Putting testing to the test: Using our body's immune response to fight COVID-19
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The effectiveness and availability of accurate tests has largely dictated each country's response to COVID-19. As the world emerges from the crisis, testing will continue to be key and will demand significant investment in time and innovation. Even as the focus shifts from diagnosis to understanding immunity, we will be confronted with more questions on whom to test and what test to use.
Testing is crucial to limit the spread of COVID-19, and there are two main methods:
- Diagnostic testing confirms the virus is present in a patient. It requires specialised scientific equipment in a laboratory and takes time (hours to days). In addition, these tests yield results only when the patient is actively shedding the virus – not before or after. Many countries are still trying to scale up diagnostic testing to meet the high demand.
- Antibody testing determines if a person has had the disease and developed an immune response. It is administered after infection and identifies the presence of antibodies to COVID-19 in the blood. When applied widely, it can also measure to what extent the virus has penetrated the population. Reliable tests are still under development but once proven, they should be inexpensive, easy to use (with possible distribution as a home test) and fast – requiring minutes instead of days.
Antibody testing can be quite straightforward: a few drops of blood are washed over a testing strip which then changes colour if positive. This approach can take just 15 minutes and can be easily performed at a hospital bedside or at home. Although no antibody tests have been approved as a global standard for mass use due to concerns of accuracy, we expect these tests will be cheaper and easier to develop, easier to manufacture at scale and to distribute.
While an immune response is crucial to antibody testing, the body's response differs with gender and age. Women have a much higher immune response than men and this is partially why this virus is more lethal to men. Younger people have larger numbers of immune cells that can specialise in fighting off new infections compared with older people who have fewer of these cells.
This fact, combined with a typically reduced overall health capacity and more underlying chronic conditions, is why the virus has been more lethal in older people. This weakening of the elderly population's immune system, known as "immunosenescence" may also cause an issue for any potential COVID-19 vaccine. We see a similar effect with influenza vaccines where a typical 70-90% immune response for those under 65 goes down to 30-40% for those over age 65. Different strategies are therefore necessary to improve the immunological response in the elderly, such as booster doses or the use of adjuvants.
Several companies have raced to produce an immunity test and await approval for mass use. Such tests must be specific enough to only show immunity to COVID-19 and sensitive enough to detect of the right number of COVID-19 antibodies. Without the correct balance, there is a high degree of false positives and thus a false (and dangerous) sense of safety.
Those who test positive most likely have gained immunity that lasts for a few months to two years, thanks to the antibodies circulating in their blood stream1. Although still experimental, trials are already underway where antibody-rich blood is taken from recovered patients and donated to those in a critical state. Research into this, as well as a vaccine, is ongoing.
There are many challenges and unknowns in dealing with a new virus such as COVID-19. The science behind antibody testing is rigorous and well-understood, but this is only one aspect of the battle. For society to recover, testing will need to be supplemented by treatment and population-wide vaccination programmes. These are all still in the early stages of development. Such a multi-pronged approach facilitated by advances in medical science will be required to combat COVID-19.
This paper offers a scientific dive into immunity testing and why it is a key component of the medical interventions necessary to tackle the virus. This includes an understanding of why immunity is different among different ages and genders, how various tests work, the risks of testing and what else is needed beyond successful testing to support society's recovery.
The challenges of current diagnostic testing
Diagnostic testing is a slow process that needs highly specialised equipment
Like many viruses, COVID-19 transmits its genetic material through RNA (ribose nucleic acid). There are two fundamentally different ways to detect the presence of COVID-19:
1. Identify fragments of viral RNA
2. Detect prior infections by testing if the body has developed an immune response to the virus
A test must be able to distinguish COVID-19 infections from other circulating coronaviruses. Since the 1960s, seven different types of coronavirus that affect humans have been identified. Common coronaviruses such as 229E (alpha) and OC43 (beta) are frequent causes of the common cold, which infects 2-20% of the population each winter. The closest relative of the COVID-19 virus led to the 2002-2004 SARS outbreak. These two related viruses share 80% of their genome. The 20% that's different has led to mutations in every one of the viruses’ four structural proteins, including the characteristic spike protein that latches on to the host's cells.
