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Roger Highfield, Science Director, explains the central importance of testing for dealing with the COVID-19 pandemic.

Is testing for coronavirus important for curbing the pandemic?

Critical. Until effective coronavirus vaccines or drugs are available, testing is a powerful way to monitor and manage the pandemic.

‘We have a simple message to all countries – test, test, test,’ WHO Director General Tedros Adhanom Ghebreyesus told a news conference in Geneva earlier this month.

‘All countries should be able to test all suspected cases – they cannot fight this pandemic blindfolded,’ he said, calling the pandemic ‘the defining global health crisis of our time’.

Why have some countries, notably South Korea, adopted WHO advice faster than others, such as the USA?

Coronavirus cases have dropped sharply in South Korea as a result of the most expansive and well-organized testing program in the world.

The reason for its quick response is an encounter in 2015 with an outbreak of another kind of coronavirus, called Middle East respiratory syndrome (MERS) which, like COVID-19, is likely to have originated from bats.

That experience of MERS taught them the importance of rapid testing, prevention and control, so they were well prepared.

After the COVID-19 coronavirus emerged in China, South Korea’s Centers for Disease Control and Prevention had approved its first test early in February, when the country had a handful of cases, and distributed it to health centres. When infected people are identified, they can be isolated along with the people they have been in most recent contact with.

The South Korean government also has the authority to collect data from people who test positive – such as from their credit card and mobile phone – to reconstruct their recent whereabouts and share anonymised data through apps that allow others to determine whether they may have crossed paths with an infected person.

How much testing is the UK doing?

The UK has done more testing than many other countries, testing 828 people per million of its population by mid-March, though this falls far short of the 5,000 tests per million in South Korea.

On 11 March, NHS England said it intended to greatly expand testing capacity for COVID-19 – up to 10,000 tests per day.

On 24 March Health Secretary, Matt Hancock said that the government has purchased 3.5 million antibody tests, though at the time of writing it remains unclear exactly when they will be rolled out, or what the format of the testing will be or what the tests will detect.

Exactly how this programme will work remains uncertain and there have been critics of the UK’s approach to testing and negative press coverage.

What is the current extent of coronavirus infections?

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.

How do you test for coronavirus infections?

Broadly speaking, there are two ways to do it – a direct test for the genetic code of the virus (using a technology called PCR), or an indirect test (by looking for antibodies in blood) which reveals whether a person has been infected with the virus.

As well as helping to distinguish COVID-19 from colds and other infections common at this time of year, these tests give different insights, one revealing the presence of the SARS-CoV-2 virus itself and the other whether a person has encountered the virus.

How do you test for the virus itself?

Current laboratory tests seek the characteristic genetic signature of the coronavirus in a swab taken from the nose or throat.

Viruses use the chemicals DNA or RNA to store their genetic code, which provides instructions – in the form of genes – for human cells to make new copies of the virus.

In the case of the coronavirus, SARS-CoV-2, its genetic material is in the form of RNA and for the test it has to first be converted into DNA code which can then be amplified by a standard method called the polymerase chain reaction (PCR – see this prototype). The test shows that the virus is present by detecting tell-tale  SARS-CoV-2 genes with dull names such as ORF1ab, RdRP and N.

Quicker and potentially portable methods are under development, for instance loop mediated isothermal amplification, or a gene-editing method called CRISPR.

However, these tests are not faultless as an infected person may not be shedding the virus into the nose or throat at very early or late stages of the infection.

Who’s going to do the lab testing?

Increased testing capacity for frontline NHS staff will be delivered by an alliance that includes Thermo Fisher Scientific, Amazon, Boots, Royal Mail and Randox, alongside the Wellcome Trust and leading universities.

There is no shortage of volunteers, according to Prof Matthew Freeman of the Dunn School of Pathology, University of Oxford: ‘There are many university departments and research institutes with all the equipment and expertise to do both type of testing. We have offered our services (as have many others). Our offer has not yet been taken up. I can see that it’s complex and possibly not efficient to set up lots of small testing centres, but it’s reassuring to know that there’s an army of expert volunteers.’

