Episode 78: convalescent plasma, vaccines, reinfection and aerosols

Episode 78: convalescent plasma, vaccines, reinfection and aerosols

1. Is convalescent plasma (CP) the next therapeutic myth in COVIDology?

I keep looking for evidence that CP actually works, but, until now, very little “hard evidence” has been published, despite the fact that tens of thousands have already received the treatment.

• An interesting opinion in CID “FDA Emergency Use Authorization: Glass Half Empty?” in CID criticizes the authorization of CP, because it was based on very weak evidence from open label use. The few RCT that have been done in the meantime show no convincing benefit yet. Obviously, care should be taken that plasma with high neutralizing capacity are selected and that patients receive this treatment early enough, probably best before they develop an humoral response of their own?
• In this regard, there is an interesting preprint from Mass Gen “COVID-19 neutralizing antibodies predict disease severity and survival” in medRxiv.  We already knew from previous papers that both ELISA titers and neut titers in fact are higher in severely ill patients, which at first view is not a very good sign to believe in humoral immunity as a potential protective factor against disease progression.  However, this paper elegantly shows that the ratio between neut/ELISA (NT50/IgG), “neutralization potency index” (or avidity?) could be interesting, as a high  NT50/IgG is associated with better survival (see Fig 3 L and M p. 36).  Clearly, these data are not super-solid and should be confirmed, but they are inspiring, as the authors point out that:
  • This index may be a risk-stratifying factor for COVID patients
  • A high index may guide the choice of a good vaccine candidate.
  • Conversely, a low index may be a risk factor for ADE (antibody-dependent enhancement.

Based on their own data, the authors also speculate that plasma therapy may be indicated in immunodeficient patients.

• Interestingly, I found this case report “Sustained response after remdesivir and convalescent plasma therapy in a B-cell depleted patient” in CID. Admittedly, it is only one case….

2. Also much trouble and questions about vaccine development:

According to this article in STAT this time FDA shows signs of cold feet over emergency authorization of Covid-19 vaccines. While in a follow-up the journal warns that It may be time to reset expectations on when we’ll get a Covid-19 vaccine.  

It seems that Pfizer-BioNTech (developing an mRNA encoding the receptor binding domain or RBD), will probably be the first one to show efficacy data on the primary endpoint, i.e. prevent 50% symptomatic infections (but with minimal statistical power) in November and then wants to unblind the study, giving vaccine access to the “placebo’s”.  That type of action will prevent to reach the “secondary endpoints”, including the appreciation if the vaccine works equally well in all subgroups (older people, minorities) and, of course, it will also limit very much information on longer term (side) effects.   The articles also refer to the problems with the Astra-Zenica and Janssen Adeno vaccines.  A new players is Novavax, developing a protein based vaccine with a proprietary adjuvant.  I add some results of phase 1-2 trials.

We can expect more heated and politicized debates about when to release the vaccines, now  that the virus hits us so hard.  Will science or fear prevail?

3. Reinfections is another topic of importance that is not yet well documented in the international scientific literature.  In this regard, a report from the Dutch RIVM on 52 cases is of interest. The full report is added in Dutch and there is an English translation of the main parts. Some salient findings:
   • Most re-infections occurred after a symptom-free period of> 60 days (57-133 days)
   • Serology:  a strongly increased antibody concentration, as well as a stronger binding of the antibodies (higher avidity) and antibody functionality (higher virus neutralization titers
   • Sequencing in 8 patients showed a different lineage in 5 of them.
   • Symptoms: in most patients the second episode was accompanied by comparable or milder symptoms. In only a few patients the symptoms were worse in the second episode.
   • Presently unclear to what extent these patients are contagious.

4. I guess many of you have seen the Lancet paper on non-pharmaceutical intervention in 131 countries?   It is a huge study and one wonders how the authors were able to disentangle the various measures in the complex mixes and sequences they were applied.  If you look at the most appealing (to me) Fig 3, you would think that school closures and banning gatherings of people are amongst the most effective measures.  However, I understand that this massive “big data” study, similar to some of the previous ones, is already under attach from people, who know how to deal with this type of data.  So, let’s be careful and avoid drawing too far reaching conclusions in this time frame, where panic more than analytical reasoning seems to inspire political decisions…..   

5. Aerosols: I know I do not need to convince you any more about the importance of airborne transmission neither about face masks and ventilation as preventive measures.  But the added papers (two from El Pais and one from Science) contain such nice didactic material that I thought I should share them with you.

Best wishes and keep safe.

Guido