June 24, 2020

expert reaction to letter and investigation about a roll-out of antibody testing for SARS-CoV-2

A letter and investigation, published by the BMJ, look at the roll-out of antibody testing for SARS-CoV-2.

Prof Sanjeev Krishna, Professor of Molecular Parasitology and Medicine, St George’s, University of London, said:

“All tests have to be used intelligently.  Whether testing for the virus or antibodies, results can give false positives and false negatives – but no one would deny their value when used effectively.

“For antibody testing, without question the tests have to be examined rigorously so that their limitations and strengths can be understood quickly.  High quality tests can give results for an ‘infection passport’ – identifying those who have been exposed to the virus.  We will then rely on these test results to study the whole idea of an ‘immunity passport,’ so we can identify those who may be immune.

“If we don’t use these tools to study antibodies, then we won’t be able to understand if they provide immunity or not, which is something we need to find out.  In the end, all testing has to be understood in the context of its use, whether for diagnosis of infection, epidemiological surveys for past infections or for judging immunity to infection.  Antibody testing is here to stay, providing it is applied appropriately.”

Prof Eleanor Riley, Professor of Immunology and Infectious Disease, University of Edinburgh, said:

“Carefully designed, properly resourced, population-based studies of immune responses to SARS-CoV-2 (the virus that causes COVID-19) are urgently needed to help us understand how far the virus has spread, how far it is continuing to spread, and whether we are likely to see a second wave this coming winter.  Measuring the population prevalence of antibodies to SARS-CoV-2 will, to a small degree, underestimate the true extent of the epidemic (as not everyone who has been exposed to the virus makes antibodies and those antibodies may not persist for very long in some people) but it will give us an idea, and it will allow us to monitor trends over time.  If antibody prevalence continues to increase, it tells us the virus is still spreading and how quickly, and if prevalence increases in some places but not others, this tells us where the virus is continuing to spread.  Ongoing monitoring (for virus as well as antibodies) may also allow us to see an uptick in transmission before we start to see cases arriving at hospital if there is a second wave later in the year.

“One situation in which individual testing may be justified clinically is for patients who are severely ill in hospital with suspected COVID-19 but who repeatedly test negative for the virus: we know that severe disease tends to develop a week or more after first onset of symptoms and by the time the patient is admitted to hospital the virus may well have been cleared.  The presence of anti-SARS-CoV-2 antibodies in these individuals – particularly if the concentration of antibodies is increasing over time – would be highly indicative that they did indeed have COVID-19.

“However, random testing of individuals without any clear research purpose or clinical indication does not, in my opinion, make sense.  Because the test is not 100% accurate, whatever the result, the information is essentially meaningless to the individual (although at a population level it would still be useful for monitoring the epidemic).  A negative test does not completely rule out prior infection and a positive test does not necessarily mean that you are immune to reinfection.  There is currently no validated  “immunity certificate” that anyone can rely on to inform their risk or their behaviours.  I would like to see the antibody tests that are available reserved for large scale epidemiological studies that can inform the risk for us all and help us to plan for the future rather than see them wasted on testing individuals for no obvious benefit.”

Dr Rob Shorten, Chair of the ACB Microbiology Professional Committee at the Association for Clinical Biochemistry and Laboratory Medicine, said:

“We are still learning about infection and immunity of this novel virus and the presence of antibodies is only one aspect of the immune response.  NHS and Public Health laboratories perform hundreds of thousands of various tests each day – for COVID-19 and many other conditions – and each of these results generates subsequent actions.  Interpreting these results and understanding the implications of them is key and it is not clear what the detection of antibodies to SARS CoV-2 means to an individual.

“Antibody tests are widely used in the detection and management of infectious diseases.  They can be used to establish previous infection and probable immunity, but this depends very much on the infectious agent.  Antibody tests for SARS CoV-2 have been rapidly developed and rolled out by NHS and Public Health laboratories and tens of thousands of tests are being performed daily.  However, we still do not know what the presence of antibodies means in an individual patient.  Immunity to future infection cannot be guaranteed and therefore ‘immunity passports’ should be avoided.  Furthermore, even a highly accurate test can generate significant numbers of false positives (and potentially false reassurance), especially when the numbers of true infections are low.  With these details in mind, individuals undergoing antibody tests have been asked to give written consent.  Healthcare workers are asked to agree to continue with standard infection control practices, including using PPE, even if they have antibodies.

“These new antibody tests could be very useful in our actions against COVID-19, however, at this stage we just don’t know how to interpret the results.  Resources would be best directed if these tests were performed as part of coordinated research studies.  One such study (PHE SIREN) is already underway to help us understand if previously infected healthcare workers are protected from re-infection.”

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

“Antibody tests measure the amount of certain antibodies produced against a specific infection.  People who were infected with other coronaviruses like SARS and MERS produced antibodies against these illnesses following infection, for up to three years in some cases.  However, it is not clear whether the presence of these antibodies means that a person is immune to a repeat infection.  Antibody tests for SARS-CoV-2, the novel coronavirus that causes Covid-19, have been developed but their accuracy is still being evaluated.

