SARS Cross-Immunity from T-cells

The functions of helper T cells in increasing immune activity (A) and killer T cells in killing virus-infected cells (B).

The breaking news is in an accelerated preview article at Nature SARS-CoV-2-reactive T cells in healthy donors and patients with COVID-19. Excerpts in italics with my bolds.

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the rapidly unfolding coronavirus disease 2019 (COVID-19) pandemic1,2 . Clinical manifestations of COVID-19 vary, ranging from asymptomatic infection to respiratory failure. The mechanisms determining such variable outcomes remain unresolved. Here, we investigated SARS-CoV-2 spike glycoprotein (S)-reactive CD4+  T cells in peripheral blood of patients with COVID-19 and SARS-CoV-2-unexposed healthy donors (HD). We detected SARS-CoV-2 S-reactive CD4+ T cells in 83% of patients with COVID-19 but also in 35% of HD. S-reactive CD4+ T cells in HD reacted primarily to C-terminal S epitopes, which show a higher homology to spike glycoproteins of human endemic coronaviruses, compared to N-terminal epitopes. S-reactive T cell lines generated from SARS-CoV-2-naive HD responded similarly to C-terminal S of human endemic coronaviruses 229E and OC43 and SARS-CoV-2, demonstrating the presence of S-cross-reactive T cells, probably generated during past encounters with endemic coronaviruses. The role of pre-existing SARS-CoV-2 cross-reactive T cells for clinical outcomes remains to be determined in larger cohorts. However, the presence of S-cross-reactive T cells in a sizable fraction of the general population may affect the dynamics of the current pandemic, and has important implications for the design and analysis of upcoming COVID-19 vaccine trials.

Discussion

Our study demonstrates the presence of S-reactive CD4+ T cells in COVID-19 patients, and in a considerable proportion of SARS-CoV-2  unexposed HD. In light of the recent emergence of SARS-CoV-2, our data raise the intriguing possibility that such pre-existing S-reactive T cells represent cross-reactive clones, probably acquired in previous infections with endemic HCoVs. HCoVs account for approximately 20% of “common cold” upper respiratory tract infections, are ubiquitous, but display a winter seasonality30–32. Based on epidemiological data, it may be extrapolated that adults contract an HCoV infection on average every two to three years. Protective antibodies may wane mid-term but cellular immunity could remain13,33. Although the overall amino acid sequence homology of S is relatively low compared to spike glycoproteins of HCoVs, there is an overlap of MHC-II epitopes especially in the C-terminal domain of the here used peptide pools (Fig. 1a, Extended Data Fig. 1). This may explain the preferential reactivity of CD4+ T cells to the C-terminal domain in one third of HD.

The biological role of pre-existing S-cross-reactive CD4+ T cells in 35% of HD remains unclear for now. However, assuming that these cells have a protective role in SARS-CoV-2 infection, they may contribute to understanding the divergent manifestations of COVID-19, and the striking resilience of children and young adults to symptomatic SARS-CoV-2 infection.  Especially children in day care centers but also young adults have more frequent social contacts than elderly, and thus may have a higher HCoV prevalence. This hypothesis requires further investigation in future longitudinal studies assessing the presence of pre-existing SARS-CoV-2-cross-reactive CD4+ T cells and their impact on the susceptibility to SARS-CoV-2 infection and age-related clinical outcomes of COVID-19.

SARS-CoV neutralizing antibodies are associated with convalescence, and they have been detected 12 months after disease9 . However, the durability of neutralizing antibody responses against SARS-CoV-2 remains unknown. Although antibodies against HCoV can wane within months after infection, HCoV re-infection is accompanied by low-level and short-lived virus shedding with only mild symptoms of short duration pointing towards humoral-independent residual immunity10. Cellular immunity has not yet been studied in this context. In mouse models, however, CD4+ as well as CD8+ T cell responses directed against structural proteins such as spike or nucleocapsid protein of SARS-CoV critically contributed to viral clearance15,34,35. Understanding the extent to which and how SARS-CoV-2-specific humoral or cellular immunity mediates durable protection against reinfection is of critical importance in the coming months.

Our study reveals pre-existing cellular SARS-CoV-2-cross-reactivity in a substantial proportion of SARS-CoV-2 seronegative HD. This finding might have significant epidemiological implications regarding herd immunity thresholds and projections for the COVID-19 pandemic. Our results provide a decisive rationale to initiate worldwide prospective studies to assess the contribution of pre-existing, potentially region-dependent SARS-CoV-2-cross-reactive immunity to the diverse clinical outcomes of SARS-CoV-2 infections. Together with currently introduced novel serological tests, the data generated by such studies may critically inform evidence-based risk evaluation, patient monitoring, adaptation of containment methods, and last but not least, vaccine development.

