April 18, 2020

expert reaction to comments made by Dr Maria van Kerkhove at the WHO that there is no evidence antibody tests can show that an individual is immune or is protected from the infection

In the WHO’s (World Health Organisation’s) daily press conference on 17th April, Dr Maria van Kerkhove the WHO’s technical lead for COVID-19, said that there was no evidence yet that antibody tests can show that an individual is immune to or protected from the disease.

Prof Adam Finn, Professor of Paediatrics, University of Bristol, said:

“In people who have had the virus, there is specific immunity – immunity to a particular thing – which is made up of two parts: B cell responses (antibodies) and T cell responses (which don’t involve antibodies). Both are involved in the immune response to the virus and for this virus we don’t know how important each type is, but most likely both matter to some extent. These parts of the immune system respond to different components of the virus called antigens and different parts of each antigen, called epitopes or, in the case of T cells, peptides. When infected, you make responses to multiple epitopes from multiple antigens – some are useful in protecting against future infection and some are not.

“Most of the time we do tests for antibody responses. It’s possible to measure T cell responses too but more difficult to do and more difficult to interpret. But it’s important to realise that someone might fail to make protective antibody responses but still be protected by their T cells.

“Detecting immune responses, usually in blood but also in mucosal fluids like saliva, can be useful markers of the fact you have had the infection even if you did not get sick. But other viruses, including other common coronaviruses that cause mild disease, that look somewhat similar to the immune system can induce immune responses that suggest the person has had SARS-CoV-2 virus before when they have not and are not protected by their immunity. Such cross-reactive non-protective responses have turned out to be a problem for some of the available tests, so that they are not useful because they return false-positive results.

“What we know from other coronaviruses is that although you do make an immune response – otherwise you wouldn’t recover – the protection doesn’t seem to be life-long but only lasts maybe one year or two.

“We don’t yet know how long lasting naturally acquired protection will be in people who have had COVID19. This is likely to vary from one person to another. But detecting antibody responses that are definitely due to SARS-CoV-2 will help us judge how many people in the population have been exposed to the virus – which is called seroprevalence. Many labs including ours are working to develop such tests and we are all trying to do so in similar ways and to cross-compare our results to make them reliable and consistent and to avoid false-positive results.

“But there will also be ways to work out if antibodies are not just there but also protective against future infection – although developing that sort of test is not as easy as making antibody tests that can just give an idea of the degree of spread of infection in the population. In a test tube in the lab you can put the virus with the antibodies from a person who has had the infection and see whether they stop the virus from infecting cells – this is called a virus neutralisation test. We can also make tests called targeted immunoassays where we use specially-made pieces of the viral antigens known to be critical for its ability to bind to cells. We can then see whether antibodies in the blood bind to those particular parts – called the virus’ “Achilles Heel”. Viral neutralisation tests are tricky to do and they take time. Immunoassays are quicker and can be scaled up more easily. By comparing the results of these two approaches by testing blood samples containing antibodies both ways, we may end up with a quick test that can be done on large numbers of samples that predicts not only previous exposure but also protection. We don’t have that yet, but labs like ours which can do viral neutralisation and make synthetic antigens are working hard to develop them.

“Then there is vaccine-induced immunity. Most if not all the vaccines being developed are not using the whole virus – they mostly use either DNA or RNA coding for the viral spike protein, or version of that protein itself or parts of it. The spike protein is on the outside of the virus and can easily be bound by antibodies. Both B and T cell responses that are induced by such vaccines will be measures only of immunity to that spike protein and not to other viral antigens. We hope that this streamlined or focussed immunity will protect against the infection even though they are only directed against one part of the virus. One way to tell whether a person has immunity caused by a vaccine rather than by the infection is to check whether they only have responses to the vaccine antigen and not to other viral antigens that are not in the vaccine.

“If a vaccine induces immune responses that can neutralise the virus, it is more likely that that it will be effective. Tests in animals are being set up to do this in many labs working on different candidate vaccines right now, including ours. If a vaccine can do this, it makes sense to test it to see if it can prevent infection and disease in real life both in animals and in people.

“It also makes sense to have antibody tests that detect protective antibodies to use in human vaccine trials. When used this way they are called correlates of protection. It is much easier and quicker to do blood tests on someone who has been vaccinated to track how strong and long lasting their protection is, than to wait and see whether they get the infection or not.

