The COVID-19 Pandemic of 2020 (Part 1)

Part 1. The Biology of the COVID-19 Pandemic

Covid-19 is a portmanteau for corona virus disease, first cases in 2019.

The Virus

The coronavirus family is a group of RNA viruses for which their natural host and reservoir is bats. Viruses are either composed of short stretches of DNA, DNA viruses, or RNA, RNA viruses, wrapped in an envelope. An example of a disease caused by a DNA virus is chickenpox (varicella), and therefore, of course, herpes zoster (the virus that causes shingles). It, usually, is referred to as the varicella- zoster virus. After initial infection, the virus goes dormant in the cell bodies of nerves and, in a fraction of patients who had chicken pox, decades later, reactivates to cause shingles. Measles is an example of a disease caused by an RNA virus. RNA viruses are much more likely to mutate, as is the case with influenza virus, making vaccine development difficult and imperfect. Moreover, mutation may lead to a far more virulent strain, or a less virulent one. That is why the virulence and severity of the annual influenza strain varies from year to year.

On the evolutionary scale, viruses are primitive structures that do not have the machinery to act as a single-cell organism, as do bacteria. They are inert and cannot replicate, unless they can gain access to a plant, animal or human cell in which they can multiply and cause disease in their host. When a virus infects a host cell, its coat is removed and the viral RNA or DNA genome captures the host cell’s machinery to transcribe and translate the viral genetic sequences into proteins. The infected cell then supports replication and assembly of the viral RNA or DNA into thousands of viral progeny, which can, for example, rupture and kill the host cell. In the case of a disease-causing virus, this massive viral load then goes on to infect more host cells.

The first virus discovered, the tobacco mosaic virus, was identified in the late 19th century because of a disease it induced in plants, which severely blighted tobacco crops. Through a series of experiments it was found that it was not a small bacterium, as originally proposed, and was given the name “virus” from the Latin for poison to distinguish this mysterious entity from bacteria. The structure of a virus, the nature of its genome, the diverse types of viruses, the diseases a virus can cause, the mechanism of its infectivity, and many other features of scientific understanding followed over many years of research. The application of the term “virus” to computer malware “infection” was introduced by David Gerrold in a 1972 book he published. A computer virus is “a parasitic program written with malicious intent so as to enter a computer without the user’s permission or knowledge”, an apt metaphor.

Respiratory Viruses

There are several respiratory diseases caused by one or another strain of coronavirus, including the common cold. It has been estimated that several hundred viruses can cause the common cold. Rhinovirus is thought to cause approximately 35 percent of colds on average, but at certain periods in the fall it may be responsible for a much greater percentage. They can adapt to the nasal cavity’s moist and warm environment and flourish there. Adenovirus, respiratory syncytial virus, and parainfluenza and several strains of coronavirus are other viral causes of the common cold. It has been estimated that on average four strains of coronavirus may be responsible for, perhaps, 20 percent of colds. Because so many viruses in our environment can cause the cold, one never builds immunity to all of them, so school aged children have many colds a year and adults may have several per year.

The coronavirus has mutated to develop several strains that cause severe respiratory illnesses involving the lungs with a relative high fatality rate. Two recent coronavirus mutant strains caused both the Middle Eastern Respiratory Syndrome (MERS) and the first Severe Acute Respiratory Syndrome (SARS). Although the most likely natural host of these viruses is considered the bat, and, thus, they are zoonoses, diseases passed from animal hosts to humans, there may be an intermediate host or vector. A zoonosis can be caused by viruses, bacteria, or other types of microbes. In the case of MERS, the virus is thought to have gone from bats to camels to humans and in the case of SARS from bats to civets to humans.

The Source of the Virus

In the case of the virus, initially referred to as 2019-nCoV, now SARS-CoV-2, the official designation for the new coronavirus virus strain given by the International Committee on the Taxonomy of Viruses, the cause of COVID-19, the designation for the disease, the intermediate host is suspected to be either pigs, civets or pangolins. The pangolin is a highly endangered small mammal that is highly prized for its scales and meat in China and other countries in Southeast Asia. Its meat is considered a delicacy and its serving a status symbol. Its scales are used to prepare a type of Chinese traditional medicine and its illicit trade in China is thought to have been a possible source for introducing SARS-CoV2 into the human population there. Chinese scientists have been comparing the RNA of the coronavirus in civets, pigs, and pangolin with the human cases and have found similarities, but not close enough (99%+) to indicate either of those three animals were intermediate hosts. It requires virtual perfect identity to make such a claim. It could be trafficked pangolin from other countries, they conjecture. The closest identity they have found was with the coronavirus isolated from a bat. They still suspect an intermediate host, but cannot establish with any degree of certainty which animal it was as yet.

