20 November 2021 Episode 190 Nice reviews, more on origin and cross-reactivity

Sat, 11/20/2021 - 21:00

Dear colleagues,


First I “stumbled” on some nice reviews that might be a useful source of didactic slides.


Next, I will discuss the most recent data on two controversial issues: SARS-CoV-2 origin and importance of cross-reactive immunity to “common cold” coronaviruses.  I hope you will enjoy…


Didactic overviews


Ep 190-1 A: A very clear overview on how SARS-CoV-2 infects cells in  Nature, with a video.


Ep 190-1 B:  An comprehensive overview on beta-coronaviruses with clear illustrations.


Ongoing controversy about SARS-CoV-2 origin


Ep 190-2:  A critical review in Cell (August 2021) on the origin, with 22 mainly Anglo-Saxonian authors. I highlighted the salient sentences in the text.  This is the conclusion:  

  • There is substantial scientific evidence supporting a zoonotic origin. The animal reservoir for SARS-CoV-2 has not been identified, but the key species may not have been tested,
  • The possibility of a laboratory accident cannot be entirely dismissed and may be near impossible to falsify. Nevertheless it is highly unlikely relative to the numerous and repeated human- animal contacts that occur routinely in the wildlife trade.


Note also that the importance of the “furin cleavage site” as an “unnatural” sequence, which has been used by proponents of the “lab leak” hypothesis (see Episode 178 and 179) is strongly played down here (see page 4851-2).  


Ep 190-3: is the paper in Science by Michael Worobey that received a lot of media attention during the last couple of days.   He is co-author of  the Cell paper (Ep 190-2) and also defended the zoonotic hypothesis in the Science debate (see Episode 179-1). In this paper, he further supports the  origin at the live animal Huanan market by analyzing early case reports from December 2019 in several Wuhan hospitals, with clear links to the market .


Remarkably, however, the first patients he describes in the 4th paragraph (an elderly couple that presented at the Hubei Provincial Hospital) has no apparent link to this market, but to another one (Yangchahu, were no live animals were sold). 

In the third last paragraphs, he discusses the fact that in the early days two sublineages (A and B) were noted, with no intermediate.  He suggests that there have been two separate (and almost simultaneous) zoonotic jumps at Huanan market, although the earliest patients, infected with sublineage A had no direct link with this market.

His reasoning is a bit difficult to follow and, as he admits in the next paragraph, impossible to prove, since no collection of samples from live animals was done: they were all killed and all the markets were thoroughly disinfected…..


This paper brings some new analysis, but leaves also questions and doubts.  Not surprisingly, Alina Chan, a virulent, eloquent scientific proponent of the lab leak hypothesis (see Episode 179-1) , immediately posted a tweet:

This is like trying to guess the shape of an iceberg when you can only see what's above the surface. Where are the November case data? We know that by December there had been a superspreader event at the seafood market and cases numbered in the hundreds.


It seems that this debate will continue with both scientific and other (emotional, ideological…) arguments.  Whether the new WHO investigation will bring the “final answer” is unsure.


Ep 190-4: An interesting paper from 2015 (tempore non suspect), discussing the only well-documented case of an “unnatural” epi/pan-demic: the 1977 H1N1 flu. This virus was identical to strains from the early fifties and hit young people (with no immunity to the 1950 strain) preferentially.  Three hypotheses are considered:

  1. Bioweapon (mainly Russian): not very likely.
  2. Samples from the 1950 strain used as a potential vaccine or challenge after vaccination: in the US or China?  
    • there was a fear for a 1976 swine H1N1 to become the next pandemic
    • live attenuated virus as a vaccine was popular at the time
  3. Lab leak: it carries a hallmark of lab manipulation by subculture on cell lines (temperature sensitivity) and it is genetically very close to the 1950. 


The simultaneous  appearance of the 1977 strain in three separate Chines areas seems more compatible with option 2.


This much debated case has been an argument for a US ban on genetic manipulation experiments of “gain of function” in viruses.  


