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By Roger Highfield on

Coronavirus: Ending the pandemic

Science Director Roger Highfield examines the vaccines under development which may help bring the coronavirus crisis to an end.

What are the merits of COVID-19 vaccines compared with treatments?

Vaccines will take longer than treatments to develop – one to two years – but they do offer the one exit strategy from the current pandemic that will work whatever the circumstances because they provide vaccinated people with a long-term immunity ‘memory’ to fight the virus.

The reason treatments for patients already infected with the novel coronavirus will emerge more quickly than vaccines is that some tried-and-tested drugs already look promising as a result of a massive effort to screen existing drugs for ones that can be repurposed for the fight.

For example, a clinical trial of camostat mesylate – a drug originally used to treat pancreatitis – started last week at Aarhus University in Denmark after a study suggested it can prevent the novel coronavirus, SARS-CoV-2, entering human cells.

There are also ways to harness antibodies using an old-fashioned method in which a seriously ill COVID-19 patient is treated with blood plasma collected from a recovered patient. There is already evidence that debilitated patients rally after a dose of survivors’ blood.

The United States has launched a national effort to roll these blood-based therapies out as soon as possible.

Update, December 8: Margaret Keenan, 90, becomes the first person in the world to be given the Pfizer-BioNTech RNA vaccine as part of a mass vaccination programme in the UK.

Will vaccines offer a better solution than drugs?

Yes. Vaccines are a highly cost-effective way to prevent an illness developing in the first place, halting the spread of the disease.

This is preferable to treatment, particularly when you bear in mind that the current generation of ‘one-size-fits-all drugs’ do not work for everyone. 

Why do we need a new vaccine when coronaviruses are among the families of virus that cause the common cold?

When it comes to the pandemic virus, SARS-CoV-2, we lack immunity because this particular virus is new to humans, having jumped from another species.

The pandemic virus is closely related to bat and pangolin coronaviruses, perhaps even a blend of bat and pangolin viruses that emerged in a bat, pangolin or another species.

We need a vaccine to prepare our immune system for an encounter with COVID-19 so it can immediately spring into action.

Scientists have warned that a pandemic of this magnitude was inevitable because viruses that normally infect animals are increasingly infecting humans as we continue to exploit the Earth’s ecosystems.

That was the story of HIV, of SARS, of Ebola, of MERS and now of COVID-19: coronaviruses are endemic in lots of animal species.

However, the world is better organised to deal with the threat than ever before, not least thanks to the efforts of the Coalition for Epidemic Preparedness Innovation (CEPI), an international nongovernmental organization funded by Wellcome, the Bill and Melinda Gates Foundation, the European Commission, and eight countries (Australia, Belgium, Canada, Ethiopia, Germany, Japan, Norway and the UK).

If there is one good thing that could come out of the crisis, it is the infrastructure to develop vaccines at pandemic speed.

How many vaccines are under development?

A lot. CEPI is already supporting eight vaccine projects—one of which began a trial in humans just 60 days after the virus was first identified.

Dozens more vaccine candidates are being developed around the world, under the oversight of the World Health Organisation. Overall, at least 40 COVID-19 vaccines are under development.

Is there a particular challenge in creating a COVID-19 vaccine?

It is always hard to create a vaccine but one particular challenge with coronavirus vaccines is the lack of good animal models for testing, a legal requirement.

Various animals are being investigated, such as GM mice that produce a human version of the protein ACE2 (which SARS-CoV-2 uses to enter human cells), rhesus macaques, African Green monkeys, mice, hamsters, and ferrets. Animal models have characteristic limitations which must also be overcome.

One radical proposal to speed the deployment of vaccines is that scientists infect healthy people with the coronavirus and study whether those who get a prototype vaccine escape infection.

But some teams would not consider conducting a so-called ‘challenge trial’ without an effective treatment.

Why are some people turning away from vaccines generally?