Don’t Fence Me In!

Implications of This Research are explained in a previous post Herd Immunity Already?

Professor Sunetra Gupta provides a wise, wholistic perspective on the pandemic in her interview published at Reason We may already have herd immunity.  Excerpts in italics with my bolds. H/T Paul Yowell.

I particularly appreciate her sense of the complexity of multiple factors and values, and humility in the challenge of getting the balance right.  This contrasts with so many narrow and overly confident technical pronouncements we read and hear in the media.

Are we already immune to coronavirus? Professor Sunetra Gupta, a theoretical epidemiologist at Oxford University, discusses her recent study on the herd immunity threshold, as well as her views on the social costs of lockdown, the inaccuracy of epidemiological models, and the curtailment of academic debate.

A study produced by a team at Oxford University indicated that some parts of the United Kingdom may already have reached herd immunity from coronavirus. A significant fraction of the population, according to the study published last week, may have “innate resistance or cross-protection from exposure to seasonal coronaviruses”, making the proportion vulnerable to coronavirus infection much smaller than previously thought.

The Oxford team is led by Sunetra Gupta, a professor of theoretical epidemiology. In recent months, she has argued that the cost of lockdown will be too high for the poorest in society and questioned the language and quality of debate on the pandemic’s impact.

Reaction interviewed Professor Gupta about these matters and more, with questions from Maggie Pagano, Alastair Benn and Mutaz Ahmed.

Cross-immunity Matters

Yes, exactly. The principle of protection from exposure to related viruses, and indeed any kind of pathogen, is one that we’ve known for a very long time. The very first vaccine we had, which is smallpox, was based on the idea that cowpox protects against smallpox. This idea was already there well in advance of us knowing that smallpox was a virus – and indeed in advance of germ theory having been properly established. So we knew about this cross protection even before we knew that diseases were caused by germs. It’s a very old idea.

In my own studies, beginning with malaria and then later thinking about flu, the role of cross-immunity in protecting against disease seemed to be something that very much needed to be factored into our thinking. Most of the people who die from malaria are children, and they die upon their first exposure, because they have no immunity at that stage. That was one of the first things that struck me when I was working on malaria.

And then later when I was working on flu, it seemed to me a very good way of explaining why the 1918 flu had killed so many people, but why that didn’t seem to be repeating itself, was that it was likely that people hadn’t been exposed to flu. Many people would have not had the flu at all. So then that built up this population of naive immunity in people under the age of thirty who were very badly affected when the pandemic came through.

Having those ideas in mind, when the Covid-19 virus started to spread, I was pretty certain it wouldn’t have a huge, devastating impact in terms of mortality, because we had all these other coronaviruses circulating.

What I didn’t anticipate was that some of our responses to previous exposure to seasonal coronaviruses might actually protect us from infection. It’s one thing to get infected and not ill, but what the new studies are showing is that people are actually fighting off infection. So at an even more basic level, the pre-existing antibodies or T-cell responses against coronaviruses seem to protect against infection, not just the outcome of infection.

Low Seroprevalence May be a Good Thing

What we know is that the seropositivity rates in many parts of the world are much lower than we’d expect them to be if we assume that the epidemic has passed through and that people are resistant. If you take a very simple scenario where everyone is susceptible, you’d expect 60-70% of them to have some marker of exposure. And that is not what’s been observed.

One of the things that’s been done in reporting the seroprevalence, which is not correct, is that they’ve been homogenised. When people say only 5-6% of the UK population has been exposed, that’s not correct. I think very few people would agree that exposure rates in London are less than 20%.

The picture that we’re getting is heterogeneous. But even in hotspots, apart from a few reports, they’re still quite low. So why is that?

One reason might be that lockdown stopped the spread of infection, so it was halted at a stage when, say, 20% of people were immune and the rest of the people were still susceptible to infection. Well, under those circumstances, the easing of lockdown should result in fairly rapid growth of cases. And that’s not something we’re seeing.

So we’ve got those two bits of information. The third bit, the missing piece of the puzzle, is this idea that some people are fully resistant to infection, because they just have really good defences. That could just be part of our innate immunological makeup. It’s also becoming clear that some of the people that have beaten it off have had responses to other coronaviruses which could have played a role.

The other bit of the puzzle is that some people do get infected and they make antibody responses, but those responses die very quickly. So if you’re trying to measure exposure, you won’t get the full picture. Some of the measures of seroprevalence might be underestimates.

