Cross Reactive Covid 19 Immunity From Exposure to Endemic Coronaviruses

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morrobay
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Summary:
About 80% of Covid Cases are Mild or Asymptomatic
https://onlinelibrary.wiley.com/doi/10.1002/jmv.26958. Since the majority of Covid cases are mild or Asymptomatic one possible factor could be existence of cross immunity in a population as a result of previous exposure to other Endemic Coronaviruses.
 

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  • #2
atyy
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Interesting hypothesis. But I wonder whether the apparently lower IFR in India in 2020 holds up after their second wave in April-May 2021?
 
  • #3
atyy
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Posted January 06, 2021
https://www.medrxiv.org/content/10.1101/2021.01.05.21249264v1
Representative Estimates of COVID-19 Infection Fatality Rates from Three Locations in India
R. Cai, P. Novosad, V. Tandel, S. Asher, A. Malani

https://www.news-medical.net/news/2...lity-rates-in-India-during-waves-1-and-2.aspx

Posted May 27, 2021
https://www.medrxiv.org/content/10.1101/2021.05.25.21257823v1
Estimating the wave 1 and wave 2 infection fatality rates from SARS-CoV-2 in India
Soumik Purkayastha, Ritoban Kundu, Ritwik Bhaduri, Daniel Barker, Michael Kleinsasser, Debashree Ray, Bhramar Mukherjee
 
  • #4
See also the study "SARS-CoV-2-reactive T cells in healthy donors and patients with COVID-19":
https://www.nature.com/articles/s41586-020-2598-9

There exists also a study from the University of Tübingen in Germany about SARS-CoV-2 T-cell cross-reactivity.
https://www.researchsquare.com/article/rs-35331/v1

The researchers published a statement about related misinformation in the media (translation):
Initial results of studies on cross-reactive T cell recognition are currently being misrepresented in the media. The research group has written a statement on this. This cross-reactive T-cell recognition is NOT synonymous with immunity to SARS-CoV-2.
...
How this cross-reactive T-cell recognition affects an infection with SARS-CoV-2 and the severity of the disease in 81% of the population, the research group will now prospectively investigate in further studies.
Source:
https://www.medizin.uni-tuebingen.de/de/das-klinikum/pressemeldungen/281
 
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  • #5
pinball1970
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Posted January 06, 2021
https://www.medrxiv.org/content/10.1101/2021.01.05.21249264v1
Representative Estimates of COVID-19 Infection Fatality Rates from Three Locations in India
R. Cai, P. Novosad, V. Tandel, S. Asher, A. Malani

https://www.news-medical.net/news/2...lity-rates-in-India-during-waves-1-and-2.aspx

Posted May 27, 2021
https://www.medrxiv.org/content/10.1101/2021.05.25.21257823v1
Estimating the wave 1 and wave 2 infection fatality rates from SARS-CoV-2 in India
Soumik Purkayastha, Ritoban Kundu, Ritwik Bhaduri, Daniel Barker, Michael Kleinsasser, Debashree Ray, Bhramar Mukherjee
And Brazil, Manaus.
https://www.thelancet.com/article/S0140-6736(21)00183-5/fulltext
 
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  • #6
atyy
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I confess I wonder whether the seroprevalence was hugely over estimated the first time. I'm not that surprised that one can be reinfected by a different variant. But I would expect the first infection to provide protection against severe disease, yet the hospitalization rates rose very steeply for second wave of infections.

Would it be possible that for malaria antibodies to have been mistaken for COVID antibodies?
https://phcfm.org/index.php/PHCFM/article/view/2501
https://www.mdpi.com/2075-4418/11/7/1163
 
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The paper, posted April 05, 2021, "Cross-reactive CD4+ T cells enhance SARS-CoV-2 immune responses upon infection and vaccination" has interesting results regarding age-dependency of severe symptoms and the high effectiveness of mRNA vaccines.
Abstract said:
While evidence for pre-existing SARS-CoV-2-cross-reactive CD4+ T cells in unexposed individuals is increasing, their functional significance remains unclear. Here, we comprehensively determined SARS-CoV-2-cross-reactivity and human coronavirus-reactivity in unexposed individuals. SARS-CoV-2-cross-reactive CD4+ T cells were ubiquitous, but their presence decreased with age. Within the spike glycoprotein fusion domain, we identified a universal immunodominant coronavirus-specific peptide epitope (iCope). Pre-existing spike- and iCope-reactive memory T cells were efficiently recruited into mild SARS-CoV-2 infections and their abundance correlated with higher IgG titers. Importantly, the cells were also reactivated after primary BNT162b2 COVID-19 mRNA vaccination in which their kinetics resembled that of secondary immune responses. Our results highlight the functional importance of pre-existing spike-cross-reactive T cells in SARS-CoV-2 infection and vaccination. Abundant spike-specific cross-immunity may be responsible for the unexpectedly high efficacy of current vaccines even with single doses and the high rate of asymptomatic/mild infection courses.
Source:
https://www.medrxiv.org/content/10.1101/2021.04.01.21252379v1
 
