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COVID-19: A Look at the Virus, its Epidemiology, Therapeutic and Vaccine Development Efforts and Impacts of the Pandemic

COVID-19: A Look at the Virus, its Epidemiology, Therapeutic and Vaccine Development Efforts and Impacts of the Pandemic

Apr 07, 2020PAO-Q2-20-NI-001

The coronavirus pandemic is affecting every aspect of daily life. Millions are quarantined, hundreds of thousands are known to be infected, and many thousands have died. Attempts to halt or at least slow down spread of the SARS-CoV-2 virus have led to travel bans, school closures, and cancellation of events involving large numbers, from professional sports and concerts to community dances and weddings. The biopharma industry and regulators are working urgently to develop safe and effective medicines and vaccines while facing the enormous challenges created by these pandemic conditions.

Part One: The Nature of SARS-CoV-2, the COVID-19 Virus 

What is COVID-19?

The genus Coronavirus in the subfamily Coronavirinae in the family of Coronaviridae of the order Nidovirales includes many large, enveloped, viruses that have high mutation rates.1 As zoonotic pathogens, coronaviruses are present in both humans and a variety of different animal species (livestock and birds, bats, mice, and other wild animals) and typically cause infections in respiratory, gastrointestinal, hepatic, and neurologic systems.2

Until recently, human coronaviruses (HCoVs) have had minimal health impacts and generally been associated with the common cold. Four HCoVs are believed to cause 10–30% of upper respiratory tract infections in adults worldwide.3

The first highly pathogenic novel coronavirus (nCoV) appeared in 2002-2003, causing severe acute respiratory syndrome (SARS) in China. The second –– Middle East Respiratory Syndrome Coronavirus (MERS-CoV) –– emerged in the Middle East several years later. The third, and the source of the current outbreak, appeared in December 2019 in Wuhan State of Hubei Province in China and was initially dubbed 2019-nCoV. The virus has since renamed by the World Health Organization as SARS-CoV-2 and the related disease as COVID-19.

Genetic Makeup

The subfamily Coronavirinae includes four genera: Alphacoronavirus, Betacoronavirus, Gammacoronavirus, and Deltacoronavirus.2 The first two typically infect mammals, while the latter two generally infect birds and fish. These CoVs are single‐stranded, positive‐sense RNA (+ssRNA) viruses with a 5′‐cap structure and 3′‐poly‐A tail. In the host, the genomic RNA is used as a template to encode nonstructural proteins (nsps) that form a replication–transcription complex (RTC), which synthesizes messenger RNAs (mRNAs).

The genome sequence alignment of different CoVs suggests that the nsp-coding region is similar, while variations occur in the structural protein‐coding region.2 In addition, the CoV genome is much larger (~30 kb) compared with most RNA viruses (10 kb), which is believed to be due to the special nature of the RTC.2

The genetic sequence for SARS-CoV-2 was released to public databases on Jan. 10, 2020 by the Shanghai Public Health Clinical Center & School of Public Health.3 SARS-CoV-2 has been shown to have a typical CoV genome structure and has been assigned to the cluster of betacoronaviruses that includes Bat‐SARS‐like (SL)‐ZC45, Bat‐SL ZXC21, SARS‐CoV, and MERS‐CoV.2

Structural CoV Proteins

There are four structural proteins important for the assembly and infectivity of coronavirus virions (virus particles),2 which are typically around 120 nm in diameter.4 Spike (S) proteins form spikes on the surface of virus particles and participate in binding to host cell receptors. Membrane (M) proteins dictate the shape of the virus particles and bind to nucleocapsids. Envelope small membrane (E) proteins participate in virus assembly, release, and pathogenesis. Nucleoproteins (N) are involved in virion formation and facilitate viral replication.

Rapid Structural Determination of the COVID-19 Virus

Understanding the structure of the SARS-CoV-2 virus is essential for determining its specific mechanisms of action, identifying possible drug targets, and developing effective therapeutics and vaccines. There have, consequently, been significant efforts to obtain structural information about SARS-CoV-2 and the spike protein.

The National Institute of Allergy and Infectious Diseases' (NIAID) Rocky Mountains Laboratories (RML) released scanning and transmission electron microscope images of SARS-CoV-2 in mid-February.5 A National Institutes of Health–funded team at the University of Texas at Austin designed and produced stabilized samples of the S protein of SARS-CoV-2 within two weeks of gaining access to the genome sequence and used cryo-electron microscopy (CEM) to reconstruct an atomic-scale 3D structural map of the S protein locked into the shape it takes before fusing with human cells.6

Evaluation of the 3D structure of the S protein has led researchers to believe it binds more tightly to human cell surface receptors than SARS-CoV, which may contribute to its greater infectivity.7 It is also possible that the S protein itself or components of the S protein could serve as vaccines against SARS-CoV-2.8

Google’s artificial intelligence unit DeepMind has also used AlphaFold, a computer model introduced in 2018, to predict the structures of six different SARS-CoV-2 proteins using data from the Universal Protein Resource.9

Importance of the Spike (S) Protein for Infectivity

The nature of the S glycoprotein is believed to determine the main infectivity properties of each coronavirus. Once parts of the S protein bind to a human cell, other portions of the spike fuse the membranes of the virus and the human cell, enabling the virus to enter and infect the cell. Notably, the S protein is also typically the target of neutralizing antibodies.

