by Judy Yeo
In the continuing series on the COVID-19 outbreak, APBN takes a closer look at coronaviruses to help readers better understand the feverish pace of work undertaken by researchers and scientists in the race to find solutions to the COVID-19 outbreak which has wreaked havoc in most parts of Asia and across at least 60 countries outside of China.
What is a virus?
A virus is a microscopic infectious agent which is generally smaller than bacteria. While a virus contains nucleic acids (DNA or RNA) wrapped in a coat of proteins, it lacks the capacity to independently read and act upon information contained within the nucleic acid. According to a professor of molecular biosciences at the University of Texas at Austin, Jaquelin Dudley, a virus is a parasite that requires a host cell to enable replication. A host's cellular machinery enables transcription - where a virus produces RNA from its DNA - and translation - a process where a virus builds proteins based on the instructions encoded in its RNA.
Some common viral pathogens, including those that cause the flu, are RNA viruses which are known to mutate rapidly.
What does SARS-CoV-2 look like?
Five genomes of SARS-CoV-2 had been isolated from samples obtained from Wuhan and reported by 12 January 2020. By 11 February 2020, there were 81 genomes. According to a report,1 the 42 samples studied are highly related with few mutations relative to a common ancestor. This suggested the outbreak either started from “a single introduction into the human population or a small number of animal-to-human transmissions of very similar viruses” which most likely occurred in November or early December 2019.
Another study published on 7 February 2020 in Cell Host & Microbe showed how researchers from the Chinese Academy of Medical Sciences and Peking Union Medical College annotated three SARS-CoV-2 genomes.1The study identified similarities and differences of the genome as compared with genomes of other coronaviruses including that of SARS-CoV. In the study, researchers discovered that the coronavirus behind the COVID-19 outbreak seemed to be most closely related to bat SARS-like coronaviruses which formed the source from which SARS-CoV, the virus behind the 2002-2003 SARS pandemic, evolved. The study noted that the genome of SARS-CoV-2 “has the highest similarity with that of a SARS-like bat CoV (MG772933)” and that in comparison, SARS-CoV-2 “is distant from and less related to the MERS-CoVs”. Researchers have noted that SARS-CoV-2 and SARS-CoV belong to different phylogenetic branches though SARS-CoV-2 displays high sequence similarity to SARS-CoV.
Both SARS-CoV-2 and SARS-CoV may be traced back to a bat coronavirus. However, of the two, SARS-CoV-2 is closer to the original bat virus with one study reportedly stating that it displayed 96 percent of a bat coronavirus genome sequence. Furthermore, SARS-CoV-2’s spike gene “shares a 39-base insertion with a type of soldierfish that swims in the South China Sea” according to geneticist and science writer Ricki Lewis.1
HOW DOES SARS-COV-2 INFECT HUMANS?
Coronaviruses use different proteins to replicate and invade cells with the spike protein acting as the principle surface protein that is used to bind to a human cell receptor, which is itself another protein that facilitates entry into the human cell.
In a Journal Watch piece in the New England Journal of Medicine,1 it was noted that while SARS-CoV-2 was “more closely related at the genome level to the bat SL-CoV, its receptor binding domain (RBD) shared more homology with that of the SARS-CoV”. More significantly, both SARS-CoV and SARS-CoV-2 use the same human receptor.
A team of researchers from the Chinese Academy of Sciences modelled the interface points of SARS-CoV-2 and declared in a letter1 to the editor of Science China on 20 January 2020 that SARS-CoV-2 S-protein interacts with and binds to human Angiotensin Converting Enzyme 2 (ACE2) molecules. They concluded that SARS-CoV-2 “poses a significant public health risk for human transmission via the S-protein–ACE2 binding pathway”.
THE GLOBAL RACE FOR A VACCINE
As the COVID-19 outbreak gathers pace, scientists, researchers and pharmaceutical companies have stepped up efforts to create a vaccine. APBN highlights some of the more significant endeavours in this direction:
- SPIKE PROTEINS MAPPED
A team from University of Texas at Austin mapped the spike proteins of SARS-CoV-2 using cryogenic electron microscopy and published their findings in Science on 19 February 2020.6 This was significant as the ability of the spike protein to bind to the human cell receptor is a key step in the process of infection. Once attached, the viral membrane fuses with human cell membrane and this allows the genome of the virus to enter human cells, thereby triggering infection. Senior author of the study, Jason McLellan, noted in an interview with LiveScience7 that theoretically, the spike protein itself was "potentially either the vaccine or variants of a vaccine".
