Tuesday, December 27, 2022

Nature: Strong Attenuation of Omicron BA.1 & Increased Replication of the BA.5 Subvariant in Human Cardiomyocytes

Emergence of Omicron - Credit Our World In Data
 

#17,197

Just over a year ago the trajectory of the SARS-CoV-2 epidemic shifted dramatically with the emergence of a highly mutated Omicron variant, which - while causing less severe pneumonia than Delta - spread far more efficiently. 

As a result, the number of infections soared, but a much smaller percentage of patients developed severe illness and/or died (see chart above).  

The hope was the virus was losing its punch, and COVID would eventually join the plethora of seasonal respiratory diseases we deal with every year. And while that may still happen, we continue to see evidence that COVID is more than just `a bad cold' (see below). 

The Lancet: Neurological and Psychiatric Risk Trajectories After SARS-CoV-2 Infection

MMWR: Post–COVID-19 Symptoms and Conditions Among Children and Adolescents

More Evidence On The Long-term Impact of SARS-CoV-2 Infection

Nature: Long COVID After Breakthrough SARS-CoV-2 Infection

BMJ: Elevated Risk Of Blood Clots Up To 6 Months After COVID Infection

The Omicron variant (BA.1) that replaced Delta is long gone, having been supplanted by series of newer Omicron variants (e.g. BA.2, BA.5, BQ.1, and soon XBB), and while we've not seen a return to the severe pneumonia that Delta often produced, we have seen studies suggesting that Omicron may be gaining virulence in other ways.

Yesterday, in Preprint: Omicron BA.5 Infects Human Brain Organoids and is Neuroinvasive and Lethal in K18- 2 hACE2 Mice, we looked at research out of Australia finding that Omicron BA.5 infects and replicates in (lab grown) human brain cells more readily than earlier (BA.1) Omicron variants, and was more pathogenic in laboratory mice. 

Today we've a letter,  published in the Journal Nature, which looks at and compares the infectivity, and functional impact, of BA.5 and older Omicron variants on lab grown iPSC-derived human cardiomyocytes; the type of cells responsible for the contraction of heart muscle. 

We've seen considerable evidence linking SARS-CoV-2 infection with cardiac complications, including myocarditis, arrhythmias, and even sudden cardiac death (see Nature: Long-term Cardiovascular Outcomes of COVID-19).  

While most pronounced during the pre-Omicron phase of the pandemic, today's report suggests that BA.5 may be regaining some of COVID's ability to infect, and disrupt, the cardiovascular system.  

As we've discussed often, laboratory results don't always translate into real-world impacts - and we don't know if this trend will continue with XBB and whatever comes next - but it (along with yesterday's report) remind us that the trajectory of COVID is unpredictable going forward. 

I've only reproduced some excerpts from the letter, so follow the link to read it in its entirety.  I'll have a brief postscript when you return. 


Letter
Open Access
Published: 25 December 2022
Strong attenuation of SARS-CoV-2 Omicron BA.1 and increased replication of the BA.5 subvariant in human cardiomyocytes

Signal Transduction and Targeted Therapy volume 7, Article number: 395 (2022) Cite this article

Dear Editor,

Since its first description in South Africa in November 2021, the SARS-CoV-2 Omicron variant rapidly outcompeted the previously dominating Delta variant. Omicron is the fifth variant of concern (VOC). It contains an unusually high number of mutations compared to previous VOCs, especially in the viral Spike protein, and shows high transmissibility and efficient escape of neutralizing antibodies. Due to these characteristics, it received this designation much faster than the four previous VOCs Alpha, Beta, Gamma, and Delta.
 
However, the original BA.1 Omicron variant seems to be less pathogenic than early SARS-CoV-2 strains and other VOCs.1 While SARS-CoV-2 primarily infects the respiratory tract, Coronavirus disease 19 (COVID-19) is a multi-organ disease, and patients show infection and disorders in the gastrointestinal, cardiovascular, and neurological systems. Thus, the ability of the various SARS-CoV-2 variants to infect and propagate in different cell types and organs clearly plays a key role in viral pathogenicity. Especially, cardiomyocytes express high levels of the primary SARS-CoV-2 receptor ACE2 and are highly permissive for viral replication.2