Researchers at the University of Washington School of Medicine and the Fred Hutchinson Cancer Research Institute have elucidated more information about the viral structure, function, and chemical binding affinities of the SARS-CoV-2 S protein using CEM and other analytical methods.10 In particular, they have determined that SARS-CoV-2 enters human cells by binding to the cell surface receptor angiotensin-converting enzyme 2 (ACE2), the same receptor used by SARS-CoV. They have also identified antibodies that inhibit cellular fusion by both SARS-CoV and SARS-CoV-2. These results have also been confirmed by other research groups.

These Seattle scientists did find one notable difference in the S protein of SARS-CoV-2: a furin cleavage site at a boundary between two subunits that may contribute to its ability to infect more types of cells and/or enhance its transmissibility.10 Researchers in China also found an “HIV-like mutation" that gives SARS-CoV-2 unusual properties.11 They believe this mutation gives the virus a packing mechanism that is more similar to HIV and the Ebola virus.

Meanwhile, scientists at Northwestern’s Feinberg School of Medicine have mapped Nsp15, a non-structural protein that helps SARS-CoV-2 replicate and could be a drug target. They propose that inhibition of Nsp15, which is essential to the life cycle and virulence of coronaviruses, could slow viral replication and thus be effective as a treatment.12

At Least Two Strains

As the COVID-19 outbreak spreads, it appears that the situation may be complicated by virus mutations. In early March, researchers at Peking University’s School of Life Sciences and the Institut Pasteur of Shanghai reported the identification of a second strain of the SARS-CoV-2 virus.13 They noted that of the two strains –– one more and one less aggressive –– the former accounted for 70% of the strains they analyzed and was found to be more prevalent during the first stages of the outbreak in Wuhan, China, but its frequency decreased after early January.

The scientists also believe that this new strain suggests that other mutations are likely to have formed. It should be noted that only strains from China were evaluated initially. As a result, there was “an urgent need for further immediate, comprehensive studies that combine genomic data, epidemiological data, and chart records of the clinical symptoms of patients with coronavirus disease 2019 (COVID-19).”13

More Research Underway

Indeed, research is being actively pursued to better understand the structure and function of the SARS-CoV-2 virus and to determine if other mutations and/or recombination have occurred. Scientists are using not only the genomic sequence and the structural mapping results reported to date, but also virus isolates such as those produced by the U.S. Centers for Disease Control to conduct a variety of experiments, including antiviral research, pathogenesis investigations, and virus stability studies.14


Part Two: Epidemiology of COVID-19

Animal Origins

Like the two other recent outbreaks based on coronavirus –– severe acute respiratory syndrome (SARS) in China Middle East Respiratory Syndrome Coronavirus (MERS-CoV) –– the latest coronavirus disease, named by the World Health Organization (WHO) as COVID-19, is believed to have been transferred to humans from animals.

This conclusion is based on the evaluation of the initial cases of infection in Wuhan, Hubei Province, China. A large percentage of these people had visited a seafood and wet animal wholesale market in the city, suggesting that the virus causing COVID-19, referred to as Sars-CoV-2 or 2019-nCoV, is zoonotic in origin.15 In this market, live animals are sold regularly. Genomic sequence analysis of the virus revealed significant similarity to two bat-derived severe acute respiratory syndrome (SARS)-like coronaviruses.

Rapid Spread of COVID-19

Following initial reports of the first five cases or patients with a new form of acute respiratory distress syndrome in late December, 2019, the number of people suffering from the new diseases rose rapidly. By January 2, 2020, 41 patients had been hospitalized with laboratory-confirmed COVID-19 infection, many of whom were thought to have been infected while in that hospital.15 Because only patients that showed symptoms were tested, a far greater number of people were likely infected. By January 22, 2020, 571 cases of COVID-19 were reported in 25 Chinese provinces and 17 people had died. The number of infected people in mainland China jumped to nearly 2000 to 5500 by January 25, depending on the source.

By the end of January, the virus was present in Taiwan, Thailand, Vietnam, Malaysia, Nepal, Sri Lanka, Cambodia, Japan, Singapore, Republic of Korea, the United Arab Emirates, the United States, the Philippines, India, Australia, Canada, Finland, France, and Germany.15 The World Health Organization (WHO) declared COVID-19 a Public Health Emergency of International Concern on January 30, 2020. The first case of human-to-human transmission of SARS-CoV-2 was reported in the United States on that date. By mid-February, over 51,000 cases of COVID-19 were reported by the WHO worldwide, with more than 1660 people having died.15

With more than 118,000 cases of infection and over 4000 deaths occurring in 114 countries and the numbers expected to rise further, the WHO declared COVID-19 a pandemic on March 11, 2020.16 At this point, more than 90% of the cases were in four countries, and China and South Korea were observing “significantly declining epidemics,” according to the WHO. But over the previous two weeks, the number of cases of COVID-19 outside China increased 13-fold, while the number of countries with infected citizens tripled.

The number of cases and deaths climbed to 167,500 and 6600, respectively, by March 16, 2020.17 Nearly 14,000 new cases were registered and more than 860 people died during the previous 24 hours. By this point, slightly less than half of the cases were in China.

Transmission

Evaluation of COVID-19 cases suggests that the disease is mainly spread through person-to-person contact, as well as through exposure to droplets spread by coughing, sneezing, or even talking by people infected with the virus.18 The virus released in respiratory secretions passes into the mucus membranes of healthy people. Fortunately, virus-containing droplets typically do not travel more than six feet and generally do not last long in the air. Transmission is also possible, however, if a healthy person touches a surface exposed to infected droplets and then touches his/her eyes, nose, or mouth.