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pinball1970
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I confess I wonder whether the seroprevalence was hugely over estimated the first time. I'm not that surprised that one can be reinfected by a different variant. But I would expect the first infection to provide protection against severe disease, yet the hospitalization rates rose very steeply for second wave of infections.
Plenty of malaria/Dengue in Brazil ( note Manaus)so your paper could explain a significant percentage that could have been false positives.
https://www.google.com/search?q=bra...ient=mobile-gws-wiz-serp#imgrc=da3VlX6xOlXl3M
And Dengue
https://www.cdc.gov/dengue/areaswithrisk/around-the-world.html
And schistosomiasis. Zika too was mentioned but not part of the study.

https://www.google.com/search?q=bra...ient=mobile-gws-wiz-serp#imgrc=dHxhFxuQfdZyLM
 
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  • #10
Ygggdrasil
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Here's another article supporting the hypothesis that prior infection with one of the endemic, common cold-causing coronaviruses could offer some degree of protection against severe COVID-19:

Recent endemic coronavirus infection is associated with less-severe COVID-19
Sagar et al. J. Clin Invest. 131: e143380
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773342/

Abstract:
Four different endemic coronaviruses (eCoVs) are etiologic agents for the seasonal common cold, and these eCoVs share extensive sequence homology with human SARS coronavirus 2 (SARS-CoV-2). Here, we show that individuals with, as compared with those without, a recent documented infection with eCoV were tested at greater frequency for respiratory infections but had a similar rate of SARS-CoV-2 acquisition. Importantly, the patients with a previously detected eCoV had less-severe coronavirus disease 2019 (COVID-19) illness. Our observations suggest that preexisting immune responses against endemic human coronaviruses can mitigate disease manifestations from SARS-CoV-2 infection.
 
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  • #11
pinball1970
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Here's another article supporting the hypothesis that prior infection with one of the endemic, common cold-causing coronaviruses could offer some degree of protection against severe COVID-19:

Recent endemic coronavirus infection is associated with less-severe COVID-19
Sagar et al. J. Clin Invest. 131: e143380
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773342/

Abstract:
This is reassuring to me as I get the seasonal flu jab every year.
 
  • #12
atyy
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This is reassuring to me as I get the seasonal flu jab every year.
The flu jabs are for the flu virus, which is different from the already endemic coronaviruses that are among the causes of a cold.
 
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  • #13
pinball1970
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The flu jabs are for the flu virus, which is different from the already endemic coronaviruses that are among the causes of a cold.
Ok Thanks, just had a look. I should have remembered from when I looked at this A-D
The "sense" part I have not come across.
 
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atyy
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Plenty of malaria/Dengue in Brazil ( note Manaus)so your paper could explain a significant percentage that could have been false positives.
https://www.google.com/search?q=bra...ient=mobile-gws-wiz-serp#imgrc=da3VlX6xOlXl3M
And Dengue
https://www.cdc.gov/dengue/areaswithrisk/around-the-world.html
And schistosomiasis. Zika too was mentioned but not part of the study.

https://www.google.com/search?q=bra...ient=mobile-gws-wiz-serp#imgrc=dHxhFxuQfdZyLM
After looking at how common Malaria and Dengue are, maybe they are not such a big concern for the Manaus study that estimated 76% infection before a second wave. In a bad year, Malaria affects about 1% of Manaus and Dengue affects about 7%. However the cross reactivity between the COVID and the Malaria or Dengue tests seems to be about 20% or less, so the 76% would be corrected down by less than 5%, which would still be surprising.

Maybe it is more relevant the paper itself mentions that the 76% may have resulted from over-correction upwards to account for antibody waning. Their raw number is about 50%. Estimates for the reduction in vaccine effectiveness against infection by the Delta variant range from 10-25%. From lab tests of antibodies against Delta and P.1 we expect P.1 to cause a similarly large reduction. So the 50% raw number may be effectively 30-40% for P.1. From that point of view, the second wave in Manaus seems consistent with a first infection providing a lot of protection against severe disease if reinfected by a variant.

