With newspaper headlines reporting it is unlikely that a coronavirus vaccine will be ready to manufacture on a mass scale until the second half of 2021—caveat being that this will depend on successful trial results—the race is on to accelerate the time scale.
Background
Coronaviruses include a range of organisms that can cause diseases, including the common cold and the current SARS-CoV-2. Despite the original severe acute respiratory syndrome (SARS) coronavirus emerging in 2003, the current pandemic, caused by the related novel coronavirus, COVID-19, appears to have taken the world by surprise.
The 2003 SARS epidemic never reached pandemic proportions but nonetheless affected 26 countries. It resulted in more than 8000 cases and nearly 800 deaths (World Health Organization (WHO), 2020a), but a vaccine was never developed. A similar disease, Middle East respiratory syndrome (MERS), also caused by a coronavirus, emerged in Saudi Arabia in 2012.
Fortunately, for the development of a vaccine for COVID-19 several vaccines for MERS are in the development stages, and these can hopefully trigger the development of antibodies and T cell immunity. Because MERS is caused by a close relative of COVID-19, the basis for a successful vaccine appears promising (Drug Target Review, 2020).
All NHS trusts have pandemic plans in place as part of their winter pressure initiatives. These set out a response to a pandemic, with clearly described roles and responsibilities, and the plans are assessed by the Care Quality Commission during its routine hospital inspections. However, it was recently revealed that in 2016 the NHS as a whole had failed a major cross-government test of its ability to handle a severe pandemic. The three-day Emergency Preparedness, Resilience and Response (EPRR) exercise, or Exercise Cygnus, looked at the impact of and response to an influenza pandemic of similar magnitude and death rate to what we are experiencing with COVID-19. The report on the significant impacts on health delivery that a widespread pandemic in the UK would trigger was kept for ministers eyes only and not made public.
EPRR is a core function of the health service, which requires organisations and providers of NHS-funded care to demonstrate their ability to deliver safe patient care in emergency situations, while maintaining essential services. After the exercise, ministers were informed that the UK would be quickly overwhelmed by a severe pandemic due to a shortage of critical care beds, morgue capacity and inadequate supplies of personal protective equipment. The alarming unpreparedness flagged up by Exercise Cygnus were not addressed, which became clearly evident this year as COVID-19 swept across countries whose citizens had no natural immunity to the disease and whose healthcare organisations were ill prepared (Gardener and Nuki, 2020).
What are viruses?
Virology is the study of viruses, in essence intracellular parasites, which means that they can survive only within a host cell and depend on that cell for their own reproduction. It is therefore not in the best interest of a virus to kill all the hosts it infects. We have all seen diagrams of the coronavirus, which like others resembles a horse chestnut when it falls from the tree.
When a virus enters the body its spiked coat penetrates the outer membrane of a host cell to inject its genetic material. The virus then replicates itself to ensure its own survival. Viruses can either be made up of DNA or RNA, which is the case with COVID-19. The latter are especially prone to mutation because RNA viral replication does not involve the same error-checking mechanisms within the host cell as DNA replication. Hence, RNA viruses regularly mutate, so it is likely that COVID-19 will also do so. Influenza is an RNA virus, which explains why each year new flu vaccines are required to prevent annual epidemics.
Even if a vaccine is developed to provide immunity for the current strain of COVID-19, there is no certainty that this will offer long-term immunity to this strain or future variants. In contrast, the virus that causes smallpox, variola, is a DNA virus that is not so prone to frequent mutation, which explains why vaccination in childhood brings lifelong immunity to this once-feared disease.
Once a virus has entered the host cell it uses the cell's own metabolic processes to replicate itself. In a scene reminiscent of the Alien movies the new viruses subsequently burst out to colonise new cells and in turn find new hosts. The virus itself has no mechanism of transport so it relies on the host to spread it through:
- Touch (and touching contaminated surfaces). Some viruses can survive for long periods outside a host and the smallpox virus, for example, can survive for years
- Airborne transmission: being exhaled from one person and inhaled by another, or through exchange of saliva, coughing or sneezing. It has been established that COVID-19 can stay suspended for about half an hour, especially in confined spaces
- Sexual contact
- Contaminated food or water
- Insects that carry viruses from one person to another, such as dengue fever.