Around the world, almost every diagnostic test until now has used a reverse-transcriptase polymerase chain reaction (RT-PCR) test to identify viral RNA. These tests can only be processed in a laboratory with specialised equipment. The process uses swabs of the nose and mouth and samples from the lower respiratory tract to provide viral genetic material, which is amplified to provide a test result. The first RT-PCR tests were ready two weeks after COVID-19 was identified in January 20202. Laboratories around the world are producing millions of tests. However, there are several key challenges:
- Limited time: Each RT-PCR test takes four hours to complete, with the time roughly evenly split between preparing the sample and performing the test. If collection and notification are included, turnaround can take hours to days.
- Limited supply of reagents: Each test requires specific reagents and production is struggling to keep up with demand. Lysis buffer is currently among the most in-demand of all reagents. This liquid helps break open the cells to expose the viral RNA. While it is generally not difficult to source, the global surge in RT-PCR has stretched the capacity of supply chains. Some laboratories are looking to produce their own versions to mitigate supply issues.
- Limited detection window: As shown in Figure 1, the RT-PCR test can only show positive if the virus is being actively shed. The RT-PCR test will miss those with a prior infection several weeks old. This is particularly challenging when many only experience mild symptoms or may be entirely asymptomatic3. There is no way to differentiate the protected from the vulnerable.
Figure 1: Timeline of Detection for COVID-19.
Antibody testing still faces hurdles
Antibody testing is still under development, but it could become a simple test to do in the hospital or at home
Antibody testing can be straightforward: a few drops of blood are washed over a testing strip covered with proteins that react to specific antibodies. If antibodies are present and attached to the testing strip, it changes colour. The process can take as little as 15 minutes and can be done anywhere. Although antibody tests are still awaiting approval for public use, we expect they will be inexpensive and easier to develop, easier to manufacture at scale and to distribute.
Several companies have produced antibody tests to detect COVID-19. Although some are still in trials, none has received regulatory approval for mass use because they still produce too many false positives. This raises a key trade-off: specificity versus sensitivity. A test must be specific enough to only show immunity to COVID-19 but it must also be sensitive enough to detect the right number of COVID-19 antibodies. Without the correct balance, there will be a high degree of false positives. False positives are misleading, and with presumed immunity, people resume social interaction. This may cause a secondary surge in cases at a time when a country is trying to loosen its mitigation measures.
Because of the diagnostic testing challenges, there is interest in developing a serological (blood) test that detects the presence of antibodies to COVID-19. This test not only helps diagnose the infection but can verify that a person is immune, is unable to spread the infection and can safely return to work.
The body develops two types of antibodies in response to any foreign invasion:
- IgM is the first line of defence, with 10 locations able to bind to pathogens (the "antigen binding sites") but these are produced in limited amounts and are only found in the blood and lymph fluid.
- In contrast, IgG is smaller, with only two antigen binding sites. It can be produced in much greater quantities and provides long-term immunity against future infections.
IgG antibodies have been getting most of the attention because IgM antibody concentrations tend to peak during the period when RT-PCR testing is effective.
RNA viruses are prone to mutation. If this were to happen, then any immunity to COVID-19 could be lost. From SARS experience, we know immunity can last from a few months to three years1,5. However, coronaviruses have lower mutation rates than other RNA viruses such as influenza. Coronaviruses use enzymes to act as proofreaders, ensuring that each generation of the virus is far closer to its ancestors than would be common in influenzas6. This is an advantage because tests can target a wider range of proteins on the coronavirus, since many remain there, generation after generation. It also means that coronaviruses are less likely to change their symptoms or lethality.
Cases where individuals seem to have had more than one episode of COVID-19 infection are more likely to be the result of false-positive tests than failing immunity. This is mainly noticed in countries where the outbreak occurred earlier, such as China and South Korea.
Different immune responses require varied approach
Our immune systems are not all equally effective. Women and young people have a stronger response than men and older people
Women have more highly developed immune systems, so they respond more strongly to infections and vaccinations. This is partly because several key genes that regulate the immune response are located on the X chromosome. Men, who have a single X chromosome, are more vulnerable. In addition, higher levels of testosterone seem to inhibit the strength of the immune reaction7. The additional benefits for women are clear in terms of lower cancer incidence rates and longer life expectancy, but conversely, women are more likely to develop autoimmune diseases such as rheumatoid arthritis and multiple sclerosis8.
