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Trouble in testing land – Oxford University blog by Chair of Oxford Academic Health Partners

Professor Sir John Bell explores the challenges of antibody testing for Covid-19, noting that no tests to date have performed well.

The UK government has been creating a testing strategy that is intended to manage all aspects of Covid-19, including PCR tests on swabs from the nose or throat to detect the virus (which is being done in UK super labs in three locations across the country), as well blood testing to detect people who might have had the virus and hence be protected with immunity. These people would be able to go back to work without the fear of being infected again because they are now immune to the disease. This combination will give UK citizens all the information they and the health system need to manage those with the disease by giving access to rapid disease diagnosis and manage the population as a whole to ensure we will not put ourselves or others at risk while the virus is circulating.

Long-term protection to this virus comes from antibodies, small proteins produced by your immune system that attack the virus and neutralise it so it cannot be spread and cannot do any more damage to the person infected. These antibodies emerge during an infection and peak 28 days after the infection. They then remain for months afterwards continuing to provide protection, and the cells that produce them also are available to fight off the infection if it returns. These antibodies see anything foreign (like a virus) and bind to many different parts of the virus. Some antibodies are better than others at providing protection; they are called neutralising antibodies. There is obviously much interest in developing tests that detect these antibodies so that people know they will be safe even if exposed to those with the infection. It may be that many people get this infection without severe symptoms so many may have protection and not know it. Large scale testing is therefore a strategy which will be crucial for getting us back to our normal lives in the coming months. One strand of the government strategy has been to use home testing kits to allow people to test and see whether they have long term immunity and hence can confidently go back to work.

Creating home test kits is, however, not easy. They detect antibodies in blood by capturing these antibodies on virus components held in the test kit. Blood flows from one end to the other, the anti virus antibodies are captured and a signal appears as a line on the test device. This can be read by the person at home or on their mobile phone camera. If there are no antibodies no line appears. There are many challenges to creating accurate tests; hence these tests need to be validated carefully. Other countries such as Spain have already sent tests back because they don’t work. There are 100 or more such tests kits from different suppliers available for identifying Covid-19 antibodies, and it is important that each of these is checked for accuracy before making them available to the public. Crucially it is essential that the test does not tell you are positive for anti-Covid serology when you are not; otherwise you might return to work when you are not immune. Similarly, it is important that the test does not tell you that you are not immune when you actually are.

To validate these tests you need to obtain a range of tools. You need a gold standard test so you know the correct answer and you need sera from patients who have recovered from the virus infection they had approximately 28 days before. You also need blood from people who donated before the epidemic so you know whether you falsely see positive tests when there is no Covid-19 in the sample. For example, there are a number of other coronaviruses circulating that might stimulate antibodies that cross react to Covid-19 proteins. It has taken some time to gather these tools for validation but the UK is now uniquely positioned to evaluate and find the optimal test for this disease. We clearly want to avoid telling people they are immune when they are not, and we want all people who are immune to know accurately so they can get back to work.

Multiple tests have been provided for evaluation, and a range of convalescent sera has been used to determine whether the tests can identify both low and high levels of antibodies. We have been very careful to test using gold standards checked against a sensitive enzyme-linked immunosorbent assay (Elisa) of the spike protein and other viral proteins. Sadly, the tests we have looked at to date have not performed well. We see many false negatives (tests where no antibody is detected despite the fact we know it is there) and we also see false positives. None of the tests we have validated would meet the criteria for a good test as agreed with the MHRA. This is not a good result for test suppliers or for us.

Interestingly we are not the only ones who having difficulty identifying commercial tests that work in a home test kit format. The Spanish apparently returned test kits that were not working, and the Germans who are developing their own sensitive kits believe they are three months away from getting these available and validated. Not test has been acclaimed by health authorities as having the necessary characteristics for screening people accurately for protective immunity.

What next? We will of course continue to look for a test that meets the criteria of an acceptable test. There is a point in evaluating these first-generation tests where we need to stop and consider our options. We effectively need an Elisa on a membrane, with the same sensitivity and specificity that can be used at home. That should be achievable, and the government will be working with suppliers both new and old to try and deliver this result so we can scale up antibody testing for the British public. This will take at least a month.

Professor Sir John Bell, GBE, FRS
Regius Professor of Medicine, Oxford University
Government Advisor on Life Sciences