It is important to recognize that a full understanding of the transmission risk has not yet been obtained.18 Rates of transmission from infected individuals showing symptoms have varied from one location to another, partially due to varying control strategies. In addition, the rates of transmission from infected people that are not showing symptoms are unknown.

Respiratory Illness

The incubation period for COVID-19 is thought to last up to 14 days following exposure, with four to five days being the most common.18 Symptoms of infection with the SARS-CoV-2 virus are those of a respiratory infection. Fever, dry cough, and fatigue are most common at the onset of infection, but other symptoms may include phlegm production, headache, and diarrhea. In patients that experience severe infections, the clinical features associated with pneumonia are observed. In the most severe cases, additional features associated with SARS diseases are observed, including acute respiratory distress syndrome, acute cardiac injury, increased inflammation due to a heightened immune response, and organ failure.

With regard to the severity of the illness experienced by infected people, the range covers a spectrum from mild to fatal. It appears that approximately 80% of infected individuals experience no symptoms or symptoms associated with mild pneumonia, 15% suffer from a severe form of the disease, and 5% are critical, with respiratory failure, shock, and multiorgan dysfunction.18 The fatality rate appears to be on the order of 2.3%, with all deaths occurring among critical patients.

SARS-CoV-2 infects individuals of all ages, from the very young to the very old.19 Young, healthy people tend to be asymptomatic or experience only mild forms of the disease. Most severe and critical cases have occurred in elderly people and people with compromised immune systems (i.e., that are already fighting other diseases and disorders).  The highest death rate is among people 80 years and older (14.8%), followed by those 70–79 (8.0%). Patients reported having no other medical conditions experienced a fatality rate of 0.9%, while the rate was as high as 13.2% for those with cardiovascular disease, 9.2% for those with diabetes, 8.4% for those with hypertension, and 7.6% for those with cancer.

In a study of 1099 patients with laboratory-confirmed COVID-19 from 552 hospitals in various locations in China through January 29, 2020, it was found that the median age was 47 years with a male/female ratio of 58/42.20 The median incubation period was four days. Patients often presented without fever, and many did not have abnormal radiologic findings. Treatments included intravenous antibiotic therapy, oseltamivir therapy, oxygen therapy, and mechanical ventilation. Of the nearly 1,100 patients, 67 experienced sufficiently severe illness to require admittance to the ICU (5.0%), invasive mechanical ventilation (2.3%), and/or death (1.4%).

Comparison of COVID-19 to SARS and MERS

There are many similarities between COVID-19 and the previous coronavirus outbreaks known as SARS and MERS.21 SARS was determined to be caused by a novel coronavirus (nCoV) transmitted to humans from bats via palm civets in markets in Guangdong Province, China. MERS is also believed to have an nCoV transmitted from bats, but via dromedary camels in Saudi Arabia.

All three diseases have similar initial symptoms, including fever and dry cough, and typically lead to lower respiratory tract disease. They also have the severest impact on the elderly and people with other health conditions.

The rate of spread of infection by SARS-CoV-2 is much higher, however, with much occurring outside the hospital setting through close contact. Most secondary transmission of SARS and MERS, however, occurred in the hospital setting.

SARS was determined to be contained in mid-2003 by the WHO, with a total of 8,098 cases and 774 deaths in 26 different countries. MERS is not yet contained but is attributed to just under 2,500 cases and 858 deaths in 27 countries. COVID-19 has caused many more deaths than SARS and MERS combined owing to its rapid spread around the globe and its higher infectivity, which has led to much larger numbers of cases.

Understanding the Pandemic Determination

Pandemic does not refer to the severity of the illness caused by the disease, but its spread around the world.22 The WHO considers a new disease to be pandemic if it occurs worldwide or at least over a very wide area, including crossing international borders, if it affects a large number of people, and if transmission occurs almost simultaneously on a global basis. Simultaneous transmission in multiple locations makes it much harder to prevent further spread of a disease, leading to a shift from containment to mitigation. New diseases are also challenging because no treatments or vaccines exist.

The WHO’s decision to label COVID-19 a pandemic was intended to let people around the globe know that everyone is facing this outbreak. It was also a call to action for governments around the world to take immediate action to limit the virus.

Part Three: Progress on Therapeutic and Vaccine Development for COVID-19

Focus on Accelerated Development

The COVID-19 pandemic sweeping across the globe is creating a furor of activity in the biopharma industry. Efforts have been devoted to developing simpler, rapid diagnostic tests to facilitate screening of those potentially infected with the SARS-CoV-2 virus. Numerous clinical trials with patients infected with SARS-CoV-2 in China are investigating the effectiveness of existing and experimental treatments, some of which were initially developed in response to other coronavirus outbreaks (severe acute respiratory syndrome (SARS) and Middle East Respiratory Syndrome (MERS)).23

Meanwhile, philanthropic and advocacy groups have provided funding to accelerate the development of novel therapeutics and vaccines using new platform technologies by emerging biotech companies. In March, the Bill and Melinda Gates Foundation, Wellcome, and Mastercard contributed a total of $125 million to launch the COVID-19 Therapeutic Accelerator, an initiative dedicated to speeding up the development of and access to treatments and make them available and affordable for vulnerable communities.24

In late January 2020, the Coalition for Epidemic Preparedness Innovations (CEPI) announced the funding of three programs to develop novel vaccines against COVID-19.25 By early March, the group committed several million more dollars to additional firms working on novel vaccine technologies.26,27 By the middle of that month, the organization indicated that at least $2 billion was needed to effectively accelerate the development of COVID-19 vaccines.28

The World Health Organization (WHO) has also been creating a roadmap for the development of COVID-19 vaccines.29 The priorities include drafting a target product profile (TPP), designing a master protocol to test multiple vaccine candidates in parallel, and coordinating international work on animal models and standards. By mid-February, Biocentury reported that at least 37 companies and academic groups, including 25 in China, were working on vaccines for COVID-19.29

While many of the firms involved in the development of vaccines and drugs targeting SARS-CoV-2 are small and emerging biotech, Big Pharma is active as well, looking to leverage existing portfolios and technologies in the fight against COVID-19.

