key: cord-0835321-4wwkv621 authors: Bachar Ismail, Mohamad; Al Omari, Sarah; Rafei, Rayane; Dabboussi, Fouad; Hamze, Monzer title: COVID-19 in children: could pertussis vaccine play the protective role? date: 2020-09-28 journal: Med Hypotheses DOI: 10.1016/j.mehy.2020.110305 sha: 0426a15973684cbe54aab3c4bcb43170b575bc5e doc_id: 835321 cord_uid: 4wwkv621 While COVID-19 continues to spread across the globe, diligent efforts are made to understand its attributes and dynamics to help develop treatment and prevention measures. The paradox pertaining to children being the least affected by severe illness poses exciting opportunities to investigate potential protective factors. In this paper, we propose that childhood vaccination against pertussis (whooping cough) might play a non-specific protective role against COVID-19 through heterologous adaptive responses in this young population. Pertussis is a vaccine-preventable infectious disease of the respiratory tract and it shares many similarities with COVID-19 including transmission and clinical features. Although pertussis is caused by a bacterium (Bordetella pertussis) while COVID-19 is a viral infection (SARS-CoV-2), previous data showed that cross-reactivity and heterologous adaptive responses can be seen with unrelated agents of highly divergent groups, such as between bacteria and viruses. While we build the arguments of this hypothesis on theoretical and previous empirical evidence, we also outline suggested lines of research from different fields to test its credibility. Besides, we highlight some concerns that may arise when attempting to consider such an approach as a potential public health preventive intervention against COVID-19. ABSTRACT 24 While COVID-19 continues to spread across the globe, diligent efforts are made to 25 understand its attributes and dynamics to help develop treatment and prevention 26 measures. The paradox pertaining to children being the least affected by severe illness 27 poses exciting opportunities to investigate potential protective factors. In this paper, 28 we propose that childhood vaccination against pertussis (whooping cough) might play 29 a non-specific protective role against COVID-19 through heterologous adaptive 30 responses in this young population. Pertussis is a vaccine-preventable infectious 31 disease of the respiratory tract and it shares many similarities with COVID-19 32 including transmission and clinical features. Although pertussis is caused by a 33 bacterium (Bordetella pertussis) while COVID-19 is a viral infection (SARS-CoV-2), 34 previous data showed that cross-reactivity and heterologous adaptive responses can be 35 seen with unrelated agents of highly divergent groups, such as between bacteria and 36 viruses. While we build the arguments of this hypothesis on theoretical and previous empirical 38 evidence, we also outline suggested lines of research from different fields to test its 39 credibility. Besides, we highlight some concerns that may arise when attempting to 40 consider such an approach as a potential public health preventive intervention against 41 COVID-19. The novel coronavirus disease pandemic, caused by severe acute 48 respiratory syndrome coronavirus 2 (SARS-CoV-2), has posed challenging questions 49 to researchers about the dynamics of its interaction with the immune system of the 50 human host. One of the main questions concerns the consistent observation that the 51 disease is less frequent and severe in children and adolescents than in adults [1] [2] [3] [4] . 52 Indeed, current epidemiological evidence shows that this young population has 53 accounted for only 1%-5% of diagnosed COVID-19 cases, with significantly milder 54 clinical presentations and extremely rare deaths [2] . 55 Several explanations have attempted to explain why adults who have mature 56 immunity seem to be more strongly hit than children whose immunity is incompletely Heterologous immunity is that resulting from an encounter with a specific pathogen, 73 providing protection against another unrelated pathogen [11, 12] . Such non-specific 74 immunity can, therefore, broaden the protective effects of vaccinations and natural 75 resistance to infections [12] . Non-specific heterologous immunity is normally not as 76 effective as specific homologous immunity, but it may decrease the severe course of 77 heterologous infections, thus reducing their related morbidity and mortality [12, 13] . The longstanding concept of vaccine heterologous effects can be virus-induced, as in 79 the case of measles and oral polio vaccines [14, 15] , or bacteria-induced as resulting immunity [11, 12, [17] [18] [19] . 