COVID-19 & The `M' Word

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If you want to ensure a lot of clicks for your infectious disease story, one surefire way is to include the `M' word - `Mutation' - in the headline. For most people, the `M' word evokes a sense of dread - a belief that something  undeniably `bad' has happened.

A notion fostered, I suspect, by scores of grade-B Sci-Fi movies over the past 70 years that always seem to use `mutations' as the genesis of their `monsters'.

The truth is, viruses are constantly mutating. It's what they do. It's part of the evolutionary process.

And single-stranded RNA viruses - like influenza and coronaviruses - are particularly prone to `duplication errors' during replication, and are constantly introducing mutations (see Mechanisms of Viral Mutation).

Most mutations end up being of  little consequence, and do nothing to affect the transmissibility, replication, host range, or virulence of the virus. Some even prove detrimental, making the virus less `fit' than its predecessors, or attenuating its virulence. 

And mutations are random (although they can be nurtured by host adaptation), and that means the odds of a virus coming up with the `right' set of mutations to spark, or worsen, a pandemic virus is a relatively rare event. 

None of which is to say it never happens. Viruses make trillions of copies of themselves each day.  Eventually one is bound to get `lucky'. 

We are in the midst of this pandemic because a novel coronavirus defied long odds and mutated into a human-adapted virus.  Similarly, MERS-CoV mutated from bat-borne virus (see Two Mutations Were Critical for Bat-to-Human Transmission of Middle East Respiratory Syndrome Coronavirus) in order to successfully jump to camelids, and then to humans.

A few past examples include:

• The H275Y mutation in seasonal H1N1 back in 2007-2008 pretty much negated the effectiveness of NAI (Neuraminidase Inhibiting) antiviral drugs (see CIDRAP article With H1N1 resistance, CDC changes advice on flu drugs). Luckily that virus was supplanted by the 2009 H1N1 virus, which remains susceptible the drug.
• For avian flu, researchers have determined the (E627K) substitution in the (PB2) protein makes the an influenza virus better able to replicate at the lower temperatures (roughly 33C) normally found in the upper human respiratory tract (see Eurosurveillance: Genetic Analysis Of Novel H7N9 Virus).
• And a mutation in the envelope protein gene (E1-A226V) of the CHKV virus allowed Aedes Albopictus or `Asian tiger’ mosquito to transmit the virus more efficiently (see A Single Mutation in Chikungunya Virus Affects Vector Specificity and Epidemic Potential).

Obviously viral mutations can have a negative impact on humans, and so we watch the evolution of hundreds of viruses with great interest, even though our understanding of the impact of single amino acid changes in most viruses is limited. 

Understandably, new mutations in - or new variants of -  SARS-CoV-2 are of great importance, since they could potentially affect the `fitness' and virulence of the virus, the effectiveness of any future vaccine, and its ability to re-infect a human host. 

Hardly a day goes by without seeing a new (usually preprint) article or study, suggesting that SARS-CoV-2 has mutated in some significant way.  These `preprint' articles are a wonderful way to get an early look at the latest scientific evidence and thought, but have not been rigorously peer-reviewed.

One that has been making a stir the past week or so identifies a SARS-CoV-2 mutant in India that appears to alter its RBD (Receptor Binding Domain) that could negatively impact vaccine development (see Newsweek FIRST 'SIGNIFICANT' CORONAVIRUS MUTATION DISCOVERED IN PRELIMINARY STUDY).

Analysis of the mutation dynamics of SARS-CoV-2 reveals the spread history and emergence of RBD mutant with lower ACE2 binding affinity

Yong Jia, Gangxu Shen, Yujuan Zhang, Keng-Shiang Huang, Hsing-Ying Ho, Wei-Shio Hor, Chih-Hui Yang, View ORCID ProfileChengdao Li, Wei-Lung Wang

doi: https://doi.org/10.1101/2020.04.09.034942

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Summary

Monitoring the mutation dynamics of SARS-CoV-2 is critical for the development of effective approaches to contain the pathogen. By analyzing 106 SARS-CoV-2 and 39 SARS genome sequences, we provided direct genetic evidence that SARS-CoV-2 has a much lower mutation rate than SARS. 