There is a general agreement that new therapeutics to treat COVID-19 infections will be approved and available before any vaccines. New vaccines must be developed based on the specific genetic code of the virus and require the full gamut of safety and efficacy testing. Many of the investigational drugs developed to treat SARS and MERS, however, have already undergone that testing and could potentially be effective against COVID-19.30 And while vaccine development is being accelerated, some experts still do not believe a new vaccine will be approved and available for use within 12–18 months.31

First Rapid Diagnostics Approved

One of the first things the medical community had been pushing for was access to rapid, easy-to-use diagnostics for the SARS-CoV-2 virus. By mid-March, the U.S. Food and Drug Administration had granted Emergency Use Authorization to two: one from Roche32 and another from Thermo Fisher Scientific.33

Roche’s cobas SARS-CoV-2 test was the first approved commercial test. It can be run on the company’s automated cobas 6800 and cobas 8800 Systems, which are widely used by hospitals and reference labs. Nearly 100 results can be obtained in three hours using the test on these systems. Thermo Fisher Scientific’s test detects a nucleic acid unique to SARS-CoV-2 and is performed using Applied Biosystems TaqPath Assay technology. Results are obtained within four hours of sample receipt by the lab. After approval, both companies were prepared to ship over a million tests and rapidly scale up production.

Small Molecule Therapy Efforts

Many established antiviral medications are small molecule drugs, a number of which target virus RNA activities. Some are being explored as possible treatments for COVID-1934 with Gilead Science’s remdesivir receiving the most attention. It was originally developed for Ebola and has also been investigated against other RNA viruses, including the coronaviruses that cause SARS and MERS. There are several clinical trials underway around the world to evaluate the effectiveness of remdesivir against COVID-19. Gilead has also signed an agreement with the U.S. Army Medical Research and Development Command to provide remdesivir to U.S. troops with confirmed SARS-CoV-2 infections.35

Numerous other antiviral drugs are also being tested, such as the neuraminidase inhibitor oseltamivir (Tamiflu) and HIV protease therapies. For instance, AbbVie is evaluating its HIV combination therapy Kaletra/Aluvia (lopinavir/ritonavir) as a COVID-19 treatment in partnerships with health authorities and institutions in several countries.36

Even older drugs, such as chloroquine phosphate (Resochin® from Bayer), initially developed as an antimalarial, may be effective according to in vitro screens, and several clinical trials are underway in China, with others planned in the United States. The U.S. FDA has approved the off-label use of chloroquine phosphate.34

In some cases, drugs not initially developed as viral treatments are being investigated.37 One example is Roche’s idiopathic pulmonary fibrosis drug pirfenidone (Esbriet®). Another is Pharmstandard’s membrane fusion inhibitor umifenovir (Arbidol), developed as a treatment for influenza.

For novel drug development, researchers are targeting the spike (S) protein on the virus surface and the ACE2 receptor protein on human cells to inhibit viral entry and RNA activity to prevent viral replication.34 NanoViricides, for instance, is developing a COVID-19 treatment based on its nano-scale virus-binding ligand technology targeting ACE2. Meanwhile, the nucleoside RNA polymerase inhibitor galidesivir (BCX4430) from Biocryst, designed to disrupt the viral replication process, exhibits broad-spectrum activity in vitro against more than 20 RNA viruses in coronaviruses and viral disease families.

Biologics Under Investigation

Not surprisingly given that biologic drugs have become increasingly popular and now account for a large percentage of the top-ten selling drugs today, many biomolecules (existing and under development) and even next-generation cell therapies are being explored to target the SARS-CoV-2 virus.

Many of these potential COVID-19 treatments are monoclonal antibodies (mAbs). Regeneron Pharmaceuticals signed an agreement with the U.S. Department of Health and Human Services (HHS) to use its VelociSuite® technologies to rapidly identify, validate, and develop antibody candidates as coronavirus therapies, such as REGN3048 and REGN3051. Beijing Staidson Biopharma and InflaRx are evaluating IFX-1, an anti-C5a monoclonal antibody in development for COVID-19 and hidradenitis suppurativa in clinical trials in China.38

Leronlimab (PRO 140), CytoDyn’s humanized IgG4 monoclonal antibody CCR5 antagonist with potential for multiple therapeutic indications, has successfully completed nine clinical trials, according to the company, which is planning a phase II study for COVID-19 patients.37 Vir Biotechnology and WuXi Biologics are also collaborating on the development and manufacture of human mAbs that bind to SARS-CoV-2 using Vir’s antibody platform, which has been successful in the development of antibodies against Ebola hepatitis B virus, influenza A, malaria, and other viruses.37

