Sunday, February 13, 2022

A COVID Recombination Review



Over the past 24 hours the internet and news media have taken notice of an announcement (well buried in the UK's SARS-CoV-2 variants of public health interest: 11 February 2022) that the UKHSA is monitoring and investigating a Delta x Omicron Recombinant (UK) virus. 

A variant the media has dubbed `Deltacron'. A few of the more restrained headlines overnight include:
Deltacron warning as twin variant confirmed – Omicron and Delta form mutant strain

COVID-19: UK monitoring hybrid delta-omicron strain called 'deltacron' 

Covid variants merge: Country confirms 'Deltacron' case
Admittedly, this story has everything a headline writer could want. A `catchy' new (unofficial) variant name; one that conjures up the worst fears of a pandemic weary readership.  And the chance to use the word `mutant', because that always ensures clicks.  

A similar story arose last month out of Cyprus, which was quickly dismissed as likely due to lab contamination (see Nature news Deltacron: the story of the variant that wasn’t).  

Regardless of what was (or wasn't) detected in Cypress, the UK's announcement is a reminder that SARS-CoV-2 continues to evolve - and while we have zero information about the threat that may (or may not) be posed by this particular variant - it is premature to declare the pandemic over and done with. 

For this Delta x Omicron Recombinant variant to pose any significant threat, it must be able to compete successfully with Omicron (BA.1 or BA.2), and right now, we have no evidence that it can.  Nor do we have information regarding its severity relative to Omicron. 

Most variants are evolutionary failures.  They emerge, and may even flourish briefly, but eventually are replaced by more biologically `fit' viruses.  There have been literally thousands of failed COVID variants for every `Delta' or `Omicron' success story. 

We probably won't know how much of a threat this latest variant poses - if any -  for quite some time, but concerns over recombination events with COVID are genuine, and so the topic deserves some discussion. 

Recombination is the sharing of genetic material between similar genomes that simultaneously infect a single host.  The resultant hybrid is called a recombinant. 

In influenza, we frequently talk about reassortment; the swapping of entire gene segments. With recombination - due to the way coronaviruses copy their RNA - smaller bits of genetic material may be exchanged. 

While the media is buzzing over the term, we've been talking about recombination since the earliest days of COVID's emergence.  

First, as more of a theoretical concern (see More COVID-19 (SARS-CoV-2) Mutation Reports), but in March of last year we saw a preprint by researchers from the Viral Diseases Branch, Walter Reed Army Institute of Research, MD, USA, that found moderate evidence for 8 SARS-CoV-2 recombination events.

In May of 2021,  another study published in PLoS One, titled SARS-CoV-2: Possible recombination and emergence of potentially more virulent strainspresented evidence of possible recombination events that may be driving some of COVID's evolution.

Whether through recombination (which requires dual infections), or simple replication errors (i.e. antigenic drift), SARS-CoV-2 continues to reinvent itself at an impressive rate. 

Over the past year, we've seen a number of recombinant COVID variants emerge, but fail to thrive (e.g. B.1.628 recombinant of (B.1.631 and B.1.634) &  B.1.1.7 + B.1.617.2 (Recombinant)). When new ones appear, they go on a watch list, but most end up in the evolutionary dust bin. 

Past performance being no guarantee of future results, it is worth monitoring new ones as they appear. 

With SARS-CoV-2 increasingly jumping species, recombination with other coronaviruses is considered a possibility as well, although no one knows how likely that is. MERS-CoV, which is endemic in camels in the Middle East, and occasionally jumps to humans, is an obvious concern. 

The Recombination Potential between SARS-CoV-2 and MERS-CoV from Cross-Species Spill-over Infections

COVID recombination events were discussed last summer in UK SAGE: Can We Predict the Limits of SARS-CoV-2 Variants and their Phenotypic Consequences?, where they envisioned the potential emergence of a more severe COVID variant.

Scenario One: A variant that causes severe disease in a greater proportion of the population than has occurred to date. For example, with similar morbidity/mortality to other zoonotic coronaviruses such as SARS-CoV (~10% case fatality) or MERS-CoV (~35% case fatality).

This could be caused by:

1. Point mutations or recombination with other host or viral genes. This might occur through a change in SARS-CoV-2 internal genes such as the polymerase proteins or accessory proteins. These genes determine the outcome of infection by affecting the way the virus is sensed by the cell, the speed at which the virus replicates and the anti-viral response of the cell to infection. There is precedent for Coronaviruses (CoVs) to acquire additional genes or sequences from the host, from themselves or from other viruses. 

2. By recombination between two VOC or VUIs. One with high drift (change in the spike glycoprotein) from the current spike glycoprotein gene used in the vaccine and the other with a more efficient replication and transmission determined by internal genes, for example, a recombination between beta and alpha or delta variants respectively. Alternatively, recombination may occur between two different variants with two different strategies for overcoming innate immunity, combining to give an additive or synergistic change of phenotype resulting in higher replication of the virus – and potentially increased morbidity and mortality. 

Likelihood of genotypic change in internal genes: Likely whilst the circulation of SARSCoV-2 is high. 

Likelihood of increased severity phenotypeRealistic possibility. 

Impact: High. 

Unless there is significant drift in the spike glycoprotein gene sequence, then the current spike glycoprotein-based vaccines are highly likely to continue to provide protection against serious disease. However, an increase in morbidity and mortality would be expected even in the face of vaccination since vaccines do not provide absolute sterilising immunity i.e. they do not fully prevent infection in most individuals.

 What can we do? 

• Consider vaccine booster doses to maintain protection against severe disease.
• Reduce transmission of SARS-CoV-2 within the UK (to reduce risk of point mutations, recombination).
 Minimise introduction of new variants from other territories (to reduce risk of recombination between variants).
• Targeted surveillance for reverse zoonoses, and if necessary, consider animal vaccination, slaughter, or isolation policies.
• Continue to monitor disease severity associated with variants (to identify changes in phenotype).
• Continue to develop improved prophylactic and therapeutic drugs for SARSCoV-2 and disease symptoms.
• Consider stockpiling prophylactic and therapeutic drugs for SARS-CoV-2.
One of the topics SAGE explores in this section is the potential for a more virulent virus to emerge via reverse zoonosis, something we've covered repeatedly over the past few months (see below).

CCDC Weekly Perspectives: COVID-19 Expands Its Territories from Humans to Animals

As far as `Deltacron' is concerned, there is too little data right now to even begin to worry.  That said, it is worth watching. 

It does remind us, however, that Omicron is unlikely to be COVID's last hurrah. And we should be prepared for more surprises in the months and years ahead.