COVID: genetic mutations in second wave in Texas

 A disturbing article was just published in pre-print and pre-peer review form of a large second wave of Covid-19 infections in Houston, with clear evidence of significant genetic changes in the virus (see covid genetic change houston 2nd wave in dropbox, or https://www.medrxiv.org/content/10.1101/2020.09.22.20199125v2.full.pdf). this article was mentioned in a recent Washington Post article: https://www.washingtonpost.com/health/2020/09/23/houston-coronavirus-mutations/?arc404=true 

 

Details: 

-- the 1^st cases of Covid-19 in Houston were reported on March 5, 2020. The epidemic curve peaked around April 11-15 (peaking at around 200 cases per week), followed by a decline until May 11 

-- there was a sharp uptick in confirmed cases on June 12 (peaking at about 1400 cases per week) 

    -- the 1^st wave was defined as March 1 through May 11; and the 2^nd wave as May 12 through July 7 

-- patients in the 2^nd wave were considerably younger, had fewer comorbidities, were more likely to be Latinx, and lived in ZIP Codes with lower median incomes 

-- genome sequencing was done in 5085 specimens of the infecting SARS-CoV-2 virus beginning with the first confirmed Covid cases, 1026 from wave 1 and 4059 from wave 2 

 

Results: 

-- genotypes from the 1^st wave represented major viral clades identified globally (mostly clades G, GH, GR, and S), suggesting that this 1^st wave of infections appeared in Houston from many different independent sources: these SARS-CoV-2 viruses originated from Europe, Asia, South America, and elsewhere in the US 

-- the 2^nd wave also had diverse genotypes, but with a dramatic increase in the Gly614 genetic variant. And, this change took only weeks-to-months to happen. 

    -- strains with the Gly614 amino acid variant in the spike protein represented 82% of SARS-CoV-2 strains in wave 1 and 99.9% in wave 2 (p<0.0001) 

        -- of note only 71% of the earliest specimen sequenced in March had this variant 

    -- the SARS-CoV-2 viral load was significantly higher in patients with the Gly614 mutation, with cycle threshold of about 34 in those who did not have the mutation vs 29 in those with this mutation, p<0.0001 (the lower the Ct, the higher the viral load)

 

--relationship to disease severity: 

    -- there was also no simple relationship with sex, age, or ethnicity 

    -- there was no clear relationship between virus clades and Covid-19 disease severity looking at the highest level of required care (ICU, intermediate care unit, inpatient, or outpatient) 

    -- virus genome sequencing did not add to the predictive model for disease severity, which was similar to random chance. Adding the patients’ age, sex, and ethnicity increased the model by 5 to 10%, still not much difference from chance 

    -- there was a mortality correlation with Rh positive blood type and increasing age, explaining 22 to 27% of the variation in mortality 

    -- machine learning/troving through immense amounts of data did not find any specific SNPs (single nucleotide polymorphisms) associated with increased viral severity or outcomes 

 

-- of some concern, 6 of the amino acid changes could potentially interfere with either remdesivir binding or RNA synthesis, though none were in the precise 2 positions associated with in vitro resistance 

-- some of the mutations in the receptor binding domain region of the spike protein could lead to increased ability to escape humoral immune pressure but otherwise retain strong ACE2 home binding affinity 

 

Commentary: 

-- Houston is the 4^th largest and the most ethnically diverse city in the US, with a population of about 7 million 

-- the 1^st Covid cases in Houston were reported on March 5, 2020 with community spread one week later 

-- this study documented significant genetic mutations in the SARS-CoV-2 virus in the matter of several weeks, with the emergence of strands consistently with a spike protein mutation (Gly614) that could have important clinical and epidemiologic consequences 

    -- for example, the fact that this Gly614 genetic variant started off at 71% in the 1^st wave but then increased to an overall 82% is consistent with the dramatically higher viral load associated with this variant and likely associated increased transmissibility

-- Other studies have also suggested that the Gly614 variant also had increased replication in human lung epithelial cells in vitro, as well as increased virus fitness in the upper respiratory tract (the latter finding was in animals) 

