3 Oct Serum therapy, monoclonal antibodies for Trump. Progress and critical remarks on COVID vaccine. Prognostic significance of viral load. The Economist review.

1. I’m constantly screening the literature to look for results of  convalescent plasma therapy, but the harvest is meager, despite the many thousands who are/have receiving/received . this therapy. First attachment is the abstract of a paper in JAMA on a trial in Wuhan (I could not get the full pdf).  Clearly, the results were not convincing and the trial was stopped early.

2. Presumably, most of the present trials pre-screen the plasma for “neutralizing” activity, which is a tedious task, because you have to perform an in vitro culture, preferably with live virus (pseudovirus could be used as well).  The recent paper in Nature Biotechnology offers a simple ELISA alternative, using plate-coated ACE2 receptor and soluble marked spike protein. If neutralizing Ab are present in serum, they will interfere with this binding and thus lower the ELISA signal (Fig 1 p.2).  The test was shown to be sensitive and specific: only limited cross-neut from with SARS-CoV-1 sera (Fig 3c p.5),  as could be expected, since both viruses are related and use the same receptor.  Clearly useful to screen for neutralizing activity (e.g. in vaccine or plasma therapy studies).  In addition, however, the cross-neutralization could also be used to “hunt for the animal reservoir or intermediate hosts” i.e. antibodies against very related viruses in animal species that could be the “bridge” between the bat virus and the human.    

3. Now, as we have discussed earlier: in vitro neutralization at a serum (i.e. polyclonal) level is NOT the Holy Grail to immunotherapy or vaccination, as there are many examples in virology, where neutralizing activity in vitro is NOT correlated with in vivo protection.  Also in  COVID it is striking that the neutralizing antibodies are higher in patient with severe versus mild disease.

However, human monoclonal antibodies with very strong neutralizing activity could be v ery useful and many have been identified already.

Earlier this week, there was an announcement from Regeneron Pharmaceuticals (a company that received $ 450 million from the US government), to produce and test a cocktail of 2 potent SARS-CoV-2 neutralizing antibodies.  It appears that those  Ab indeed reduce the viral load and alleviate symptoms in sero-negative COVID patients (who haven’t yet Ab of their own).  Another company, Lily, earlier reported that another neutralizing monoclonal also reduced the severity of disease.  Both reports are preliminary and not peer-reviewed or published.  My guess is that DJ Trump receives the Regeneron Ab at this very moment….

4. A very nice overview of the “state of the art” of vaccine development by Florian Krammer in Nature, with very illustrative figures and tables at the end.  It is likely we will have several SARS-CoV-2 usable vaccines next year.  But will those vaccines solve all of the problem?  Two very recent comments (one in Nature, the other in NYT) argue that the present trials:
   1. Do NOT address the most important question: will they protect elderly or otherwise vulnerable people from infection and especially severe disease?
   2. There is still lack of transparency about the monitoring and especially the way side effects are handled (e.g. in the Oxford-Astra Zeneca trial).
   3. By design and hurry, there will be no data on longer term (> 3months) efficacy nor side effects.
   4. Neither will we have sufficient data on children, adolescents and pregnant women.  While pregnant women are a risk group for severe disease, the former two groups obviously are less so. But, for all these vulnerable groups (including the elderly), it will be difficult to judge the risk/benefit ratio upfront, when the vaccine(s) is/are being rolled out.  
   5. In general, too much political pressure on the agencies (FDA, CDDC, EMA).

5. The assumption that high viral load (lower Ct value ) at admission is associated with a higher  chance on severe disease and death, is confirmed in two single-center studies.  However, this is a very delicate assay (collection method, sample storage, PCR method…). Therefore, it should be interpreted with caution, until we find a more standardized approach.

6. Finally, a very nicely illustrated review by The Economist on the ”state of the epidemic” in the world at the end of September.  Take home messages:

• The number of infected subjects may be about 15 times higher than the confirmed cases. Hence about 500 million people worldwide.
• The number of deaths may be twice the official number: hence 2 million.
• To prevent as much new infections as possible a vaccine should be rolled out at a very high pace. “Quicker more important than sooner”.

Have a nice WE.

Guido