Clearly, this “influenza case” is very different from the SARS-CoV-2 case, where the distance to the most related animal (bat) viruses is about 1000 mutations.  Although technology has evolved a lot since 1977, it remains hard to believe that the Wuhan Institute would have been able to “create” SARS-CoV-2 from the bat progenitor in vitro or in animal models.  


But I have to admit that I’m not a molecular virologist….   


Role of cross-reactive immunity in protection?


It is a controversial topic as well.  Obviously, the seasonal coronaviruses are related to SARS-CoV-2, but rather distantly.  See Table below from Ep 190-5

Is this similarity enough for cross-reacting antibodies and T cells to have a significant impact on SARS-CoV-2?


  1. Recent evidence in favor of protective role by cross-reacting T cells


Ep 190-6 A and B: Swadling et al suggest that some highly exposed health care workers, who remain SARS-CoV-2 PCR and antibody negative, have avoided infection by cross-reactive CD4 and CD8 T cells against the RNA polymerase (which is more conserved than the structural proteins in Table 2).


Obviously, it is difficult to prove that these HCW really have been “abortively infected”.  An argument in favor is that they show increased levels of an interferon-induced gene IF127, which has been associated with early SARS-CoV-2 infection (but which, undoubtedly, also increases after other viral infections).


This situation reminds of the repeatedly reported HIV-specific CD8 T cell responses, observed in “highly exposed persistently seronegative” subjects.  In case of HIV, there is no argument of cross-reactivity (since there are no related “benign epidemic human retroviruses). In both cases (SARS-CoV-2 and HIV), repeated low dose exposure could result in protective T cell responses, preventing an infection to get established. Hence “abortive infections”, remaining “seronegative” (no antibodies).   


  1. Role of cross-reactive antibodies?


Ep 190-7 A: Rachel Brazil explains the related concepts of “original antigenic sin” and “immune imprinting”, which have been shown to influence the immune response to influenza for instance. 


After a first exposure to a particular Flu strain as a young child, a person, when confronted with a novel strain, will tend to expand the “memory T and B cells”, specific for this strain rather than to the “new epitopes”. Obviously, if there is enough resemblance between the new and the original strain this will lead to quick and efficient protection.  However, if the new strain is too divergent, the “immune imprinting may result in inadequate responses, not specific and strong responses to the new strain.


In case of Dengue, this phenomenon is known to even promote the life-threatening “dengue hemorrhagic shock” syndrome, because reactivation  of antibodies to 1 subtype not only fail to neutralize another subtype, but even enhance the infection.  


Ep 170-7 B: Elisabeth Anderson Cell April 2021 finds that pre-existing cross-reactive Ab to common CoV are boosted by SARs-CoV-2 infection, but do not protect against hospitalization.


Ep 170-7 C: Gouma (JCI Insight 2021) finds that HCW with high Ab against common beta CoV (OC43 and HKU-1), as evidence of recent exposure, when infected with SARS-CoV-2 showed a lower duration of symptoms.  


Ep 190-7 C: Elisabeth Anderson (same as 7 B) now compare infection and mRNA vaccination:

  • SARS-CoV-2 mRNA vaccines elicit higher levels of antibodies than SARS-CoV-2 Infections.
  • The first dose of an mRNA vaccine generates both S1 and S2 responses while the second dose boosts primarily S1-specific antibodies. (Remember that the fusion part (S2) is more conserved amongst beta coronaviruses, while S1 is more specific: contains the receptor binding site. See Table 2 above.
  • SARS-CoV-2 infections, but not mRNA vaccinations, elicit high levels of antibodies that bind strongly to seasonal coronaviruses but weakly to SARS-CoV-2.


Clearly, while cross-reacting Ab behave rather like “original sin” after infection, it seems that mRNA vaccination elicits Ab that are more specific to SARS-CoV-2.


Although this episode doesn’t give final answers with regard to the origin nor the significance of cross-reactivity, I hope it has provided you with some “insights”…..


Best wishes,