“So, you can see that it’s very important that we develop good tools for measuring and understanding immunity as well as many different vaccines to ensure that a few of them and at the very least one is found soon that works and works well. The wise punter does not put all their money on one horse, especially if it’s a steeple chase.

“We are just starting out on this work. We don’t know who will succeed and who will fail but we do know that this can be done.”

Prof Andrew Easton, Professor of Virology, University of Warwick, said:

“An infection leads to the production of a range of antibodies directed against the infectious agent, in this case the coronavirus. It is well understood that while some of these, called neutralising antibodies, have the ability to inactivate the invading virus, others do not, these are non-neutralising antibodies. The neutralising activity of different antibodies can use different mechanisms to prevent the virus from causing an infection.

“When people are infected the proportions of neutralising and non-neutralising antibodies can differ. It is not always understood what makes an antibody neutralising and another non-neutralising or why an infection leads to production of more of one of these types of antibodies. The initial immune response immediately following infection sets the memory of the immune system so if the person had generated mostly non-neutralising antibodies the next time that person encounters the same virus they may not be able to prevent an infection. A serology test does not discriminate between neutralising and non-neutralising antibodies; a discriminatory test is much more complex and slow.

“Vaccines avoid this problem because they are tested to ensure that they generate protective immunity in most or all people being treated. This efficacy test is one of the critical assessments alongside safety testing that is required for all new vaccine candidates before they are deployed. Failure to generate protective immunity would mean the vaccine candidate would not be approved for use.”

Prof Stephen Evans, Professor of Pharmacoepidemiology, London School of Hygiene & Tropical Medicine, said:

“Dr van Kerkhove is technically absolutely correct. We do not know for certain that someone with antibodies will not be re-infected. If the virus mutates at a sufficiently high rate, then it will be possible to be re-infected by a markedly different strain. It is usually the case that even if re-infection with a different strain occurs, then the second infection will not result in as severe disease as the first.

“Similarly, with a vaccine, there will usually be some protection even if it is not complete. We will have to await the large trials, and possibly even seeing the results after the vaccine is given to millions of people as to how long in time its efficacy lasts. We cannot be absolutely sure that any vaccine will give permanent protection until it is in use.

“Usually we find that plasma from recovered patients has antibodies to the disease and will protect someone not previously infected or even in some circumstances it will be effective in treating a patient with the disease (this has been done for example with Lassa fever for which no vaccine is currently available).

“We should not to be complacent in assuming that a vaccine is guaranteed to be 100% effective and give lasting protection, but based on current knowledge, it will be expected to have good efficacy and to last a few years at least. We need trials to determine how good any vaccine is.

“This all has consequences for antibody tests. Firstly we need to be really sure that they are extremely good at detecting the SARS-Cov-2 virus antibodies. They could be good at detecting that and other similar cold viruses in which case they would be useless. They need to not just detect SARS-Cov-2 well but NOT detect other viruses that are not causing Covid 19. The technical words for this are sensitivity (detecting the virus well) and specificity (not detecting other viruses or suggesting presence of antibodies when there aren’t any). Secondly, as was said by Dr Maria van Kerkhove from the WHO, we cannot be sure that the presence of antibodies, even if really well detected by a test, guarantees that someone will be immune to the virus in future. In general with viral diseases, it is possible to be re-infected, usually by a slightly different strain and we have not had this disease around long enough to be sure that re-infection does not occur. There have been reports of re-infection, but this could be the result of inaccurate tests either in the assumed first infection or the re-infection.

“Being cautious is absolutely reasonable, but absolute pessimism that no immunity is conferred, either by having been infected once or by having received a vaccine, is not warranted either.

“We will have to live with the uncertainty for some time yet.”

Prof Paul Hunter, Professor in Medicine, UEA, said:

“If you recover from COVID-19, you recover because your immune system has done its job and you have developed immunity. We do not know how long this immunity will last – for SARS it was about two years, at least based on antibody levels. But it can vary between people, and not everyone’s antibodies last for a long time.

