Selective and cross-reactive SARS-CoV-2 T cell epitopes in unexposed humans
Preexisting immune response to SARS-CoV-2
Abstract
Epitope repertoire in SARS-CoV-2–unexposed individuals
Epitope distribution by ORF of origin
Sequence homology of the identified SARS-CoV-2 epitopes to other common HCoVs
Direct evidence of reactivity to HCoV epitopes homologous to SARS-CoV-2 epitopes
Identification of SARS-CoV-2 epitopes cross-reactive with other common HCoVs
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2 October 2020
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- Jose Mateus et al.
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RE: COVID-19 and older adults immunity
Article "Selective and cross-reactive SARS-CoV-2 T cell epitopes in unexposed humans" reports the discovery that pre-existing memory T-cells in people previously unexposed to SARS-CoV-2 have an affinity to both SARS-CoV-2 and common cold coronaviruses. The authors point out that the effect of pre-existing immunity to common cold coronaviruses on the clinical presentation of COVID-19 is unknown. [1]
I want to point out that the highest mortality and higher hospitalization rate due to COVID-19 were universally reported for older adults. [2,3] While comorbidity could be a factor contributing to a worse outcome, some speculate that the age-related decline in immune function could also play a role and urge to consider this factor in vaccine development. [4]
Reversely, based on the data of Mateus J, et al., it is possible to hypothesize that older people have a worse outcome of COVID-19 because they had more opportunities to encounter common cold coronaviruses through their life-time and developed immunity. With this, antibodies that cross-react with SARS-CoV-2 were formed, leading to "cytokine storm" or a reaction similar to antibody-dependant enhancement. At the same time, many younger people might not have been exposed to common cold coronaviruses yet, thus, do not have pre-existing antibodies able to cross-react with SARS-CoV-2 and, as a result, milder inflammatory response and clinical presentation. This hypothesis can be tested comparing immunity to common cold coronaviruses between people with mild and severe COVID-19. Knowing the impact of pre-existing immunity to common cold coronaviruses seems important for vaccine development.
References:
1. Mateus J, et al., Selective and cross-reactive SARS-CoV-2 T cell epitopes in unexposed humans. 2020 Aug 4;eabd3871. doi: 10.1126/science.abd3871. Online ahead of print.
2. Verity R, et al., Estimates of the severity of coronavirus disease 2019: a model-based analysis. Lancet Infect Dis. 20(6), 669-677 (2020). doi: 10.1016/S1473-3099(20)30243-7
3. Center for Disease Control and Prevention, COVIDView, A weekly surveillance summary of U.S. COVID-19 activity. August 29, 2020 Available online: https://www.cdc.gov/coronavirus/2019-ncov/covid-data/pdf/covidview-09-04... (accessed on 9 September, 2020)
4. Koff WC, Williams MA, Covid-19 and Immunity in Aging Populations — A New Research Agenda. N Engl J Med. 383(9): 804-805 (2020), doi: 10.1056/NEJMp2006761
RE: T-cell inflammatory response: devastating!
COVID-19 decimates our beloved elderly population by triggering cascading inflammatory T-cell response which induces catastrophic organ failure & vascular embolisms. Perhaps the T-cell memory proven in this study finally gets to the heart of why the elderly are disproportionately affected by this novel virus. Could a life-time of Corona-type virus exposure trigger a cascade memory T-cell response. And the inflammatory syndrome associated with child death cases from COVID-19, are there any studies to see if T-cell cascade was present? Perhaps influenced by recent Corona-type virus or vaccination/booster timing? While T-cell immune response is being sought in vaccine studies, is there any study to prove/verify the TH1 is off-set by healthy TH2?
In the most severe cases and deaths, the body's own inflammatory response seems to play a part. This study possibly explains the case symptom severity differential. Are there any data regarding T-cell levels in COVID-19 cases with cascading inflammatory response leading to severity/death?
Today's pause in Phase III for AstraZeneca may point to unwanted inflammatory response to vaccine, and pose possible argument as to why NOT to seek T-cell response in potential vaccine.
RE: Pay attention to cross-reactivity of SARS-CoV-2 spike- and non-spike peptide with the antibody generated from other human coronaviruses in clinical investigation
To The Editor:
Serological testing is a key investigative tool in the coronavirus disease (COVID-19) epidemic and can identify an infected family or school cluster, especially children or patients with mild illness. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serological testing may help diagnose suspected patients with negative polymerase chain reaction (PCR) results and those with mild or asymptomatic infections (1). This will allow a more accurate determination of the percentage of infected people.
