In a recent study published in NatureYan and colleagues demonstrated that NeoCoV, a potential ancestor of MERS-CoV in bats, can use bat ACE2 as an entry receptor and that the pseudotyped virus NeoCoV S, which contains a T510F mutation in the receptor binding domain (RBD), enters cells expressing human ACE2 (hACE2).1 The results reveal a potential zoonotic threat that MERS-CoV could, during its evolution, acquire the ability to use hACE2 as an entry receptor and, therefore, could also co-infect ACE2-expressing cells with SARS. -CoV-2.
Sarbecoviruses, such as SARS-CoV-2 and SARS-CoV, are generally thought to use angiotensin-converting enzyme 2 (ACE2) as an entry receptor, while merbecoviruses, such as MERS -CoV, HKU4 and HKU25, use dipeptidyl peptidase 4 (DPP4) as an entry receptor. Some alveolar cells and small intestinal cells in the human body can express both ACE2 and DPP4, providing an opportunity for co-infection with SARS-CoV-2 and MERS-CoV. With an even greater scope of infectivity, SARS-CoV-2 can use its alternative receptors, such as CD147, NRP1, ASGR1, KREMEN1 or AXL, to enter host cells and can co-infect 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 the discontinuous transcription of the viral genome, eventually driving the recombination of SARS-CoV-2 and MERS-CoV.
Co-infection of SARS-CoV-2 and MERS-CoV can lead to the emergence of recombinant β-CoV, SARS-CoV-3 or MERS-CoV-2, thus calling for the development of a pan-CoV vaccine. A Due to the identical infection cycle of SARS-CoV-2 and MERS-CoV, recombination can occur when ACE2 using MERS-CoV co-infects with SARS-CoV-2 in cells expressing the ACE2 ①or when SARS-CoV-2 and MERS-CoV co-infect a cell expressing both ACE2 and DPP4 ②or when MERS-CoV co-infects with SARS-CoV-2 in cells expressing DPP4 and one of the alternative ACE2-independent receptors (such as CD147, NRP1, ASGR1, KREMEN1, and AXL)③, resulting in an emerging β-CoV, SARS-CoV-3 or MERS-CoV-2, via genetic recombination between SARS-CoV-2 and MERS-CoV. (b) The SARS-CoV-2/MERS-CoV recombination calls for the development of a pan-β-CoV vaccine to prevent infection of the newly emerged β-CoV, SARS-CoV-3 or MERS-CoV-2. The illustration was created by the author (Lujia Sun) using the program BioRender (http://www.biorender.com)
Indeed, genetic recombination between different coronaviruses has been well documented. For example, the MERS-CoV outbreak in 2015 resulted from genetic recombination between various MERS-CoV lineages.2 In addition, the XD and XE recombinant lines of SARS-CoV-2 were generated by the recombination of SARS-CoV-2 Delta and Omicron variants and Omicron BA.1 and BA.2 subvariants, respectively. Additionally, Omicron’s XBB sub-variant emerged via the recombination of Omicron’s BA.2 BJ.1 and BM.1.1 sub-variants. Therefore, recombination between coronaviruses is a well-established phenomenon.
Even though SARS-CoV-2 continues its global spread, MERS-CoV remains a threat. MERS-CoV is the most virulent human pathogenic coronavirus known to date, although only sporadic infections have been reported in the Middle East since 2016. More recently, it was warned that the Qatar 2022 FIFA World Cup and camel show championships could increase the risk of transmission and global spread of MERS-CoV.3 In 2015, a similar case occurred with an individual returning from Saudi Arabia to Seoul, resulting in 184 infections and 36 deaths.2 As a reminder, no vaccine against MERS is available, even though the case fatality rate of MERS-CoV infection is surprisingly high, around 35%, or 100 times higher than that of COVID-19.
Even more concerning is the risk of emergence of a new β-CoV clade, SARS-CoV-3 or MERS-CoV-2, via genetic recombination between SARS-CoV-2, in particular the subvariant Omicron, and MERS-CoV. Furthermore, it is likely that such a new β-CoV clade could have high SARS-CoV-2-like transmissibility as well as high MERS-CoV-like case fatality rate, which would have catastrophic repercussions.
Thus, the sharing of receptors by the parents of SARS-CoV-2 and MERS-CoV makes simultaneous infection by two different coronavirus clades more likely, even leading to a higher probability of RNA-RNA recombination in the same cell. Several cases of SARS-CoV-2/MERS-CoV co-infection have recently been reported in Saudi Arabia,4 possibly prefiguring a recombination between these two β-coronaviruses. Thus, in places still infected with MERS-CoV, it is particularly necessary to use quantitative real-time PCR for screening for MERS-CoV in patients infected with SARS-CoV-2.
The increasing likelihood of SARS-CoV-2/MERS-CoV recombination calls for the development of broad-spectrum vaccines and effective therapeutic drugs against pan-β-coronaviruses, especially those sharing the same host receptor (Fig. 1b). Many research teams have attempted to develop pan-β-CoV vaccines. For example, DIOSynVax researchers used 3D computer modeling to design payloads of vaccine antigens and deployed them in β-CoV vaccines based on mRNA, viral vectors or proteins.5
Vaccines containing multiple conserved neutralizing antibody epitopes or T-cell epitopes from different β-CoVs, but simultaneously displayed on one type of carrier, such as nanoparticles, are expected to elicit cross-reactive immune responses against multiple β-CoVs. Our team identified a STING antagonist adjuvant, called CF501,5 which can be used for the development of highly effective and durable β-CoV vaccines.
The two broad-spectrum neutralizing antibodies B6 and S2P6 targeting a conserved stem helix epitope in the S2 subunit of the SARS-CoV-2 spike protein are equally effective against neo-CoV infection, which suggests that antigens containing the stem helix region can be used for the development of pan-β-CoV vaccines.1 Another broad-spectrum neutralizing antibody, 76E1, was found to target a highly conserved S2′ cleavage site and fusion peptide epitope in the S2 subunit, indicating that these regions can also be used for pan-vaccine development. -β-CoV.5
In sum, given the high risk of SARS-CoV-2/MERS-CoV recombination, the development of pan-β-CoV vaccines as well as therapies based on CoV entry and replication inhibitors is urgently needed. emergency to combat pandemics or epidemics caused by emerging SARS-CoV-3 or MERS-CoV-2 in the future.