Viral immunity
Once the virus has entered the body through one of the many routes of infection, but especially via coughing or sneezing, it invades the cells of the host and starts to replicate. However, the immune system of humans has evolved in parallel with that of viruses, specifically the human body's response is to hunt and kill these invaders via a range of sophisticated mechanisms that include:
Cytotoxic cells
Once inside a cell, the virus becomes invisible to the body's defence mechanism, but the cell itself is able to send out signals that it has been invaded. It does this by releasing molecules, known as class I major histocompatibility complex proteins (MHC class I), which contain some of the proteins of the infecting virus DNA or RNA. Floating round in the blood and other bodily fluids are natural killer cytotoxic T (NKT) cells produced by the hosts immune system that respond to the presence of MHC class I and whose function is to find and destroy infected cells, to prevent survival of the invading virus.
Interferons
The contaminated cells containing the virus produce and release small proteins called interferons that work in conjunction with the immune system to offer protection against viruses. Cellular interferon stops viruses from replicating within the cell and works in harmony with cytotoxic T cells by acting as signalling molecules, which allows adjacent cells to increase the production of MHC class I and thus act as beacons for T cells.
Antibodies
Viruses act as antigens and, as antigenic molecules, they induce an immune response in the body but especially through the production of antibodies. Antibodies are produced by B cells, which are part of the body's immune system, and they amalgamate themselves to the antigenic virus. Once bonded to the virus, the antibody neutralises it to prevent infection of other cells, which it does primarily through phagocytosis, a process during which the amalgamated antibody/antigen molecules, are engulfed, destroyed and eliminated by phagocyte white blood cells, which are also part of the immune system.
However, despite the highly evolved human immune system, some viruses can escape unscathed and cause death in certain individuals. At the time of going to press, there were more than 6 million confirmed COVID-19 cases globally, with around 380 000 deaths (WHO, 2020b).
Historical aspects of viral pandemics
There is no doubt that, throughout history, humanity has been in constant battle with infectious disease. In response, the process of evolution has enabled the human body to develop a complex immune system.
The earliest recorded pandemic—the plague of Athens—happened during the Peloponnesian War in 430 BC. This early pandemic killed an estimated 75 000–100 000 people, or as much as two-thirds of the population at the time. Since then, pandemics of even greater magnitude have continued to haunt humanity, including the Antonine plague of 165-180 AD, named after the emperor Marcus Aurelius Antoninus Augustus. This pandemic, which is now attributed to an early emergence of smallpox, killed about 5 million people, including the emperor himself.
In context, viral smallpox has been a big killer over the centuries, with an attributed 56 million deaths. When Europeans arrived in the New World, they are thought to have brought smallpox with them, decimating the indigenous populations, which lacked immunity to such infectious diseases (Patterson and Runge, 2002). However, the biggest biological killer in history has been the Black Death, which caused the deaths of up to 200 million people. It killed 30-50% of the population of Europe and it took 200 years for the population to recover. Although the Black Death was attributed to the Yersinia pestis bacteria, scholars now think that it might have been caused by a haemorrhagic virus, perhaps similar to Ebola (Duncan and Scott, 2005).
In terms of magnitude, the Black Death is followed by the Spanish flu pandemic of 1918-19, estimated to have killed up to 50 million. It was almost as virulent as the Plague of Justinian of 541-542 AD, which is thought to have hastened the fall of the Roman Empire. It killed 30–50 million or almost 26% of the known world's population at the time. This catastrophic pandemic was originally thought to have been caused by a plague bacteria, but is now thought to have been caused by a similar virus to that which caused the Spanish flu (Altschuler and Kariuki, 2008).
It should be remembered that the biggest viral killer in living memory is HIV, which has killed 25–35 million people since it was first recognised in the early 1980s and for which no vaccine has as yet been developed (LePan, 2020).
Developing vaccines
The development of vaccines represents some of the most important medical achievements in history, beginning with smallpox. Although the discovery of vaccination to prevent smallpox is attributed to Edward Jenner, evidence suggests that the Chinese were inoculating against smallpox more than 1000 years ago. They did this by a process of variolation, which was inoculation through a puncture in the skin that involved the scabs or pus from a recovering smallpox sufferer being rubbed into the skin breach. In many cases, this conferred immunity to the disease (Boylston, 2012).
However, the era of vaccines arrived with Jenner's ground-breaking work in using lymph from cowpox blisters to immunise children against smallpox. When he scratched exudate from a cowpox blister into the skin of an 8-year-old boy in 1796, this was the first attempt at immunising a person against the deadly smallpox. Two months later Jenner inserted liquid from a genuine smallpox blister into the boy's skin and young James did not subsequently develop the disease, thus proving that immunisation through inoculation was a successful method of preventing smallpox.
