Whatever happened to antibody testing?

Whatever happened to antibody testing?

So after much discussion in the press about the role of “antibody” testing, to determine whether an individual has been exposed to SARS-CoV-2 virus and may, by implication, have some form of immunity, it seems to have gone quiet. Attention is focused once more on “antigen” testing. Unfortunately, there is less debate about the value of testing for the virus itself and more about just how many tests have been carried out, as the press looks for yet more means by which to harry the Government.

While the rationale for antibody testing, or “Pillar 3” as the Government designated it, was on the surface fairly clear, it was underpinned by many simple and, perhaps understandably, basic assumptions: infected individuals would naturally develop an adaptive immune response to the virus, producing first IgM and then IgG antibodies, whose role would be to “neutralise” the virus. These could be detected by well-developed and relatively cheap technologies. Suddenly there was a surfeit of devices and tests, with technologies ranging from cheap lateral flow devices (akin to home pregnancy tests), based on a finger-prick volume of blood, to sophisticated high-throughput technologies for lab-based tests using blood drawn by a phlebotomist. Then the arguments began about sensitivity and specificity. When infected patients demonstrated no evidence of antibodies, this was ascribed to poor sensitivity of the technology. The FDA in the US and PHE in the UK carried out careful evaluations of the technologies and came up with short-lists of “approved” technologies, setting a high bar for both sensitivity and specificity, arguing that it was critically important to demonstrate correctly who had “immunity” and who had not. And then “T-cells” raised their heads, and the issue of immunity to SARS-CoV-2 was once again thrown wide open.

In the most basic language, the so-called “adaptive” or “acquired” immune system, the system that develops to protect us against specific pathogens, is composed of two elements: a humoral response, based on antibodies and other proteins in the blood, and a cellular response, based primarily on T-lymphocytes (T-cells). A key moment in our understanding of the natural history of this infection came when evidence was published showing that a high percentage of patients who had recovered from COVID-19 had T-cells recognising the SARS-CoV-2 virus. More importantly however, patients who had recovered from the SARS outbreak in 2003 still had T-cells recognising the original SARS virus 17 years later, but they also recognised the new SARS-CoV-2 virus as well. And then the final twist: individuals who had never been exposed to SARS, or more recently SARS-CoV-2, had T-cells reactive with both viruses! So it appears that a proportion of the population already have (T-cell-based) immunity to SARS-CoV-2. Several studies in different parts of the world now indicate that 20-50% of the population may have such immunity. Furthermore, this cellular immunity is not directly associated with antibody levels, suggesting an “antibody test” has less utility than previously thought.

So why not test everyone for T-cells reacting with SARS-CoV-2? Unfortunately, the technology for this is complex and significantly more expensive and time-consuming than antibody tests. Nevertheless, the importance of these findings is such that the UK government and others have seen fit to award grants for the development of a rapid and cost-effective T-cell test. It may be some time coming.

As we construct this increasingly complex and detailed picture of our biological relationship with the SARS-CoV-2 virus, questions arise about how we dealt with the pandemic initially and how we are dealing with it now. To me it seems clear that a very significant proportion of the population is at no risk whatsoever from this virus. The current obsession with coronavirus “antigen” testing is creating unnecessary anxiety and socioeconomic chaos. Recent evidence suggests that the test is so sensitive that it may vastly over-estimate the number of potentially infective individuals. On top of this we now know that a very large number of people are already protected by T-cell immunity.

I’m a strong advocate of more research dedicated to determining what makes individuals susceptible to the condition COVID-19, and less to screening large populations with tests of questionable utility. It is clear to all that certain populations within our communities are at increased risk of severe illness and death due to COVID-19, perhaps for genetic reasons. Exciting work from Tel Aviv University, just published, has demonstrated that carriers of two specific mutations in the SERPINA1 gene, which encodes the protein alpha1-antitrypsin, are at high risk from COVID-19. The correlation between severity and risk of death, and the presence of the mutations appears to be global, occurring in 67 countries on all continents. This is the way forward, understanding the biology of coronaviruses, and focusing on those at risk.

28/9/20