SARS-CoV-2 and seasonal "common cold" human coronaviruses patients have cross-reactivity of SARS-CoV-2 T cell epitopes. Mateus et al. (2) demonstrated that memory CD4+ T cells recognizing four common cold coronaviruses can exhibit substantial cross-reactivity to the homologous epitope in SARS-CoV-2. Grifoni et al. (3) investigated donors who were not exposed to COVID-19. Approximately 40–60% SARS-CoV-2 non-spike-specific CD4+ T cell responses in COVID-19 cases were detected among non-contact donors. It was determined that non-contact donors have cross-reactivity to SARS-CoV-2 non-spike peptide. If the patient shows a non-spike cross-reaction and an anti-spike and nucleocapsid protein combination detection kit is used, it may affect the evaluation of the disease severity (1,3).
SARS-CoV-2 and SARS-CoV patients have cross-reactivity of spike RBD and non-RBD. Lv et al. (4) reported 15 plasma samples of patients with COVID-19 that showed significant cross-reactivity with SARS-CoV spike non-RBD. However, only 5 of the 15 samples showed convincing cross-reaction with SARS-CoV RBD. The author also reported 7 plasma samples from patients with Severe Acute Respiratory Syndrome (SARS) that could significantly cross-react with SARS-CoV-2 spike non-RBD and RBD (4).
Steensels et al. (5) reported SARS-CoV-2 IgG positive rates were 6.4% in hospital staff and 13.7% in suspected household contacts, respectively. However, negative control samples from seasonal "common cold" were not investigated using the nucleocapsid protein test kit, which could affect the SARS-CoV-2 IgG positive rate in two populations.
1. Q.Long, B. Liu, H. Deng, G. Wu, K. Deng, Y. Chen, P. Liao, J. Qiu, Y. Lin, X. Cai, D. Wang, Y. Hu, J. Ren, N. Tang, Y. Xu, L. Yu, Z. Mo, F. Gong, X. Zhang, W. Tian, L. Hu, X. Zhang, J. Xiang, H. Du, H. Liu, C. Lang, X. Luo, S. Wu, X. Cui, Z. Zhou, M. Zhu, J. Wang, C. Xue, X. Li, L. Wang, Z. Li, K. Wang, C. Niu, Q. Yang, X. Tang, Y. Zhang, X. Liu, J. Li, D. Zhang, F. Zhang, P. Liu, J. Yuan, Q. L, J. Hu, J. Chen, A. Huang, Antibody responses to SARS-CoV-2 in patients with COVID-19. Nat. Med. 26, 845-848 (2020).
2. J. Mateus, A. Grifoni, A. Tarke, J. Sidney, S. I. Ramirez, J. M. Dan, Z. C. Burger, S. A. Rawlings, D. M. Smith, E. Phillips, S. Mallal, M. Lammers, P. Rubiro, L. Quiambao, A. Sutherland, E. D. Yu, R. S. Antunes, J. Greenbaum, A. Frazier, A. J. Markmann, L. Premkumar, A. Silva, B. Peters, S. Crotty, A. Sette, D. Weiskopf, Selective and cross-reactive SARS-CoV-2 T cell epitopes in unexposed humans. Science. eabd3871 (2020).doi: 10.1126/science.abd3871.
3. A. Grifoni, D. Weiskopf, S. I. Ramirez, J. Mateus, J. M. Dan, C. R. Moderbacher, S. A. Rawlings, A. Sutherland, L. Premkumar, R. S. Jadi, D. Marrama, A. M. de Silva, A. Frazier, A. F. Carlin, J. A. Greenbaum, B. Peters, F. Krammer, D. M. Smith, S. Crotty, A. Sette, Targets of T cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals. Cell 181, 1489–1501.e15 (2020). doi:10.1016/j.cell.2020.05.015pmid:32473127.
4. H. Lv, N. C. Wu, O. T. Tsang, M. Yuan, R. A. P. M. Perera, W. S. Leung, R. T. Y. So, J. M. C. Chan, G. K. Yip, T. S. H. Chik, Y. Wang, C. Y. C. Choi, Y. Lin, W. W. Ng, J. Zhao, L. L. M. Poon, J. S. M. Peiris, I. A. Wilson, C. K. P. Mok, Cross-reactive antibody response between SARSCoV-2 and SARS-CoV infections. Cell Rep. 31, 107725 (2020). doi: 10.1016/j.celrep.2020.107725.