“It is possible that IgG antibodies (one class of antibodies), which an antibody test would probably measure, will indicate a past infection but may not protect against future COVID-19 infections as another class antibody (IgA) are more important in viral respiratory infections. However, immune responses to viral infections can be complex involving both the production of different antibody classes and cellular immunity. How important antibodies are in relation to cell mediated immunity for COVID-19 is not yet known. I suspect but do not know for certain that antibodies will be found to play an important role. Even if blood testing for antibodies are not a good general marker of immunity, antibody tests will probably still be useful. A positive test this year will show that someone has had a relatively recent infection and so will likely be immune for a time at least.

“Relationships between antibody responses and vaccine effectiveness tend to be good for some infections but not others. For example, with influenza there is a correlation between Hemagglutination-inhibition antibodies and protection. Hemagglutinin is the part of the influenza virus that binds to human cells. The equivalent in the COVID-19 virus is the spike protein or S antigen and it is likely that antibodies directed against this antigen will prevent cell entry. S antigen is a likely target for vaccine development. So personally I suspect that properly validated antibody tests against the S antigen will give a reasonably good indication of immunity at least at the time that the test was performed. But antibody tests will not be 100% reliable either way or necessarily indicate immunity even six months later.

“The question raised here in the comments from the WHO is: can an antibody test predict immunity? I strongly suspect it will do during the course of this year and into next year – after that it will be more difficult because anti COVID-19 antibodies are likely to reduce with time. But that does not necessarily mean that people may then lose their immunity. Sometimes protection to future infection lasts longer than detectable antibodies do. For many viral infections, if you get a repeat infection relatively early then the clinical course is less severe.

“Usually, in other diseases, a severe infection elicits a stronger immune response than a vaccine does – sometimes vaccines need to be repeated every year or two such as influenza vaccines. We don’t know what will happen with a COVID-19 vaccine but I am confident we will have a good COVID-19 vaccine sooner or later. The big uncertainty is around how often it will need to be given. Will this just be a once in a life-time immunization or will the vaccine need to be given every one or two years? I suspect the latter.”

Dr Rupert Beale, Group Leader, Cell Biology of Infection Laboratory, Francis Crick Institute, said:

“At present we do not know how well the presence of antibodies predicts whether someone will be immune to infection. It’s very important that someone offered a test understands this, as they must still take precautions to avoid infection even if they are shown to have some antibodies. It may well be possible to predict immunity more accurately when we have better tests and when we understand this virus more. It does not mean we won’t be able to develop a vaccine.”

Prof Gordon Dougan, Department of Medicine, University of Cambridge, said:

“People are being tested in some countries e.g. China for antibodies to SARS2-Cov19 in their blood or other clinical samples using antibody tests. Provided the test is specific and sensitive (unfortunately many being sold are not!), it tells us if our immune system has seen (detected) the virus or that we have been exposed to it or infected. However, the presence of antibody in the blood to the virus itself does not mean people are protected in the case of COVID-19. Antibody for some diseases does not correlate with protection after infection or even after vaccination.

“In addition to simply testing for antibody, we can test for antibodies that kill or neutralise the virus but those tests are not so easy to run and will not be offered widely. Even a neutralising antibody does not absolutely mean you are protected. There is still much to learn in this regard with COVID-19.

“For vaccine development, developers will try to use an immunological correlate of protection to license a COVID-19 vaccine. This could be a neutralising (blocking) antibody titre that prevents viral growth or even kills the virus. The problem is that for many vaccines neutralising titres do not completely correlate with protection e.g. rotavirus vaccines. Some viruses need intracellular as well as extracellular neutralisation complicating the situation. Not so simple I am afraid. We will likely know in the coming months where all of this ends up.

“I have written more about COVID-19 vaccine development in a blog, which you can see here: https://gordondougan.blog/.”

Prof Babak Javid, Principal Investigator, Tsinghua University School of Medicine, Beijing, and Consultant in infectious diseases at Cambridge University Hospitals, said:

“The WHO is being precise in its language, but for most viral infections, and including coronaviruses, antibody responses (and particularly neutralizing antibody responses) correlate strongly with protection. What isn’t known now is what magnitude of response is protective. The phase I trials of the vaccine candidates will determine whether neutralizing antibody responses are elicited with the vaccine and to what extent, and phase II (efficacy) trials will determine whether the vaccine is protective, and if so, does this correlate with neutralizing (and total) antibody responses or other forms of immunity. It’s possible that other immune responses, such as from T cells, also contribute to protection against SARS-CoV2. However, the human re-challenge studies with common cold coronaviruses performed in the UK in 1970s and 1980s suggest that antibody responses are, at the very least, highly correlated with protection.”