With respect to COVID-19, this stronger immune reaction appears to translate into lower hospital admission and mortality rates in women than in men, as Figure 2 demonstrates. While all four geographies show an even distribution of reported cases between males and females, it's clear that a significantly greater proportion of men in all four areas get hospitalised and die. While women are generally more likely to seek treatment for medical issues early on, it is likely that men also have a higher level of co-morbidities than women, putting them at greater risk to adverse development.
Figure 2: Males are equally diagnosed with COVID-19 but have higher rates of hospitalisation and mortality.
Source: Situation reports for each country as of 28th April 2020
The ability to generate adequate immune responses also varies by age. A lifetime of infections means that older individuals have fewer generic or "naïve" B and T immune cells that are especially capable for fighting new infections4. As a person's immune system is exposed to infections throughout their life, the number of available naïve cells decreases. This limits the body's ability to mount an effective response against novel infections and is exacerbated by reduced immune cell interactions and greater reliance on the production of less specific, short-lived IgM9.
The Centers for Disease Control and Prevention (CDC) in the US estimates that because of immunosenescence (decreased immune response at older ages), the effectiveness of the influenza vaccine in those over age 65 is typically 30-40%, compared to 70-90% in those under 65. Therefore, different strategies are necessary to improve the immunological response in the elderly. One strategy can be to give a higher dose of a vaccine, or follow up with a booster dose several months later. This has proven to be effective for the herpes zoster (shingles) and avian influenza vaccines. Another approach is to change the route of administration. Some seasonal influenza vaccines have moved from intramuscular injections to intradermal, a shallow injection below the skin.
The third approach is to use an adjuvant – a chemical which helps the immune system. Typically, aluminium is used to stimulate a more active immune response after vaccination. Thanks to a novel group of adjuvants, the Shingrix vaccine developed by GlaxoSmithKline (GSK) now has an effectiveness of 90% compared to 51% for the previous vaccine. GSK, along with other companies, are now making a range of adjuvants available to speed COVID-19 vaccine development. We will look at this topic in a future Trend Spotlight.
Identifying an adjuvant for a potential COVID-19 vaccine could be crucial. It would promote the creation of new antigens to the infection, often meaning that immunity is gained faster. The use of an adjuvant could also mean that fewer vaccinations are required for immunity; ideally, only one injection.
This difference in immune response between the young and the old leads to an age asymmetry among COVID-19 patients who get hospitalized and die. We can see in Figure 3 that even when the cases vary by age across geography, those over 65 are most likely to be hospitalised. In the Netherlands, Spain and Switzerland, nearly everyone who died has been over 65. In New York City, 75% of deaths have been people over 65.
Figure 3: Most hospitalisations and nearly all fatalities come from the 65+ age group.
Source: Situation reports for each country as of 28th April 2020
Diagnostic tests range from simple to complex
While most tests need a swab of the nose or throat, serological (blood) tests need nothing more than a finger prick
The first serological (blood) tests for COVID-19 were developed in Singapore and China, and have been used in limited numbers in China, Singapore and South Korea. These tests use the lateral diffusion approach, which requires a testing strip with fixed specific viral proteins attached to it. The patient's blood sample is washed over the strip so any antibodies will stick to it. A positive test is indicated by the appearance of coloured lines for IgG and/or IgM antibodies. These serological tests can be mass produced and distributed and can be done at home with a finger prick.
More sophisticated serological tests are generally performed in labs and are usually of a higher quality. ELISA (enzyme-linked immunosorbent assay) tests first expose the patient’s blood to viral antigens. If COVID-19 antibodies are present, they will bind to the viral antigens to form complexes. Further antibodies with fluorescent markers then detect the presence of the complexes and allow a quantitative estimate of IgG/IgM antibodies in the patient’s blood. This will also test for the strength of the immune response and provide insights into the longer-term immune protection.
There are different serological tests which target different sites of the coronavirus, any of which can confirm the presence of COVID-19. The first is the coating of the coronavirus known as an envelope, a hard shell that surrounds the far more sensitive RNA inside it. Without the envelope, a coronavirus is nearly always destroyed. Another method is to identify certain crucial proteins on the virus, such as the nucleocapsid proteins that form part of the envelope. The final target is the key spike protein. The spike protein allows the virus to hijack the body's cells and begin the process of injecting viral RNA into the host cell.
Testing options come with trade offs
Millions of serological tests have already been purchased by governments around the world but have not been deployed. So why the delay? And why do we continue to rely on the RT-PCR tests?