It’s baffling. Vaccination prevents 2-3 million deaths a year. The World Health Organisation has identified vaccine hesitancy – the reluctance or refusal to vaccinate despite the availability of vaccines – as one of the top global health threats, in a list that includes pandemics, superbugs and climate change.

‘Anti-vaxxers’ now threaten to reverse progress made in tackling vaccine-preventable diseases, with a significant rise in diseases such as measles.

Even before this pandemic, a further 1.5 million deaths annually could be avoided if global coverage of vaccinations improved.

Contemporary concerns about vaccine safety can be traced to claims of a link between the MMR (measles, mumps, and rubella) vaccine and autism.

These claims have been debunked many times over and psychologists are investigating the psychology of science denial even when people are confronted with irrefutable evidence of the moon landings, anthropogenic climate change, or the benefits of vaccination.

However, opposition to vaccination dates back centuries. When the Vaccination Act of 1853 introduced mandatory smallpox vaccination in England and Wales for infants it was opposed by people who demanded the right to control their bodies and those of their children.

Edward Jenner’s ivory vaccination points

How did vaccines get their name?

The term comes from vacca, referring to how cowpox was used by Edward Jenner in the first vaccine in 1796 to fool the immune system of James Phipps into thinking it had seen smallpox, then a highly infectious endemic disease.

The Science Museum Group cares for the ivory vaccination points (above) that Jenner used to give smallpox vaccinations.

How do vaccines work?

Vaccines introduce inactivated virus (or parts of the virus) to our immune system to train the body’s defences to recognise them as an invader so, if ever exposed to the actual virus, the body knows how to fight the infection.

In the past decade, molecular biology has vastly expanded the different ways we can make a vaccine and accelerated the speed with which we can develop vaccines, exploiting viruses themselves, viral genes and even the trick that viruses use to pirate the molecular machinery of human cells to turn them into virus factories.

In the Science Museum Group Collection you can find vaccines for smallpox, malaria, diphtheria, polio, leprosy,  influenza and more.

Sample of malaria vaccine SPf66, part of the Science Museum Group Collection

Isn’t that a bit like homoeopathy?

No. Homeopathic ‘treatments’ are no better than placebo in effectiveness and are not based on science.

Apart from the fact that homeopathy (unlike vaccination) is not effective, the claim of homeopaths that ‘like cures like’ does not apply to vaccines because they are designed so as not to cause the disease that they prevent.

How does our immune system normally deal with viruses?

When the immune system is exposed to coronavirus, it ramps up the production of cells – called B lymphocytes – that produce antibodies that bind to viral proteins that the virus needs to infect cells.

A second part of the immune response is the stimulation of a type of white blood cell, called T lymphocytes – which can kill infected cells.

Antibodies stop the spread of infection between cells and T-cells stop the virus once it is inside a cell.

But there is a balance to be struck.

Lymphocytes (and other cells) also produce immune signalling chemicals called cytokines. If produced in excess this can cause a cytokine ‘storm’, which in extreme cases can result in the shut-down of vital organs including the lungs, heart and kidneys.

Thus, a vaccine must confer immunity without causing this runaway inflammation.

Once someone has recovered from a viral infection, the cells of the immune system ‘remember’ the virus. You now have resistance to a second infection by the same virus. You are immune to that virus.

How quickly can we roll out a COVID-19 vaccine?

A lot faster than even a decade ago.

Traditionally it could take a decade or more to license a vaccine, and the process would cost at least half a billion dollars, probably more.

Yet the first human clinical trial for a potential coronavirus vaccine, developed by the company Moderna, has already started on 45 people.

The speed of vaccine development is unprecedented: scientists at the Shanghai Public Health Clinical Centre only deduced the genetic code of the COVID-19 virus on 11 January 2020.

Is it enough to come up with a vaccine that is effective and safe?

No. A key issue is whether this and other approaches will be scalable or that existing capacity can produce enough quantities of a COVID-19 vaccine fast enough.

