Friday, February 28, 2020

Something Stinks in Wuhan


nature |   "Therefore, to examine the emergence potential (that is, the potential to infect humans) of circulating bat CoVs, we built a chimeric virus encoding a novel, zoonotic CoV spike protein—from the RsSHC014-CoV sequence that was isolated from Chinese horseshoe bats1—in the context of the SARS-CoV mouse-adapted backbone. The hybrid virus allowed us to evaluate the ability of the novel spike protein to cause disease independently of other necessary adaptive mutations in its natural backbone. Using this approach, we characterized CoV infection mediated by the SHC014 spike protein in primary human airway cells and in vivo, and tested the efficacy of available immune therapeutics against SHC014-CoV"

So they create a "chimeric" SARS-CoV virus that can cause disease (in humans)?

They continue:

"we synthesized the SHC014 spike in the context of the replication-competent, mouse-adapted SARS-CoV backbone (we hereafter refer to the chimeric CoV as SHC014-MA15) to maximize the opportunity for pathogenesis and vaccine studies in mice (Supplementary Fig. 2a). Despite predictions from both structure-based modeling and pseudotyping experiments, SHC014-MA15 was viable and replicated to high titers in Vero cells"

So they "maximize the opportunity for pathogenesis". Very interesting...

And then they continue saying:
"To test the ability of the SHC014 spike to mediate infection of the human airway, we examined the sensitivity of the human epithelial airway cell line Calu-3 2B4 (ref. 9) to infection and found robust SHC014-MA15 replication, comparable to that of SARS-CoV Urbani (Fig. 1c). To extend these findings, primary human airway epithelial (HAE) cultures were infected and showed robust replication of both viruses"

So in the last paragraph they have found that the new chimeric virus they have created (they called it SHC014-MA15) "show robust replication" in human cells. A great success I guess...

But they continue with the research and say:

"We next analyzed infection in more susceptible, aged (12-month-old) animals. SARS-MA15–infected animals rapidly lost weight and succumbed to infection"

So they test the new chimeric virus (they call it SARS-MA15 and also SCH014-MA15) in mice and they saw a high pathogenicity in the lungs of the animals, more acute in older ones

Then they continue with the trials of the SHC014-MA15 chimeric virus:
"Similarly, antibodies 230.15 and 227.14, which were derived from memory B cells of SARS-CoV–infected patients13, also failed to block SHC014-MA15 replication (Fig. 2b,c). For all three antibodies, differences between the SARS and SHC014 spike amino acid sequences corresponded to direct or adjacent residue changes found in SARS-CoV escape mutants (fm6 N479R; 230.15 L443V; 227.14 K390Q/E), which probably explains the absence of the antibodies' neutralizing activity against SHC014. Finally, monoclonal antibody 109.8 was able to achieve 50% neutralization of SHC014-MA15, but only at high concentrations (10 μg/ml) (Fig. 2d). Together, the results demonstrate that broadly neutralizing antibodies against SARS-CoV may only have marginal efficacy against emergent SARS-like CoV strains such as SHC014."

So it seems that the new chimeric virus they created is quite resilient to the antibodies normally used to treat SARS

Still more about the risks of chimeric virus:
"the creation of chimeric viruses such as SHC014-MA15 was not expected to increase pathogenicity. Although SHC014-MA15 is attenuated relative to its parental mouse-adapted SARS-CoV, similar studies examining the pathogenicity of CoVs with the wild-type Urbani spike within the MA15 backbone showed no weight loss in mice and reduced viral replication23. Thus, relative to the Urbani spike–MA15 CoV, SHC014-MA15 shows a gain in pathogenesis (Fig. 1). On the basis of these findings, scientific review panels may deem similar studies building chimeric viruses based on circulating strains too risky to pursue, as increased pathogenicity in mammalian models cannot be excluded"

So they recognize they have created a very dangerous chimeric virus with a high pathogenesis, easily transmitted in human cells and hard to fight by antibodies, and they said at the end "building chimeric viruses based on circulating strains too risky to pursue, as increased pathegenicity in mammalian models cannot be excluded"

Say What?

At the end of the article they finally said:
"Coupled with restrictions on mouse-adapted strains and the development of monoclonal antibodies using escape mutants, research into CoV emergence and therapeutic efficacy may be severely limited moving forward. Together, these data and restrictions represent a crossroads of GOF research concerns; the potential to prepare for and mitigate future outbreaks must be weighed against the risk of creating more dangerous pathogens. In developing policies moving forward, it is important to consider the value of the data generated by these studies and whether these types of chimeric virus studies warrant further investigation versus the inherent risks involved "

So I have some questions:
a) What are the probabilities that an strange new SARS virus, never seen before, very easily transmitted and very pathogenic, started exactly some hundred meters from the same research lab where theses people were creating chimeric viruses one day and the following?

b) What are the probabilities that a new "wild" virus be so similar to this chimeric virus created in 2015 for this study? Could it be a self-fulfilling prophecy?

c) What are the probabilities that the Wuhan Virology Instute have developed a very accurate test for the brand "new" virus in just some days after the outbreak? Do they have some knowledge in advance of what kind of virus it was?