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COVID-19: Social Distancing & the Future of Pandemics

Najung Lee (Pembroke) & Ragavi Vijayakumar (Downing). April 20, 2020.

Social distancing

Social distancing means keeping space between yourself and other people outside of your home. The basic reproductive number (R0) is the expected number of cases directly generated by one case. The Signer Laboratory has made the following assumptions1 in order to mathematically model the effects of social distancing on R0:
  • Under normal conditions, each infected person is expected to infect 2.5 other people.
  • Infected people can transmit the disease for a five-day period while they are asymptomatic.
  • After five days a person will begin experiencing symptoms, quarantine and no longer infect others.
  • There is a direct linear correlation between social interaction and R0. For instance, R0 is reduced by 50% (R0=1.25) when social interactions are reduced by 50%.

Figure 1. Simplified infographic on the impacts of social distancing1

The Future: Recurring global health threat and what do we need to learn

After the discovery of vaccines and antibiotics and with the improvement in hygiene, the number of deadly infectious diseases had rapidly declined. We were in hopes of eradicating them. Unfortunately, there have been new strains of infectious pathogens emerging from the 1970s and recently, the period between subsequent outbreaks has become shorter.

Why is this phenomenon happening despite the remarkable development of medical technology? The common feature shared by most of the diseases is that they are zoonotic viruses, which means they can infect both animals and humans. Researchers found out that more than 60% of emerging infectious diseases (EIDs), whose incidence has increased in the past 20 years, are caused by zoonotic pathogens2.

HIV came from many cross-species transmission from primates in Africa3. H1N1 is a type of swine influenza virus (SIV), which is a strain of the influenza family of viruses that circulate in pigs4. SARS-CoV, MERS-CoV, and SARS-CoV-2 are originally bat-borne coronaviruses. The noticeable point here is that the viruses have all crossed the species barrier from their natural host, and this phenomenon of cross-species transmission is called ‘Spillover’.

Figure 2.
Schematic diagram of zoonotic transmission dynamics12.

70% of the zoonoses have originated from wildlife5 with most of them being of viral origin. Pathogens from livestock have already crossed the barrier during the formation of agrarian society, hence excluding them from the suspect of a novel disease outbreak.

There exist other factors, primarily the increase in the frequency of human and wildlife contact, which is accelerating the emergence of novel outbreaks6. Deforestation, rapid urbanisation, bushmeat hunting, and wet markets are forcing wild animals to move away from their natural habitats and to have greater contact with humans. This increases the risk of Spillover as there is a greater chance for the mutated virus within wild animals, which could infect another animal species, to be transmitted.

Most of the zoonotic infection cases also involve ‘intermediate hosts’ that connect between natural hosts – which are reservoirs of different viruses – and humans. The intermediate hosts can amplify the pathogen transmission and/ or introduce a genetic variation7. The ‘mixer vessels’ species, such as pigs, can recombine different viruses and produce a completely new recombinant strain of virus that gives greater biological variation; the swine flu pandemic in 2009 was caused by a novel influenza virus that has obtained the ability to spread between humans by genetic reassortment of avian, human and/or swine flu viruses in pigs8. There are also many reported endemic cases with the likely source of human transmission being infected livestock9. This is maybe warning us that we are opening Pandora’s box ourselves by allowing pathogens to overcome the cross-species barrier and infect intermediate hosts, which can essentially be any animals around us.

Furthermore, a massive increase in the frequency of air travel is providing an optimum environment for rapid transmission of infectious disease not only within certain communities but also across the globe6. Therefore, it is worth noting that any contagious disease in a single region is not the problem of a specific country or area; rather, the entire world needs to collaborate to achieve ‘One Health,’ which is an objective by the World Health Organization (WHO) to achieve better public health outcomes10. In such a globalised world, a complacent attitude towards an outbreak might result in failure in early prevention. In this process, WHO should also need to take an active step in constructing a global network to identify the regions with potential risks and to circulate up-to-date information transparently and promptly.

The vast majority of the world has been focusing on post-outbreak responses to a pandemic such as the development of vaccines and medical treatments. However, pre-outbreak measures are also vital to prevent initial mass infection, which can easily lead to uncontrollable situations. Early detection, surveillance, and mass testing are essential to block the inflow and nation-wide spread of the disease by improving preventive measures against epidemics to minimise considerable damage.