- SET OF POTENTIAL VACCINE TARGETS IDENTIFIED
Headed by data scientists Prof. Matthew McKay and Dr. Ahmed Abdul Quadeer, a team at the Hong Kong University of Science and Technology identified a set of potential vaccine targets for SARS-CoV-2.8 Noting the genetic similarity between SARS-CoV-2 and SARS-CoV, the HKUST team “identified a set of B cell and T cell epitopes derived from the spike (S) and nucleocapsid (N) proteins that map identically to SARS-CoV-2 proteins”. The team noted that because “no mutation has been observed in these identified epitopes among the 120 available SARS-CoV-2 sequences (as of 21 February 2020), immune targeting of these epitopes may potentially offer protection against this novel virus”.
- VACCINE DEVELOPMENT EFFORTS
One of the first groups to produce a vaccine sample is Moderna Therapeutics, a Massachusetts-based biotech company. Their vaccine was created a mere 42 days after the genetic sequence of SARS-CoV-2 virus was released in mid-January 2020. Moderna has shipped the first vials to the National Institutes of Health which is expected to prepare the vaccine for human testing.
According to Time,9 Moderna was able to develop its vaccine in record time because it is packed with mRNA, a subtype of RNA which is created during transcription and which carries a portion of the DNA code to other parts of the cell for processing. The mRNA is coded for the right coronavirus proteins and is then processed by “immune cells in the lymph nodes [which] can process that mRNA and start making the protein in just the right way for other immune cells to recognize and mark them for destruction”.
The vaccine development is part of a program funded by the Coalition for Epidemic Preparedness Innovations (CEPI).
The following is an overview of some of the other more significant candidates and participants in the vaccine race as it stands:
- REPURPOSED VACCINES
Tonix Pharmaceuticals and Southern Research
TNX-1800 is a modified horsepox virus developed using Tonix’s proprietary horsepox vaccine platform. According to a news report,10 TNX-1800 is designed to express a protein derived from the virus that causes the coronavirus infection.
Some vaccines in development for the Middle East Respiratory Syndrome (MERS) are being repurposed for use against SARS-CoV-2. They include Novavax’s MERS coronavirus vaccine candidate developed in 2013 as well as Inovio Pharmaceuticals’ INO-4700.
- COLLABORATIVE EFFORTS
Inovio Pharmaceuticals and Beijing Advaccine Biotechnology
Inovio Pharmaceuticals is working with Beijing Advaccine Biotechnology Company to advance the development of Inovio Pharmaceuticals’ INO-4800. Pre-clinical testing for clinical product manufacturing has started. A US$9 million grant from CEPI supports the development. The other collaborators in the development include the Wistar Institute and VGXI, a fully-owned subsidiary of GeneOne Life Science.
Clover Biopharmaceuticals and GSK
Recombinant subunit vaccine
Clover Biopharmaceuticals is developing a recombinant subunit vaccine based on the trimeric S protein (S-Trimer) of SARS-CoV-2, which is responsible for binding with the host cell and causing a viral infection. The company has identified the antigen-specific antibody in the serum of fully recovered COVID-19 patients. By using its patented Trimer-Tag© technology, the company successfully produced the subunit vaccine in a mammalian cell-culture based expression system.
On 24 February 2020, the company announced that it has entered into a research collaboration with GSK for its protein-based coronavirus vaccine candidate (COVID-19 S-Trimer). Under the terms of the collaboration agreement, GSK will provide Clover with its pandemic adjuvant system for further evaluation of S-Trimer in preclinical studies.
LineaRx (Applied DNA Sciences) and Takis Biotech
Linear DNA Vaccine
A joint venture was formed between LineaRx, Applied DNA Sciences’ subsidiary, and Takis Biotech in February to develop a linear DNA vaccine as a treatment for COVID-19. The joint venture is expected to use Polymerase Chain Reaction-based DNA manufacturing technology to develop the vaccine. The advantages of PCR technology include high purity, increased production speed, as well as the absence of antibiotics and bacterial contaminants. The vaccine gene developed through PCR technology is expected to be effective without being inserted into the patient’s genome.
- USE OF PROPRIETARY PLATFORMS AND TECHNOLOGY
Multiple vaccine candidates
US-based biotechnology company Novavax has constructed multiple nanoparticle vaccine candidates and begun testing them in animal models prior to identifying an optimal candidate for human testing. A clinical trial is expected to begin in May or June 2020.
