COVID-19: Understanding the Virus, the Pandemic, and the Path Forward

COVID-19: Understanding the Virus, the Pandemic, and the Path Forward

July 01, 2020PAP-Q2-20-NI-004

The Next-Generation Issue: Coping with Covid-19

The coronavirus pandemic will continue to affect every aspect of daily life as hundreds of thousands have died, and millions have been infected. Attempts to halt, or at least slow, the spread of the SARS-CoV-2 virus, involved travel restrictions, quarantine, and business closures, with the exception of those businesses deemed essential. In most parts of the world, people and economies are slowly emerging after weeks under stay-home/stay-safe orders. Since the virus first appeared, the biopharma industry and regulators have been urgently working to develop safe and effective medicines and vaccines while facing the enormous challenges created by these pandemic conditions.

Part 1: The Nature of SARS-CoV-2

What Is Covid-19? 

The genus Coronavirus (subfamily Coronavirinae, family of Coronaviridae, order Nidovirales) includes many large, enveloped viruses that have high mutation rates.1 As zoonotic pathogens, coronaviruses are present in 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 have 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, was first reported in December 2019 in Wuhan State of the Hubei Province in China and was initially dubbed 2019-nCoV. The virus has since been renamed SARS-CoV-2 by the World Health Organization, 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

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.

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 SARS-CoV-2 is essential for determining its specific mechanisms of action, identifying possible drug targets, and developing effective therapeutics and vaccines. There have 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. 


The aforementioned Seattle scientists found 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 nonstructural 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


More Research Underway

Ongoing research is being actively pursued to better understand the structure and function of the SARS-CoV-2 virus and to determine if mutations other than the less-aggressive strain identified in early March13 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 

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.



Part 2: Epidemiology of COVID-19

Animal Origins

Like the two other recent outbreaks based on coronavirus — severe acute respiratory syndrome (SARS) in China and Middle East Respiratory Syndrome Coronavirus (MERS-CoV) — 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 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 2,000–5,500 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 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 1,660 people having died.15 


With more than 118,000 cases of infection, over 4,000 deaths occurring in 114 countries, and 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 6,600, 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.



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 is released in respiratory secretions, which pass 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, though less likely, 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 as 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 1,099 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 of patients was 47 years, with a male/female ratio of 58/42.20 The median incubation period lasted 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%) and/or invasive mechanical ventilation (2.3%) or to result in 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 higher 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 this outbreak can occur everywhere. It was also a call to action for governments around the world to begin limiting the spread of the virus immediately.



Part 3: Progress on Therapeutic and Vaccine Development for COVID-19

Focus on Accelerated Development

The COVID-19 pandemic has created a furor of activity in the biopharma industry. As of early June 2020, nearly 230 treatments were being evaluated, and 159 vaccines for COVID-19 were in development, according to the Milken Institute.23 Efforts have also been devoted to developing simpler, rapid diagnostic tests to facilitate the screening of those potentially infected with the SARS-CoV-2 virus. 


As the virus spread from Asia to Europe, the United States, and eventually Latin and South America, numerous clinical trials were initiated to evaluate marketed and investigational drugs in patients stricken with COVID-19. Meanwhile, philanthropic and advocacy groups provided funding to accelerate the development of novel therapeutics and vaccines. For instance, The Bill and Melinda Gates Foundation, Wellcome, and Mastercard contributed $125 million to launch the COVID-19 Therapeutic Accelerator,24 while the Coalition for Epidemic Preparedness Innovations (CEPI) committed millions to the development of novel vaccines against COVID-19.25,26,27,28


The WHO created a roadmap for the development of COVID-19 vaccines,29 and, in early June, the vaccine alliance launched the Gavi Advance Market Commitment for COVID-19 Vaccines (Gavi Covax AMC), a new financing instrument meant to incentivize vaccine manufacturers to produce sufficient quantities of eventual COVID-19 vaccines that will be affordable for developing countries.30


New therapeutics to treat COVID-19 infections are generally expected to be approved and available before any vaccines. Many of the investigational drugs developed to treat SARS and MERS have already undergone safety testing,31 while new vaccines must be developed based on the specific genetic code of the virus and require the full gamut of safety and efficacy testing. Although 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.32 One exception is Moncef Slaoui, former GlaxoSmithKline vaccine head and current leader of the U.S. “Warp Speed” group, who has indicated confidence that a vaccine will be available by the end of 2020.33  


