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      What about the original antigenic sin of the humans versus SARS-CoV-2?

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      Medical Hypotheses
      Elsevier Ltd.

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          Abstract

          The term «original antigenic sin» (OAS) was coined by T. Francis Jr at the Michigan University in the late 1950s to describe patterns of antibody response to influenza vaccination [1]. The basic concept has been recently summarized by the slang «first flu is forever», which depicts how is important the first imprinting of a dominant viral or bacterial antigen throughout life [2]. In the 70s, T. W. Hoskins of the Christ's Hospital in the West Sussex, working with his collaborators on influenza vaccination, noticed that the development of A/England/42/72 hemagglutinin antibody was less frequent after revaccination of young male students, in whom the A/Hong Kong/68 hemagglutinin antibody had been already induced by previous vaccination [3]. This strange phenomenon went down in history as the «Hoskins paradox», a classical example of OAS. In practice, it refers to the propensity of the human immune system to exploit the immunological memory B and T cells, selected on the basis of a previous contact with a specific epitope, when a new, slightly different, version of the original antigen is encountered, in order to gain time in the attempt to fight the infection. However, in this way, the immune system gets entrapped inside the first response against the antigenic determinant, becoming unable to mount potentially more effective responses during subsequent infections from the mutated pathogen (Fig. 1 ). OAS has been reported not only in relation to influenza virus, but also to dengue virus and human immunodeficiency virus (HIV) [4], [5]. On March 11th, the World Health Organization has declared the ongoing ‘coronavirus-disease-2019’ (COVID-19) an emerging pandemic due to the widespread severe-acute-respiratory-syndrome-coronavirus-2 (SARS-CoV-2), the etiological agent of the disease, first identified in Wuhan [6]. The positive-sense single-stranded RNA of SARS-CoV-2 is almost identical to bat and pangolin coronaviruses; therefore, an animal origin from spillover event is alleged [7]. A recent study on 95 full-length genomic sequences of SARS-CoV-2 strains has highlighted that there may be selective mutations inside the virus [8]; a further study concerning with 86 complete or near-complete genomes of SARS-CoV-2 has provided evidences of genetic diversity and rapid evolution of the virus [9]. The metatranscriptome sequencing of the bronchoalveolar lavage fluid coming from 8 SARS-CoV-2 patients has confirmed that the virus evolves in vivo after infection, a feature which may determine its virulence, infectivity and transmissibility [10]. If we exclude conspiracy theories, SARS-CoV-2 can be hypothetically considered as the natural result of an antigenic shift from SARS-CoV, the etiological agent of the ‘severe acute respiratory syndrome’ (SARS), since they share about 80% of the whole genome and almost all the encoded proteins [11]. During SARS outbreak, it was observed that the onset of ‘acute respiratory distress syndrome’, the most dramatic complication of the disease, overlapped with antiviral immunoglobulin G seroconversion in 80% of patients [12]. Besides, it was found that patients who developed more quickly the anti-spike neutralizing antibody showed a higher risk of dying from the disease [13]. In addition to the formation and tissue deposition of pro-inflammatory immunocomplexes, these alarming data have been explained by means of complement-dependent enhancement and antibody-dependent enhancement (ADE), immunological escape mechanisms also exploited by other viruses, such as dengue virus, Ebola virus and HIV [14], [15], [16], [17], [18]. Briefly, an ineffective immune response against the mutated virus due to OAS can produce a large amount of sub-neutralizing cross-reactive antibodies, which raise inflammation and may paradoxically facilitate the virus entry into host cells, e.g. macrophages, complement mediated or via fragment crystallizable (Fc) receptors. The intracellular presence of the pathogen triggers a pyroptosis process with subsequent release of danger-associated molecular patterns (DAMPs) aimed to invoke in loco further inflammatory cells, which in turn secrete a massive number of cytokines; both ADE and pyroptosis could well explain the «cytokine storm», which has been described in the fatal cases of COVID-19 [19]. J.A. Tetro of the Guelph University has advanced the question if SARS-CoV-2 may receive ADE from other coronaviruses [20]; in this regard, 4 human coronaviruses (HCoV-HKU1, HCoV-NL63, HCoV-OC43, HCoV-229E) are spread all over the world, and they continually circulate among humans causing respiratory infections in adults and children, usually mild as common cold, while the Middle-East-respiratory-syndrome-related-coronavirus (MERS-CoV), responsible for the homonymous, often serious, respiratory illness, has been reported in over 25 countries to date [21]. Faced with this scenario and to the potential adaptive mutation of SARS-CoV-2, the development of an effective subunit vaccine appears quite complicated; therefore, the most viable solution is to focus on an alternative vaccination source able to stimulate the innate immunity rather than the acquired one. The former immunity is more active in children, where the immune system is still immature and prone to receive new antigenic stimuli, while the latter in adults: is maybe here the reason why the child population rarely experiences fatal complications during the ongoing COVID-19 pandemic?...the arduous sentence to near future research lines. Fig. 1 In an ideal immune system (on the left) to SARS-CoV-2 and its antigenic variants corresponds always a specific adaptive immunity, as shown by the color matching (red-red, blue-blue, green-green) between a symbolic antibody and the spike proteins, which surround the outer surface of the virion conferring to it the characteristic corona aspect on electron microscopy; in an OAS model (on the right), the specific adaptive immune response (red antibody) is only mounted against the original virus (red colored) and it is also used to fight the mutated versions (blue colored and green colored) of the virus, resulting in a maladaptive response less specific and less effective [the 3D illustration of SARS-CoV-2 with the spike proteins in red has been created by Alissa Eckert, MS, and Dan Higgins, MAM, at the Centers for Disease Control and Prevention (CDC) of Atlanta, Georgia, USA, placed in the public domain and thus free of any copyright restrictions]. Conflict of interest statement: no conflict of interest.

