November 2, 2020

expert reaction to preprint looking at cellular responses six months after SARS-CoV-2 infection in a group of non-hospitalised individuals

A preprint, an un-published non-peer reviewed paper, looks at cellular responses six months after SARS-CoV-2 infection in a group of non-hospitalised individuals.

This Roundup accompanied an SMC Briefing.

Dr Alison Whitelegg on behalf of the Association for Clinical Biochemistry’s Immunology Professional Committee, said:

“The study was performed by a multi-centre group of T cell experts and T cells responses to three different antigens of SARS-Cov-19 are detected in all 100 patients at 6 months.  The authors give information on the diversity (‘flavour’) of T cell responses and what this means for generation of immune memory.  The limitation is that the patients are in largely in low risk ‘COVID age’ group – mean age 41 and 77% female.

“This study shows that 95% of patients responded to the T cell immunospot assay and the other 5% demonstrated T cell responses in a different detection system (expressed different cytokines), suggesting that cellular immunity has persisted to six months in this group of people.

“As we hoped, it seems that T cells can be detected in assays that stimulate them to produce their proteins whereas antibody assays depend on detecting existing proteins that are secreted by B cells into the circulation.

“The data show that the responses are higher in people with moderate disease (compared to asymptomatic infection) but the authors comment that ‘quality’ of the T cell response may well be more important that ‘quantity’.

“It is too early to say that this study means people are protected long term after infection as we don’t yet know, but this kind of study is important and further longitudinal studies will be equally important.  These studies are also important as they demonstate antibody assays alone may not be sufficient to measure an individal’s immunity to SARSCovid 19.

“This study is promising for vaccine development and gives a feasible justification for optimism about re-infection being rare.”

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

“This is a study of a large cohort of previously healthy individuals who experienced asymptomatic or mild-to-moderate COVID-19 during the first wave in March/April 2020.  All subjects had detectable T cell mediated immune responses 6 months after their acute infection.  These T cells were predominantly of the “helper cell” type (that assist other immune cells to make antibodies or kill virus-infected cells) and they had the characteristics of cells that proliferate and  self-renew and thus promote long term memory.  The responses were comparable in magnitude to those to other acute respiratory viruses that tend to induce immunity to reinfection.  The responses were also higher in those who developed symptomatic infection rather than asymptomatic infection, which is consistent with the inflammation that causes the symptoms also driving a stronger immune response.  This is all very good news and bodes well for the long term, in terms of both vaccine development and the possibility of long term protection against reinfection, although it is important to stress that we don’t yet know whether the people in this study are protected from reinfection.

“It is, therefore, not necessarily correct to say that this is evidence of T cell “immunity”.  Immunity is a functional term that implies resistance to infection, and this has not been directly shown in this study.  Determining whether these T cell responses are protective against reinfection would require either an experimental infection study (such studies are under active discussion) or a very large, long term study to assess the frequency of reinfection in people whose T cell responses have been measured.  Given the apparently very low incidence of reinfections at the current time, such a study would not currently be a high priority.  But if our worst fears are realised, and reinfection turns out to be a significant problem, then such studies would help to identify “correlates of protection” – immunological markers of protection versus susceptibility to reinfection.

“One limitation of the study is that the T cell responses were measured only once – 6 months after infection.  Without an earlier measurement – ideally 3-4 weeks after acute infection – we can’t be sure what the peak of the T cell response might be or how quickly it is falling.  However, studies conducted elsewhere at earlier time points post-infection are consistent with the data presented here.”

Prof Brendan Wren, Professor of Microbial Pathogenesis, London School of Hygiene & Tropical Medicine, said:

“This is a thorough study monitoring the cellular (T cell) immune response to SARS-CoV-2 from 100 infected health care workers over a 6 month period and comparing this to 2000 uninfected health care workers.  A significant and prolonged cellular immune response is observed in both symptomatic and asymptomatic infected individuals.  If cellular immunity is a good correlate of protection to re-infection, this provides encouraging data for long-term immunity to SARS-Cov-2 and the development of effective vaccines – however this study cannot tell us whether people are protected from re-infection, so we still need more data first.  The study also demonstrates the value of co-ordinated consortium research.”

Prof Paul Morgan, Director of the Systems Immunity Research Institute, Cardiff University, said:

“This manuscript, a collaboration led by Paul Moss in Birmingham, describes studies of T cell immunity in a well-characterised convalescent cohort comprising 100 relatively young individuals with proven Covid-19 infection; all had relatively mild disease and were not admitted to hospital.  Respiratory symptoms were reported in around half of the cohort, the rest were essentially asymptomatic.

