The match that lights the fire

Dear colleagues,

Before tackling the question in the title first an update on a few other topics:

1. Vaccine development: A nice overview from Nature Briefings (first attachment). At present there are 78 confirmed candidates.  The principles are not new: nucleic acid (DNA and RNA), virus-like particle, peptide, viral vector (replicating and non-replicating), recombinant protein, live attenuated virus and inactivated virus approaches.  Most of them are being developed by companies, some well known (Janssen, Glaxo, Sanofi), others just emerging. Nothing has been published yet, as far as I can see. The big question remains, however, can protective immunity be induced by infection or vaccination?

2. Reactivation? You may have seen this press release https://news.yahoo.com/coronavirus-reactivate-recovered-patients-experts-210938429.html. It is about patients relapsing in terms of viral RNA after recovery in Korea and China. I looked again for evidence of relapse in the literature and found a recent short paper in CID from Shenzen (China).  25 out of 172 patients had reappearing RNA in either nasopharynx (11) or rectum (14) about 1 week after the last negative swab.  The only clinical sign was a “mild cough” in 8/25.  Reassuringly, there was no worsening of CT and all patients turned negative after a few days. Comparing the “relapsers” and the “non-relapsers”, an inverse correlation was found with D-dimers and treatment duration and a direct correlation with lymphocyte count. (Sorry, but I cannot make much sense of that observation). All in all, there is ample evidence of relapse of RNA in both nasopharynx and stool (also persistence in stools, while negative in the nasopharynx) but no published evidence of clinical relapse. So, there is hope on “protective immunity” after infection.

3. Validation exercise on ELISA and POC assays:  The paper by Lassaunière et al. in medRxiv has not been peer-reviewed, but it was produced at Staten Serum Institute in Denmark, which is a quality label.  Results are rather clear-cut:
   • The Wantai SARS-CoV-2 Ab ELISA beats the Euroimmun ELISA both in terms of specificity and sensitivity. 

• The reason for better specificity may be the antigen: receptor-binding domain for Wantai and spike for Euroimmun. Spike Ab may have more tendency to cross-react with other Corona’s. 
• The reason for higher sensitivity is the format: “antigen double antigen sandwich” for Wantai versus the more classical antigen-antibody-antibody format, resulting in a better discrimination for Wantai (Fig 1A p.13).
  • Performance of the POC tests was rather good: in the rank order of AutoBio Diagnostics > Dynamiker Biotechnology = CTK Biotech > Artron Laboratories > Acro Biotech ≥ Hangzhou Alltest Biotech.

Clearly, in view of the known temporal appearance of seroconversion (see additional paper by Li Gou in CID), it can now be stated that the sensitivity of a good serological assay surpasses that of RT-PCR after about 8 days into the symptomatic phase.

4. And now about the match and the fire. In the absence of a highly active and SARS-COVID-2 specific antiviral, we keep reading on all kinds of theories and experimental treatments, until now mostly in small uncontrolled trials, with doubtful outcome.  There is the underlying presumption that even specific antivirals might not be enough, because in severe cases, “hyper-inflammation”, ‘cytokine storm” takes over at some point.  Hence, in a proportion of the patients, you might be too late with antivirals alone, when the hypoxic patient, with a lot of “ground glass” in his/her lungs, presents at the emergency department. 

Experimental trials with corticosteroids etc have certainly not been convincing.  There is a whole list of mAbs against all kinds of inflammatory mediators (IL-6, TNF, JAK/STAT…..) officially in trials now and maybe something will work. We will see.  But the thing is that, once you are in a cytokine storm, there is a number of interacting “vicious circles” of cytokines, chemokines, complement and coagulation cascades that you cannot stop anymore at one single point.  However, at some earlier point in time, there may have been a more limited (ideally a single) instigator. If you could counteract this one/these ones in time, you may prevent the storm.  How could you identify the match that lights this raging fire?

Then, I’m thinking about these stories, I hear from colleagues at the frontline, about some patients who first apparently improve and then, after a week in the hospital, when discharge is considered, suddenly deteriorate.  So, clearly, those are “ideal” to look for the match.  In a hospital setting  blood and other samples (respiratory?) are being taken on a daily basis.  So you could go back and explore either serum for a range of cytokines and chemokines or performing micro-arrays on white blood cells to discriminate between matched patients who develop (the next day) this “secondary” worsening and those who don’t and recover further.  This may help to find “the wicked needle in the haystack”.

Who takes up this challenge?

Happy Easter,

Guido