While the Omicron variant of the SARS-CoV-2 virus dominates headlines, variants of other viruses are emerging. Before the Covid-19 pandemic emerged, scientists and healthcare professionals warned of not just deadly viruses, but were mostly ignored by the global elite1. Previously, I warned that a coronavirus has been discovered in swine2. It was able to infect human cells grown in culture. Recently, Chinese scientists noticed that a previously described coronavirus needs just one more mutation to able to infect humans3-5. This virus was found in a species of bats (Neoromicia cf. zuluensis) and named NeoCoV6. The goals of this article are to describe this virus and efforts to develop pan-coronavirus vaccines that can protect us not only from that virus, but almost all coronaviruses and the diseases that they cause.
The NeoCoV is a coronavirus that closely resembles the coronavirus called MERS-CoV that caused Middle East Respiratory Syndrome (MERS) in 20124. However, the S1 subunit of its spike (S) protein is highly divergent, when compared with MERS-CoV3. MERS was transmitted from camels to humans and continues to cause sporadic and localized outbreaks. MERS-CoV belongs to the linage C of Beta-Coronavirus. It has a case-fatality rate of approximately 35%. The Chinese scientists found that one mutation in the mRNA that codes for the viral proteins enables NeoCoV and another coronavirus (called PDF-2180-CoV) to bind to the human angiotensin-converting enzyme-2 (ACE2) receptor and infect human cells3. This mutation changes a threonine into a phenylalanine at amino acid number 510, so it’s abbreviated T510F. The scientists used low temperature electron microscopy (Cryo-EM) to look at the structure of the virus and found a part of it that binds to the ACE-2 receptor in human cells. This part is called the receptor-binding motif (RBM) by some and receptor binding domain (RBD) by others. After the T510F mutation was produced, the NeoCoV efficiently infected human cells grown in cell culture. Notably, antibodies elicited by the current coronavirus disease 2019 (Covid-19) vaccines and targeting SARS-CoV-2 was not able to prevent the infection. They concluded that there was a significant threat because of the high rates of viral transmission and fatality of MERS-CoV-23.
It should be added that there are many more potentially deadly animal viruses that we have not yet discovered2. Viruses are the most abundant biological entities in all habitats. They are a major reservoir of genetic diversity affecting biogeochemical cycles and ecosystem dynamics. However, relatively few genomes of viruses have been deposited into databanks7. We need to support the Global Virome Project that will identify and characterize the global diversity of viruses, with a special emphasis on viruses in humans and animals that may currently host the next virus that will infect humans8,9. It is estimated that there are at least 500,000 undiscovered animal viruses that are capable of being transmitted to humans9.
We need to support not only a global virome project but also the development of pan-coronavirus vaccines that will be effective against all coronaviruses. In a previous article, I described a relatively new approach that uses the gene editing technology called CRISPR (based on clustered regularly interspaced short palindromic repeats)10. Scientists and engineers have learned to use CRISPR to edit genes and make new types of RNA, called CRISPR RNA, or crRNA. CRISPR is being used to improve livestock and seafood production, create better animal models of diseases, help in the development of improved vaccines and new prescription drug, and possibly eventually eradicate malaria. It can also be used in the field of synthetic biology to make entirely new organisms and may be able to bring back extinct species, such as the wooly mammoth. CRISPR has been predicted to become one of the key technologies that will be part of the fourth industrial revolution.
So, a new CRISPR-based antiviral strategy called PAC-MAN (Prophylactic Antiviral CRISPR in huMAN cells) targets the mRNA of the SARS-CoV-2 virus11. It was used to make CRISPR RNAs (crRNAs) that targeted either the H1N1 influenza virus or over 90% of 1087 recently sequenced coronaviruses11. PAC-MAN technology was combined with bioinformatics to prepare a possible treatment for Covid-1912. First, they identified conserved regions in SARS-CoV-2 RNA. Then, they designed several crRNAs that targeted the different coronaviruses that have been identified and sequenced to date. One key advantage of this technology is that it can be adapted to treat multiple coronaviruses. It could use a single cocktail containing different crRNAs that target conserved regions in coronaviruses. Their computational analysis predicted that just three crRNAs could be enough to target the coronaviruses that cause SARS, MERS, and Covid-19. By using several crRNAs, mutants that emerge could be easily targeted. PAC-MAN technology may even be applied to other viruses that infect animals like bats that pose a future threat. PAC-MAN could be used to prepare potential treatments before a pandemic can occur12.
Another approach being used by researchers is to make mosaic nanoparticles that display the RBD of SARS-CoV-2 or co-displaying SARS-CoV-2 RBD along with RBDs from animal betacoronaviruses that represent threats to humans13. These mosaic nanoparticles have four to eight distinct RBDs. Mice immunized with RBD nanoparticles produced antibodies with superior cross-reactivity of several different RBDs when compared to sera from patients who had Covid-19. Hopefully, a single immunization with mosaic RBD nanoparticles will protect against SARS-CoV-2 and emerging coronaviruses that can be transmitted from animals into humans.
A Phase I clinical trial has begun to see if such a vaccine is safe and effective14. Scientists and researchers at the Walter Reed National Military Medical Center made a vaccine that can recognize multiple spike proteins at once by using ferritin, a protein that contains iron. Ferritin has 24 places on its structure that can have a different viral protein attached. By using ferritin in a pan-coronavirus vaccine, the nanoparticles can produce an array of varying coronavirus antigens not just from SARS-CoV-2 variants but other coronavirus species and strains. Hopefully, the clinical trial will show that this vaccine will stimulate immunity and produce broad protection14.
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2 Smith, R.E. The next deadly pandemic. We must invest in research and education. Wall Street International, 24 November, 2020.
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9 Global Virome Project.
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11 Abbott, T.R. et al. Development of CRISPR as an antiviral strategy to combat SARS-CoV-2 and influenza. Cell, Volume 181, pp. 865-876, 2020.
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13 Cohen, A.A. et al., Mosaic nanoparticles elicit cross-reactive immune responses to zoonotic coronaviruses in mice. Science, Vol. 371, pp. 735-741, 2021.
14 Shasteen, H. BioSpace. U.S. Army begins human trials of pan-coronavirus vaccine. 31 Jan., 2022.