“Samples were taken 6 months after infection and T cell responses to SARS-CoV2 proteins assessed using a raft of laboratory tests of T cell specificity and function.  Strong T cell responses to the viral proteins were found in all individuals with stronger responses in those who had reported respiratory symptoms – the more severe in this mild disease cohort. 

The “helper” CD4 T cell response was particularly strong, and these cells were producing interleukin-2, a potent anti-viral cytokine.  Overall T cell response correlated with the peak antibody response to the same viral proteins, demonstrating that these two arms of the immune system were both engaged in the response.

“This is an important manuscript, building on a number of published studies that demonstrate T cell responses to SARS-CoV2 and showing that T cell responses occur even following mild or asymptomatic infections and persist for at least 6 months.  These findings increase confidence that SARS-CoV2 infection can induce robust T cell immunity, at least in this relatively young, mild/asymptomatic disease cohort, and that this immunity persists even when antibody levels are falling.  The authors make a strong case for measuring T cell immunity more widely and for including this in assessments of response to vaccines as these become available.

“Overall, the work provides a welcome dose of optimism that SARS-CoV2 infection (and immunisation?) can induce a robust and sustained protective immune response, although this does not yet prove immunity to further infections which will require longer term surveillance and larger cohorts.”

Prof Arne Akbar, President of the British Society for Immunology, said:

“This new study is a step forward in our understanding of immunity against SARS-CoV-2, one of the most critical questions for long-term control of the COVID-19 pandemic.  By analysing the contribution of T cells to immunity after infection, we are moving closer to discerning a clearer picture of the complex question of individual protection after SARS-CoV-2 infection.

“This is one of largest cohorts studied in the world for cellular immunity against SARS-CoV-2 and, as such, has important implications for the development of an effective COVID-19 vaccine.  One of the main conclusions is that T cells that are directed against the virus are maintained for at least six months after the infection.  Therefore, while the levels of antibodies against SARS-Cov-2 may wane in patients who have recovered from the infection, as shown in other studies, T cell immunity is maintained during this same period.  Consequently, loss of antibody alone does not predict loss of specific immunity to the virus.

“This pre-print study looks into COVID-19 immunity six months after asymptomatic and mild/moderate infection and does not investigate patients with severe disease.  It will be important to investigate the durability of this protection by T cells beyond the six month mark, as well as how it may be different in patients with severe COVID-19.

“Rapid learning about immunity to the virus is crucial to minimise negative public health impact and the national approach taken by the UK Coronavirus Immunology Consortium is helping us to increase our knowledge about different aspects of COVID-19 immunology.  While more research is undertaken to unravel the complexity of COVID-19 immunity, we must continue to take measures to slow the spread of the disease and protect public health.”

Prof Charles Bangham FRS FMedSci, Chair of Immunology, Imperial College London, said:

“This excellent study provides strong evidence that T-cell immunity to SARS-CoV-2 may last longer than antibody immunity.  The data are consistent with previous observations on T-cell immunity to SARS – with SARS some patients had T-cells more than 10 years after infection, though we don’t yet know whether this will be the case with COVID-19.  The helper (CD4+) T cells that the authors observed are critically important in helping the immune response to re-infection – both the antibodies and cytotoxic T cells are helped by the CD4+ T cells.

“These results provide reassurance that, although the titre of antibody to SARS-CoV-2 can fall below detectable levels within a few months of infection, a degree of immunity to the virus may be maintained.  However, the critical question remains: do these persistent T cells provide efficient protection against re-infection?  It will also be important to follow the antibody and T cell immunity in people who develop the syndrome of Long Covid – the persistent and sometimes debilitating condition that follows acute SARS-CoV-2 infection in a still uncertain proportion of people.  Finally, the data in this paper reinforce the need for care in interpreting the results of serological (antibody) tests: it is still unclear how well either the antibody titre or the T cell frequency correlate with actual protection against reinfection.”

Preprint (not a paper): ‘Robust SARS-CoV-2-specific T-cell immunity is maintained at 6 months following primary infection’ by Zuo J et al was under embargo until 11.30am UK time on Monday 2 November 2020.  This work is not peer-reviewed.

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

www.sciencemediacentre.org/tag/covid-19

Declared interests

Prof Eleanor Riley: “Eleanor Riley is a member of the UKRI Covid-19 taskforce that approved funding for the CIC consortium and of the British Society for Immunology that is providing administrative support for the consortium.  She had no role in the design, execution, analysis or reporting of this study.”

Prof Arne Akbar: “I receive funding form the Medical Research Council, The Leo Skin Foundation (Denmark), The British Skin Foundation and Dermatrust.”

None others received.