Regeneron, with partner Sanofi, is also initiating trials with their anti-interleukin-6 receptor (anti-IL6R) rheumatoid arthritis drug asilumab (Kevzara) for the treatment of COVID-19 symptoms.39 Chugai Pharmaceutical and Zhejiang Hisun Pharmaceutical are evaluating tocilizumab, their humanized mAb targeting IL-6.37 Tiziana Life Sciences is also hoping its anti-IL6R mAb will be effective for COVID-19 patients. China has already approved Roche’s rheumatoid arthritis drug tocilizumab (Actemra) for treatment of patients developing severe complications from COVID-19.39

AIM ImmunoTech’s immunomodulatory double-stranded RNA drug rintatolimod (Ampligen) has shown a 100% survival rate in SARS animal studies, suggesting that it might be effective against the SARS-CoV-2 virus.40 Japan’s National Institute of Infectious Diseases (NIID) is testing the therapy for COVID-19.41

Vienna-based CEL-SCI is using its Ligand Antigen Epitope Presentation System (LEAPS) peptide platform technology to design immunotherapeutic peptides that target the NP protein of SARS-CoV-2 and elicit cytolytic T cell responses. The company has achieved successful results in animal models for herpes simplex virus (HSV) and influenza A. Beroni Group, meanwhile, is advancing a nanobody-based COVID-19 treatment being developed using information on the SARS-CoV-2 nanobody sequence and the complex crystal structure of the virus.

Apeiron Biologics has launched a pilot investigator–initiated clinical trial in China to evaluate its recombinant human angiotensin-converting enzyme 2 (rhACE2) APN01 –– developed for the treatment of acute lung injury, acute respiratory distress syndrome, and pulmonary arterial hypertension –– in COVID-19 patients.37

Pneumagen believes that its lead carbohydrate binding molecule (mCBM) Neumifil™, generated using its proprietary GlycoTarge™ platform, may be effective against COVID-19. The drug candidate is being developed for the universal treatment of respiratory tract infections (RTIs), including influenza virus (IFV) and respiratory syncytial virus (RSV), and now coronaviruses. The company says mCMBs work by masking glycan receptors in patients’ airways thus preventing viral entry –– a new mechanism of action that can offer protection against all viral strains.42

Another approach to the development of treatments for COVID-19 involves harnessing the antibodies of patients that have been infected but since recovered. Plasma-derived therapies, according to Takeda, have proven to be effective against other severe acute viral respiratory infections.43 The company is working to develop a plasma-derived anti-SARS-CoV-2 polyclonal hyperimmune globin (TAK-888).

Cell therapies are also in the pipeline. Celularity and Sorrento Therapeutics are collaborating on the development and manufacturing of CYNK-001, an allogeneic, off-the-shelf, placental-derived natural killer (NK) cell therapy for the treatment of COVID-19.37

Leveraging Novel Vaccine Platform Technologies

Viral vaccines have traditionally comprised attenuated versions of dead or, in some cases, live virus. Using the virus itself ensures a strong immune response, but demonstrating the safety of these vaccines can be a years-long process. Many novel vaccine technologies are, therefore, being pursued with the hope of dramatically reducing the time it takes to develop a vaccine for COVID-19 and get it approved for global distribution.

Many of these new approaches focus on one or more important viral components that can elucidate robust immune responses yet eliminate the safety concerns associated with use of the whole virus.44 Examples include DNA- and RNA-based vaccines, such as those being developed by Inovio Pharmaceuticals and Moderna and CureVac, respectively. All three of these companies have received grant funding from CEPI.

Inovio previously developed a vaccine (INO-4700) against MERS-CoV and was the first to get such a candidate into human trials. Its COVID-19 candidate INO-4800 entered animal testing in February 2020, and the company hopes to begin human safety testing in early summer 2020.45 Moderna partnered with the Vaccine Research Center (VRC) of the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), to develop its COVID-19 mRNA vaccine candidate (mRNA-1273) ,46 for which NIAID has already initiated phase I clinical testing.47 CureVac also has an mRNA platform technology, as well as proprietary lipid nanoparticle (LNP) carrier molecules and The RNA Printer, a mobile, automated production unit for rapid supply of LNP-formulated mRNA vaccine candidates.48

CEPI is also funding work at Australia’s University of Queensland (UQ) School of Chemistry and Molecular Biosciences, where researchers are applying proprietary rapid response technology based on molecular clamp technology to create subunit vaccines against class I and III enveloped viruses, such as SARS-CoV-2, by stabilizing the pre-fusion form of viral fusion proteins using a polypeptide “clamp.”49 The UQ researchers created a COVID-19 vaccine candidate in the laboratory in just three weeks and hope to begin clinical testing in the summer.

Some companies are focused on the development of vaccines comprising virus-like particles (VLPs). GeoVax and BravoVax are developing a coronavirus vaccine based on GeoVax’s Modified Vaccinia Ankara (MVA)-VLP platform, which the company says enables enhanced expression and stable transgenes during the manufacturing process and the production of vaccines that provide full protection in a single dose.50 iBio, meanwhile, is developing a plant-derived, VLP coronavirus vaccine (IBIO 200) using iBio’s FastPharming System.™51 

Other partnerships include Takis Biotech and Evvivax,50 LineaRx (Applied DNA Sciences) and Takis Biotech, and GlaxoSmithKline and Clover Biopharmaceuticals (funded by CEPI).37 Companies working on their own include Altimmune (intranasal vaccine designed to provide systemic immunity), Generex Biotechnology (Ii-Key peptide vaccine), Novavax (antigens derived from the coronavirus spike (S) protein using the company’s proprietary recombinant protein nanoparticle technology, funded by CEPI), Sanofi (DNA vaccine), and Vaxart (oral recombinant vaccine based on its proprietary VAAST™ Platform).37

Researchers at the University of Washington are taking a very different approach. They are using synthetic biology to design and build nanoparticles out of proteins and repetitively attach viral antigens that elicit a strong immune response.52There is potential to include molecules from multiple coronaviruses to generate a vaccine that is effective against several original viruses (SARS, MERS, COVID-19) and mutated versions.