“I share the concerns raised by the authors of the letter to the BMJ that antibody testing is being rolled out before we fully understand the immune response to SARS-CoV-2, what the results of these tests may mean, and what actions to take based on test results.  There remain many unknowns.  These include: how long SARS-CoV-2 antibodies will last following infection; whether having these antibodies means that a person is immune to and safe from further SARS-CoV-2 infection; and how well the tests work in vulnerable groups including BAME, older people, and those with underlying illnesses.  Another critical unknown is what advice to give someone who has a positive or negative antibody test and how the result and such advice might influence their behaviours, including social distancing, and thereby impact upon SARS-CoV-2 transmission.

“In short, although antibody testing could play an important role in understanding and controlling the Covid-19 pandemic, we don’t yet have sufficient evidence on accuracy and interpretation of antibody tests.  Before such evidence is generated, it is difficult to see how a safe, comprehensive, and scientifically sound strategy for scale-up of antibody testing in the UK could be devised.”

Prof Sheila Bird, Formerly Programme Leader, MRC Biostatistics Unit, University of Cambridge, said:

(Please note Sheila is mentioned in the BMJ press release as she is quoted in the investigation piece, but she is not an author of the letter)

“Experimental design can help to address efficiently the legitimate concerns raised in today’s BMJ about rapid roll-out of SARS-CoV-2 antibody testing.

“In evidence recently before the House of Lords Inquiry into Science in COVID-19, I recalled the British Doctors Study of 1951 by Doll and Hill, former Director of MRC Biostatistics Unit.  They had the good sense to request that doctors should complete their study’s well-designed self-questionnaire, about smoking especially, and give permission for linkage to death records.

“I suggested that, in the era of COVID-19, healthcare workers (male or female; working age or retired; different ethnicities) have professional, occupational and personal interests in discovering how well SARS-CoV-2 antibody tests perform and about persistence of antibodies as time since symptom-onset elapses.  As healthcare professionals, they recognise the importance of linking a well-designed self-questionnaire (about symptomatology, swab-test, and progression) with an initial biological sample (at onset-date + d1 days) and with at least one subsequent blood sample (at onset-date + d1 + R1 days).

“The time-interval R1 to the second blood-sample should be randomly chosen; but also purposefully to yield information both within-person and between individuals about antibody-persistence.  Ideally, the blood-volume from each participant on each occasion would be sufficient for analysis by two or three differently-targeted antibody tests.  Good experimental design is key to learning unbiasedly and efficiently.”

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

“Antibody testing is an important component of the public health response to the COVID-19 outbreak.  These antibody tests, given the data that we have seen, seem to be working as well as the equivalent tests for other diseases, although this information will rapidly increase as their large-scale use begins.  If used successfully, the data generated will be important surveillance information for understanding the effectiveness of control measures put in place.

“In my mind, the controversy is related to their use for purposes outside of surveillance and potentially for “immunity passports”.  Sufficient numbers of people have not yet been serologically tested and monitored for long enough to interpret if the antibodies detected offer protection against re-infection, or indeed, how long they may last.  Based on our knowledge of other diseases, we would suspect that at least short-term protection is provided, but it is difficult to imagine how this information could be used productively with current health infrastructure.  We know that in some other situations, people are asked to provide evidence of a vaccination history – to enable their own or group protection; but with vaccines we have a good understanding of their effectiveness and the longevity of the protection provided.  To use potentially short lived and currently unknown levels of protection would require a whole new approach that would not only be technologically but also conceptually challenging (as WHO have warned).  In addition, there seem to be few situations where this information on current antibodies would be useful (because of the uncertainty).

“However, as more information is gained about the importance of these antibodies, we should be thinking carefully about how as a society we could use this information, because this will be similar to what will happen if we are able to develop a vaccine.  Will we require some groups of people to be vaccinated (perhaps nursing home workers)?  And what evidence will we need to ensure that their antibody status (and thus their protection from infection) is up to date?”

Letter: ‘Rapid roll out of SARS-CoV-2 antibody testing—a concern’ by Monique Andersson et al. was published in the BMJ at 23:30 UK time on Wednesday 24 June 2020.

DOI: 10.1136/bmj.m2420

Feature: ‘Why covid-19 antibody tests are not the game changer the UK

government claims’ by Stephen Armstrong was published in the BMJ at 23:30 UK time on Wednesday 24 June 2020.

DOI: 10.1136/bmj.m2469

Feature: ‘Covid-19 antibody tests: a briefing’ by Chris Baraniuk was published in the BMJ at 23:30 UK time on Wednesday 24 June 2020.

DOI: 10.1136/bmj.m2284

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

www.sciencemediacentre.org/tag/covid-19

Declared interests

Prof Eleanor Riley: “No conflicts to declare.”

Dr Tom Wingfield: “I am a part-time Consultant for the World Health Organisation.”

Prof Sheila Bird: “As member of RSS COVID-19 Taskforce, SMB critiqued PHE’s evaluation of the Roche and Abbott . The RSS COVID-19 Taskforce has also liaised with the Medicines and Healthcare products Regulatory Authority on evaluation criteria for SARS-CoV-2 antibody tests.”

Prof Martin Hibberd: “No conflicts of interest to declare.”

None others received.