Dr Simon Clarke, Associate Professor in Cellular Microbiology, University of Reading, said:

“I agree with Dr Maria van Kerkhove from the WHO. The overconfident assertion by some that having antibodies to the coronavirus causing CoViD-19 gives immunity, has been made without any evidence and by some people who should know better. It is reasonable to assume that, as someone recovers from the infection, the immunity they generate will persist for some time, maybe weeks, months or years, but nobody actually knows. We simply don’t yet know what would make someone immune to CoViD-19 or whether long-term immunity is even possible.”

Prof Richard Tedder, Visiting Professor in Medical Virology, Imperial College London, said:

“When someone has been infected with the Covid-19 virus, there is an immunological response to the virus which includes the production of antibody. It is correct to say that we are not certain that the presence of this recovery antibody will necessarily protect the person against re-infection. There are a number of reasons for this uncertainty.

“Firstly it has proved very difficult to produce an antibody test which is both sensitive enough to detect antibody in all recovered patients and of sufficient accuracy not to generate false-positive results. Globally there has been an immense amount of work in developing a range of antibody tests some of which are excellent and some of which are not. In addition, the level of the antibody in the recovered person varies quite widely with a number of studies showing that mild infections are associated with a lower antibody response in recovery.

“Secondly, there are reports of re-infection, but whether these instances are re-infections as such or the persistence of shedding of the virus at low level in the recovery period remains to be defined.

“These observations quite understandably raise the question of whether the recovered individual whose blood contains detectable and virus specific antibody can be re-infected or is immune to further infection.

“Finally, as with a number of virus infections, the antibodies present in the blood of somebody who has recovered will be directed at various component parts of the virus. Considerable effort is directed at determining which part of the virus generates antibody which could protect against virus infectivity and the development of antibody tests for detecting this “virus-neutralising” antibody.”

Dr Tom Wingfield, Senior Clinical Lecturer and Honorary Consultant Physician, Liverpool School of Tropical Medicine, said:

“Antibody tests measure the amount of antibody produced against a specific infection. People who were infected with other coronaviruses like SARS and MERS produced antibodies against these illnesses for up to 3 years following infection. However, it is not clear whether the presence of these antibodies means that a person is immune to a repeat infection.

“In the case of SARS-CoV-2, the coronavirus that causes Covid-19, we just don’t know what the antibody response will be. Even when an antibody test is developed for SARS-CoV-2, we don’t know how long SARS-CoV-2 antibodies will last following infection, and if it means a person is immune to further SARS-CoV-2 infection.

“There are multiple studies ongoing here in Liverpool (https://www.lstmed.ac.uk/covid-19) and across the UK, which are looking to answer these questions.”

Prof Martin Hibberd, Professor of Emerging Infectious Disease, London School of Hygiene and Tropical Medicine, said:

“These comments raise some questions about what the antibody tests are actually measuring. While they may not be directly measuring protective antibodies, we can assume that they are reflective of the general immune response – that may contain these protective antibodies. At the moment, we have very limited data on how well protected those individuals who have recovered from SARS-CoV-2 are from subsequent infections. However, there is some anecdotal evidence that serum from recovered individuals may be beneficial to those with COVID-19, which gives us hope that protective antibodies are made during the infection. Clinical trials are urgently needed to confirm this.

“Experience from infections by other coronavirus also give us hope that there is some protective immunity, although for how long is still under scientific debate as there is insufficient data to be conclusive.

“For SARS-CoV-2, following widespread testing for these antibodies, we will start to build a picture of how often (if ever) people with reported antibodies succumb to a second infection, giving us the data we need to be conclusive about how well and for how long the immune response is protective. Until then we need be cautious in their interpretation, but in my opinion we can be fairly confident of at least short term protection.

“There is also the problem of the accuracy of the tests. While carefully conducted laboratory based (ELISA) tests on blood samples can give accurate information, we need to be careful interpreting rapid point-of-care tests that may not be as accurate and may give false positive and negative results that would confuse their interpretation further.”

Prof Chris Dye, Oxford Martin School, University of Oxford, said:

“The WHO are right to highlight that any antibody test, if we get one, won’t be able to definitely say whether someone is immune to the infection, because we just don’t know enough yet about how immunity works with COVID-19.