Initially an outbreak, it became an epidemic because of the high level of contagion of this virus and the absence of any prior immunity to it, and, subsequently, because of the extent of world travel, it became a pandemic. The Huanan Seafood Wholesale Market in Wuhan, a “wet” food market that sells seafood, all sorts of meat (e.g. pork, fruit bat meat), poultry and has live as well as raw products (and, ostensibly, sometimes illicit wild products), mixed together with human clients, has been identified as the likely source of the virus in Wuhan. The market did not have pangolin on its inventory of products, but there are severe penalties for the trafficking in this endangered mammal, so it would be trafficked surreptitiously.

The suspicion about the Huanan Seafood Wholesale Market is based on the very large proportion of early cases in Wuhan that had visited the Market. A nearby Chinese laboratory was studying bat viruses and some have raised questions about mismanagement of security and the release of SARS-CoV-2, inadvertently, from that location. The United States government has made illusions about germ warfare, but experts have determined that the virus was natural and not manufactured. Therefore this new, naturally occurring virus could not have been in the Chinese laboratory, as it had never been isolated before. Moreover, it was the most devastating, initially, to the Chinese, so any charge of intentionality seems irrational. Unfortunately, the authoritarian government in China did not act responsibly, initially, failing to advise the World Health Organization of the early outbreak, although several of its physicians tried to do so.

Testing

Much has been made of the United States’ initial feeble response to testing. It is a very valid criticism. The state of science throughout the world is amazing. The first case of COVID-2019 was reported on December 31st 2019 from Wuhan. Within a few weeks the new virus genome was sequenced by the Chinese and immediately shared with the world, a requirement for the development of the most sensitive and specific test for its presence, the polymerase chain reaction test or PCR test. This procedure was developed by Kary Mullis, a technologist at Cetus Corporation, and its importance in almost every area of molecular biology and in diagnostic and therapeutic medicine was recognized by his receiving the Nobel Prize in Chemistry in 1993.

PCR is an essential technique for genetic cloning, sequencing and measurement of gene expression. PCR is used to precisely identify microbes. PCR is used for the analysis of human DNA to identify gene mutations and gene polymorphisms, and for precise typing of tissues and blood. PCR-based DNA “fingerprinting” is the most consequential advance in forensic analysis in our lifetime. PCR has also revolutionized the field of molecular paleontology, since DNA can be sequenced from dried or fossilized specimens that are thousands or even millions of years old.

In effect, PCR works by amplifying trace (infinitesimally small) amounts of DNA a million times in the laboratory, providing material for specific identification. The usual process in human cells proceeds from DNA to RNA to protein. The first step, DNA-directed RNA synthesis is called “transcription”. The second step, RNA- directed protein synthesis is called “translation”. RNA, however, can be converted to complementary DNA, reflecting the precise genomic sequence of the original RNA, through an initial step called “reverse transcription” – reverse transcribing RNA to DNA, using the enzyme reverse transcriptase. So with RNA viruses (or any source of RNA), reverse transcription PCR or RT-PCR can accomplish the same thing starting with an RNA virus as PCR does with a DNA virus, first converting the RNA to its exact complementary DNA, and then identifying the nature of the original RNA, precisely, from the complementary DNA.

In the case of infectious diseases, one can approach identifying affected individuals at the time of onset for diagnosis and treatment by using PCR, or after the fact by using a quite different test that looks at antibodies in the patient’s plasma (blood) that develop as an immune reaction to a prior infection. The latter test called an enzyme–linked immunosorbent assay, referred to by the acronym ELISA, can determine if someone had the disease and, thereby, determine the past prevalence of the infection in a population. It, also, can provide information as to the presence of potentially protective antibodies.