This approach has advantages over DNA- and RNA-based vaccines, according to the scientists, because these vaccines self-assemble and include viral antigens that elicit a direct immune response, rather than requiring cells to first produce viral proteins that then generate an immune response. Computer modeling helps to identify the optimum shape and protein composition. With support from the Gates Foundation, the researchers hope to advance a vaccine based on their synthetic biology approach against COVID-19.

Part Four: Broader Impacts of the COVID-19 Pandemic 

Focus on Limiting Further Spread of the Virus

In the weeks since the new coronavirus outbreak caused by SARS-CoV-2 (2019-nCoV) and named COVID-19 was declared a pandemic by the World Health Organization, the focus of governments across the world has been on minimizing further impacts.

While efforts are underway in the biopharma industry to determine the safety and efficacy of established and investigational therapies already in the pipeline and develop novel therapeutics and vaccines as rapidly as possible, actions have been taken by governments at the national, state/province, and local levels in an attempt to limit further spread of the virus through their communities. In many cases, businesses and other organizations, such as educational institutions, have moved ahead of mandates in order to protect their employees, customers, and students.

The new coronavirus, as a result, although invisible to the naked eye, has not only caused serious illness and death for tens of thousands of people, it has upended the daily lives of billions of individuals around the globe.

Government Responses

National responses have occurred at different rates as the outbreak spread outward from China to other Asian countries, Europe, the United States, Central and South America, and the Middle East and Africa. While harder-hit countries implemented restrictions, others yet to be impacted continued to allow mass gatherings, such as religious pilgrimages.53 Now that the virus has reached nearly every country in the world, government actions are aligning. Many have declared a state of emergency, enabling access to additional resources.

Early on, countries including Israel and the United States placed travel restrictions on people coming from countries with larger numbers of COVID-19 cases. The next phase involved limiting the number of people that could gather in any one place in countries with rising cases of infected people. The SARS-CoV-2 virus is mainly spread through person-to-person contact and exposure to contaminated droplets produced by infected persons when they cough, sneeze, or even talk.

The main mechanism for avoiding infection, therefore, is termed social distancing –– staying 6 feet or more away from other people (regular and extensive hand washing is also an important preventive measure) . Countries have thus placed restrictions on public gatherings of all kinds. In the United States, for instance, the size of allowed gatherings has decreased as the number of affected people has risen. As of March 18, the recommendation was to keep groups to 10 people or less in order to allow for effective distancing, although greater restrictions are evolving at the state and local levels.

In many countries, public schools are closed nationwide. In the United States, that decision has been left to states and local communities; most elementary, middle, and high schools are closed, with many providing some level of remote learning opportunities for older children. They have also been creative in devising means for providing for children that receive meals when in school to continue to receive food assistance. Most colleges and universities have also closed their campuses and moved to online classes. All group activities, such as sports (think the “March Madness” basketball tournament), theater performances, and invited lecture series have been postponed or canceled outright.

On a larger scale, international relations have been affected in many ways. Perhaps the most vivid example is the cancelling of negotiations between the UK and EU regarding the UK’s exit from the European Union (Brexit). These types of discussions, and many others from World Bank and town council meetings to business conferences, TV analysis shows, and individual singing lessons and doctor visits, are now taking place virtually.

Another ugly side effect of the COVID-19 pandemic has been an increase in anti-Chinese sentiment. Chinese people and people of East Asian descent experienced an increased level of racist attacks in the United States and Europe.54

Many Business Impacts

Travels restrictions and bans on large gatherings are affecting everyone, from governments to business to individuals. Airlines, hotel groups, and aerospace companies have been particularly affected. Travel restrictions have reduced the number of people flying, leading to cancellations and staff layoffs at most airlines. Many hotel groups have also reduced headcounts due to reduced demand as the result of the COVID-19 pandemic. The same is true for companies like Boeing.

The sports and entertainment industries have also been particularly affected. The entire Broadway theater district in New York City is closed. Many concerts have been cancelled or postponed. Theme parks, particularly the major ones  –––Disney World, Disneyland and Universal Studios, for instance  –– temporarily closed in the middle of “spring break” season, one of the busiest times of the year. Professional Sports organizations from the National Basketball Association and Major League Baseball in the United States to the Union of European Football Associations have cancelled or postponed games. The 2020 European Soccer Championships and the 2020 Olympic Games, for instance, have been delayed until 2021.

Many restaurants have stopped serving people directly and shifted to take-out and delivery options only. Workout gyms, if they have stayed open, have instituted specific cleaning requirements and are limiting the number of people that can be present at any one time. Nonessential retail stores have closed, while others are staying open; the latter typically have limited hours and request patrons pursue social distancing behaviors.