Edit: I think (not sure) @Ygggdrasil or someone else posted an Economist article about the Manaus study. I've just looked it up. It gives more reasons to suspect the 76% infections above is way overestimated. https://www.economist.com/the-ameri...ity-thought-it-had-herd-immunity-it-was-wrong:
"It could be that the study’s methodology is flawed and that 76% was an overestimate. Blood donors are more likely to leave the house, and therefore to get infected, than most people, says Pedro Hallal, an epidemiologist at the Federal University of Pelotas. A nationwide study he co-ordinated, with population samples picked at random, found that just 15% of Manaus residents had antibodies in June. He thinks the preprint’s authors were “not cautious enough” in interpreting their findings."

Here is the study co-authored by Pedro Hallal.
https://www.thelancet.com/journals/langlo/article/PIIS2214-109X(20)30387-9/fulltext
SARS-CoV-2 antibody prevalence in Brazil: results from two successive nationwide serological household surveys

The approximately 15% seroprevalence for Manaus is explicitly stated in Supplementary Table 3: https://www.thelancet.com/cms/10.10...631cd171-0374-4f7a-a228-17341b53a866/mmc1.pdf
 
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If cold virus coronavirus mitigate severity of COVID 19, could the inverse be true also; that COVID vaccines could provide some protection against some of the common cold varieties?
 
  • #17
atyy
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If cold virus coronavirus mitigate severity of COVID 19, could the inverse be true also; that COVID vaccines could provide some protection against some of the common cold varieties?

It seems plausible. See the paper by Penaloza-MacMaster and colleagues. I think it depends on how conserved various parts of the viruses are, and which parts of the viruses are used in making the vaccines. There's also related work about trying to make a vaccine that protects broadly against subtypes of coronaviruses.

https://www.the-scientist.com/news-opinion/the-quest-for-a-universal-coronavirus-vaccine-68934
"Penaloza-MacMaster and his colleagues ... In mice, they demonstrated that various SARS-CoV-2 vaccines, including mRNA vaccines such as the shot from Pfizer/BioNTech and viral-vector vaccines such as Johnson & Johnson’s version, generated immune responses against SARS-CoV-1 and OC43.
...
viral vector–based SARS-CoV-2 vaccines reduced viral load in animals after OC43 infections."

https://www.biorxiv.org/content/10.1101/2021.06.01.446491v1
SARS coronavirus vaccines protect against different coronaviruses
Tanushree Dangi, Nicole Palacio, Sarah Sanchez, Jacob Class, Lavanya Visvabharathy, Thomas Ciucci, Igor Koralnik, Justin Richner, Pablo Penaloza-MacMaster

https://www.the-scientist.com/news-opinion/the-quest-for-a-universal-coronavirus-vaccine-68934
"The ultimate universal vaccine would protect against all coronaviruses, but the genetic diversity that exists among the four groups makes such a goal very difficult to achieve. Instead, most research groups have zoomed in on the beta coronaviruses—and, more specifically, a subgroup known as sarbecoviruses that includes SARS-CoV-1 and SARS-CoV-2, which are more genetically similar to one another than to MERS-CoV, OC43, or HKU1. Kevin Saunders, a vaccine researcher at the Duke Human Vaccine Institute in North Carolina, says that he sees the universal coronavirus vaccine efforts as going forward in two phases: first focusing on finding a vaccine for sarbecoviruses, then broadening to MERS-like beta coronaviruses.

It may be possible to one day generate a truly universal coronavirus vaccine. But before that happens, “a lot of research has to be done to figure out how far you can push this kind of cross-reactive immune recognition,” says Pamela Björkman, a structural biologist at Caltech."

Here is a paper by Kevin Saunders and his colleagues.
https://www.nature.com/articles/s41586-021-03594-0
Neutralizing antibody vaccine for pandemic and pre-emergent coronaviruses.
Saunders, K.O., Lee, E., Parks, R. et al.
Nature 594, 553–559 (2021).

https://jamanetwork.com/journals/jama/fullarticle/2781521
"Zeichner and Meng synthesized VFPs for SARS-CoV-2 and porcine epidemic diarrhea virus (PEDV)—a coronavirus that sickens pigs
...
Unexpectedly, their SARS-CoV-2 vaccine also protected pigs against severe PEDV, suggesting the VFP could be a target for a broadly protective coronavirus vaccine, Zeichner, Meng, and their coauthors concluded."

