What do we know about Coronaviruses and how do they affect us?
There are hundreds of coronaviruses, most of which circulate among mammals (pigs, camels, bats, cats, etc.). Those that jump to humans (spill-over event or zoonosis) cause upper respiratory tract disease. Seven human coronaviruses have circulated in the UK for decades generally occurring in the winter and causing mostly mild symptoms which are typical of the common cold. These coronaviruses cause about 15% of cases, while about 50% of colds are caused by rhinoviruses; the rest by respiratory syncytial viruses, parainfluenza viruses, adenoviruses and some infections are caused by, as yet, unidentified viruses.
A spill-over event into an immunologically naïve human population may result in a serious disease because immune cells have not ‘seen’ the virus before and therefore antibodies to the virus are absent.
Is the Covid-19 pandemic unique?
No, there were two critical pandemics in the twentieth century:
The first was the 1918 influenza virus pandemic. When influenza viruses originating from birds or pigs recombine with existing strains in host cells, then a more virulent strain may emerge.
The second pandemic was AIDS (acquired immunodeficiency syndrome), first reported in 1981, and caused by HIV (the human immunodeficiency virus). HIV, untreated, gradually destroys the immune cells but if patients adhere rigidly to their drug regimen a normal life style can follow. There is still no cure on the horizon for AIDS.
Three new coronaviruses have recently infected humans:
The severe acute respiratory virus (sars-cov-1) was the cause of SARS (2003) in South East Asia;
The Middle East respiratory virus (mers-cov) was the cause of MERS (2012);
Sars-cov-2 is the cause of COVID-19 (2019). The nomenclature follows an internationally agreed system so that, for example, rubeola virus causes MEASLES.
The WHO estimated that the total number of SARS infections was 8096 and the number of deaths was 774 (9.6%) and for MERS the total number of infections was 2494 with 858 deaths (34.4%). The low number of total cases in the 2003 and 2012 outbreaks occurred because humans were primarily infected by animals directly and that any subsequent person to person transmission (horizontal transmission) was very low. The low horizontal transmission rates allowed the SARS and MERS outbreaks to be easily controlled by using public health measures, such as wearing surgical masks, washing hands well and isolating patients. However, morbidity rates were comparatively high.
How is Covid transmitted?
Sars-cov-2 has recently evolved to spread easily via horizontal transmission. The wet markets, common in South East Asia, are thought to be the origin of covid-19. Trillions of virus particles are released each day and a chance mutation giving some virus particles the ability to transmit very easily from person to person is enough to start a pandemic. Epidemics grow exponentially unless transmission rates (reproduction rates) are slowed.
The high reproduction rate of sars cov-2 is caused because its viral spikes (S) binds to human cell surfaces easily which then allows it to ‘inject’ its RNA into the host cell very efficiently. The host intracellular enzymes (proteins) complete the process of viral maturation and millions of progeny viruses are produced and released into the host’s lungs and trachea. The human immune system has no innate memory of this new infection so a wide spectrum of disease has been observed. These range from infections without serious symptoms (mostly in the under sixties) to a huge mortality in the elderly who have serious underlying health problems.
The current thinking is that Covid-19, unlike other respiratory diseases has a pronounced effect on the vascular system (veins and arteries). SARS-CoV-2 is thought to bind via its spike (S) protein to ACE2 receptors (angiotensin converting enzyme 2). These receptors are exposed on the surface of cells that line the respiratory tract in the nose and throat, the air sacs in the lung and the surrounding blood vessels. Coughing causes the breakdown of some blood vessels creating a local immune response and inflammation of the vascular endothelium (thin layer of cells lining the vessels). Blood vessel damage may explain why people with pre-existing conditions like high blood pressure, high cholesterol, diabetes, and heart disease are at a higher risk for severe complications from a virus that was originally thought just to infect the lungs. A small number (100 plus) of children in the UK with covid-19 have developed a generalised inflammation of arteries throughout the body. The inflammation tends to affect the coronary arteries, which supply blood to the heart muscle. The condition is successfully treated with high doses of immunoglobulin (IVIG) and corticosteroids.
How do we treat virus infections?
Treating serious virus infections has two approaches: antiviral drugs and vaccines. At the moment two drugs are being used to treat Covid-19; Remdesivir (originally developed to treat Ebola infections), is a drug which slows the replication of viral RNA in the host cell and shortens hospitalisation by about 4 days, although there is no evidence it reduces mortality. Dexamethasone, an anti-inflammatory steroid, reduces mortality by about 25% in the patients who have serious underlying health problems. A recent clinical study has shown that the use of statins and ACE inhibitors resulted in higher rates of survival following covid -19 infections. These drugs are already used by many millions of people for controlling cardiovascular disease.
Although vaccines for respiratory viruses are difficult to develop there is some hope that the novel corona spike attachment protein (S) on the surface of the virus may present a realistic target. Stopping a virus from entering the cell in the first place is ideal as replication is then impossible.
It is estimated that there are over 150 laboratories world-wide designing vaccines. The main technologies are:
Inactivated vaccines that are made using ‘wild type’ viruses which have been grown in a culture medium and then inactivated by heat or chemicals. Viral proteins such as the attachment spikes (S) can be separated from the mix and used as the immune stimulant. Examples of inactivated vaccines are hepatitis A and influenza.
Live attenuated vaccines are ‘weakened’ viruses produced by growing the virus in culture for a long time. The vaccine still causes a mild ‘disease’ but produces a strong and long-lasting immune response in the recipient. Examples are chickenpox, polio, measles, mumps and rubella (MMR) vaccines.
The Jenner Centre at the University of Oxford are using benign live adenoviral (common cold) vectors and recombinant DNA technology to express the S proteins in humans to generate an immune response. The results of the clinical trials are expected soon.
How wrong can you be?
In the late seventies smallpox had been eradicated and there were safe vaccines for measles, polio and other serious childhood infections. Many people in medical schools considered virology to be at an end and departments could be run down. However, with a growing world population, increased international travel, climate change and increased environmental degradation it is now clear that infectious diseases are on the increase.
The Way Forward
The genetic sequencing of DNA and RNA is now so routine it is possible to isolate many thousands of viruses from mammals and birds and study their genomes. Thus new pathogenic viruses can be predicted before they actually cause an epidemic. The present pandemic has shown the UK to be very slow in developing diagnostic tests and to use them in sufficient numbers. This is something I find difficult to understand given the first class record we have in the UK for medical research and the strength of our biomedical industries.
We need to be more responsive and to reduce the time to develop candidate vaccines and drugs from one or two years, to a few months. Diagnostic tests should follow a similar time scale. I am confident that progress in medical science will allow this to happen. Many of our traditional manufacturing cities, such as Wolverhampton, have a fine record of industrial expertise which could be drawn on to set up new biomedical industries.
Derek Kinchington PhD, FRCPath, Scientific Advisor to Intelligence Forums
Dr. Kinchington studied smallpox/human monkey pox genomes, DNA tumour viruses and spent about 15 years developing anti-HIV drugs. Derek is a Fellow of the Royal College of Pathologists