The problem is not a lack of potential candidates. FIND, the Foundation for Innovative New Diagnostics, maintains current data on tests and testing for COVID-19, which is a valuable resource for policymakers and healthcare providers. As of 8 April 2020, FIND had identified 62 different immunoassay tests that were ready for production and had received regulatory approval. However, governments have expressed scepticism that the tests are sufficiently sensitive and specific.
In any test there's going to be a degree of trade-off between sensitivity and specificity. A test that’s highly sensitive will flag almost everyone who has the disease and not generate many false-negative results. However, public health officials expect cumulative improvements with each new generation of serological tests. According to Prof Chris Whitty, the UK’s Chief Medical Officer, “the best candidates would not be expected at the start of the pandemic.”
Even with mass production of a test, initial demand will far exceed available supply. Data collected by COVID Symptom Tracker app (through 29 March 2020) indicated that in many urban areas in the UK, up to 15% of the app's users reported persistent coughs and up to 6% reported fever. Combining such data sources with the likelihood of asymptomatic infections indicates that many millions will want to learn if they have been infected.
The risks of false positives and immunity certificates
Current clinical guidance says that serological tests should not be regarded as diagnostic. Instead, they should be considered indicative, prompting further investigations with RT-PCR testing. The concern is that a serological test usually isn't specific enough to one particular viral strain. It will confirm the presence of antibodies to coronaviruses, but it could also detect coronaviruses other than COVID-19. Quantitative testing will assess the strength of the protective immunity, which may also suggest how long a person is likely to remain immune.
Allan Wilson, president of the Institute of Biomedical Science, stated on 6 April 2020 that across those tests that had been evaluated "at least one in 10 people who test positive on the antibody test – and are therefore considered to have immunity – will be false positives". These people will think and act as if they are immune when, in fact, they are not. Some tests have already demonstrated sensitivity and specificity is in excess of 90% on studies with hundreds of subjects. The key questions are:
- What thresholds are acceptable?
- What is realistic and necessary?
There is an obvious risk that vulnerable people are falsely diagnosed as immune, and therefore contract the disease, but individual governments must set the threshold of how many susceptible people can be exposed to COVID-19 in a “normal” situation.
People with tests that indicate immunity will want more than peace of mind. They will want to use the information to return to work, to be free of social distancing restrictions and to regain some degree of normalcy in their daily life. This degree of certainty is unlikely to be derived from an unsupervised home-testing kit.
The Helmholtz Centre for Infection Research in Braunschweig, Germany, is investigating the issue of certificates of immunity after blood tests for antibodies. Dr Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, has said that a similar process of issuing immunity cards is being considered in the US. These certificates will likely require an agreed level of testing to a specific standard. However, the WHO has not yet confirmed that patients are fully immune for an extended length of time after recovering from COVID-19, which suggests immunity certificates needs more investigation. If they are successful and are widely issued, it may place new strains on the enforcement of social distancing and restrictions on movement. At the same time, issuing these certificates may be one method that makes returning to work easier and helps restart economies. Still, some areas will not wait for these to be issued before reopening businesses, restaurants and factories.
Where do we go from here?
COVID-19 presents a novel virus to which we have little or no prior immunity. Antibody tests simply confirm that an individual had the disease, they do not help with treatment or prevention. What they can do is help plan exit strategies for easing non-pharmaceutical interventions like social distancing. The development of mass immunity, either through vaccines or widespread infection, is the key to limiting the spread of the disease long term. Vaccine development is picking up, and while COVID-19 will remain a threat throughout 2020, antibody testing may allow us to better track and monitor it across time and geographies.
For the insurance industry, monitoring the development of the various medical interventions to address COVID-19 is key. This will help to anticipate potential social and policy response to address to pandemic, which will in turn inform commercial strategy, product development and risk management. The hope is that immunity testing together with better diagnostic information will provide relief while drugs and vaccines are being developed. Other developments in the medical space include blood plasma therapies that can potentially also promote immunity these topics and their implications for society will be covered in upcoming Trend Spotlights. Stay tuned!
We offer more risk knowledge for uncertain times at: swissre.com/coronavirus.
Contributing author: Dan Ryan, Chief Scientific Officer, COIOS Research
Managing editor: Susan Imler
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Sources for Figures 2 and 3
- Reports accessed on 28th April 2020 from RIVM (Netherlands), RNVE (Spain) NYC Health (NYC), OFSP/MT (Switzerland)