Here is the paper by Zeichner, Meng and colleagues
https://www.pnas.org/content/118/18/e2025622118
Killed whole-genome reduced-bacteria surface-expressed coronavirus fusion peptide vaccines protect against disease in a porcine model.
Maeda et al
Proceedings of the National Academy of Sciences May 2021, 118 (18) e2025622118
 
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  • #18
Laroxe
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I think we need to be careful when looking at the work on cross reactive antibodies. We have known for some time that there are cross reactive antibodies produced by other coronavirus infections, but just because there is some reactivity isn't the same as saying they offer any significant protection.
In fact, it seems that while high levels of antibodies offer good cross variant protection, we don't maintain these levels for very long. It seems it is the vaccines that stimulate different kinds of immune responses and particularly those that establish good immune memory is where the focus of research is shifting. The B and T cells of the immune memory appear to recognise all the variants, and while the time taken to respond may allow for infection, it is still fast enough to prevent serious illness or death.
 
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  • #19
morrobay
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I think we need to be careful when looking at the work on cross reactive antibodies.
The main focus of this topic is more about cross reactive T cell response from exposure to other Endemic Coronaviruses. More so than antibodies. https://www.researchsquare.com/article/rs-35331/v1. https://www.cebm.net/covid-19/what-...n-why-immunity-is-about-more-than-antibodies/ *** I have a related question for the talented clinical here: If someone has not had any flu vaccines for the common 4 coronaviruses and has not had a flu for many years. Does that imply they would have innate immunity for the virus that causes covid 19 ?
 
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Laroxe
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The main focus of this topic is more about cross reactive T cell response from exposure to other Endemic Coronaviruses. More so than antibodies. https://www.researchsquare.com/article/rs-35331/v1. https://www.cebm.net/covid-19/what-...n-why-immunity-is-about-more-than-antibodies/ *** I have a related question for the talented clinical here: If someone has not had any flu vaccines for the common 4 coronaviruses and has not had a flu for many years. Does that imply they would have innate immunity for the virus that causes covid 19 ?
The 4 common coronaviruses are described as causing colds, influenza is caused by different viruses so the flu vaccines offer little to no immunity to these coronaviruses. The only reason I say "little" is that any vaccine may prime the immune system for action, but they don't afford any specific protection, for that we need the natural or artificial (vaccine) exposure to the specific virus. We all have some level of innate immunity, its what we are born with, and its effectiveness varies based on all sorts of things, age for example. Its difficult to say if the innate immune system is responsible for avoiding specific infections, though it often is, but it might just be an issue of avoiding exposure. We have seen how the precautions against Covid 19 have had a massive impact on the incidence of flu, but it's the adaptive immune system that produces the antibodies and memory cells that offers the best protection and it needs exposure to the specific antigens to "learn" how to do this.

Thanks for posting the papers, I thought the cebm paper provided a good overview but was less impressed by the reasearchsquare paper which didn't really discuss their results in a way to make them meaningful.

A major issue, and one which reflects the huge investment in research is in the improved understanding of our immune system. When we are exposed to a virus a whole cascade of responses are generated which effect the local cells, and attract immune cells, these responses make virus particles available to our immune cells, some of which chew up the particles into small molecules. A lot of our adaptive immune responses are based on these immunoreactive particles and the various actions they stimulate but there are potentially a very large number which doesn't appear to be reliably known, however some 122 unique SARS-CoV-2 epitomes have been identified that interact with the CD8+ T cell, a single part of a complex system. The mapping of the epitome is important in the identification of function of the various antibodies produced and its this that allows researchers to identify potentially cross reactive antibodies and their usefulness. Its actually quite a difficult process, most studies relying on full-length recombinant antigens which can be unstable and vary in quality, its suggested that these issues may lead to ambiguous detection outcomes and spurious evidence of cross reactivity. This might be the case for SARS-CoV-2 when using proteins from genetically similar, human coronaviruses that are responsible for common cold. When we consider the highly variable results from the various studies of cross reactivity and immunity, this seems entirely credible.

