On Wednesday 27 May, our Connecting on coronavirus webinar was presented by former BSI President Professor Peter Openshaw and Dr Ryan Thwaites on the topic of 'Controversy in immunity to COVID-19: do we want an immune response or not?'. If you missed the live webinar, you can catch up and watch again here.
Professor Peter Openshaw, Professor of Experimental Medicine at Imperial College London, and Dr Ryan Thwaites, Research Associate at Imperial College London, discussed initial findings from the ISARIC 4C consortium of doctors and scientists committed to answering urgent questions about COVID-19. They examined current research and their own early results from almost 44,000 recruited patients, looking at which characteristics predispose individuals to suffer from severe COVID-19 disease.
We had over 900 live attendees, showing the extensive enthusiasm and interest from the community. Due to time constraints, there were a substantial number of questions from the audience that went unanswered. Here we talk more with Dr Ryan Thwaites for further thoughts and comments on your questions around demographics, pathogenesis, immunity and vaccines for COVID-19.
Audience question: When the cold-causing coronaviruses transferred to humans in the past, are they likely to have caused a similar pandemic that was simply lost in the 'noise' of a higher baseline death rate from infectious diseases?
Ryan Thwaites: Yes, it is likely, but we don’t know very much about how coronaviruses have evolved over time. Drawing some comparisons with influenza, this new coronavirus pandemic is similar to a new influenza pandemic in which the new virus encounters a totally naïve population providing fertile ground for rapid transmission. It’s likely that when those common cold coronaviruses emerged, they will have spread rapidly but it’s unknown if they were more or less severe than SARS-CoV-2. Most severe infections of COVID-19 are predominantly in older people and historically, we’ve never had such an aged population in human history. If this virus had emerged in 16th century, it might not have been as severe because of the very different population structures.
Q: What do we currently understand about why COVID-19 seems to affect children differently, with the majority experiencing only minor symptoms, but a small number experiencing a major inflammatory response?
RT: We know very little about the immunity to COVID-19 in children but it’s a very active area of study. It’s important to stress that a very large majority of children have minor symptoms and only few hundred cases of severe disease globally. The unusual aspect with the severe responses is that they don’t necessarily seem to be during the first acute phase of infection. It might be that they have a relatively normal initial infection in the airways, which then precipitates an inflammatory immune response that leads to damage to the vasculature like Kawasaki’s disease. Very little is known about it and it’s very rare, hopefully we’ll know more in a few months.
Q: Is there any strong evidence to explain why there seems to be a disparity between male and females in terms of susceptibility and severity of disease?
RT: We don’t have any particular evidence about why but there are many different hypotheses. The only current evidence is that men are at disproportionately increased risk of severe disease after accounting for other demographic factors, such as age, BMI and diabetes. In terms of why this is, that will take some time to unstitch.
Q: What do we understand about why older people are more susceptible to COVID-19? Is there any evidence that cross-reactive antibodies could be generated from the previous exposures to the coronaviruses that can cause antibody dependent enhancement and explain why we see more severe disease the elderly population?
RT: At the moment we don’t have evidence. It’s important to clarify that older people aren’t more susceptible to infection but they may be more prone to severe disease if they catch SARS-CoV2. Antibody dependent enhancement (ADE) is an interesting hypothesis which could mediate severity and antibodies could be cross reactive. Antibody tests for SARS-CoV-2 look for antibodies against the spike protein which is similar in other coronaviruses but sufficiently different that the antibodies used to measure historical infection are distinguishable. There could be other antibody types that cross react and ADE could explain increased severity in the elderly population. There are also many other things that could explain this, it’s one of many hypotheses that needs testing.
Q: Is the higher antibody response in more severe cases a cause or effect?
RT: It’s likely to be an effect. During severe disease there are a few things that can elevate antibody responses. Firstly, the viral load might be higher in severe cases (but this may not be true in all respiratory infections); this would mean there’s more antigen to activate B and T cells. Secondly, the virus might take longer to clear which also leads to more B and T cell help. Finally, if severe disease leads to large inflammatory response the cytokine milieu might favour larger antibody response.
Q: Do we have any information about the influence of the respiratory microbiota on the development of disease severity?
RT: At the moment, studies of airway microbiome in COVID-19 are either preliminary or incompletely published and suggest that there isn’t a very strong microbial coinfection during severe disease. More intricate studies of the microbiota during early and late severe disease are ongoing and are likely to play some part in disease severity. Whether it’ll be a strong component as in other infections, only time will tell.
Q: What do you think the implications are for patients who have disorders such as common variable immunodeficiencies which mean they don't make antibodies?
RT: As far as I’m aware there’s only one paper that describes this. They studied two patients with X‐linked agammaglobulinemia, a genetic condition that means they can’t make IgG. Both patients had SARS-CoV-2 infection and had typical diseases which resolved in a reasonably normal timescale. This preliminary study suggests that those patients aren’t at risk of unusual severity but what this means for their long-term immunity is unknown. Much larger studies are in development and are needed to answer those questions.
Q: How do the antibody/immune findings feed into any possibility of developing an effective vaccine?
RT: The real thing we need to know is whether people who have had COVID-19 can be re-infected, so we need to have long-term follow-up studies on this first wave of patients over the next few years. This will allow us to look at correlates of protection, which are immunological factors (such as antibody titre, neutralising capacity of antibodies, abundance of T cells) that best predict protection to reinfection. These studies will tell us what immune responses we need vaccines to produce. For example, does a vaccine need to generate lots of IgG, or lots of IgA in the respiratory tract, or a strong CD8 T cell response to protect from infection? These are long term studies which might inform which vaccines are most likely to succeed through late phase clinical trials in the months and years to come.
Q: What do you suggest as an appropriate viral challenge for vaccine evaluation?
RT: The WHO issued key criteria for the ethical acceptability of COVID-19 human challenge studies, where human volunteers are deliberately infected with SARS-CoV-2. We’re a long way from such studies now but the value of them is large. However, this is a serious virus and we don’t know enough about the risk factors for severe disease even among a young healthy population (who might volunteer) and the long-term health effects of infection with SARS-CoV-2. Until those factors are well understood, we’re probably some time away from conducting those human viral challenge studies.
We’d like to thank Professor Peter Openshaw and Dr Ryan Thwaites for their time and expertise in both presenting and answering these questions.