What can we, as in individual, do during the period of the outbreak? Along with individual protection measures such as wearing masks and washing hands frequently, having correct information and knowledge about the infectious disease is indeed very crucial. Fake news with incendiary titles instigates the public, triggering fear and panic. Such behaviour rather hinders the effort made by scientists and the government to control the situation. Hence, greater engagement of the public to the scientific background of infectious disease would make us better prepared for the unknown future.

Disease X

In 2018, WHO announced “Disease X” – representing a hypothetical, unknown pathogen that could cause a serious international epidemic11. Currently, COVID-19 fits the Disease X category. There is no guarantee that a pandemic like COVID-19 would not happen again soon; “Disease X” can appear in any form at any time. We need to learn from what has happened and thoroughly prepare so that future outbreaks would not lead to disastrous consequences.

The above article was written for the purposes of general public education about updates on the COVID-19 outbreak. It should not replace information provided by medical professionals and government officials.

References

1 Signer Laboratory. (n.d.).

2,5 Jones, K. E., Patel, N. G., Levy, M. A., Storeygard, A., Balk, D., Gittleman, J. L., & Daszak, P. (2008). Global trends in emerging infectious diseases. Nature, 451(7181), 990–993.

3 Sharp, P. M., & Hahn, B. H. (2011). Origins of HIV and the AIDS Pandemic. Cold Spring Harbor Perspectives in Medicine, 1(1). 

4 Smith, G. J. D., Vijaykrishna, D., Bahl, J., Lycett, S. J., Worobey, M., Pybus, O. G., … Rambaut, A. (2009). Origins and evolutionary genomics of the 2009 swine-origin H1N1 influenza A epidemic. Nature, 459(7250), 1122–1125.

6Alirol, E., Getaz, L., Stoll, B., Chappuis, F., & Loutan, L. (2011). Urbanisation and infectious diseases in a globalised world. The Lancet Infectious Diseases, 11(2), 131–141.

7 Cui, J.-A., Chen, F., & Fan, S. (2017). Effect of Intermediate Hosts on Emerging Zoonoses. Vector-Borne and Zoonotic Diseases, 17(8), 599–609.

8 Kong, W., Wang, F., Dong, B., Ou, C., Meng, D., Liu, J., & Fan, Z.-C. (2015). Novel reassortant influenza viruses between pandemic (H1N1) 2009 and other influenza viruses pose a risk to public health. Microbial Pathogenesis, 89, 62–72.

9 Kilpatrick, A. M., & Randolph, S. E. (2012). Drivers, dynamics, and control of emerging vector-borne zoonotic diseases. The Lancet, 380(9857), 1946–1955.

10 One Health. (n.d.).

11 List of Blueprint priority diseases. (2018, July 20).

12 Lloyd-Smith, J. O., George, D., Pepin, K. M., Pitzer, V. E., Pulliam, J. R. C., Dobson, A. P., … Grenfell, B. T. (2009). Epidemic Dynamics at the Human-Animal Interface. Science, 326(5958), 1362–1367.

 

Written by Krishna Amin on . Posted in Featured

COVID-19: Current and Potential Treatments


Ragavi Vijayakumar (Downing) & Najung Lee (Pembroke). April 13, 2020.

Current treatments

As of now, there is no vaccine against SARS-CoV-2 – the virus strain that causes COVID-19. Researchers are currently working on creating a vaccine specifically for this virus, as well as potential treatments for COVID-19. Antibiotics are ineffective because COVID-19 is a viral infection, not bacterial.

There is some evidence that certain medications may have the potential to be effective in treating the symptoms of COVID-19. However, researchers need to perform properly randomized controlled trials in humans before these medications become available as a treatment method for COVID-191. It is also important to realise the fact that the efficacy and side effects of the drug can differ from person to person.

Here is a treatment option that is currently being investigated for protection against SARS-CoV-2 and treatment of COVID-19 symptoms.

Remdesivir

Remdesivir was initially developed by Gilead Sciences. It has a similar structure to adenosine, so it shuts down viral replication by inhibiting a key viral enzyme, RNA polymerase2,3. Researchers did testing with Remdesivir in the past during the Ebola outbreak, however, it did not show any promising improvement.

Remdesivir was given a chance to shine again. In the United States, a COVID-19 patient was given Remdesivir when his condition worsened; his symptoms showed improvements the next day, according to a case report in The New England Journal of Medicine (NEJM).