Over the coming decades and centuries, many more vaccines would be developed to prevent infectious diseases in childhood. It was not until 8 May 1980, however, that the World Health Assembly announced that the world was free of smallpox.
Despite the obvious success of vaccines in immunising people from diseases that can kill, fear of vaccine side effects are as old as Jenner's success in preventing smallpox. Fear of vaccine side effects is not confined to the past and vaccination remains stubbornly controversial in many contemporary societies. In 2019, newspapers and television news frequently covered the issue of immunisation and vaccine safety. For example, one newspaper reported that booklets distributed in some Jewish communities in New York contradicted the scientific consensus that vaccines are safe and highly effective, giving the false information that vaccines caused autism and contain cells from aborted human fetuses (Pager, 2019).
In many other societies across the world, vaccines designed to immunise children against infectious diseases arouse similar fears, ranging from the false link between MMR and autism in parts of North America and Europe to claims that tetanus vaccines are a vehicle to covertly administer birth control agents in Kenya and Nigeria. Similarly, in Afghanistan, the Taliban has strongly opposed the administration of polio vaccine because of fears that this is an attempt by the West to use it as a method of sterilising Muslim children. These public fears of vaccines are often fuelled through the voices of respected and powerful people in public office, fanning the fear among the less educated public (Glasper, 2019). Even before a vaccine for COVID-19 has been developed, some critics have expressed antivaccine sentiments, spreading misinformation about its supposed dangers (Klepper and Dupuy, 2020).
Vaccines are proven to be safe and offer the optimum way of protecting people from COVID-19, but it is important to stress that, like flu vaccines, a new vaccine will protect only against the current strain identified and will not be effective if the virus mutates in the next season. As researchers endeavour to develop a vaccine to combat COVID-19, a test to determine whether people have previously been infected with coronavirus and have antibodies to the virus has been approved by Public Health England.
How are vaccines made?
Vaccines are designed to generate an immune response that will protect the individual during future exposure to the disease. Different techniques are used to manufacture different types of vaccines, which can be (Vaccine Knowledge Project, 2019):
- Attenuated vaccines: Such vaccines reduce the severity, virulence or vitality of the disease caused by the virus. They are developed by using a weakened form of the virus. The process diminishes the potency of the virus, making it less virulent, but not killing it. These vaccines allow the body to recognise the virus and produce antibodies that will mount a response if the person encounters the virus in future. An example is the attenuated influenza vaccine. Theoretically, however, live, attenuated (or weakened) vaccines are capable of causing illness because they can still replicate
- Inactivated vaccines (killed vaccines). These are developed by first destroying the virus and then using it to elicit an antibody response. Such vaccines cannot cause illness, so it is impossible for people inoculated with these to become ill with the disease, eg hepatitis A
- Subunit or acelluar: These vaccines do not contain whole cells, and recombinant vaccines only use specific parts of the virus molecule, but they still deliver a very strong immune response, such as the vaccine for Human papillomavirus
- A recombinant vaccine is one produced through recombinant DNA technology whereby different parts of the virus are recombined; this stimulates an immune response without inactivating the original infecting virus; for example, to make the hepatitis B vaccine, part of the DNA from the hepatitis B virus is inserted into the DNA of yeast cells, which are subsequently able to produce one of the surface proteins from the hepatitis B virus; this is then purified and used as the active ingredient in the vaccine
- Toxoid vaccines: these are primarily used to immunise against bacterial infections, such as diphtheria.
Conclusion
Many countries are collaborating in trying to develop an effective vaccine for COVID-19. The team from the University of Oxford, which is working with a well-known pharmaceutical company, is believed to be a front runner in producing a viable vaccine. However, claims that the vaccine is fully effective have been dashed and the quest therefore continues, but it casts doubt on the development of a vaccine before 2021. This novel coronavirus undoubtedly presents an unprecedented challenge for medical scientists across the world.
KEY POINTS:
- With coronavirus deaths nearing 40 000 in the UK alone, countries around the world are collaborating to develop an effective vaccine
- A 3-day exercise conducted in 2016 revealed that the UK would be quickly overwhelmed by a severe pandemic amid a shortage of critical care beds, morgue capacity and inadequate supplies of personal protective equipment
- Viruses can spread through touch, airborne transmission, sexual contact, contaminated food or water or via vectors such as insects
- Vaccines are safe and offer the optimum way of protecting people from COVID-19