5. D. Steensels, E. Oris, L. Coninx, D. Nuyens, M. Delforge, P. Vermeersch, L. Heylen, Hospital-wide SARS-CoV-2 antibody screening in 3056 staff in a tertiary center in Belgium. JAMA. 324, 195-197 (2020).
RE: Do pre-existing cross-reactive T-cells provide immunity to COVID-19 among urban slum dwellers in South Asia?
In their article, "Selective and cross-reactive SARS-CoV-2 T cell epitopes in unexposed humans" (August 04, 2020), Mateus and colleagues reported the presence of pre-existing memory CD4+ T cells in SARS-CoV-2 unexposed individuals that are equally cross-reactive to SARS-CoV-2 and other common cold coronaviruses such as HCoV-OC43, HCoV-229E, HCoV-NL63, or HCoV-HKU1(1). Earlier reports also show T-cell reactivity to SARS-CoV-2 antigens in 20-50% of individuals, from different countries, who had not been exposed to SARS-CoV-2 (1-3). These findings may explain why the rates of severe disease and death from COVID-19 among urban slum dwellers in South Asia are low, despite high incidence of infection.
In India, Pakistan and Bangladesh 24%, 45% and 55% of urban population live in slums or informal settlements (4). Urban slum dwellers in these countries are expected to be highly susceptible to COVID-19 infection because of: crowded living conditions with shared facilities (toilets, kitchens and water source); low socioeconomic status; and inability to maintain the hygiene and sanitary standards. The World Health Organization (WHO) recommended preventive measures such as handwashing, social distancing and home quarantine are impractical in these settings, thus increasing the risk of COVID-19 transmission (5, 6).
Recently, after a large seroprevalence survey in Mumbai, 57% of the people living in slum areas tested positive for antibodies against SARS-CoV-2, whereas only 16% of people living outside slums in the same areas had detectable antibodies (7). Although seroprevalence data is not available for Dhaka, Bangladesh, it also has a high incidence of COVID-19 (8). However, a large faction of these cases are mild or asymptomatic, with very low fatality rates ranging from 1:1,000 to 1:2,000 (7). This is in contrast to developed countries where lower-income and minority populations are disproportionately affected by COVID-19 in terms of hospitalizations and deaths (9). This difference cannot be explained by age distributions or other genetic and demographic factors (10). However, in light of the recent evidences, it seems reasonable to speculate that slum dwellers in South Asia may have a distinct advantage of pre-existing T-cell immunity to SARS-CoV-2. People living in slum areas are likely frequently exposed to a wide range of pathogens that are more diverse than those people living in other urban communities. Therefore, it seems possible that slum dwellers possess stronger and more diverse, pre-existing T-cell responses that may have arisen from exposure to 'common cold' coronaviruses or other unknown pathogens. Testing SARS-CoV-2 uninfected slum dwellers for their pre-existing T-cell response to SARS-CoV-2 and other coronaviruses will shed some light on the low mortality from COVID-19 in these communities and establish more accurate epidemiological models of herd immunity.
References and Notes:
1. J. Mateus et al., Selective and cross-reactive SARS-CoV-2 T cell epitopes in unexposed humans. Science, (2020).
2. N. Le Bert et al., SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls. Nature, (2020).
3. A. Grifoni et al., Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals. Cell 181, 1489-1501 e1415 (2020).
4. UN, "United Nations Millennium Development Goals Indicators," (2015).
5. T. Islam, M. G. Kibria, Challenges to the prevention of COVID-19 spread in slums of Bangladesh. J Public Health (Oxf), (2020).
6. J. Corburn et al., Slum Health: Arresting COVID-19 and Improving Well-Being in Urban Informal Settlements. J Urban Health 97, 348-357 (2020).
7. S. Biswas, in BBC. (2020).
8. S. Mollah, Z. Islam, in The Daily Star. (2020).
9. W. J. Wiersinga, A. Rhodes, A. C. Cheng, S. J. Peacock, H. C. Prescott, Pathophysiology, Transmission, Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19): A Review. JAMA, (2020).
10. N. Hatekar, S. Rode, Truth about Hunger and Disease in Mumbai: Malnourishment among Slum Children. Economic and Political Weekly, 4604-4610 (2003).
RE: Possible connection to "Influenza" 1889
The "Influenza" in 1889 acted like cowid19, according to a new study, that is yet to be published. Wiki did an update on its english article, but unfortunately the only thorough text was found in Danish national TV media https://www.dr.dk/nyheder/viden/kroppen/overraskende-opdagelse-coronavir...