Minimum Evolution phylogeny analysis revealed the putative original status of SARS-CoV-2 and the early-stage spread history. The discrepant phylogenies for the spike protein and its receptor binding domain proved a previously reported structural rearrangement prior to the emergence of SARS-CoV-2. Despite that we found the spike glycoprotein of SARS-CoV-2 is particularly more conserved, we identified a mutation that leads to weaker receptor binding capability, which concerns a SARS-CoV-2 sample collected on 27th January 2020 from India. 

This represents the first report of a significant SARS-CoV-2 mutant, and raises the alarm that the ongoing vaccine development may become futile in future epidemic if more mutations were identified.

Highlights

• Based on the currently available genome sequence data, we proved that SARS-COV-2 genome has a much lower mutation rate and genetic diversity than SARS during the 2002-2003 outbreak.

• The spike (S) protein encoding gene of SARS-COV-2 is found relatively more conserved than other protein-encoding genes, which is a good indication for the ongoing antiviral drug and vaccine development.

• Minimum Evolution phylogeny analysis revealed the putative original status of SARS-CoV-2 and the early-stage spread history.

• We confirmed a previously reported rearrangement in the S protein arrangement of SARS-COV-2, and propose that this rearrangement should have occurred between human SARS-CoV and a bat SARS-CoV, at a time point much earlier before SARS-COV-2 transmission to human.

• We provided first evidence that a mutated SARS-COV-2 with reduced human ACE2 receptor binding affinity have emerged in India based on a sample collected on 27th January 2020.

Another potential game changer (assuming the evidence holds up), is being heavily hyped by the mainstream press the past couple of days (see Extremely dangerous virus mutation).

The paper, authored by Professor Li Lanjuan and colleagues from Zhejiang University in Hangzhou, China claims to have found `. . . direct evidence that the SARS-CoV-2 has acquired mutations capable of substantially changing its pathogenicity.'  

The link to the preprint follows. 

Patient-derived mutations impact pathogenicity of SARS-CoV-2

Hangping Yao, Xiangyun Lu, Qiong Chen, Kaijin Xu, Yu Chen, Linfang Cheng, Fumin Liu, Zhigang Wu, Haibo Wu, Changzhong Jin, Min Zheng, Nanping Wu, Chao Jiang, Lanjuan Li

doi: https://doi.org/10.1101/2020.04.14.20060160 

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Abstract

The sudden outbreak of the severe acute respiratory syndrome-coronavirus (SARS-CoV-2) has spread globally with more than 1,300,000 patients diagnosed and a death toll of 70,000. Current genomic survey data suggest that single nucleotide variants (SNVs) are abundant. However, no mutation has been directly linked with functional changes in viral pathogenicity. 

Here we report functional characterizations of 11 patient-derived viral isolates, all of which have at least one mutation. Importantly, these viral isolates show significant variation in cytopathic effects and viral load, up to 270-fold differences, when infecting Vero-E6 cells.

We observed intrapersonal variation and 6 different mutations in the spike glycoprotein (S protein), including 2 different SNVs that led to the same missense mutation. 

Therefore, we provide direct evidence that the SARS-CoV-2 has acquired mutations capable of substantially changing its pathogenicity.

During the fall of 2009 - during the height of the H1N1 pandemic - we saw Hyperbolic Headlines of deadlier strains circulating in Europe, causing severe lung damage.  While most of those reports were overblown, it turned out that a very small percentage of H1N1 infections (< 2 %) carried the `Norway’ or D222G (D225G in influenza H3 Numbering) mutation. 

A mutation that favors a lower respiratory infection by the virus, often resulting in a more severe illness (see EID Journal: Emergence of D225G Variant A/H1N1, 2013–14 Flu Season, Florida).

Had this mutation been more prevalent, H1N1pdm could have been a much deadlier pandemic. We've also seen evidence of significant Differences In Virulence Between Closely Related H5N1 Strains, again suggesting that minor changes in the virus can yield big changes in its impact. 

If (and it's a big `if') there are more virulent strains of SARS-CoV-2 circulting in Europe, and that is what is behind the seemingly higher CFRs reported by countries like Italy and Belgium, then that would be a major concern.  

And the same would hold true if there is `significant' mutation of the virus - one that impacts the RBD - circulating widely in India. 

And both are certainly possible.  

But we'll need more corroboration, rigorous peer-review, and hopefully some direct evidence of sustained transmission of these mutated viruses before we can begin to evaluate how much of an impact they may or may not have.

In the meantime, SARS-CoV-2 will undoubtedly continue to evolve, as must our coverage of this pandemic.  

Stay tuned.