Tuesday, March 21, 2023

Nature: CoV Recombination Potential & The Need For the Development of Pan-CoV Vaccines


Although I would heavily stress the world `Potential' in its title, a recent research article published in Nature suggests the possibility that MERS-CoV could someday recombine with SARS-CoV-2, and produce either a `SARS-CoV-3' or `MERS-CoV-2virus. 

How likely that is to happen is a subject of considerable debate, but it appears to be at least theoretically possible.     

This isn't the first time this topic has been broached. In the summer of 2020 the  published a paper called Co-infection of MERS-CoV and SARS-CoV-2 in the same host: A silent threat by Buket Baddal) which warned:

Considering the evolutionary trajectories of CoVs, the current co-circulation of SARS-CoV-2 and MERS-CoV represents a threat to public health where a possible co-infection in a human host may result in the emergence of a both highly transmissible and highly fatal new CoV.

Emergence of such recombinant CoV would require development of diagnostic assays for continuous surveillance in endemic areas, and would have implications for treatment and immunity as neutralizing antibodies in CoV-infected individuals are raised against the spike protein and would not provide protection against re-infection with a novel recombinant CoV.
In May of 2021 - long before the emergence of highly successful recombinant variants like XBB -  another study published in PLoS One, titled SARS-CoV-2: Possible recombination and emergence of potentially more virulent strains, presented evidence of recombination events that they felt might be driving some of COVID's evolution.  

Given the high recombination rates detected in SARS-CoV-2, we speculate that in co-infections recombination is feasible via TRS and/or clusters of homologies. Accordingly, here we recommend mitigation measure and testing for both MERS-CoV and SARS-CoV-2 in ME countries.

Later that same summer, in UK SAGE: Can We Predict the Limits of SARS-CoV-2 Variants and their Phenotypic Consequences?, UK experts also discussed the possibility of a recombination event that could produce a SARS virus with the transmissibility of COVID and the CFR (est. 35%) of MERS-CoV. 

There are, of course, plenty of other ways that SARS-COV-2 could reinvent itself, including via its continued expansion into non-human hosts (see Nature: Comparative Susceptibility of SARS-CoV-2, SARS-CoV, and MERS-CoV Across Mammals), which could provide the virus with new and unpredictable evolutionary pathways to follow. 

The future course and trajectory of SARS-Cov-2 (or its descendants) is unknowable.  We may get a year or two (or hopefully more) of relative quiescence, but as pervasive as it has become in both human and non-human hosts,  it seems unlikely to simply fade away.

The authors of this week's report call for the development of a Pan β-CoV vaccine - along with new therapeutics - that would protect against both SARS-CoV-2 and MERS-COV, and potentially any recombinant offspring. 

I've posted the link, and some excerpts below.  Follow the link to read it in its entirety.  I'll have a brief postscript after the break. 

Research Highlight
Open Access
Published: 15 March 2023

Potential recombination between SARS-CoV-2 and MERS-CoV: calls for the development of Pan-CoV vaccines

Qiao Wang, Lujia Sun & Shibo Jiang

Signal Transduction and Targeted Therapy volume 8, Article number: 122 (2023) Cite this article

In a recent study published in Nature, Yan and colleagues demonstrated that NeoCoV, a potential MERS-CoV ancestor in bats, can use bat ACE2 as its entry receptor and that NeoCoV S pseudotyped virus, which contains a T510F mutation in the receptor-binding domain (RBD), enters cells expressing human ACE2 (hACE2).1 The findings reveal a potential zoonotic threat that MERS-CoV could, during its evolution, be gaining the ability to use hACE2 as an entry receptor and, thus, could also coinfect ACE2-expressing cells with SARS-CoV-2.

It is generally believed that sarbecoviruses, such as SARS-CoV-2 and SARS-CoV, use angiotensin-converting enzyme 2 (ACE2) as the entry receptor, while merbecoviruses, such as MERS-CoV, HKU4, and HKU25, utilize dipeptidyl peptidase 4 (DPP4) as the entry receptor.