Emphasis on Diagnostic Development

One of the first things the medical community prioritized was access to rapid, easy-to-use diagnostics for the SARS-CoV-2 virus. The U.S. FDA granted its first two Emergency Use Authorizations to PCR-based tests from Roche34 and Thermo Fisher Scientific35 in mid-March. By early May, it had authorized more than 80 COVID-19 tests,36 and has continued to approve many others, including an antigen-based test from Quidel,37 a loop-mediated isothermal amplification (LAMP)-based assay from Color,38 and multiple self-collection (saliva, nasal swab) kits from companies such as LabCorp,39 Everlywell,40 Quest,41 and LetsGetChecked.41 


The FDA also granted emergency authorization to a test from Roche designed to identify COVID-19 patients with the potential to develop severe complications.42 Several other rapid tests for detection of the SARS-CoV-2 virus remain in development, such as a “naked eye” test from the University of Maryland that could potentially provide a visual result in 10 minutes without any laboratory equipment.43


Demand for antibody tests that can confirm exposure to COVID-19 is also substantial now that various countries and regions have eased lockdown restrictions. However, questions about the accuracy and validity of antibody tests (for the detection of IgM and IgG antibodies to the novel coronavirus) abound. The FDA responded by publishing the results of independent validation tests for 12 antibody-based diagnostics for which the agency had granted emergency authorizations (from Cellex, Roche, Abbott, and others).44 Results varied significantly by test, with some providing high positive predictive values above 90% and others as low as 55% — at an assumed 5% prevalence rate; most had high negative predictive values. 


Small Molecule Therapy Efforts

Many established antiviral medications are small molecule drugs, a number of which target viral RNA metabolism. Some are being explored as possible treatments for COVID-19,45 with Gilead Science’s remdesivir, originally developed for Ebola, and already investigated for SARS and MERS, demonstrating positive results in clinical trials. This has led the FDA to grant emergency authorization for treating SARS-CoV-2 infections.46 With remdesivir already in short supply, Gilead signed multiple nonexclusive licensing agreements with outsourcing partners in India and Pakistan to produce the drug for distribution in 127 countries.47


Numerous other antiviral drugs are also being tested. For instance, AbbVie is evaluating its HIV combination therapy lopinavir/ritonavir (Kaletra/Aluvia) as a COVID-19 treatment in partnerships with health authorities and institutions in several countries.48 The older drugs hydroxycholoroquine and chloroquine, initially developed as antimalarials, created excitement, but results from clinical trials suggest they do not provide effective prophylaxis or treatment against COVID-19.49 In late April, the FDA issued a warning against their use outside medical facilities, and in late May the WHO halted clinical trials in COVID-19 patients.


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.45 NanoViricides, for instance, is developing a COVID-19 treatment based on its nanoscale 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 coronavirus  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 best-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 REGN3051.50 The company began a clinical trial with its antibody cocktail in June 2020.51


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.52 Eli Lilly began dosing COVID-19 patients in a phase I trial of its AbCellera-partnered antibody LY-CoV555 in late May.53 


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, and is planning a phase II study for COVID-19 patients.52 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.52


Regeneron, with partner Sanofi, is also initiating trials with their anti-interleukin-6 receptor (anti-IL6R) rheumatoid arthritis drug sarilumab (Kevzara) for the treatment of COVID-19 symptoms.51 Chugai Pharmaceutical and Zhejiang Hisun Pharmaceutical are evaluating tocilizumab, their humanized mAb targeting IL-6.52 Tiziana Life Sciences is also hoping its anti-IL6R mAb will be effective for COVID-19 patients.54 China has already approved Roche’s rheumatoid arthritis drug tocilizumab (Actemra) for treatment of patients developing severe complications from COVID-19.52 


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 SARS-CoV-2.55 Japan’s National Institute of Infectious Diseases (NIID) is testing the therapy for COVID-19.56


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.52 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.52


Apeiron Biologics has launched a pilot investigator–initiated clinical trial in China to evaluate its recombinant human ACE2 (rhACE2) APN01 — developed for the treatment of acute lung injury, acute respiratory distress syndrome, and pulmonary arterial hypertension — in COVID-19 patients.52


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.57


Another approach to the development of treatments for COVID-19 involves harnessing the antibodies of patients that have been infected but since recovered.58 Plasma-derived therapies, according to Takeda, have proven to be effective against other severe acute viral respiratory infections. The company has joined forces with CSL Behring (the CoVIg-19 Plasma Alliance) and other plasma developers to advance a single, unbranded polyclonal hyperimmune globulin treatment against SARS-CoV-2. The Alliance is working with the National Institute of Allergy and Infectious Diseases (NIAID) to conduct a clinical trial, which will be initiated in the summer of 2020.