Even politics has not proceeded as usual. Several U.S. states have postponed their democratic presidential primary elections. Tech and many other companies that generate work products using computers gave permission or required their employees to work from home.55 Amazon removed products claiming to cure SARS-CoV-2 infections and others for price gauging. On a personal level, items such as toilet paper and hand sanitizer rapidly disappeared from shelves, causing considerable difficulty for many.

Mental Health Concerns

In addition to not so insignificant inconveniences caused by store, school, and restaurant closings, psychiatrists have warned that an upswing in mental illness should be expected as a result of the COVID-19 pandemic.56 In addition to sickness due to viral infection, stress and anxiety-related disorders and sleep disturbances are often common during widespread disease outbreaks. Depression also often rises among sick people in general and can be potentially greater under pandemic conditions.

Consequences for the Healthcare System

The impact of COVID-19 on hospitals and the overall healthcare system is expected to be substantial.57 In the United States, for instance, due to recent reductions in the number of hospitals and hospital beds, hospitals under normal circumstances operate near full capacity and cannot easily increase services. There also already exists a shortage of healthcare workers, and emergency rooms tend to be overwhelmed. Those numbers would be reduced as these people become infected due to exposure to patients and the need to care for sick family members. Others will not come to work to avoid exposure.

Complicating the situation is limited access to tests for COVID-19 and advanced equipment, such as ventilators, needed to support patients with severe cases. In fact, in Italy, a country with a well-regarded healthcare system, hospitals could not meet the needs of the large number of patients who became critically ill all at the same time.58 Elective surgeries were halted and even some semi-elective surgeries postponed. Patients not infected with SARS-CoV-2 but needing hospitalization for other illnesses and injuries often contracted COVID-19 while hospitalized. Most alarmingly, doctors were forced to choose which patients received ventilators (those likely to survive prolonged intubation) and those that did not (often elderly people with pre-existing conditions).

Similar resource limitations exist in many developed countries, including the United States, and are more extensive in emerging regions.

Supply Chain Concerns

As the COVID-19 outbreak spread around the world, consumers responded by stockpiling many basic household supplies, from toilet paper to canned and frozen goods and bottled water.59 Hand sanitizers and medical face marks were out of stock by early March, with no projections on when they would be available again.

In China, online ordering was helping retailers keep their stores stocked during the early days of the outbreak, but by mid-March, even in the United States, many products such as toilet paper could not be purchased online from domestic sources. Suppliers were predicted to be available by late April at the earliest.

Looking even further back into the supply chain, the chemical and allied industries have been significantly impacted by the outbreak given that many basic raw materials are produced in China.60 The country accounts for more than 50% of global capacity for polyester, purified terephthalic acid, polyvinyl chloride, methanol, and methyl tertiary butyl ether, according to the ICIS Supply and Demand Database.

The challenge for all countries is to achieve a balance between continued production of essential materials and protecting the health of citizens. People in China began returning to work in March once the spread of COVID-19 slowed in the country, but the ramifications of reduced output for more than two months and restrictions on shipping have affected various supply chains.

In addition, China is a huge consumer of chemicals and allied products –– for instance, nearly 50% of global polymer demand, according to ICIS. The slowdown in manufacturing in the country will mean reduced conversion of those polymers into downstream products. 

Drug Shortages

The COVID-19 pandemic is not only affecting consumer and chemical industry supply chains. Approximately 80% of pharmaceuticals sold in the United States, and a larger percentage sold in many other countries around the world, are produced using raw materials, intermediates, or active pharmaceutical ingredients (APIs) manufactured in China.61

Most antibiotic APIs and heparin used in blood-thinner drugs for open-heart surgery, kidney dialysis, and blood transfusions are almost exclusively produced in China. India, which manufactures many low-cost generic drugs sold around the world, gets nearly 70% of the APIs it uses to produce those drugs from China.62

The closure of manufacturing plants in China in order to slow the spread of SARS-CoV-2 in the country has limited supply of those APIs. By early March, the Indian government had restricted the export of 26 different APIs and formulated products –– approximately 10% of its export capacity, including antibiotics, several vitamins, and paracetamol, the API used in acetaminophen products.63 Prices rose dramatically in response. According to various reports, the costs for paracetamol and the antibiotic azithromycin climbed by 40% and 70%, respectively.64

Quarantine procedures and disruptions in logistics services due to transportation restrictions have contributed to the supply chain issues too. The hoarding of APIs by traders has exacerbated the situation and driven up prices as well.62 The U.S. Food and Drug Administration reported the first drug shortage related to the COVID-19 pandemic in late February.65 The agency did not name the drug, but said the shortage was due to an issue with manufacturing the API. It also noted other alternatives were available for patients. The FDA also indicated that there are 20 drugs with APIs solely sourced from China.

China also happens to be the largest supplier of medical devices to the United States and elsewhere, including various types of testing instruments and diagnostic tests and even surgical gowns.61 Shortages of personal protective equipment (PPE) began within six weeks of recognition by the international community that COVID-19 was a significant epidemic with potential global ramifications.

Other Consequences for the Biopharma Industry

Disrupted drug supply is not the only concern for the biopharmaceutical industry. The blood supply is also vulnerable.66 With many people choosing to stay home for their own safety, the number of donors has dropped precipitously. According to the Red Cross, there is no evidence that SARS-Co-V2 or any other respiratory viruses are transmitted by blood transfusions. Even so, the group screens donors for temperature, blood pressure, and hemoglobin level. In addition, there have been no readily available diagnostic tests to confirm that blood donors are free of the SARS-CoV-2 virus.67 As a result, there is a potential for severe shortages.