-- the coronavirus was initially felt to be relatively stable and more resistant to genetic mutations, given that it has more intrinsic ability than some other viruses (eg flu) to repair its own mutations (eg see https://www.tandfonline.com/doi/full/10.1080/07391102.2020.1778536 ) 

 

so, this article is not clearly a worst-case scenario, but it does bring up some really important issues: 

--there are very likely to be more and more major genetic mutations in the virus, especially in light of how widespread the virus is (another reason why it was so terrible that the US overall did not really lockdown early  and with very aggressive contact tracing/isolation/mask wearing/etc,  leading us still to have at least 35,000+ cases a day with a huge viral reservoir for continued mutations) 

--at this point we do not know if those identified cases of likely re-infection were related to genetic changes creating decreased disease-induced immunity to the newer variants, but it is good that there are more genotypes being done to help elucidate this in the future (for a blog on likely reinfection: see http://gmodestmedblogs.blogspot.com/2020/05/covid-reinfection-cases-and-risk.html )

    --the real concern is that if there is a major mutation, that prior infection or vaccination may not provide resistance to future infection. sort of like the flu, where the actual components change pretty much annually to improve efficacy. So, we could need potentially rapidly evolving vaccines (given how quickly the Gly614 mutation happened) and given that, unlike flu, Covid-19 seems quite a bit less confined to cold weather seasons 

--another issue is that there may need to be vaccines with several different specific genetic sequences of the virus (again like the flu). i hope that our current vaccine approach, with many different countries and companies working independently (and for likely huge profits), will not hamper the potentially very important scientific cooperation that may be needed for effective vaccine and therapeutic developments

 

-- it is really a hugely positive step in Houston that they have such a large genomic database of the 1^st and now an even larger database of the 2^nd wave of Covid-19 infections, and will likely serve to be very important as 3^rd and subsequent waves of infection occur (likely to happen in the absence of a very effective and well-accepted vaccine and/or effective levels of herd immunity, as Covid-fatigue settles in, especially in the colder months with more indoor activities, and as the profound economic, psychologic and social effects we are currently facing become less tolerable 

 

Limitations:

--this is a basic science assessment of genetic mutations, with plausible clinical implications.  But we don’t know til we know (ie clinical studies)

   --ie, this study raises very real issues about:

      -- the high viral load with the Gly614 variant: ?leading to increased viral transmissibility

      -- the potentially easier access of the virus to the ACE2 receptors: the Gly614 variant weakens the contact between the S1 and S2 subunits of the spike protein, decreasing the need for the virus to dissociate S1 from S2 and then refold after fusion with the virus

      -- the potential for remdesivir resistance with the Gly614 variant and with future mutations that might also affect other therapies

      -- the potentially increased virulence of the virus with the Gly614 variant: not found in this study, but the potentially higher pulmonary viral load is concerning

      -- the potential effects on the durable efficacy of vaccine

      -- the potential effects on how immunity from prior infection might be diminished

--also, though the Houston hospital complex involved in the study was quite broad and involved 7 hospitals and many outpatient care centers in geographically diverse areas of the city, there may well be underrepresentation of “individuals who are indigent, homeless, or of very low socioeconomic groups”, per their assessment. This could lead to an underestimate of the true genome diversity there.

 

So, we are unable to determine from this study that there are clear clinical adverse effects in humans from the mutations found, but:

--this Gly614 mutation is a big one, with likely others to follow (especially since the reservoir of infected people with really high viral loads is so large)

--this mutation happened quickly and spread also quite quickly

--these types of mutations may really increasingly affect the potential effectiveness of therapies and vaccines being developed

 

And, this all suggests to me that we really need to reduce the amount of virus circulating and mutatable: continued vigorous isolation measures, social distancing, not allowing facilities with close personal contact to continue (bars, political rallies!!, upcoming family holidays, etc), aggressive contact tracing and isolation of positives, aggressive promotion of masks (including by the political leaders….), etc.  And, reopening economies slowly and in a very controlled manner as done in several other countries (eg see http://gmodestmedblogs.blogspot.com/2020/09/covid-second-wave-in-china-aggressively.html )

geoff

 

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