The genome sequencing pioneer J. Craig Venter has talked about distributed manufacturing of vaccines and CureVac is developing a prototype ‘RNA printer’ to deliver an RNA vaccine (more on that below) where it is needed.

Another issue is how to ensure access to vaccines is fair.

Philanthropist Bill Gates has emphasised the need for a vaccine to be available to the planet’s seven billion inhabitants if the world is to return to normal.

But researchers have warned that it might not be possible to make enough vaccine for everyone, and that rich countries might hoard supplies.

How can we make a vaccine so quickly?

One way to speed vaccine development is to borrow a trick that the COVID-19 virus uses to take over human cells.

The virus uses its genetic code (which is in the form of a chemical called RNA) to reprogram human cells to make more coronavirus.

Moderna, which is working with the US National Institute of Allergy and Infectious Disease and CEPI, has created a RNA vaccine that uses part of the virus code to hijack the machinery of human cells to replicate the virus ‘spike’ protein (which the virus uses to invade human cells).

The vaccine provides the genetic information to turn human cells into factories to make the spike protein, which provokes the immune system to make antibodies. These antibodies are then ready to go into action to protect the body if it later encounters the SARS-Cov-2 virus. 

Will this RNA vaccine work?

That’s the point of the vaccine trials.

RNA is a delicate molecule and one question is whether it will survive in the body and make enough protein. If it does, will the virus protein be enough to create a protective immune system, and for how long. And, of course, is it safe?

If it overcomes these hurdles, the good news is that RNA vaccines can be made relatively quickly and cheaply and by a manufacturing process that can be adapted to make RNA vaccines for other infectious diseases. Moderna say that if everything goes to plan they could determine by early 2021 whether the vaccine works.

German companies BioNTech (with Pfizer) and CureVac are also working on messenger RNA vaccine for the new coronavirus.

When using this approach on rabies CureVac found that one gram could vaccinate one million people. Similar approaches are being taken by the Belgian firms  Ziphius Therapeutics and eTheRNA, and the French pharma company Sanofi, working with Translate Bio.

Are we testing more traditional vaccine approaches?

Yes, using weakened or killed forms of viruses or parts of viruses, including purified proteins. Sinovac Biotech is making a SARS-CoV-2 vaccine by chemically inactivating the virus.

There are also ways to make a live ‘attenuated’, or weakened, virus for vaccines. These produce a long-lasting, stronger response than from vaccines using inactivated virus, but pose a risk to people with weakened immune systems. This approach is being tried by Codagenix and the Serum Institute of India.

What other tricks can we learn from viruses to make vaccines?

We can use viruses themselves as ‘vectors’ to introduce coronavirus proteins to train the body’s immune system to fight COVID-19.

China’s CanSino Biologics has launched small trials of COVID-19 vaccine based on a safe version of an adenovirus-5 – another virus that can cause a common cold-like illness – that has been genetically modified to also make the virus spike protein.

This month a trial will start in Oxford of another vaccine, based on a safe version of an adenovirus.

The team at the University of Oxford, led by Sarah Gilbert at the Jenner Institute, was quick off the mark because it has been working on a vaccine against another coronavirus, Middle East Respiratory Syndrome (MERS), which has been shown to induce strong immune responses.

The same approach to making the vaccine is being taken for the novel coronavirus vaccine, with the peculiar name ChAdOx1 nCoV-19, which is being made by the University’s Clinical Biomanufacturing Facility, then Italian manufacturer Advent Srl for clinical testing.

The hope is that, in someone who has been vaccinated, antibodies to the spike protein will bind to the coronavirus to prevent it from causing an infection.

This approach is being tried by others, notably in a $1 billion programme by Johnson & Johnson (J&J) and the US government to stich a gene from the coronavirus into a disabled adenovirus.

Disabled adenovirus is not the only viral vector that is being tested. Horsepox, vaccinia and measles viruses are also being tried.