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-19.52


Leveraging Novel Vaccine Platform Technologies

Viral vaccines have traditionally comprised attenuated versions of dead or 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 thus 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 the use of the whole virus.59 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 candidate INO-4800 demonstrated robust neutralizing antibody and T cell immune responses against SARS-CoV-2 in preclinical models, and the company hopes to advance to a large, randomized phase II/III clinical trial in the summer.60 


Moderna partnered with the Vaccine Research Center (VRC of NIAID) to develop mRNA-1273, for which early results of phase I clinical testing have been positive: administration resulted in an immune response similar to those seen in patients who have recovered from COVID-19.61 The first patients in a phase II study were dosed at the end of May, and a phase III trial is planned to begin in July 2020.62 Moderna has signed a manufacturing agreement with Lonza to further development.63


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.64 Preclinical results reported in mid-May indicated that a low dose of its lead candidate has the potential to induce a strong immunologic response to neutralize SARS-CoV-2. A phase I/II clinical trial was imitated in June 2020.


Pfizer has partnered with BioNTech to advance the latter’s mRNA COVID-19 vaccine candidate BNT162. The first subject in a U.S. clinical trial was dosed in early May 2020.65 Manufacturing will take place at three Pfizer sites in the United States, with BioNTech supply clinical material from its plant in Belgium.66


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.”67 The UQ researchers created a COVID-19 vaccine candidate in the laboratory in just three weeks, and a phase I safety study is pending. Large-scale manufacturing will be performed through a partnership with CSL.68


In early June, CEPI signed a $750 million deal with AstraZeneca (AZ) and Gavi, the Vaccine Alliance, to manufacture and distribute 300 million doses of the adenovirus-based COVID-19 vaccine candidate AZD1222 developed by Oxford University by the end of 2020.69 AZ also signed a licensing deal with the Serum Institute of India to provide 1 billion doses of the vaccine to low- and middle-income countries. The company also received $1.2 billion from the United States. A phase II/III study of AZD1222 is underway.


Other technologies being explored include virus-like particles (GeoVax, BravoVax, iBio),70,71 lichenase carrier immunostimulatory (LicKM) technology (iBio),71 intranasal delivery (Altimmune),52 Ii-Key peptide technology (Generex Biotechnology),52 an oral recombinant VAAST™ Platform (Vaxart),52 and synthetic biology (University of Washington researchers).72


Supporting all of these efforts are companies like GlaxoSmithKline, which has committed to manufacturing 1 billion doses of its vaccine adjuvant for use in various COVID-19 vaccine candidates,73 and Univercells, which will manufacture prefabricated vaccine facilities for the production of COVID-19 vaccines.74 Out of all of the possible candidates, Operation Warp Speed in the United States has chosen to prioritize just five — those being developed by Moderna, AstraZeneca (who has already received $1.2 billion from BARDA), Pfizer, Johnson & Johnson ($500 million from BARDA) and Merck, which only recently entered the race with two vaccine candidates.75 The five chosen will likely get additional funding, see their candidates move into large-scale randomized trials, and move into large-scale manufacturing before being fully tested or authorized to ensure that they can be rapidly deployed once approved.



Part 4: Broader Impacts of the COVID-19 Pandemic

Impossible Numbers

By June 9, 2020, the novel coronavirus SARS-CoV-2 had spread to more than 210 countries and territories. Nearly 7.1 million people had been infected, and over 406,000 people had died.76 United Nations Secretary-General António Guterres referred to the COVID-19 pandemic as “the greatest public health crisis of our generation.”77


In the weeks immediately following declaration of the COVID-19 outbreak as a pandemic, the focus of governments across the world was on minimizing further impacts. National responses occurred at different rates as the outbreak spread outward from China to other Asian countries, Europe, the United States, Central and South America, the Middle East, and Africa, but once the virus reached nearly every country in the world, government actions became more aligned. Travel restrictions; prohibition of gatherings; closure of public schools, retail shops, and bars/restaurants; stay-at-home orders; and requirements for mask-wearing and social distancing became the norm.