The Francis Crick Institute in London , the UK’s largest bioscience lab, has offered its services, invoking the ‘Dunkirk spirit.’ The nation can also draw on the support of an army of laboratory technicians , who have been described by the Gatsby Foundation as ‘linchpins of the UK economy.’

How do we detect whether a person has encountered the coronavirus?

By testing a person’s blood for evidence that they have encountered the virus in what are called serological tests. These rapid tests can be as simple to perform as an over-the-counter pregnancy test.

These serological tests will look for proteins found in a person’s blood – the antibodies that our immune system uses to defend against the coronavirus, which our bodies keep making even after the virus is eliminated.

Leaving aside critical issues of procurement, operational delivery and accuracy, these tests do not pick up infections at the earliest stage, when people are most contagious.

Only around two days to two weeks after infection (an average of around five days) with SARS-CoV-2 do people start producing so-called IgM antibodies. After another couple of days, production of IgM declines and they start making IgG antibodies.

The proteins tested for can also be antigens, proteins from the virus itself; viruses are scraps of genetic code wrapped in protein and lipids (fats).

Nobel Prize Winner Sir Peter Medawar once described them as ‘bad news wrapped up in a protein’. Though these antigen tests can spot the virus, they are not as sensitive as tests based on PCR.

Can you trust these serological tests?

In addition to the above caveats, quality control is crucial.

The Spanish government withdrew the first batch of 640,000 testing kits it had ordered from a Chinese company after it emerged that they had an accurate detection rate of just 30%.

Depressingly, Sir John Bell of the University of Oxford, Government advisor on life sciences, commented on 5 April that no home antibody tests have performed well to date.

How will these SEROLOGICAL TESTS HELP?

RELAX LOCKDOWN MEASURES:

Massively ramped-up testing, contact tracing and isolation of infected people could, once the epidemic is in decline, allow more draconian measures to be relaxed, according to Neil Ferguson of  the MRC Centre for Global Infectious Disease Analysis.

CHART THE PANDEMIC:

‘Provide a big picture of the pandemic so authorities can refine their estimates of how many people in the population will be affected and the rate of spread’, according to Public Health England (PHE), which is tracking cases in the UK.

Monitor frontline NHS workers, for instance to identify those who are immune:

The public and particularly our key workers want to understand their health status,’ said, Jenny Harries, England’s deputy chief medical officer.

This could help manage the surge in demand on the NHS, allowing doctors and nurses who are self-isolating to return to work if shown to be negative, for example. Those who have been shown to be clear could also be issued with an ‘immunity certificate’, so they could be allowed out of lockdown, for example.

Animal experiments show immunity develops but there is an important caveat: we do not yet know how long this immunity will last, though experience of other coronaviruses (SARS and MERS) suggest it’s more likely to be a matter of years than months.

Understand how covert coronavirus infections seed new outbreaks:

Scientists are rushing to gauge how many people display no symptoms or mild symptoms. One estimate is that asymptomatic or mild cases combined may represent up to half of all infections.

The reason they want to discover the extent of these covert infections is that virus shedding, as detected in the mouth or nose, is common and could occur prior to onset of symptoms and can continue for days or weeks even when a person has mild or no symptoms.

A key factor in being able to control epidemics is being able to identify infected people through their symptoms so pinning down how many symptom-free infected people there are could be transformational, not least in understanding what is driving this particular epidemic.

If a substantial number of unreported cases were in people who had mild or no symptoms but were contagious this might explain why the virus spread so quickly, though this is not known with any degree of certainty.

That is another reason why a brute force measure like a lockdown is necessary to curb mild and asymptomatic cases that are fuelling the pandemic.

Various strands of evidence point to a substantial fraction of infected symptom-free people who could still pass on the virus.