“An antibody test (blood test) will only detect infections after the immune system has produced antibodies that recognise the virus. This happens approximately 7–10 days after symptoms develop. There is substantial work ongoing to develop accurate antibody tests for coronavirus infection. To be useful in reporting past infection and immunity in individuals, these new tests must fulfil three criteria.

“First, if some people do not produce detectable amounts of the antibody used in the test after infection, or if antibody levels wane with time, the test will be insufficiently sensitive, missing too many infections (false-negative results) to be useful. Second, the test must be specific enough to give high confidence that a positive test result is correct (not a false positive). This is especially true if past infection is uncommon among those who are tested, as in the general population. Infection is likely to be more common among people at higher risk, such as health workers.

“Third, before an antibody test can be used to indicate that someone is immune to further infection, the level of protection must be demonstrated in experimental trials. While there is a clear link between the presence of the antibody and protective immunity for many common viral infections, this has not yet been confirmed for the new coronavirus. It is possible that people are temporarily protected against reinfection but the protection wanes with time, or that protection operates against current but not future strains of the new coronavirus.

“For all these reasons, antibody tests are likely to be most useful for studying past infection in whole populations to assess the scale and spread of the COVID-19 outbreak.

“For more information on testing see here: https://coronavirusexplained.ukri.org/en/article/vdt0006/”

Prof Babak Javid, Principle Investigator, Tsinghua University School of Medicine, Beijing and Consultant in infectious diseases at Cambridge University Hospitals, said:

“Strictly speaking, the WHO is correct. Serological tests, which measure antibody responses to SARS-CoV2, do not measure whether those antibodies are able to protect individuals from re-infection. That would require measurement of ‘neutralizing antibody responses’, which are not feasible for commercial testing of large numbers of people. Nor do we know what level of neutralizing antibody responses, even if we were to measure them, would be sufficient for protection, and for how long. Furthermore, any test, to be useful, would need to be highly specific, i.e. the test would need to measure antibodies to SARS-CoV2 and not measure antibodies to common cold coronaviruses. Otherwise, there is the risk of over-estimating the numbers of people who have had Covid-19.

“However, we know from common cold coronaviruses that total antibody responses do approximate (not perfectly) with neutralizing antibody responses. Furthermore, immunity to common cold coronavirus has been experimentally verified with human re-challenge studies (in 1970s and 1980s), and again, correlates with magnitude of the antibody response. So there is a reasonable scientific rationale that a good serological test may be useful. What is urgently needed is first of all identifying a high-quality test that is very specific. Once that is available, longitudinal studies, i.e. measuring antibody responses from the same individual over time will give us an idea how long antibody responses last. Correlating with neutralizing antibody responses in a research lab, as well as ‘relative protection’ by different levels of antibody (which should be feasible in an ongoing pandemic) will strengthen the case that antibody tests can guide probable immunity, and for how long.”

Prof Gary McLean, Professor in Molecular Immunology, London Metropolitan University, said:

Are the WHO saying antibody tests don’t work very well at all?

“They are saying that the antibody test measures evidence of past infection that the immune response has been triggered by the virus – it’s a marker of having been infected.

Or are they saying antibody tests could still be useful for some things but that it’s the level of immunity that infection leads to that is still unknown?

“Yes the test does not prove the immunity is protective – in fact we still don’t know what kind of immunity is needed to stop SARS-CoV2 – it may be antibodies and T cells.

What do we know from evidence so far on COVID-19 about how long immunity lasts after infection?

“Studies have not gone on for much duration yet. We know the antibodies last for 40-50 days, or at least are still there at convalescence. It is suspected that antibody protection could last for over one year but this is presumptive.

Is there anything we can know from SARS or from other coronaviruses about likely immunity after infection?

“Yes, SARS is the closest and likely to yield the most information. The best guess on SARS-CoV2 immunity would come from similar viruses. We have heard that antibodies protecting against SARS can last for many years and some SARS antibodies do cross react with the current strain.”

The relevant question asked yesterday at the WHO’s press conference and the answers given can be watched at this link; skip to 28:57:

https://www.who.int/emergencies/diseases/novel-coronavirus-2019

All our previous output on this subject can be seen at this weblink:

www.sciencemediacentre.org/tag/covid-19

Declared interests

None received.