Such evidence from individual cases is not sufficient to prove a drug’s safety and efficacy, however. Still further testing on humans is required to make a safe conclusion before its global usage as a COVID-19 treatment.

APN01 – Apeiron Biologics

Apeiron is a privately-held European biotech company based in Vienna, Austria, focused on the discovery and development of novel cancer immunotherapies. It has recently secured approvals from regulatory agencies in Austria, Germany and Denmark to conduct a Phase II clinical trial of APN01 for the treatment of COVID-1915.

APN01 is a recombinant form of human angiotensin-converting enzyme 2 (ACE2). It was previously tested in phase I and II trials for acute lung injury (ALI) and pulmonary artery hypertension (PAH) involving 89 patients14.

The drug has been hypothesised to work against SARS-CoV-2 in two ways. Firstly, since it is a recombinant form of ACE 2, the virus binds to soluble APN01, instead of ACE2 on the cell surface, which means that the virus can no longer infect the cells.

At the same time, it reduces harmful inflammatory reactions in the lungs that occur in some patients with COVID-19 and lead to ALI and acute respiratory distress syndrome (ARDS).

Vaccines

What is a Vaccine?

Figure 1. Simplified graphic on how vaccinations work4


A vaccine is typically a biological agent made from weakened or killed forms of the microbe, its toxins, or one of its surface proteins. It provides active acquired immunity to a particular infectious disease. It is important that the attenuation is done in a way that makes the pathogens incapable of causing an infection, but still able to induce an immune response to confer resistance4,5.

Vaccines encourage our adaptive immune systems to produce highly specific antibodies and immunological memory against potential future infection. Essentially, vaccines work by introducing protection without having to risk the initial exposure of the wild-type pathogen.

How is a Vaccine produced?

The Centre for Disease Control has stated that there are six stages to vaccine development: Exploratory, Pre-Clinical, Clinical Development, Regulatory Review and Approval, Manufacturing and Quality Control. On average, developing and manufacturing a vaccine takes about 8 to 12 years in total.

Figure 2. Simplified graphic on the phases of vaccine development6


Exploratory: This phase is to characterize the pathogen and identify potential antigens that might help treat or prevent a disease6.

Pre-clinical: This phase is to determine if the potential antigen has the ability to produce immunity, while not causing harm through animal testing.

Clinical development: An application for an Investigational New Drug (IND) to the U.S. Food and Drug Administration (FDA) is made. This application basically summarizes all the pre-clinical findings to date and also describes how the drug will be tested and created.

Once the proposal has been approved, the vaccine must pass three trial stages of human testing:
  • Phase I: administers the candidate vaccine to a small group (less than 100 people) with the goal of determining whether the candidate vaccine is safe and to learn more about the responses it provokes among test subjects.
  • Phase II: which includes hundreds of human test subjects, aims to deliver more information about safety, immunogenicity, immunization schedule and dose size.
  • Phase III: which can include thousands or tens of thousands of test subjects, continues to measure the safety (rare side effects sometimes don’t appear in smaller groups) and effectiveness of the candidate vaccine.
Regulatory review and approval: A Biologics License Application (BLA) has to be made to the FDA.

Manufacturing: Drug manufacturers provide the necessary support to create mass quantities of vaccines.

Quality control: Stakeholders – healthcare system and providers, academic researchers, vaccine manufacturers, etc. –  involved must adhere to procedures that allow them to monitor whether the vaccine is performing as well as anticipated. Multiple systems are designed to keep track of its performance, safety and effectiveness of an approved vaccine7.

mRNA Vaccines

What is an mRNA vaccine?

Instead of standard vaccines where viral proteins are used to immunize, an mRNA vaccine provides a synthetic viral mRNA, which the host body uses to produce viral proteins. This will allow the host body to produce necessary antibodies and immunological memory against a potential future infection8.

Figure 3. Diagram of Central Dogma
Smith, J. (2020, April 1). Analysis: Could mRNA Vaccines Fulfill Their Potential Against Coronavirus? Retrieved from https://www.labiotech.eu/medical/coronavirus-mrna-curevac-etherna/.