One team used data on Japanese nationals evacuated from Wuhan, the epicentre of the outbreak in China, to estimate that ‘less than a half of COVID-19-infected individuals are asymptomatic’.

Of the 3,711 passengers and crew on the Diamond Princess cruise ship, which had a COVID-19 outbreak in early February and were repeatedly tested, about 18% the 700 infected individuals never showed symptoms, though this population was skewed towards elderly people who tend to fare less well.

Understand how much immunity to the virus already exists in the population and for how long:

This is crucial and will determine many public health decisions taken over the coming months.

The COVID-19 virus may have reached the UK by mid-January, earlier than thought, and already have infected far more people in the UK than scientists had previously estimated — perhaps as much as half the population — according to one of the more extreme scenarios shown by computer modelling of SARS-CoV-2 in the UK by Sunetra Gupta at the University of Oxford.

If this is correct, there may already be significant “herd immunity”, the idea that the virus will be hindered from spreading because so many people already have protective antibodies.

However, Sir Mark Walport, Chief Executive of UK Research and Innovation (UKRI, which has produced its own guide to COVID-19 science), said the work had been widely criticised.

In his evidence to the Science and Technology Select Committee,  Prof Neil Ferguson, Director at the MRC Centre for Global Infectious Disease Analysis, Imperial College London, said data from villages in the viral epicentre in Italy tell a different story to the Oxford work, one ‘nowhere near the Gupta scenario’.

Prof Ferguson gave evidence, even though he himself was recovering from the virus.

As the slogan on his mug declared: ‘Keep Calm and Carry On.’

Find people with high levels of neutralising antibodies to help develop treatments:

Given it will take time to develop vaccines or drugs, even to find old drugs that could work against COVID-19, hospitals in New York City are trying an approach used a century or so ago against viral diseases such as polio, measles, mumps and influenza.

They want to infuse patients with the antibody-rich blood of those who have survived the COVID-19 infection which they hope will help them to survive, after encouraging results of using this approach on patients in China. People seriously ill with COVID-19 experienced striking improvement after receiving infusions.

At Chelsea and Westminster Hospital, Imperial College London, Professor Xiao-Ning Xu’s team will develop antibodies that target the novel coronavirus with the aim of developing a new therapy for COVID-19.

They have already identified some antibodies that might bind to proteins from the COVID-19 coronavirus, in collaboration with China.

The company Takeda, along with several others, is developing hyperimmune globulins, infection-fighting proteins isolated from the blood plasma of recovered patients.

Regeneron has isolated virus-neutralizing antibodies from mice which have been genetically-modified to have a human immune system. And a study of antibodies isolated from eight SARS-Cov-2 infected patients has already shown some that are highly potent at neutralising the virus. The world’s best-selling drug is based on British developed antibody technology.

How will results be shared with patients?

Leaving aside the issues around the tests themselves, another key question is how to get results back to patients in an overburdened health system, according to Prof Maria Zambon, Director of Reference Microbiology at Public Health England.

‘There is plenty of opportunity for innovation and digital creativity here – could systems be developed to help with access to restricted test results which would have a durable legacy?’

Are there other kinds of testing?

Yes, and they can give valuable insights into the pandemic and how to bring it to an end:

Vaccine development:

Measuring the immune response of people who receive experimental vaccines will aid research on making them as effective as possible.

At the University of Oxford, for example, a safe version of an adenovirus – another virus that can cause a common cold-like illness – has been modified to make a protein the coronavirus uses to invade human cells.

That results in the formation of antibodies to the protein, which is found on the surface of coronaviruses in the form of a spike.

The hope is that, in someone who has been vaccinated, antibodies to the spike will bind to the coronavirus to prevent it from causing an infection. Public Health England is supporting the UK’s hunt for a coronavirus vaccine .