On a larger scale, international relations were affected. Perhaps the most vivid example is the canceling 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 the World Bank and town council meetings to business conferences, TV analysis shows, lessons, and doctor visits — took place virtually. Friction within the European Union and between the United States and China increased. Chinese people and people of East Asian descent experienced an increased level of racist attacks in the United States and Europe.78


Economic Impacts

Airlines, hotel groups, and aerospace companies have been particularly affected, as have the sports, entertainment, and hospitality industries. Many major sporting events have been canceled for the first time in their histories. For those essential businesses that remained open, the challenge was to keep employees and customers safe while maintaining operations. Long-term R&D projects were postponed as companies focused on meeting immediate customer needs. Delay of civil trials for months or longer will also impact the courts and how cases are litigated, thereby further impacting businesses into the future.79

Even after the pandemic has been resolved, the workplace will likely be quite different.80 More people will continue to work from home, at least part-time. The increased flexibility may create more opportunities for women. Companies may provide regional locations with shared workspaces rather than establish central offices. Touchless fixtures (e.g., door sensors, automatic sinks and soap dispensers, voice-activated elevators) will become the norm. The use of online technologies will be much greater, and travel will be limited. Medical screening and face masks will likely be commonplace.


Mental Health Concerns

Psychiatrists have warned that an upswing in mental illness should be expected as a result of the COVID-19 pandemic.81 Stress and anxiety-related disorders and sleep disturbances are common during widespread disease outbreaks. Depression rises among sick people in general and can be potentially greater under pandemic conditions. A survey by Chapman University found that a majority of people are feeling both more anxious and more depressed than normal due to the COVID-19 pandemic.82


Consequences for the Healthcare System

The impact of COVID-19 on hospitals and the overall healthcare system has been substantial. 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.83 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 and which patients did not.


Beyond these devastating consequences, the financial impacts on the healthcare sector have been tremendous. In the United States in April 2020, hospital operating margins fell nearly 300% compared with the same period in 2019, despite large funding assistance from the federal government.84 The drop is attributed to the delay of elective procedures, severe declines in outpatient visits, and the high costs associated with treating COVID-19 patients. Emergency department visits also declined by 42% during the early COVID-19 pandemic.85 Physician and dentist practices have also suffered due to declining patient volumes and the inability to be reimbursed, leading to significant layoffs.86


The quarantining of a majority of the world’s population is also expected to have an impact on personal health. This huge change in lifestyle often comes with changes in nutritional and other habits that can have negative impacts on health, both psychological and physical, which can lead to a greater risk of cardiovascular and other diseases.87


One positive outcome: telehealth has been shown to be effective and may well become a staple within the healthcare industry, particularly to support patients in rural areas.88 It is also expected the hospitals will establish more local and effective supply chains, including the growing use of robots and drones to handle cleaning and similar activities to reduce exposure to healthcare workers.89


Highlighting Disparities

The COVID-19 pandemic in the United States has affected people of color far more than white Americans.90 Black citizens are dying at more than 2.5 times the rate of white Americans. This has thus far been attributed to several factors. More black Americans live in poverty, and owing to different access to nutrition and adequate healthcare tend to experience complicating health factors. In addition, African Americans hold a disproportionate number of essential-worker positions and have experienced the highest levels of exposure to the SARS-CoV-2 virus. Minority-owned businesses have also been less likely to get aid from the federal government stimulus program.


The systemic flaws that lead to inequality exist on a global basis. Analysis by researchers from King’s College London and Australian National University supported by the United Nations University World Institute for Development Economics Research found that an additional half a billion people could be forced into poverty due to the COVID-19 pandemic. That equates to 8% of the global population and would turn back the clock on economic improvement by 30 years.91


Supply Chain Concerns

As the COVID-19 outbreak spread around the world, consumers responded by stockpiling many basic household supplies and health-based items. Many manufactures switched production lines over to the manufacture of needed medical items, from hand sanitizer and face masks to ventilator components.