Regulatory oversight may also be challenged due to decreased headcounts as agency employees become infected with COVID-19 and must be quarantined.67 The need for social distancing is also leading to the cancellation or at least postponement of FDA Advisory Committee meetings. New Drug Application reviews may also be delayed, which would impact the rate of new drug approvals. Similarly, medical conferences at which clinical results are presented and the latest research discussed are being cancelled, which could affect drug development efforts overall.

Drug discovery and development efforts may also be impacted at biopharma companies. Reduced availability of reagents and other chemicals, reduced staffing levels, and the need for social distancing are all factors. Clinical trials are likely to be impacted as well. Hospitals dealing with COVID-19 patients will not be interested in managing clinical trials. Patients involved in current trials could drop out due to infection with SARS-CoV-2, severely impacting trials results and potentially leading to their cancellation. There will also be fewer people available to participate in any new clinical studies that are initiated.

The Industry Responds

The biopharmaceutical industry is taking many different steps in response to the challenges presented by the COVID-19 pandemic. In addition to many development programs and clinical trials pursuing therapeutics and vaccines against SARS-CoV-2, the industry is providing financial support and in-kind donations of advanced surgical equipment, antibiotics, disinfection equipment, batch virus testing devices (e.g., throat swabs), vitamins, protective clothing, goggles, masks, gloves, and more.68 Many companies have also donated investigational compounds for study as potential treatments for COVID-19.

Partnerships, such as the Innovative Medicines Initiative, which includes the European Medicines Agency, National Health Authorities across Europe as well as the World Health Organization (WHO), Centers for Disease Control and Prevention (CDC), Chinese public health authorities including the Chinese Center for Disease Control and Prevention, and many others, are supporting the healthcare community in many ways, such as determining how pandemic preparedness platforms can potentially be tailored to address the COVID-19 emergency.

Regulatory bodies are also monitoring potential supply chain issues and developing plans to mitigate any potential drug shortages. For instance, the European Medicines agency is working with the European Commission and national competent authorities in EU member states within the EU Executive Steering Group on Shortages of Medicines Caused by Major Events.69 The group is focused on establishing a strategy and specific measures for addressing the impact of the outbreak of COVID-19 on the supply of medicines in the EU.

Range of Possible Economic Impacts

With so much uncertainty about the full extent of the impact of COVID-19 on healthcare systems and populations in different countries, it is difficult to predict with any certitude the economic impact of the current pandemic. One key concern, however, is that the outbreak began in China, which is a much larger and more integrated participant in the world economy.70

Possible scenarios range from the pandemic becoming completely global but with low severity and occurring just this once in 2020 to an annual, recurring severe worldwide outbreak.70 Models to estimate the global impact of each scenario consider such factors as the percentage of people that fall ill and the case fatality rate. Indirect effects include reductions in the labor supply, hours lost due to sickness and caregiving, the rising cost of doing business, disruption of supply chains, shifts in consumption, and other factors. For a mild outbreak, the loss of real GDP in 2020 worldwide is predicted by one group the be $2.3 trillion and $420 billion for the United States.

McKinsey proposed three possible economic scenarios: a quick recovery, a global slowdown, and a pandemic-driven recession.71 The former is thought to be likely if the public health response in countries outside China has a similar level of effectiveness of that implemented in China, the SARS-CoV-2 virus is seasonal, the fatality rate is similar to that of the flu, and changes in work behaviors are localized. A global slowdown would be likely if the response is less effective, the virus is seasonal, the fatality rate varies depending on the response of individual healthcare systems, and there is a greater change in daily behaviors. A recession would be likely if the response is less effective, the virus is not seasonal, the fatality rate is higher than for the flu due to the nature of the virus, and behaviors are changed on a general basis.

By early March, the economic impacts of the COVID pandemic were greater than those of SARS (approximately $50 billion) or MERS (approximately $8.5 billion), according to the World Economic Forum.72 In the United States alone, the S&P 500 index of U.S. companies fell by 11.5% the week of February 24 and was down more than 30% by March 20.73

Federal governments and central banks around the world have taken measures to bolster their economies and help citizens impacted by the COVID-19 epidemic.73 In the United States, the Federal Reserve implemented several emergency actions, and the central bank took steps to support U.S. businesses and banks, as well as foreign central banks. Meanwhile, both the U.S. House and Senate passed massive stimulus bills that included cash payments to citizens.74

On a positive note, some digital businesses are doing well, such as those that provide virtual conferencing capabilities. The closure of restaurants to sit-down visitors is driving huge demand for delivery personnel.

Overall, however, the news is not good. The housing sector has slowed, many companies have posted profit warnings, tourism is down, the price of oil dropped precipitously, and consumer spending overall has slowed. As a result, growth is expected to be flat or negative in seven of the 10 largest economies in the first quarter of 2020. The conclusion: COVID-19 represents “an economic pandemic” that is suppressing growth on a global scale, and a global recession cannot be ruled out.75

What Can Be Expected?

In the final analysis, however, most people are concerned about themselves and their loved ones and how the COVID-19 pandemic might affect them. According to Harvard epidemiologist Marc Lipsitch, 70% of the world population is likely to be infected by SARS-CoV-2.76 Other experts at the WHO and CDC have made similar predictions. With the virus mutating, physical treatment resources limited ,and an effective cure/vaccine many months to a year or more away, if those estimates are accurate, the rest of 2020 will be a challenging year for everyone in all respects.

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