickly in a small country. But the alpha wave in the UK started in London and Kent and has steadily moved north. All three countries have learned their lessons and have maintained a fairly strict regime. In the UK, the curve has nevertheless started to rise from May 1, 2021, in a smooth movement… the delta wave.

 

Personal addition: I find the different recent evolution in Portugal, Austria and Belgium also interesting.  These 3 countries have about the same population, but

  • The fourth wave behaves differently: rather low in PT versus similar rising in BE and AU, but then coming down several weeks earlier in AU than in BE.
  • Different degree of vaccination PT = 89 %, BE = 76 %, AU = 72 %.   
  • NPI measures were taken in AU several weeks earlier and are more strictly than in Belgium.

 

AUSTRIA

 

BELGIUM

 

  

 

  1. Dr Pharm Suzy Huijghebaert on possible implication of neutrophils in “antibody-dependent enhancement”

 

ACE was looked at in monocytes/macrophages, but should we not rather look at ADE in neutrophils (ifunopposed by AAT, LEI,...) and/or in presence of trypsin(like)protease activity (relevant to co-morbidities that may be subjected to such enhanced protease activities, and so accelerated priming (TMPRSS2 in cancer, trypsin(like)/elastase effects in haemodialysis, some heart disease, eventually stroke)?

-       Calvert /Salk Institute finds enhanced infectivity in vitro in presence of neutrophils 

 

-        Asarnow: study with Abs, showing neutralization, lack of neutralization and even enhanced syncytia formation dependent on the Ab tested -> this in vitro ADE was found in a neutralizing assay  assessed in presence of trypsin  https://pubmed.ncbi.nlm.nih.gov/33974910/

 

-  To note: trypsin is used in biochemistry to 'afucolsylate' IgG antibodies... Moreover neutrophils and NADPH oxidase mediate for instance intrapancreatic trypsin activation (Gukovskaya 2002). The effect on the NaDPHoxidase is relevant , also trypsin independent, as for instance, pulmonary artery NADPH-oxidase is activated in hypoxic pulmonary vasoconstriction (Marshall 1996). 

 

- In COVID-19, ADE of SARS-CoV-2 Infection was found to be mediated by the IgG Receptors FcγRIIA and FcγRIIIA but did not contribute  to aberrant cytokine production by “macrophages “ Neutrophils were not studied… (Maemura https://pubmed.ncbi.nlm.nih.gov/34579572/ )

 

- Yet Neutrophils/Neutrophil Extracellular Traps (NETS) contribute to COVID-19 hyperinflammation and humoral autoimmunity (Torres-Ruiz J https://pubmed.ncbi.nlm.nih.gov/34685525/ ) Antinuclear antibodies (ANA), anti-neutrophil cytoplasmic antibodies (ANCA) and the degradation capacity of NETs were addressed in serum. A higher proportion of low density granulocytes (LDGs) in severe and critical COVID-19 were found. Anti-NET antibodies would be related to the presence of autoantibodies. What happens with these? Link to auto-immune disease complexation. (https://pubmed.ncbi.nlm.nih.gov/16849638/

 

- Human neutrophils express FcγRIIA, a single-chain transmembrane receptor which carries an immunoreceptor tyrosine-based activation motif in its cytoplasmic tail, as well as FcγRIIIB, an entirely extracellular molecule which is anchored to the plasma membrane by a GPI moiety  (To note: Fc type differs by species).

 

- Moreover, neutrophils also carry neonatal Fc receptor (FcRn) . FcRn is expressed within azurophilic and specific granules of neutrophils and relocates to phagolysosomes on phagocytosis of IgG-opsonized bacteria. FcRn was found to enhance phagocytosis in a pH-dependent manner which was independent of IgG recycling. More neutral pH or electrostatic forces (so also salt) may affect FcRn IgG binding and/or antigen.

 

- At last, - Arcanjo 2021, Veras 2021: SARS-CoV-2 in fact is able to induce IL-8, impair

 

phagocytosis and to activate NETosis in human neutrophils, attributed to (NADPH oxidase, PMA-alike) ROS-formation ot PAD-4 interaction. Adding a pathogen to the NETs, showed a different aggregation/loss of integrity pattern in presence of SARSCoV2 on fluorescent labeled e-microscopic images. As this exaggerated and changed response associated with NETosis is increasinly recognised to be key to infection/ARDS, this urgentlly calls for  neutralising essays of vaccins being performed in host models with neutrophils, as these are an important part of our innate immune system.

 

So, prerequisites may be presence of neutrophils,and/or trypsin(like)protease activity, and/or altered NaCl/pH (by common cold and/or virus) to test for ADE in neutralizing assays to test efficacy of vaccines. 5or at least absence of trypsin inhibitor such as FBS)

 

To note , the  sera itself -when used in neutralising assyas- contain trypsin inhibitors (I have no insights in the assay and dilutions used) so if generated  from healthy people, potentially              masking ADE manifestations in subgroups at risk. [I have no insights in, nor checked the models used]

 

If de-activation of Ab takes place, while there is sufficient systemic immunity (through anti-trypsins AAT, LEI...) , this can maybe  breakthrough symptoms with common cold symptoms after vaccination? and still hospitalization in patients at risk with co-morbidity?

 

Should Abs against the modified S2 part, developed by the vaccine (cfr. Jean Francois

Sabatier)  also be assessed as well for ADE with the VOC? Also in presence of neutrophils and/or trypsin?

 

Personal comments:

 

  • Neutrophils are playing an important role in severe disease indeed and it is known that antibody production in severe cases starts later and these Ab have lower affinity.  Whether this situation could lead to the pathogenic mechanisms that Dr. Huijghebaert proposes, merits empirical investigation.
  • With regard to vaccination, I do not see many arguments for ACE: there is no evidence that vaccination would sensitize to severe disease, even not in people with weak immune responses (who might produce lower affinity Ab).  Quite on the contrary, there is overwhelming evidence of protection  against severe disease, even in the most vulnerable populations. 
  • Although the evidence that omicron readily infects people with waning antibody responses (after infection or vaccination) is rapidly accumulating, provisionally there is no evidence that this would lead to more severe disease than in case of breakthrough infections with the previous VOC (alpha to delta).  

Tomorrow is a full day with the online conference of the Belgian Virology Society.  Presumably, I will be back with Episode 202 on either Tuesday or Wednesday.

Best wishes,

Guido