Even so, the chemical and allied industries have been significantly impacted by the outbreak, given that many basic raw materials are produced in China.92 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, providing nearly 50% of global polymer demand, according to ICIS. The slowdown in manufacturing in the country has led to reduced conversion of those polymers into downstream products.


Drug Shortages

Furthermore, 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.93 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.94


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.95 Prices rose dramatically in response. According to various reports, the costs for paracetamol and the antibiotic azithromycin climbed by 40% and 70%, respectively.96


Quarantine procedures and disruptions in logistics services due to transportation restrictions also contributed to the supply chain issues. The hoarding of APIs by traders exacerbated the situation and drove up prices as well.94 The U.S. Food and Drug Administration reported the first drug shortage related to the COVID-19 pandemic in late February.97 The FDA also indicated that there are 20 drugs with APIs solely sourced from China.


The increase in mental health issues due to the pandemic led to shortages of the antidepressant Zoloft and its generic versions.98 Similarly, shortages of anesthetics and painkillers were observed due to the large number of coronavirus patients being treated in hospitals.99


China also happens to be the largest supplier of medical devices to the United States and elsewhere, including various types of testing instruments, diagnostic tests, and even surgical gowns.93 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. Clinical diagnostic laboratories eventually experienced shortages of supplies, from the swabs and containers required for collecting and transporting samples to the kits and reagents needed for RNA extraction.100 The blood supply is also vulnerable.101


Other Consequences for the Biopharma Industry

Regulatory oversight has been challenged due to decreased headcounts.102 Cancellation or postponement of FDA Advisory Committee meetings, delay of New Drug Application reviews, and the halting of GMP inspections all impacted drug approvals. By mid-May, the agency was working with the U.S. Centers for Disease Control and Prevention to develop a “phased approach” to restarting facility inspections.103


Reduced availability of reagents and other chemicals, reduced staffing levels, and the need for social distancing impacted drug development efforts. A survey in mid-May found that nearly 100 companies had reported some level of disruption to their clinical trials due to the coronavirus pandemic.104 By the end of the month, however, more than 130 studies were slowly starting up again.105 There is concern, though, that changes to trials, such as less consistent follow-up visits, reduced movement, poorer mental or physical health, or infection with the COVID-19 virus, could impact the validity of data gathered in ongoing trials.106


The Industry Responds

In addition to pursuing development programs for therapeutics and vaccines against SARS-CoV-2, the industry provided 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.107 Many companies donated investigational compounds for study as potential treatments for COVID-19. Regulatory bodies monitored potential supply chain issues and developed plans to mitigate any potential drug shortages.108


Other actions were directed to supporting research and development activities in key disease areas other than the novel coronavirus. Pfizer, for instance, committed $500 million through the Pfizer Breakthrough Growth Initiative and access to its scientific expertise to ensure that the “most promising clinical development programs” continue during the COVID-19 pandemic.109


Devastating Economic Impacts

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.110 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 20.111


Federal governments and central banks around the world took measures to bolster their economies and help citizens impacted by the COVID-19 epidemic.111 In the United States, Congress passed a massive stimulus bill that included cash payments to citizens.112


With stay-at-home orders remaining in place for many weeks, essentially all the major leading economic indicators experienced historic declines.113 In the United States, the gross domestic product (GDP) fell 5.0% in the first quarter on an annualized basis — and that only accounted for the very beginning of the period of economic lockdown. The unemployment rate jumped to 14.7% in April. The decline was similar in Italy114 and many other countries. The International Monetary Fund expects global GDP to shrink by 4.2% in 2020.115 Global trade volumes are expected to decline between 9% and 32%. As many as 81% of workers around the world were affected by the COVID-19 pandemic, but that number began to decline in May as economies began reopening.


The Transition from Response to Recovery

Because the COVID-19 pandemic has been not only a healthcare crisis but a historical economic disaster, it is important — and a true challenge — to strike the right balance between restarting economic activity to avoid greater hardship, poverty, and increasing mortality rates due to a deeper recession and preventing further harm due to the virus itself.116


First hit by the novel coronavirus, China and other Asian countries were the first to begin easing their economic lockdowns. The challenge has been to do so without experiencing a second wave of infections. Some models have shown that reduced social distancing is accompanied by economic revival, jobs, and GDP growth — as well as an increase in the number of COVID-19 cases and deaths.117


Each country — and, in America, each state — has adopted its individual strategy for resuming economic activities. Regardless of their methods, however, nowhere is business back to “normal.” Until a vaccine is developed and the majority of the global populace is immunized, safety precautions will be necessary to prevent a resurgence of COVID-19.