Detailed patient studies:

Samples from 1,300 COVID-19 patients in the UK will be collected by Dr Kenneth Baillie, University of Edinburgh, Prof. Peter Openshaw, Imperial College London, and Prof. Calum Semple, University of Liverpool, to find who in the population is at higher risk of severe illness; what is the best way to diagnose the disease; what is happening in their immune systems to aid or harm them; how long are people infectious for and from which bodily fluids; and are people infected with other infections, such as bacterial, fungal and other viral infections, play in severe disease.

This research, among a number of projects backed by UK Research and Innovation, UKRI, and the National Institute for Health Research, can also monitor the effects of drugs used in patients with COVID-19 and, as my previous blog explained, many are under investigation and development.

Another issue is viral load, the amount of virus a patient is exposed to at the outset.

If a person inhales a massive dose of the virus (for instance, from the bodily fluids from those infected), the viral invasion of  the patient receives a jump start. Early studies suggest the viral load tends to be higher in patients with more severe COVID-19 disease. This is a particular concern for health workers, though the current evidence is tentative.

Virus sequencing studies:

Samples from patients with confirmed COVID-19 will be sent to a network of sequencing centres which can read the entire genetic code – genome – of the virus infecting a patient (this prototype gene sequencer is part of the Science Museum Group Collection). This is an unprecedented collaborative approach, science’s answer to the Blitz spirit.

The UK Consortium, supported by the government, including the NHS, Public Health England, UKRI and Wellcome, will enable clinicians and public health teams to rapidly investigate clusters of cases in hospitals, care homes and the community, to understand how the virus is spread and implement appropriate infection control measures.

The £20m investment – including £5 million from UKRI’s Medical Research Council – will enable scientists to monitor mutations in the virus at a national scale.

This research can help to understand susceptibility, guide the development of treatments, and monitor whether different strains are emerging.

SEWAGE STUDIES:

Research groups have started analysing wastewater for the new SARS-CoV-2  coronavirus as a way to estimate the total number of infections in a community. To do this, the groups will need to find out how much viral genetic material is in raw sewage, and figure out how this correlates with the number of infected people in the local population. In the long term, routine wastewater surveillance could be used to provide early-warning of new outbreaks.

Prototype Automated DNA Gene Sequencer, part of the Science Museum Group Collection.

Can we learn anything by studying the genetic makeup of patients?

Very much so. This research could reveal why relatively young and healthy people can sometimes get critically ill with COVID-19, and may reveal key mechanisms that could help choose the next treatments for clinical trials.

Efforts under way to see how a patient’s genetic make-up influence how they fare when infected include the ISARIC GenOMICC project, an open collaborative global community of scientists and doctors set up in 2016 to tackle exactly this question.

In addition Andrea Ganna of the University of Helsinki’s Institute for Molecular Medicine Finland is trying to pool COVID-19 patients’ genetic make-up and the UK Biobank, which has DNA data for 500,000 participants, now plans to include COVID-19 data.

One candidate gene of interest is for a cell surface protein (ACE2) that the virus uses to invade cells, the first step in a process in which it turns human cells into virus factories. Perhaps variations in the gene make it easier or harder for the virus to take over cells.

What have tests revealed about whether the virus can pass from mother to unborn child?

Transmission from mother to unborn child might be possible according to two studies but the jury is out on the significance of the work, which only used antibody tests rather than direct tests for the virus.

Another study followed 33 babies born to infected mothers in Wuhan, China, and reported that three tested positive for the virus in the days after birth.

They all developed signs of pneumonia, but the two who were born full-term recovered and the third, premature, eventually recovered. There is no agreed policy on whether new-borns should be isolated from their infected mothers.

Developmental scientist Prof Magda Zernicka-Goetz of Caltech, Pasadena, and the University of Cambridge adds that if a mother-to-be were to become infected and develop a severe disease, this could lead to complications:

‘Pregnancy places many demands upon the mother’s body, particularly the need to supply oxygen not only to her own tissues but also to the baby.  If the mother-to-be were to catch pneumonia as a result of COVID-19 infection, then her lungs would not work properly and the baby too would become starved of the oxygen it needs and this would be detrimental to its development.’


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

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