Advantages of mRNA vaccine 

mRNA vaccines:
  • are much safer than killed or attenuated viruses since it is non-infectious and non-integrating. There is close to no risk of infection or insertional mutagenesis
  • can be administered repeatedly
  • have the potential for rapid, inexpensive and scalable manufacturing, mainly owing to the high yields of in vitro transcription reactions. It bypasses the process of producing and purifying viral proteins for vaccines, saving time for production.
Why have mRNA vaccines not been used before?

mRNA molecules are highly unstable since they are susceptible to degradation in the cytoplasm after a short period of time. They also have high innate immunogenicity which needs to be downregulated for the safety of the vaccine. Finally, in vivo delivery of mRNA molecules is inefficient making it a bad candidate for vaccines9.

How can these problems be overcome?

mRNA degradation can be regulated using various chemical modifications:
  • addition of 5’ CAP,
  • adding an optimal length of poly(A) tail,
  • replacing rare codons with frequently used synonymous codons that have abundant cognate tRNA in the cytosol.
This will increase protein production and reduce mRNA degradation.

Immunogenicity of the mRNA can be down-modulated to further increase the safety profile.

The efficiency of in vivo delivery can be increased through the insertion of mRNA into carrier molecules – liquid nanoparticles, so that mRNA is in an injectable form – will allow rapid uptake and expression in the cytoplasm.

Moderna, Inc. – Developing an mRNA vaccine (mRNA-1273)

Moderna, Inc. is a Cambridge, Massachusetts-based biotechnology company that is focused on drug discovery and drug development based on messenger RNA. Moderna is in the process of developing an mRNA vaccine, mRNA-1273, which encodes for the SARS-CoV-2 spike protein. The first participant of the mRNA-1273 was dosed on the 16th March 2020 (Phase I trials). There’s still Phase II and III to overcome, but if every stage of the vaccine development goes smoothly, mass production of the SARS-CoV-2 vaccine could start in about a year or a year and a half, at the earliest10,11.

Another concept? RNA-based Antibodies 

Moderna Inc. is also working on mRNA vaccines which encodes an antibody protein known to attack the virus. Effective antibodies can be identified from those who have gotten immunity through infection and recovery of COVID-19. Specific antibodies against SARS-CoV-2 can be isolated and can be sequenced, such that the mRNA sequences for the antibody is identified. These mRNA, if injected into an individual, will be translated into antibody against proteins on the virus itself, conferring immunity to the disease12.

CanSino Biologics, Inc. – Developing a Viral Vector-Based Vaccine (Ad5-nCoV)

CanSino Biologics Inc. is a global vaccine company based in China. CanSino Biologics is in the process of developing a recombinant SARS-CoV-2 vaccine (adenovirus type 5 vector) candidate. In preclinical animal studies of Ad5-nCoV, the vaccine candidate was able to trigger a strong immune response and a satisfactory safety profile. It has recently received Chinese regulatory approval to start human trials13.

Figure 4. Diagram of Vector-Based Vaccine
D., D. (2017, August 8). Virally vectored vaccine delivery: medical needs, mechanisms, advantages and challenges. Retrieved from https://smw.ch/article/doi/smw.2017.14465.


This article has touched on some of the major discoveries by some companies/research groups around the world to prevent and fight COVID-19. It is just an overview, however, and the actual progress is far beyond what this article is able to cover.

The above article was written for the purposes of general public education about updates on the COVID-19 outbreak. It should not replace information provided by medical professionals and government officials.

References

1Yetman, D. (2020, April 6). Coronavirus Treatment: How Is COVID-19 Treated?

2Kupferschmidt, K., CohenMar, J., BrainardApr, J., HeidtApr, A., Ortega, R. P., CleryApr, D., & Ortega, R. P. (2020, March 27). WHO launches global megatrial of the four most promising coronavirus treatments.

3Wang, M., Cao, R., Zhang, L. et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 30, 269–271 (2020).

4Klingensmith, M. (2014, December 10). How do vaccinations work? The science of immunizations.

5Federman RS. Understanding vaccines: a public imperative. Yale J Biol Med. 2014;87(4):417-22.

6Producing Prevention: The Complex Development of Vaccines. (2019, March 6).

7How we develop new vaccines. (n.d.).

8Belluz, J., Irfan, U., & Resnick, B. (2020, March 27). A guide to the vaccines and drugs that could fight coronavirus.

9Pardi, N., Hogan, M. J., Porter, F. W., & Weissman, D. (2018, April). mRNA vaccines – a new era in vaccinology.

10LeMieux, J. (2020, March 26). Moderna’s SARS-CoV-2 Vaccine’s Fast Track to Clinical Trials.