These tests for viral infections, including the coronavirus, are carried out in laboratories licensed by the FDA. In time, simplified assays, referred to as point- of-contact assays, will be developed that will result in more rapid response times and be more convenient for physicians and patients. Antigen testing, measuring a unique marker on the virus, not requiring RT-PCR to measure the viral RNA will also facilitate ramping up testing. Many medical centers and medical institutes have the capability to develop these tests and the FDA has waived certain regulatory requirements, selectively, to permit wider availability of testing. This emergency behavior, of course, leaves the door open for tests with inadequate accuracy and precision and to scoundrels interested in revenues and not good practices.

Zoonoses

The zoonoses, diseases of humans in which there is an animal host of the pathogen transmitted to humans, is a very common source of human disease. Indeed, it has been estimated that the majority of human diseases have arisen from animal sources. In some cases they are transmitted directly as in the case of influenza, the natural host of which is birds. Rabies is another example in which the viral transmission is from infected animal’s saliva as a result of a bite from a rabid animal. In many cases, a vector intercedes between the animal host and the human victim, as in Lyme disease, a bacterial disease, which is transmitted from several animals, notably deer, to humans by a tick. The tick bites the deer and ingests the microbe, the tick, then, bites a person and deposits the microbe. In some cases, through mutation in the infected human, a virus may, thereafter, be able to undergo human to human transmission as has happened in the case of influenza virus and SARS-CoV-2, the cause of COVID-19. Occasionally, an animal host may again become the source of a different strain of the virus (e.g. swine flu, bird flu).

SARS-CoV-2

Several features of SARS-CoV-2 make it so serious. It has a surface structure that binds to a reciprocal structure on the bronchial (respiratory) epithelium leading it to develop a very high frequency of severe pulmonary infections (pneumonias), not just nasopharyngeal infections. It is highly contagious, in part because it has been shown by detailed studies of case spread among the Chinese to be transmissible before symptoms develop. The human population has never been exposed to the virus before and there is no significant immune population. It is virulent with a mortality rate based on early estimates at a minimum 10 times that of influenza on average and possibly greater. The mortality rate stratified by age indicates the mortality rate may be 50 times that of influenza, on average, in the over 65 year old population. These comparisons are approximations because enumeration of influenza deaths and Covid-19 deaths are not done using comparable methodology. Moreover, estimates may undergo dramatic corrections up or down when the pandemic can be viewed retrospectively.

This coronavirus is highly contagious, even up to several days before any symptoms develop, and because of the need to avoid infection in all age groups to prevent spread from those at lower risk, e.g. children and young adults to (i) higher risk older adults, (ii) persons with immune deficiencies, including persons being treated with chemotherapy, radiation therapy and immunotherapy, (iii) those with significant chronic illnesses, such as diabetes, closing schools, universities, businesses, and limiting social interactions at virtually every level has been required. The consequences to local, national, and world affairs and economic activity are profoundly consequential.

Antivirals and Vaccines (See Part 2 for more details)

Current antiviral agents do not seem to have effectiveness for this virus and crash programs to develop new ones are underway. One concern is short-cutting the safety evaluation of new drugs. One assumes we will reach some reasonable compromise in this case. Several countries, for example Germany and Israel, indicate they are advanced in preparing a vaccine. The National Institute of Allergy and Infectious Disease in the United States is beginning a phase 1 trial of a SARS- CoV2 vaccine in humans. Forty-five volunteers will be divided into three 15 person groups, each getting ascending doses of the vaccine to study antibody response, tolerability and safety. It is estimated a vaccine will take approximately 18 months to be approved for use, if found to be successful in clinical trials. This time frame is short as vaccine development goes, but technologies have advanced and some have been working on coronavirus vaccines for a time, although not against this virus. An antigen on the corona, a surface structure of the virus that led to the name of the virus, visualized by electron microscopy, is the target in the NIH study. The first volunteer was inoculated. Some evidence indicates this virus, SARS-CoV-2, may not mutate as readily as the influenza virus and, if this finding is accurate, could remove the requirement to prepare a new vaccine each season, as with influenza. All epidemics run out, except for the epidemic of stupidity. Given the former this will all turn around, but many lives will have been profoundly disrupted and lost in the process. The world will be changed in many ways, yet to be fully understood.

Written March 2020