Some alveolar cells and small intestinal cells in the human body can express both ACE2 and DPP4, providing an opportunity for coinfection by both SARS-CoV-2 and MERS-CoV. With an even greater span of infectivity, SARS-CoV-2 may use its alternative receptors, such as CD147, NRP1, ASGR1, KREMEN1, or AXL, to enter host cells and may coinfect with MERS-CoV in cells expressing DPP4 and one of the alternative receptors (Fig. 1a). Moreover, these β-CoVs may use identical transcriptional regulatory and conserved sequences upstream of the open reading frame to mediate discontinuous transcription of the viral genome, possibly resulting in recombination of SARS-CoV-2 and MERS-CoV.

Indeed, genetic recombination between different coronaviruses has been well documented. For example, the MERS-CoV outbreak in 2015 resulted from genetic recombination among diverse MERS-CoV lineages.2 Also, SARS-CoV-2 recombinant lineages XD and XE were generated through the recombination of SARS-CoV-2 Delta and Omicron variants and Omicron subvariants BA.1 and BA.2, respectively. In addition, Omicron subvariant XBB emerged via recombination of Omicron BA.2 subvariants BJ.1 and BM.1.1. Therefore, recombination among coronaviruses is a well-established phenomenon.

Even as SARS-CoV-2 continues its worldwide spread, MERS-CoV remains a threat. MERS-CoV is the most virulent human pathogenic coronavirus known to date, even though only sporadic infections have been reported in the Middle East since 2016. Most recently, it was warned that the Qatar FIFA World Cup 2022 and camel pageant championships might increase the risk of MERS-CoV transmission and global spread.3 In 2015, a similar instance occurred with an individual returning to Seoul from Saudi, resulting in 184 infections with 36 deaths.2 As a reminder, no MERS vaccine is available, even while the case-fatality rate for MERS-CoV infection is astonishingly high, approximately 35%, 100 times higher than that for COVID-19.

Even more concerning is the risk of a newly emerging β-CoV clade, SARS-CoV-3 or MERS-CoV-2, via genetic recombination between SARS-CoV-2, particularly the Omicron subvariant, and MERS-CoV. Furthermore, it is likely that such a new β-CoV clade may bear high SARS-CoV-2-like transmissibility along with a high MERS-CoV-like case-fatality rate, which would have catastrophic repercussions.


In sum, given the high risk of SARS-CoV-2/MERS-CoV recombination, the development of pan-β-CoV vaccines as well as CoV entry and replication inhibitor-based therapeutics is urgently needed to combat the pandemics or epidemics caused by emerging SARS-CoV-3 or MERS-CoV-2 in the future.

         (Continue . . . )

Although the number of MERS-CoV cases reported out of the Middle East has plummeted over the past 3 years (see Saudi Epi chart below), there are strong suspicions that has more to do with a lack of surveillance and reporting than any disappearance of the virus.

In last November's Update: Middle East Respiratory Syndrome Coronavirus (MERS-CoV) – Saudi Arabia, the World Health Organization cautioned:
The number of MERS-CoV cases reported to WHO has substantially declined since the beginning of the ongoing COVID-19 pandemic. This is likely the result of epidemiological surveillance activities for COVID-19 being prioritized, resulting in reduced testing and detection of MERS-CoV cases.

In addition, measures taken during the COVID-19 pandemic to reduce SARS-CoV-2 transmission (e.g. mask-wearing, hand hygiene, physical distancing, improving the ventilation of indoor spaces, respiratory etiquette, stay-at-home orders, reduced mobility) are also likely reduce opportunities for onward human-to-human transmission of MERS-CoV.

However, the circulation of MERS-CoV in dromedary camels is not likely to have been impacted by these measures. Therefore, while the number of reported secondary cases of MERS has been reduced, the risk of zoonotic transmission remains.
Even before the COVID pandemic, we'd seen estimates that the vast majority of MERS cases go undiagnosed (or unreported) in the Middle East (see EID Journal: Estimation of Severe MERS Cases in the Middle East, 2012–2016).  

Prior to COVID's emergence in 2019, MERS-CoV was viewed as having pandemic potential of its own (see 2017's  A Pandemic Risk Assessment Of MERS-CoV In Saudi Arabia), meaning it may not need a viral co-conspirator to start its own world tour. 

Like it or not, we live in an age where the the number, frequency, and intensity of pandemics are only expected to increase over time (see PNAS Research: Intensity and Frequency of Extreme Novel Epidemics). 

Which is why - as unwelcome as the topic of today's blog might be - it is something we have to seriously consider.