What about DNA vaccines and how do they work?

DNA vaccines are also being developed by companies around the world, such as a pan-European consortium involving the UK company Cobra Biologics and Inovio Pharmaceuticals, which plans safety trials for its SARS-CoV-2 vaccine this month.

Inovio designed its DNA vaccine INO-4800 in three hours after receiving the genetic sequence of SARS-CoV-2.

Their vaccine borrows a trick used by bacteria: the instructions to make spike protein are carried by rings of DNA called plasmids, which bacteria use to swap genetic instructions (notoriously, to exchange drug resistance genes).

The plasmids are injected into the muscle using a hand-held device to deliver a brief electrical pulse to open small pores in muscle cells to allow the plasmids to enter.

Once inside the cell, the plasmids begin replicating, thereby strengthening the body’s own immune response.

Once we get a vaccine, will we need an annual shot, as is the case for influenza?

Probably. We don’t know how long the immune memory will last.

Like flu virus, SARS-CoV-2 is an RNA virus. Its genetic material is stored in the form of the chemical RNA rather than the more familiar DNA (which carries the genetic code, or genome, of everything from bacteria to humans).

A characteristic of RNA viruses is their high rate of genetic mutation, which is a mechanism by which these viruses evolve into new strains to escape our body’s defences. The good news is that, unlike influenza, COVID-19 has been relatively stable so far.

How will the vaccine be administered?

Aside from the traditional jab, Altimmune is developing an adenovirus-based vaccine that can be administered as a nasal spray.

The University of Pittsburgh Medical Center is testing a microneedle array, a fingertip-sized patch of 400 tiny needles that deliver spike protein into the skin, where the immune reaction is the strongest.

What basic research is supporting vaccine development?

We already have a detailed molecular view of the spike protein that is used by the virus to invade human cells.

The protein is not fixed in shape but deforms. CEPI and researchers from the University of Queensland in Brisbane, Australia, are devising a ‘molecular clamp’ to lock the spike protein into a form that is more ‘visible’ to the immune system, so that it can be used as a more effective vaccine.

To expand the number of viral proteins that can be used in vaccines, an international consortium across Europe and USA – including CompBioMed at UCL – are using the most powerful supercomputer on the planet and the most powerful in the European Union.

One of the consortium, Richard Scheuermann, Director, La Jolla Campus of the J. Craig Venter Institute, is studying the parts of the coronavirus that stimulate the immune system, focusing on epitopes, where an antibody from the immune system binds.

The hope is they can find alternatives to the spike protein that the vaccine community can use as the basis of different vaccines.

Detailed studies of the immune response of people who receive the vaccines and of the genetic makeup of people who shrug off the infection will also provide profound insights. For instance helping epidemiologists understand the spread of the pandemic, not least by using computers to model its spread.

The molecular structure of a neutralising antibody previously obtained from a recovering SARS patient that also binds to a region of the novel coronavirus (SARS-CoV-2) spike protein has been unravelled. Another molecular insight that could inform the design of a vaccine against SARS-CoV-2.

Vaccine developers and regulators will also be seeking to define ‘correlates of protection’.

Once they have evidence of the levels of antibody that are sufficient to protect against coronavirus infection, future vaccine trials can simply measure antibody levels instead of needing to wait to see if people can still be infected.

Correlates of protection have to be defined for each type of vaccine, as they may be different for a viral-vectored vaccine compared with a vaccine made from a protein subunit of the coronavirus.

What is the current extent of the pandemic?

You can get the latest news on how far this pandemic has spread around the globe from the Johns Hopkins Coronavirus Resource Center or check the total number of UK COVID-19 cases by consulting this Public Health England webpage. There is a wealth of data on this COVID-19 portal and on Our World in Data.

This is the third in a series of blog posts from our Science Director, Dr Roger Highfield, which explores the science behind the coronavirus.

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