One key to success will be access to sufficient cost-effective, easy-to-administer, rapid, and accurate/reliable testing to identify newly infected people and to confirm when recovered patients are no longer shedding the virus.118 That has been a tremendous concern, leading to a commitment of $11 billion by the Trump administration to increase testing capabilities.119


It will also be necessary to gain the confidence of consumers and workers that effective measures are in place to ensure their safety. In late May, nearly 60% of people were not ready to visit retail stores, restaurants, or other public places, according to an ABC News/Washington Post poll.120


Most economic reopening has not taken place until it has been clear that the outbreak has peaked in the specific area involved. Typically reopening has occurred in stages, and the most successful places — notably South Korea and Taiwan — have controlled virus spread through systematic contact tracing using cell phones.117 Limiting occupancy to maintain social distancing, requiring face masks to prevent the spread of droplets, and regular temperature checks are also part of the solution for businesses that are resuming operations. Large concerts will not begin again any time soon, but some sporting events will take place under controlled conditions and likely with no or very few fans in the seats. People should also be prepared for a second lockdown if a resurgence in COVID-19 cases and deaths occurs.121


Technology is playing a major role in ensuring successful economic reopenings. Data analytics and extensive modeling have been widely used by governments and communities to gauge the impact of incremental recovery steps.122 Companies such as Apple and Google have developed digital contact tracing technologies for use by public health agencies to track incidences of COVID-19 and potentially infected but asymptomatic people.123 Microsoft, meanwhile, has introduced an app for businesses and employees that enables digital screening of COVID-19 symptoms in the workplace.124


What’s Next?

According to Harvard epidemiologist Marc Lipsitch, 70% of the world population is likely to be infected by SARS-CoV-2.125 Other experts at the WHO and CDC have made similar predictions. Despite the fact that many economies are restarting, the virus is still raging through parts of the world; Brazil recorded its highest daily death toll on the same day in early June that Las Vegas casinos were reopening.126


The pandemic has caused a health and economic crisis combined with an energy crisis and a looming humanitarian crisis in many emerging economies, creating challenges and enhancing geopolitical tensions and risks.127 “The challenge is to return to the ‘new normal’ to reconcile the natural fears we feel with acceptance of the uncertainties, aided by a risk management architecture that helps manage the trade-offs,” according to a report by the World Economic Forum.


Full economic recovery will thus take significant time — approximately 10 years in the United States, according to the Congressional Budget Office.128 A survey of chief information officers found that most expect an overall U-shaped recovery from the COVID-19 pandemic, with the first stages of growth not returning until 2021.129 Sectors such as IT/telecommunications (supporting digital connectivity) and retail/consumer (due to pent-up demand) are expected to recover the quickest, while the airline and education sectors will take much longer.


There is real uncertainty regarding what the recovery trajectory will be, according to National Retail Federation Chief Economist Jack Kleinhenz.130 “Previous downturns offer little guidance on what is likely to unfold over the next six to 12 months. There is no user’s manual in which government, businesses, or consumers can find precise solutions for what we are going through,” he said in early June.


Indeed, the Situational Threat Report Index from Bain’s Macro Trends Group reached level 7 as of June 2, 2020: “severe multiquarter economic impacts in multiple markets likely.” The consultancy recommended that businesses activate second-level contingency procedures, including “separating essential operations and services, focusing on high-priority customers and clients, and implementing operational and financial preparations consistent with a two- to three-quarter recession.”131


Greater poverty and diversion of resources away from disease prevention and treatment could lead to increased fatalities and a dramatic increase in child mortality, with young girls suffering the most. The greatest economic impact of the COVID-19 pandemic will be in sub-Saharan Africa, where “up to half of the new poor will live,” according to the United Nations.91


Overall, the increases in hunger, disease, poverty, and violence resulting from the COVID-19 pandemic could have greater negative impacts than the pandemic itself. “It’s extremely disheartening, and it’s going to be exceptionally dire,” noted Alexandra Lamarche, senior advocate for West and Central Africa at Refugees International.91


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