Cardiac injury and cardiomyopathies are common complications of COVID-19. Clinical manifestations leading to severe or even fatal outcomes include myocarditis, heart failure, arrhythmia, and Takotsubo cardiomyopathy (TCM).3 The mechanism(s) underlying heart injury in COVID-19 are not entirely clear. Direct effects of SARS-CoV-2 on cardiomyocytes are supported by their high susceptibility to virus infection and detection of viral RNA and Spike protein in autopsy cardiac tissues of COVID-19 patients.3 In addition, it has been shown that SARS-CoV-2 infects and efficiently replicates in cardiomyocytes but not in cardiac macrophages, fibroblasts, or endothelial cells.4,5 The BA.1 Spike shows altered ACE2 affinity, reduced dependency on TMPRSS2 for proteolytic activation, changes in cell tropism and reduced fusogenicity compared to the original HU-1 strain and the Delta VOC.6 However, it is currently not known whether early SARS-CoV-2 strains, Delta and Omicron BA.1, differ in their replication fitness, cytopathicity and fusogenicity in human cardiomyocytes.

(SNIP)

At the beginning of this study, BA.1 dominated the COVID-19 pandemic. Since then, several subvariants of Omicron emerged and outcompeted the original BA.1 VOC. BA.2 differs by a total of ~40 mutations from BA.1 and is the precursor of BA.5, which contains a deletion of H69/V70 and additional changes of L452R, F486V and R493Q in Spike and currently (August 2022) dominates the pandemic. Recent evidence suggests that BA.5 is not only more resistant to neutralizing antibodies but may also be more virulent than BA.1. We found that BA.5 replicates with faster kinetics and higher efficiency (Fig. 1f, Supplementary Fig. 8), produces more infectious virus (Fig. 1g), causes stronger CPE (Supplementary Fig. S9), and more rapidly disrupts beating (Fig. 1h, Supplementary movie 2) in cardiomyocyte cultures compared to BA.1, while BA.2 displayed an intermediate phenotype.

In summary, replication and cytopathic effects of the initial BA.1 Omicron VOC in spontaneously beating cultures of human cardiomyocytes are strongly attenuated compared to the early NL-02-2020 strain and the Delta VOC. However, BA.2 and especially BA.5 showed higher replication and caused stronger CPE than BA.1, consequently displaying features more similar to the Delta VOC. 

This does not come as a surprise since BA.5 shares some mutations in Spike thought to increase fusogenicity, such as L452R, with Delta. Our results add to the evidence that efficient evasion of adaptive immune responses by BA.1 came at the cost of reduced fusogenicity. However, acquisition of additional changes by BA.5 restored the full replicative potential and may potentially increase both transmissibility and virulence.

Our finding that BA.1 is strongly attenuated in iPSC-derived human cardiomyocytes suggests that this variant is less likely to cause cardiac injury and cardiomyopathies compared to other SARS-CoV-2 VOCs. It will be interesting to see whether this is confirmed by patient data and if Omicron-adapted vaccines may drive the evolution of attenuated forms of BA.5 and future SARS-CoV-2 variants.


While it is true that 98%-99% of people survive the acute phase of COVID - and most deaths have occurred among the elderly, or those with serious comorbidities - the extrapulmonary manifestations of SARS-CoV-2 infection are many, varied, and only partially appreciated.


https://twitter.com/KartikSehgal_MD/status/1281695760879202304


In the summer of 2020 (see JAMA: Two Studies Linking SARS-CoV-2 Infection To Cardiac Injury), we examined the results of 39 autopsies on COVID cases, that showed even when pneumonia is the presumed cause of death - and even without overt histopathic evidence of acute myocarditis - the heart often shows a high viral load of SARS-COV-2.

A second, and arguably even more worrisome study, found a remarkable incidence of cardiac injury and myocardial inflammation among a relatively young cohort (avg. age 49 & without pre-existing cardiac hx) of COVID patients who mainly recovered at home but continued to experience a variety of symptoms following their illness.

An accompanying editorial (see Coronavirus Disease 2019 (COVID-19) and the Heart—Is Heart Failure the Next Chapter? by Clyde W. Yancy, MD, MSc1,2; Gregg C. Fonarow, MD3,4) raised serious concerns over the long-term impact of COVID on public health.

While everyone desperately longs to get past the acute phase of this pandemic, its long-term impact on individual and public health may persist for years, or even decades.  Once again, making COVID an illness best avoided if at all possible.