I was also concerned that there little discussion of the marked effect of COVID-19 infection on the immune response. The paper noted the significance in the different responses to severe disease and the importance of the T cell response, we know that in symptomatic Covid there is a lymphopenia and the T cell response appears quite different in vaccination vs natural infection. They suggest that it's and dictate the direction of the cellular responses cross reactive antibodies that underpin this difference, the fact that we have little information about the activity of many of the antibodies produced doesn't really lend itself to this claim. There is little if any convincing evidence of the cross reactive antibodies that have been claimed having any significant protective effect.

I was also concerned that the differences in T cell responses were not really considered significant outside the person's experience of disease severity. Many of the T cells carry out important biochemical activity to modulate the immune responses, we already know that a disturbed balance in the bias of the CD4 towards Th1 and Th2 can have very serious consequences. Activation of the natural killer cells in the CD8 line, without the appropriate chemical mediators, can lead to widespread cell destruction and the T cells have an important function in secreting immune mediators like cytokines. These in fact are all associated with disease severity.

It may be that the article simply didn't provide the sort of information I would have found useful which has coloured my response and the research is difficult to keep up with.

It's difficult to know the most useful links to post, so I've gone with one that simply provides some more useful information.
https://www.ecdc.europa.eu/en/covid-19/latest-evidence/immune-responses
an earlier review of immunity
https://medicalxpress.com/news/2020-05-results-human-covid-immunology-reveal.html
and a study that describes some of the methods of epitome mapping, but its hard work.
https://scholar.google.co.uk/schola...uxLQxoUFv3QUDDPlkuMjs33xg&nossl=1&oi=scholarr
 
  • #21
atyy
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OMG - Original Antigenic Sin :eek:
Here are some references from Craig Thompson's Twitter thread.

https://www.medrxiv.org/content/10.1101/2021.05.04.21256571v1
Fatal COVID-19 outcomes are associated with an antibody response targeting epitopes shared with endemic coronaviruses

https://www.medrxiv.org/content/10.1101/2021.04.29.21256344v1
Original antigenic sin responses to heterologous Betacoronavirus spike proteins are observed in mice following intramuscular administration, but are not apparent in children following SARS-CoV-2 infection

https://pubmed.ncbi.nlm.nih.gov/34022127/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8101792/
Profiling B cell immunodominance after SARS-CoV-2 infection reveals antibody evolution to non-neutralizing viral targets

But :oldconfused: how does this fit in with "Two unrelated adults in Italy with agammaglobulinemia and no circulating B cells developed COVID-19 and fully recovered from infection (Soresina et al., 2020), suggesting that antibodies can be dispensable for protective immunity to SARS-CoV-2 in otherwise healthy adults. Many people have pharmaceutical depletion of B cells for unrelated conditions. Three studies, with a total of 31 COVID-19 cases, of subjects on B cell depletion therapy reported all COVID-19 cases resolved without intensive care (Montero-Escribano et al., 2020; Novi et al., 2020; Safavi et al., 2020). One report presented two fatal cases of COVID-19 in patients >65 years of age on B cell depletion therapy and other immunosuppressive drugs (Tepasse et al., 2020). However, no antigen-specific T or neutralizing antibody data are available from any of those reports. Separately, there are multiple reports of healthy individuals successfully controlling a SARS-CoV-2 infection with little to no neutralizing (or RBD IgG) antibodies detectable post-infection, while having significant SARS-CoV-2-specific T cell memory (Rydyznski Moderbacher et al., 2020; Nelde et al., 2021; Schulien et al., 2020; Sekine et al., 2020). Those observations imply the ability to control COVID-19 without substantial contribution from neutralizing antibodies, as long as a strong T cell response is present." https://doi.org/10.1016/j.cell.2021.01.007
 
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  • #22
Laroxe
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"OMG - Original Antigenic Sin" - is a great idea, given a suitably apocalyptic name, ideal for work during a pandemic. The idea of "antigenic seniority" is its latest incarnation but with some variations and a less inspired name.
It does help explain some of the differences we see in Covid-19 recovery and vaccination, and to a certain extent provides a rational for the potential advantages of the vaccines targeting specific epitomes.

I thought if people are interested, this links explain the idea in detail.

https://journals.asm.org/doi/10.1128/mSphere.00056-21
 
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Cross-reactive immunity may account for the unexpectedly rapid induction of immunity following primary SARS-CoV-2 immunization and the high rate of asymptomatic/mild COVID-19 disease courses.
Source:
https://www.science.org/doi/10.1126/science.abh1823

Edit: I just saw, that I posted a non-peer-reviewed version of this already here.
 
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