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          Most cited references12

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          COVID-19: consider cytokine storm syndromes and immunosuppression

          As of March 12, 2020, coronavirus disease 2019 (COVID-19) has been confirmed in 125 048 people worldwide, carrying a mortality of approximately 3·7%, 1 compared with a mortality rate of less than 1% from influenza. There is an urgent need for effective treatment. Current focus has been on the development of novel therapeutics, including antivirals and vaccines. Accumulating evidence suggests that a subgroup of patients with severe COVID-19 might have a cytokine storm syndrome. We recommend identification and treatment of hyperinflammation using existing, approved therapies with proven safety profiles to address the immediate need to reduce the rising mortality. Current management of COVID-19 is supportive, and respiratory failure from acute respiratory distress syndrome (ARDS) is the leading cause of mortality. 2 Secondary haemophagocytic lymphohistiocytosis (sHLH) is an under-recognised, hyperinflammatory syndrome characterised by a fulminant and fatal hypercytokinaemia with multiorgan failure. In adults, sHLH is most commonly triggered by viral infections 3 and occurs in 3·7–4·3% of sepsis cases. 4 Cardinal features of sHLH include unremitting fever, cytopenias, and hyperferritinaemia; pulmonary involvement (including ARDS) occurs in approximately 50% of patients. 5 A cytokine profile resembling sHLH is associated with COVID-19 disease severity, characterised by increased interleukin (IL)-2, IL-7, granulocyte-colony stimulating factor, interferon-γ inducible protein 10, monocyte chemoattractant protein 1, macrophage inflammatory protein 1-α, and tumour necrosis factor-α. 6 Predictors of fatality from a recent retrospective, multicentre study of 150 confirmed COVID-19 cases in Wuhan, China, included elevated ferritin (mean 1297·6 ng/ml in non-survivors vs 614·0 ng/ml in survivors; p 39·4°C 49 Organomegaly None 0 Hepatomegaly or splenomegaly 23 Hepatomegaly and splenomegaly 38 Number of cytopenias * One lineage 0 Two lineages 24 Three lineages 34 Triglycerides (mmol/L) 4·0 mmol/L 64 Fibrinogen (g/L) >2·5 g/L 0 ≤2·5 g/L 30 Ferritin ng/ml 6000 ng/ml 50 Serum aspartate aminotransferase <30 IU/L 0 ≥30 IU/L 19 Haemophagocytosis on bone marrow aspirate No 0 Yes 35 Known immunosuppression † No 0 Yes 18 The Hscore 11 generates a probability for the presence of secondary HLH. HScores greater than 169 are 93% sensitive and 86% specific for HLH. Note that bone marrow haemophagocytosis is not mandatory for a diagnosis of HLH. HScores can be calculated using an online HScore calculator. 11 HLH=haemophagocytic lymphohistiocytosis. * Defined as either haemoglobin concentration of 9·2 g/dL or less (≤5·71 mmol/L), a white blood cell count of 5000 white blood cells per mm3 or less, or platelet count of 110 000 platelets per mm3 or less, or all of these criteria combined. † HIV positive or receiving longterm immunosuppressive therapy (ie, glucocorticoids, cyclosporine, azathioprine).
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            Genetic diversity and evolution of SARS-CoV-2

            Tung Phan (2020)
            COVID-19 is a viral respiratory illness caused by a new coronavirus called SARS-CoV-2. The World Health Organization declared the SARS-CoV-2 outbreak a global public health emergency. We performed genetic analyses of eighty-six complete or near-complete genomes of SARS-CoV-2 and revealed many mutations and deletions on coding and non-coding regions. These observations provided evidence of the genetic diversity and rapid evolution of this novel coronavirus.
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              Is Open Access

              Systematic Comparison of Two Animal-to-Human Transmitted Human Coronaviruses: SARS-CoV-2 and SARS-CoV

              After the outbreak of the severe acute respiratory syndrome (SARS) in the world in 2003, human coronaviruses (HCoVs) have been reported as pathogens that cause severe symptoms in respiratory tract infections. Recently, a new emerged HCoV isolated from the respiratory epithelium of unexplained pneumonia patients in the Wuhan seafood market caused a major disease outbreak and has been named the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This virus causes acute lung symptoms, leading to a condition that has been named as “coronavirus disease 2019” (COVID-19). The emergence of SARS-CoV-2 and of SARS-CoV caused widespread fear and concern and has threatened global health security. There are some similarities and differences in the epidemiology and clinical features between these two viruses and diseases that are caused by these viruses. The goal of this work is to systematically review and compare between SARS-CoV and SARS-CoV-2 in the context of their virus incubation, originations, diagnosis and treatment methods, genomic and proteomic sequences, and pathogenic mechanisms.
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                Author and article information

                Contributors
                Journal
                Med Hypotheses
                Med. Hypotheses
                Medical Hypotheses
                Elsevier Ltd.
                0306-9877
                1532-2777
                7 May 2020
                7 May 2020
                : 109824
                Affiliations
                Department of Pathology and Surgery, University Hospital of Modena, Modena, Italy
                Author notes
                [* ]Corresponding author: Polyclinic Hospital, Largo del Pozzo 71 - 41124 Modena (MO), Italy emailmedical@ 123456gmail.com roncati.luca@ 123456aou.mo.it
                Article
                S0306-9877(20)30558-2 109824
                10.1016/j.mehy.2020.109824
                7204740
                32408068
                0fa33f26-e56c-4489-897c-d79cae841b1a
                © 2020 Elsevier Ltd. All rights reserved.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                History
                : 28 March 2020
                : 17 April 2020
                : 6 May 2020
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                Medicine
                Medicine

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