11BioSpace. (2020, March 16). Moderna Announces First Participant Dosed in NIH-led Phase 1 Study of mRNA Vaccine (mRNA-1273) Against Novel Coronavirus.

12Mishra, S., Carnahan, R., & Postdoctoral Scholar of Pathology. (2020, April 10). Coronavirus: A new type of vaccine using RNA could help defeat COVID-19.

13(n.d.).

14Taylor, P. (2020, April 5). Apeiron starts mid-stage trial of drug that blocks coronavirus.

15Technology Networks. (2020, April 2). Phase 2 Clinical Trial of APN01 for Treatment of COVID-19 Inititated.

Written by Krishna Amin on . Posted in Featured

COVID19: What is it and How is it Spread?


By Najung Lee (Pembroke) & Ragavi Vijayakumar (Downing). April 6, 2020. 

COVID-19 and SARS-CoV-2

Coronavirus Disease 2019 (COVID-19) is an infectious disease caused by SARS-CoV-2 virus. It was first identified in Wuhan, capital of Hubei province of China and has resulted in a global pandemic.

SARS-CoV-2 is a type of coronavirus (CoV), which is a family of enveloped positive-stranded RNA virus that infects vertebrates1. Specifically, it is a strain of severe acute respiratory syndrome-related coronavirus (SARSr-CoV) – a type of coronavirus that enters the host cell by binding to angiotensin-converting enzyme 2 (ACE2) receptor on cell membranes2. These receptors are transmembrane proteins found on lungs, arteries, heart, kidney and intestinal cells.

Bats are considered to be the reservoir of many strains of SARSr-CoV. Genetic analysis of the viral genome of SARS-CoV-2 revealed a high level of similarity to bat coronavirus, suggesting that SARS-CoV-2 is a bat-borne coronavirus3. Next-generation sequencing analysis of bronchoalveolar lavage fluid (BALF) samples from patients in Wuhan, revealed that 87.1% of the sequences matched the sequence of bat-borne SARSr-CoV. Many of SARSr-CoV strains are known to be non-human infecting species.

Figure 1. Origin and transmission of pathogenic coronaviruses. Credit: Markus Hoffmann

Pathogenic coronaviruses, such as SARS-CoV and MERS-CoV, arise from infection from the intermediate host who carries bat-borne virus and transmits it to humans. In the SARS-CoV outbreak in 2003, it was civet cats. As for MERS-CoV in 2012, it was camels. The intermediate host for SARS-CoV-2 has not been clearly identified yet (See Figure 1).

How does SARS-CoV-2 infect humans?

Figure 2. Structure of SARS-CoV-2. Credit: https://doi.org/10.1016/j.jare.2020.03.005

Cell entry is essential for cross-species transmission of animal-borne viruses like SARSr-CoV. Cryo-EM structural analysis has revealed that SARS-CoV-2 enters the cell by binding to the ACE 2 receptor. The receptor-binding domain (RBD) of the densely glycosylated spike (S) protein binds to the ACE2 receptor to promote cell entry.

The S protein is a trimeric fusion protein and undergoes structural changes between up and down conformation to promote fusion of the viral membrane and the host cell membrane4. One of the RBD is used for the initial attachment to the ACE2 receptor. The structure of the RBD showed great similarity to the one of SARS-CoV, therefore it has been (re)named from 2019-nCoV to SARS-CoV-2.

Figure 3. Life cycle of SARS-CoV-2 in host cells.
S protein binds to ACE2 receptor. After receptor binding, the conformation change in the S protein facilitates viral envelope fusion with the cell membrane through the endosomal pathway. Then SARS-CoV-2 releases RNA into the host cell. Genome RNA is translated into viral replicase polyproteins pp1a and 1ab, which are then cleaved into small products by viral proteinases. The polymerase produces a series of sub-genomic mRNAs by discontinuous transcription and finally translated into relevant viral proteins. Viral proteins and genome RNA are subsequently assembled into virions in the ER and Golgi and then transported via vesicles and released out of the cell.
Credit: https://doi.org/10.1016/j.jare.2020.03.005

After binding to the receptor, SARS-CoV-2 uses serine protease TMPRSS2 on the host cell to cleave spike5, which allows the entry of viral RNA the cytoplasm6. Once it enters the host cell, the viral genome acts as mRNA (messenger RNA), forcing the host cell to produce copies of the virus which are then disseminated to infect more cells7.