85 Heterologous adaptive lymphocyte responses generally mediate long-term effects. They may be induced by several potential mechanisms including (i) activation of 87 lymphocytes with cross-reactive antigen receptors due to molecular mimicry between 88 unrelated microbial antigens (antigen cross-reactivity), (ii) bystander activation of 89 unrelated lymphocytes that are specific for non-targeted antigens and (iii) 90 Lymphocyte-dependent activation of innate immune cells, via the production of pro-91 inflammatory cytokines (e.g interferon-gamma (IFN-γ) [11, 12, 17, 20, 21] . To note, 92 this latter state of lymphocyte-dependent induction of a heightened innate immune 93 response against a secondary infection wanes rapidly once the initial pathogen is 94 cleared [22] . However, as it is mediated by adaptive immunity induced against a 95 primary pathogen, exerting beneficial collateral effects on the innate host responses to 96 a secondary pathogen, it can be characterized as being by-products of adaptive 97 immunity [23]. Innate trained immunity 99 Innate trained immunity is mediated by the induction of a non-specific immunological 100 memory in prototypical innate immune cells, especially monocytes, macrophages, or 101 natural killer cells [24, 25] . This enhances responsiveness to subsequent triggers. Molecular mechanisms underlying this type of non-specific immunity involve both 103 epigenetic reprogramming, specifically through histone modifications, as well as 104 metabolic rewiring (e.g. the shift from oxidative phosphorylation toward aerobic 105 glycolysis) [11, 24] . However, the duration of trained immunity effects is highly 106 unlikely to be as long-lived as classical immunological adaptive memory [24] . Indeed, protected. Moreover, the current thinking is that BCG-mediated non-specific 123 protection against COVID-19 relies on innate trained immunity [30, 31] . However, as 124 mentioned above, this latter exerts short-time effects lasting for months and subsiding 125 by one year post-immunization. Yet, young adolescents are also markedly less 126 severely affected by COVID-19 than adults [3, 4] , reflecting that this feature is not 127 restricted to the early childhood months or years. Hence, short-lived trained immunity 128 induced by BCG maybe not able to completely explain the non-specific protective 129 effect against COVID-19. To note, the same logic also applies to short-term trained 130 immune responses that may be possibly induced by other vaccines or stimuli. Concerning MMR, this vaccine is known to provide specific long-term adaptive 132 immunity that lasts in adults. Indeed, according to the Centers for Disease Control and In this line of thought, the candidate vaccine should be one that is routinely used 140 worldwide but which provides relatively "medium-term" adaptive immunity that 141 confers temporary protection during childhood and adolescence, but fades away when 142 reaching adulthood, thus requiring boosters. Potential candidates for this description 143 may be pertussis vaccines, globally included in recommended immunization 7 144 schedules, and known to induce such kinds of "medium-term" immune adaptive Overall these data showed that cross-reactivity occurs between bacteria and viruses 172 and that heterologous adaptive responses are involved in non-specific immunity 173 between these two different types of microorganisms. Therefore, although this was not the case with SARS-CoV, cross-reactivity between 295 unique epitopes specific for SARS-CoV-2 and pertussis vaccines remains possible. Ag for antigen, # for the 15-mer predicted peptides by TepiTool able to bind to HLA class II 565 molecules. The accessions numbers of DTaP vaccine Ag compared to SARS-CoV-2 proteins using blastp 567 are Pertussis toxin subunit 1 (P04977), Pertussis toxin subunit 2 (P04978), Pertussis toxin 568 subunit 3 (P04979), Pertussis toxin subunit 4 (P0A3R5), Pertussis toxin subunit 5 (P04981), 569 Filamentous hemagglutinin (P12255), Pertactin autotransporter (P14283), Serotype 2 fimbrial 570 subunit (P05788), Serotype 3 fimbrial subunit (P17835), Diphtheria toxin (P00587), Tetanus 571 toxin (P04958). 2019-nCoV: Polite with children! Pediatr Rep Systematic review of COVID-19 in children shows milder cases 365 and a better prognosis than adults COVID-19 in children and adolescents in Europe: a 367 multinational, multicentre cohort study Severe Acute Respiratory Syndrome Coronavirus CoV-2) Infection in Children and Adolescents: A Systematic Review Why is COVID-19 so mild in children? 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