Novavax’s candidates are based on its recombinant protein nanoparticle technology platform that produces antigens obtained from the SARS-CoV-2 spike protein. To boost immune responses, Novavax expects to utilize its proprietary Matrix-M™ adjuvant with its COVID-19 vaccine candidate.
Oral recombinant protein vaccine
Vaxart is reportedly developing an oral recombinant vaccine based on the published genome of SARS-CoV-2 to be tested in pre-clinical models for mucosal and systemic immune responses. Vaxart plans to use replication-incompetent adenovirus type 5 vector in its VAAST proprietary oral vaccine platform to produce a vaccine aimed at the oral prevention and treatment of COVID-19.
Protein subunit vaccine
Sanofi’s vaccine reportedly consists of antigens found on the surface of SARS-CoV-2 and is created using its egg-free, recombinant DNA baculovirus expression platform technology. By February 2020, Sanofi announced plans to advance a preclinical candidate.
- LEVERAGING CHINESE EXPERTISE
Chongqing Zhifei Biological Products and Institute of Microbiology, Chinese Academy of Sciences
Chongqing Zhifei announced plans in January 2020 to begin the vaccine preparation process while the Institute of Microbiology was slated for the evaluation of the efficacy of the vaccine. By February 2020, the vaccine reportedly entered the stage of animal experimentation.
Fudan University and ID Pharma Co
By February 2020, early research has been underway on a vaccine based on ID Pharma's Sendai virus vector.
- PRIVATE PUBLIC COOPERATION
Launched in Davos in 2017, CEPI’s declared mission is to “accelerate the development of vaccines against emerging infectious diseases and enable equitable access to these vaccines” in the instance of outbreaks.
Apart from the vaccines in development by Moderna and Inovio as noted above, CEPI has also supported efforts to develop vaccines through collaboration with:
GSK is expected to use its pandemic vaccine adjuvant platform technology to develop the vaccine. By adding an adjuvant to existing vaccines to boost the immune response, a vaccine can be rapidly developed.
University of Queensland
The University of Queensland has been requested by CEPI to fast track the development of a vaccine using its rapid response technology, Molecular Clamp, which reportedly provides stability to the viral protein responsible for generating immune defence.
CEPI has given CureVac an initial funding amount of US$8.3 million to accelerate the development of a vaccine. CureVac is expected to capitalize on its technology and mRNA platform to develop and start testing the vaccine in early 2020.
- (n.d.). Retrieved from https://nextstrain.org/narratives/ncov/sit-rep/2020-01-30
- Wu, A., Peng, Y., Huang, B., Ding, X., Wang, X., Niu, P., … Jiang, T. (2020). Genome Composition and Divergence of the Novel Coronavirus (2019-nCoV) Originating in China. Cell Host & Microbe. doi: 10.1016/j.chom.2020.02.001
- Lewis, R., Yap, A., Easter, S., Mitchell, B., Radek, Jaroslaw, … Rogers, R. (n.d.). COVID-19 Vaccine Will Close in on the Spikes. Retrieved from https://blogs.plos.org/dnascience/2020/02/20/covid-19-vaccine-will-close-in-on-the-spikes/
- (n.d.). Retrieved from https://www.jwatch.org/na50823/2020/02/06/genomic-characterization-2019-novel-coronavirus
- Xu, X., Chen, P., Wang, J., Feng, J., Zhou, H., Li, X., … Hao, P. (2020). Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission. Science China Life Sciences. doi: 10.1007/s11427-020-1637-5
- Wrapp, D., Wang, N., Corbett, K. S., Goldsmith, J. A., Hsieh, C.-L., Abiona, O., … Mclellan, J. S. (2020). Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science. doi: 10.1126/science.abb2507
- Coronavirus 'spike' protein just mapped, leading way to vaccine. (n.d.). Retrieved from https://www.livescience.com/coronavirus-spike-protein-structure.shtml
- Hong Kong University of Science and Technology. (2020, February 26). COVID-19 vaccine development. ScienceDaily. Retrieved March 2, 2020 from www.sciencedaily.com/releases/2020/02/200226091227.htm
- Park, A. (2020, February 25). COVID-19 Vaccine Shipped, and Drug Trials Start. Retrieved from https://time.com/5790545/first-covid-19-vaccine/
- Tirumalaraju, D. (2020, February 27). Tonix Pharmaceuticals forms alliance to develop Covid-19 vaccine. Retrieved from https://www.pharmaceutical-technology.com/news/tonix-pharmaceuticals-covid-19-vaccine/