Lungs are the most severely affected organ, due to the abundance of ACE 2 receptors on the type II alveolar cells. Type II alveolar cells are responsible for releasing surfactant to expand the alveolus, facilitating gas exchange at type I alveolar cells. Once entering type II alveolar cells, the viral life cycle leads to a rapid increase in the population of viruses.

Once infected by SARS-CoV-2, type II alveolar cells turn into inflammatory cells, which in turn loses its original function. This leads to the development of symptoms (cough, fever, dyspnoea) and in severe cases leading to pneumonia.

Aforementioned, there are other cells that have ACE2 receptors- this leads to a wide range of symptoms associated with digestion, taste loss, diarrhoea, fatigue, and many more.

Why is SARS-CoV-2 so contagious?

The most prominent difference between the SARSr-CoV and MERS-CoV is the type of receptor protein that the virus uses to promote the entry of the viral genome into the host cell cytoplasm. SARSr-CoV uses ACE 2 whereas MERS-CoV uses DPP4 (Dipeptidyl Peptidase 4). (See Figure 2)

Figure 4. Overview of receptors which allows entry of the viral genome

Compared to SARS-CoV, SARS-CoV-2 is considered to be more contagious. Preliminary research has suggested that the RBD of SARS-CoV-2 has a greater affinity to ACE 2 receptor then SARS-CoV. Hence it binds more tightly to the receptor8.

Furthermore, there are relatively more asymptomatic cases of SARS-CoV-2 than SARS-CoV. This leads to more cases of super-spreaders than there had been in SARS-CoV and MERS-CoV.

Transmission of SARS-CoV-2

SARS-CoV-2 is mainly transmitted by respiratory droplets, which are around 5-6μm in the diameter. People can catch the virus from others through inhaling small droplets from infected people who cough or sneeze or through touching contaminated surfaces and then touching nose, mouth or eyes. It is estimated that a single droplet contains around 10-100 viruses.

A single virus entering the body does not mean that one is infected; usually, one’s immune system is capable of eradicating the virus; the problem occurs when the defence line of the immune system collapses due to the entry of a large population of the virus.

The researchers also found out that the virus can survive on various types of surfaces in the absence of the host cell9. According to papers published by NIH and Princeton University, SARS-CoV-2 can survive 3 hours in aerosol; 4 hours on a copper surface; 24 hours on cardboard; 2-3days on plastics or stainless steel. This is, in general, similar to the survival time of SARS-CoV.

Figure 5. Viability of SARS-CoV-1 and SARS-CoV-2 in Aerosols and on Various Surfaces Credit: DOI:10.1056/NEJMc2004973

The exact lifetime is hugely influenced by other factors such as ventilation, but the important point here is that it can be transmitted widely without any direct contact with the patient. Therefore, it is important to clean and sterilise personal belongings such as laptops, phones, and keys.

The above article was written for the purposes of general public education about the science behind the COVID-19 outbreak. It should not replace information provided by medical professionals and government officials. 

References

1Masters, P. S. (2006). The Molecular Biology of Coronaviruses. Advances in Virus Research, 193–292.

2 Ge, X.-Y., Li, J.-L., Yang, X.-L., Chmura, A. A., Zhu, G., Epstein, J. H., … Shi, Z.-L. (2013). Isolation and characterization of a bat SARS-like coronavirus that uses the ACE2 receptor. Nature, 503(7477), 535–538. 

3,4 Zhou, P., Yang, X.-L., Wang, X.-G., Hu, B., Zhang, L., Zhang, W., … Shi, Z.-L. (2020). A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature, 579(7798), 270–273.

5Hoffmann, M., Kleine-Weber, H., Schroeder, S., Krüger, N., Herrler, T., Erichsen, S., … Pöhlmann, S. (2020). SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 

6Millet, J. K., & Whittaker, G. R. (2015). Host cell proteases: Critical determinants of coronavirus tropism and pathogenesis. Virus Research, 202, 120–134. 

7Fehr, A. R., & Perlman, S. (2015). Coronaviruses: An Overview of Their Replication and Pathogenesis. Coronaviruses Methods in Molecular Biology, 1–23.

8Wrapp, 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, 367(6483), 1260–1263.

9Doremalen, N. V., Bushmaker, T., Morris, D. H., Holbrook, M. G., Gamble, A., Williamson, B. N., … Munster, V. J. (2020). Aerosol and Surface Stability of SARS-CoV-2 as Compared with SARS-CoV-1. New England Journal of Medicine.

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