We’ve got four pieces of the puzzle, then. If we put them all together, which is what the paper that we published on Friday does, it gives you a theoretical framework that you can use to look at how these bits connect up together.

You can see two things. You can see why the seroprevalence level might be low, and you can also infer that the level of herd immunity needed to stop the thing from exploding again is actually much lower than the figures that are currently being thrown around quite incautiously might suggest.

The fifth piece of this jigsaw could be that there is some seasonality. I suspect that in the winter it will probably come back, but hopefully only to the regions where it was kept from going by lockdown, and where the seroprevalence levels are genuinely extremely low.

We can be cautiously hopeful that in areas where the seroprevalence levels have achieved a certain value that’s compatible with there being a proportion who are resistant, that it might not come back with such vehemence.

Quality of Life Matters

What’s disappointed me about the way this has been approached is it has been approached along a single axis, which, if you like, is a scientific one. Even within that context, you could argue that it’s too one-dimensional, so we’re not thinking about what’s happening with other infectious diseases or how many people are going to die of cancer.

That’s the axis of disease, but then there’s the socioeconomic axis, which has been ignored. But there’s a third, aesthetic access, which is about how we want to live our lives. We are closing ourselves off not just to the disease, but to other aspects of being human.

I think the trade-off is very extreme. Obviously the most extreme manifestation of that trade-off is the 23 million people who will be pushed below the poverty line as a result of this sledgehammer approach. The costs to the arts is I think also incredibly profound – the theatres and all other forms of performing art. But also the inherent art of living, which I think is being compromised.

Acts of kindness are being eschewed. Someone was telling me yesterday that their mother said to them “please don’t come home, you’re going to kill us”.

Carrying On with Living is Social Responsibility

Because actually, the only way we can reduce the risk to the vulnerable people in the population is, for those of us who are able to acquire herd immunity, to do that.

Even if there is a little bit of a risk. I’m 55 years old, there’s some slight risk out there. But I would be willing to take that, just as I do with the flu. There’s a risk I might die of flu, but I’m willing to take that risk, because I know that if I don’t then flu will appear as it did before, it will enter the population of immunologically naive individuals, and then there will be a high risk of infection which will have a disproportionate effect on the vulnerable sector of the population.

Maybe the way to counter it now is to say, actually, not only is it a good thing for young people to go out there and become immune, but that is almost their duty. It’s a way of living with this virus. It’s how we live with other viruses. Flu is clearly a very dangerous virus, but the reason we don’t see more deaths from flu every year is because, through herd immunity, the levels of infection are kept to as low a level as we can get.

The truth is that herd immunity is a way of preventing vulnerable people from dying. It is achieved at the expense of some people dying, and we can stop that by preventing the vulnerable class in the process. In an ideal situation, you would protect the vulnerable as best you can, let people go about their business, allow herd immunity to build up, make sure the economy doesn’t crash, make sure the arts are preserved, and make sure qualities of kindness and tolerance remain in place.

We live, it seems, in this state of terror. Yes, international travel facilitates the entrance of contagion, but what it also does is it brings immunity.

Good Thing It’s Not Our First Coronavirus

If coronavirus had arrived in a setting where we had no coronavirus exposure before, we might be much worse off. It also seems that in addition to protection against severe disease as a result of exposure to related coronaviruses, some fraction of us seem to be resistant to infection.

That’s just fantastic news, actually. Hopefully that will be consolidated at a scientific, laboratory level. We ourselves are looking at how antibodies to seasonal coronaviruses can impact on protection against infection and disease.

Maybe we will be able to build up a picture that will reassure the public that actually we are much better off having been exposed to related coronaviruses. We are in a better place to fight off this infection than we actually thought.

The paper is The impact of host resistance on cumulative mortality and the threshold of herd immunity for SARS-CoV-2

Abstract
It is widely believed that the herd immunity threshold (HIT) required to prevent a resurgence of SARS-CoV-2 is in excess of 50% for any epidemiological setting. Here, we demonstrate that HIT may be greatly reduced if a fraction of the population is unable to transmit the virus due to innate resistance or cross-protection from exposure to seasonal coronaviruses. The drop in HIT is proportional to the fraction of the population resistant only when that fraction is effectively segregated from the general population; however, when mixing is random, the drop in HIT is more precipitous. Significant reductions in expected mortality can also be observed in settings where a fraction of the population is resistant to infection. These results help to explain the large degree of regional variation observed in seroprevalence and cumulative deaths and suggest that sufficient herd-immunity may already be in place to substantially mitigate a potential second wave.

 

 

One comment

  1. Hifast · July 29

    Reblogged this on Climate Collections.

    Like

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