The Burden of Memory: Response to Ortega
Authors: Ger Rijkers
Journal: Trends in Immunology (2020)

At the time of writing a response to the letter from Enrique Ortega in this issue of Trends in Immunology [1.Ortega E. Is immunological memory a burden in times of Covid-19?.Trends Immunol. 2020; (Published online August 12, 2020. https://doi.org/10.1016/j.it.2020.08.004)Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar], on 15 July 2020, PubMed returned 31 963 results for the search term 'COVID-19'i and the preprint server MedRxiv, another 5175 manuscriptsii. Despite this overwhelming amount of data, it is still unclear what constitutes a protective immune response, while such a protective response of the immune system is key to survival of coronavirus disease 2019 (COVID-19). In my TrendsTalk, I stated that 'In times of COVID-19, it would seem as if loss of memory is the key to survival' [2.Rijkers G. Ger Rijkers: persistence of memory in times of COVID-19.Trends Immunol. 2020; 41: 453Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar]. Dr Ortega stresses the importance of immunological memory, and I agree. Indeed, having survived a primary infection with a given pathogen does not guarantee a favorable outcome of a subsequent infection with that same pathogen. During the primary response of the immune system, effector cells and molecules are generated, as well as (T and B) memory cells. Upon re-exposure to the same pathogen, the memory cells are activated, generating a faster, higher, and better response, in many cases so effective that the infection is cleared before any clinical symptoms occur. The progressive decrease in frequency and severity of upper and lower respiratory infections during early childhood is the best example of development of immunological memory in practice [3.Grüber C. et al.History of respiratory infections in the first 12 yr among children from a birth cohort.Pediatr. Allergy Immunol. 2008; 19: 505-512Crossref PubMed Scopus (141) Google Scholar]. In times of COVID-19, the situation is completely different. The global population, young and old, is exposed to a novel virus, requiring an effective primary immune response for survival. For this strain of coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the existing memory against circulating coronaviruses does not appear to offer clinical protection. It can even be argued that the major reason why SARS-CoV-2 could rise to pandemic proportions is the lack of cross-reactivity of existing memory against other circulating coronaviruses, although this remains unknown. From an evolutionary perspective, it is vital for the survival of populations that the young build up immunological memory against prevalent pathogens. The accumulation and persistence of long-lived memory cells offers protection during childhood, into adulthood, and well above the reproductive age. The current pandemic has taught us that a risk factor for severe COVID-19 includes age: hospital mortality is <5% among patients younger than 40 years, but increases to 35–60% for patients aged 70 years and older [4.Wiersinga W.J. et al.Pathophysiology, transmission, diagnosis, and treatment of Coronavirus disease 2019 (COVID-19): a review.JAMA. 2020; (Published online July 10, 2020. https://doi.org/10.1001/jama.2020.12839)Crossref Scopus (3313) Google Scholar]. A marked difference between infants and older individuals is a progressive shift from an immune system comprising many naïve lymphocytes (both T and B cells) and few memory cells to one that contains mostly memory cells and a smaller pool of naïve cells [5.Siegrist C.A. Aspinall R. B-cell responses to vaccination at the extremes of age.Nat. Rev. Immunol. 2009; 9: 185-194Crossref PubMed Scopus (474) Google Scholar]. The price to be paid might be that, at advanced age, an immune system comprising mainly memory cells precludes the generation of a robust and effective primary response against a newly emerging pathogen. ihttps://pubmed.ncbi.nlm.nih.gov/?term=COVID-19&sort=date&size=200 iiwww.medrxiv.org/search/COVID-19 Is Immunological Memory a Burden in Times of COVID-19?Enrique OrtegaTrends in ImmunologyAugust 12, 2020In BriefIn a recent TrendsTalk in Trends in Immunology, Ger Rijkers [1] concluded that 'In times of COVID-19, it would seem as if loss of memory is the key to survival'. We are witnessing the emergence of a new disease caused by a novel virus (severe acute respiratory syndrome coronavirus 2; SARS-CoV-2), and the mechanisms used by the human immune system to eliminate the infection in individuals recovering from the disease are yet unknown. Thus, the field is open to speculation. Nonetheless, various considerations make it difficult to visualize immunological memory as a factor contributing to coronavirus disease 2019 (COVID-19) mortality. Full-Text PDF Ger Rijkers: Persistence of Memory in Times of COVID-19 et al.Trends in ImmunologyApril 13, 2020In BriefIn a review paper published 20 years ago, Rolf Zinkernagel asked the question: Why do we need immunological memory [1]? His argument was that if you and your immune system survived a given infection once, then why wouldn't you survive it a second time? You wouldn't need a better response for that. And of course, if you did not survive the first infection, having developed memory would be irrelevant. Full-Text PDF