In a talk hosted by the UCL Medical Society, Professor Benny Chain reports on the frontiers of immunological research related to the ongoing pandemic.
Writer: Pauline Münchenberg
Editor: Eleanor Mackle
Artist: Sophie Maho Chan
The recent emergence of SARS-CoV-2 has caused a global public health crisis. The RNA virus that causes COVID-19 is highly transmissible, so safe and effective pharmaceutical interventions are urgently required. In order to develop these, researchers need to understand our immune response to the virus.
Benny Chain, Professor of Immunology at the UCL Division of Infection and Immunity, is a leading expert in this field. His work focuses on computational immunology, with an aim to understand the fundamental rules that govern our immune responses to pathogens. In a recent Zoom lecture, organised by the UCL Medical Society, Professor Chain discussed his work in relation to SARS-CoV-2.
To find an effective treatment for COVID-19, it is crucial to understand how the virus enters host cells, makes copies of itself and causes symptoms. In his talk, Professor Chain emphasised that the body mobilises all of its immune resources, from both the innate and adaptive systems, in the fight against SARS-CoV-2.
The innate immune system is the first line of defence, which works to prevent harmful pathogens spreading throughout the body. During the early stage of infection with SARS-CoV-2, interferons (IFNs) are released by infected cells and alert the immune system to the presence of a viral intruder. Therefore, scientists think that the magnitude and timing of the IFN response are key determinants of disease progression and of the levels of virus in the body.
Professor Chain pointed to studies that show that COVID-19 is more likely to be life-threatening in people who have inborn malfunctions in type I IFN immunity. For example, researchers found that loss of function mutations in genes involved in type I and type III IFN responses were enriched in patient populations with severe COVID-19. Additionally, high levels of neutralising autoantibodies against type I IFN have been observed in about 10% of patients with severe COVID-19, which impair innate antiviral responses. Interestingly, these findings have been mainly found in men.
T cells are a major component of the adaptive immune system, and play a crucial role in clearing the virus out of the body by recognising and killing virus-infected cells. Professor Chain explained that the T cell response to SARS-CoV-2 is highly variable between individuals. If a patient shows serious symptoms, T cell activity is likely to be stronger than in asymptomatic or mild cases. A very rapid reaction takes place in severe COVID-19 cases with a robust T cell response occurring within 1-2 weeks of infection.
Finally, it is important to study antibody responses to SARS-CoV-2, as antibodies neutralise viruses in extracellular fluids to promote their elimination. There is increasing evidence that higher levels of total anti-SARS-CoV-2 antibodies are associated with a greater disease burden and more severe symptoms.
Antibodies are also important because their presence in the blood can be used to determine whether an individual has been infected with SARS-CoV-2 in the past. However, different antibodies have different kinetics. For example, antibodies against the spike (S) protein, a structural protein that sits on the surface of the virus, have a faster clearance rate than other anti-SARS-CoV-2 antibodies. For this reason, antibody tests need to be especially sensitive and accurate, to avoid false-negative test results, which are still a big problem.
The rapid production of vaccines has been a triumph for science. So far, all ten of the vaccines that are currently in phase 3 clinical trials target the S protein, as it plays a key role in facilitating viral entry into cells and determining host range. The first vaccines to achieve licensure in December were RNA vaccines, which use relatively new technology. Unfortunately, RNA vaccines are unsuitable for developing countries, because RNA is very unstable and needs to be stored at around ‒80°C. Professor Chain emphasised that many open questions regarding these vaccines remain. For how long will they grant protection? What is their safety profile? Will they block transmission or only prevent severe disease? Another theoretical concern that needs to be considered is antibody-dependent enhancement, where antibodies act in a way that is beneficial to the virus. And, of course, population-wide anxiety about vaccines needs to be addressed with careful, rigorous information campaigns.
Overall, Professor Chain’s talk highlighted the importance of each component of human immunity in intercepting SARS-CoV-2 and safeguarding against disease. Whilst detailed knowledge of the S protein has been exploited to create promising vaccines, there are still public health, medical and theoretical concerns that remain. One promising approach to developing a treatment for COVID-19 is to identify the T cell receptors involved in a SARS-CoV-2 infection, and to test whether stimulating T cells could be beneficial. As the death toll continues to mount, the pursuit of treatments and rollout of vaccines becomes ever more pressing.
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