24 Nov 2021 Episode 191 : Children, cross-reactivity and innate immunity

Wed, 11/24/2021 - 18:41

Dear colleagues,


Responding to a request of colleagues-pediatricians, I will come back on the question of why children are generally less ill from COVID and whether cross-reactivity with common cold coronaviruses (CCCoV) or other factors play a role. This episodes is an extension of Ep 172 (from which some important papers are included here again.


Ep 191-1 and 2:  Two science journalists reviews in Nature that I will work out and complement with additional info below. 


Ep 191-3: Huang in Nat Comm March 2020 reviews the early evidence of cross-reactivity between and amongst human alpha and beta CoV.  Even before the advent of SARS-CoV-2, it was evident that cross-reactivity was limited, that antibody titers waned over months and that immunity to CoV is rather short-lived: repeated infections with “common cold CoV” (CCCoV) are in fact the rule.


Ep 191-4 A: Kevin Ng in Science Dec 2020 finds Ab in uninfected children and adolescents that are not only cross-reacting CCCoV but also neutralize SARS-CoV-2. These Ab react with both the more conserved S2 (fusion) and the more specific S1 (with RBD) parts of Spike.


He then concludes:

  • Epidemiological studies of seasonal CCCoV transmission suggest that cross-protective immunity is unlikely to be sterilizing or long-lasting, as supported by repeated reinfection
  • A possible modification of COVID-19 severity by prior CCCoV infection may account for the age distribution of COVID-19 susceptibility, in which higher CCCoV infection rates in children than in adults correlate with relative protection from COVID-19


Ep 191-4 B: Frailey Naty Comm May 2021 investigated SARS-CoV-2 (cross)-reactive Ab in more detail and identified regions in the spike protein that are commonly recognized by antibodies from many SARS-CoV-2-infected or SARS-CoV-2 cross-reactive antibodies detected in seronegative individuals.

Fig 1 clearly shows that these “cross-reactive Ab

  • are not selective for SARS-CoV-2 negative children, but also present in adults
  • focus mainly nucleoprotein and S2 (= more conserved core and fusion part of S)
  • have >> log lower concentration than in SARS-CoV-2 positive subjects


This study did not evaluate the functional characteristics (e.g. neutralization).  


Ep 191-4 C: Selva in Nat Comm Apr 2021 confirms “moderate levels of cross-reactive, but non-neutralizing, SARS-CoV-2 antibodies in pre-pandemic healthy individuals


There are differences in subclass and functionality according to age:

  • Healthy elderly more cross-reactive IgA and IgG versus IgM in healthy children
  • Children have stronger Fc responses

→  Children have fewer hCoV exposures, resulting in less-class switched but more polyreactive antibodies

A full maturation of antibody function only after infection (or vaccination?)


Ep 191-5:  Tossif Nat Comm Nov 2020 : Children of PCR-positive parents can mount an antibody response to SARS-CoV-2 without virological confirmation of infection, raising the possibility that immunity in children can prevent the establishment of SARS-CoV-2 infection.


Ep 191-6: Pierce in Sc Trans Med Oct 2020 comparing hospitalized adult and pediatric patients in NYC:

  • Children clinically better off (as we known)
  • Serum interleukin-17A (IL-17A) and IFN-γ, but not TNF or IL-6: higher in children
  • The neutralizing antibody titer correlated positively with age and negatively with IL-17A and IFN-γ serum concentrations, meaning that children in fact tended to have LOWER levels of specific neutralizing antibodies. See Fig 5 p. 7.
  • There was NO difference in antibodies against CCCoV between children and adolescent, also irrespective of disease severity (in hospitalized patients).  See Fig 4 p. 6.
  • Adults mounted a more robust T cell response to the viral spike protein compared to pediatric patients as evidenced by increased expression of CD25+ on CD4+ T cells and the frequency of IFN-γ+ CD4+ T cells.


This study shows that adaptive immunity (T and B) responses is rather stronger in adults than children, although the latter are clinically better off. 


This suggests (but does not prove) that factors of innate immunity control the infection earlier and better in children.  The raised levels of IL17 and IFN-γ could be an indication.

On the other hand, the adaptive immunity in adults seem “over-reactive” and potentially pathogenic.


Ep 191-7: These findings are confirmed by Cohen in Nat Comm July 2021 in Hong-Kong

  • Infected children have lower CD4+ and CD8+ T cell responses to SARS-CoV-2, and reduced CD4+ T cell effector memory, as compared to adults.
  • Children have lower levels of antibodies to CCCoV β-coronaviruses than adults
  • The quality (polyfunctionality and exhaustion markers) of T  cell responses was however similar in children and adults
  • Children presented with higher recruitment of T helper follicular cells (important for antibody maturation).
  • Also lower levels of inflammatory monocytes in children.


Reduced prior β-coronavirus immunity and reduced T cell activation in children might drive milder COVID-19 pathogenesis ?


Ep 191-8: Li-En Hsieh in Eur J Imm Oct 2021 investigated T cell responses in children with SARS-CoV-2 associated hyperinflammatory MIS-C or Kawasaki syndromes versus convalescent control children. Very remarkably:

  • T-cell specificities in MIS-C did not correlate with disease severity and were similar to SARSCoV-2 convalescent controls.
  • T-cell memory and cross-reactivity to CCCoV in MIS-C and SARS-CoV-2 convalescent controls were also similar.

The only potentially difference is a lower proportion of myeloid dendritic cell precursos in the MIS-C patients, which the authors interpret as “tolerogenic” and potentially impairing the anti-inflammatory response….


Ep 191-9: Silverstein (Bruce Walkers group) in medRxiv Oct 2021 turns his attention to the so-called “Innate Lymphoid Cells” (or ILC). 

ILCs lack clonotypic antigen receptors but overlap developmentally and functionally with T cells. Based on expression of characteristic transcription factors and specific cytokines, ILCs are classified into ILC1, ILC2, and ILC3 subsets that are analogous to TH1, TH2, and TH17 cells respectively. 

Physiologically, ILCs decrease more than 7-fold over the human lifespan — T cell subsets decrease less than 2-fold — and are lower in males than in females.


The question in this paper is how this relates to COVID, but the answer is complex:

  • In adults: ILCs, but not T cells, were lower in hospitalized with COVID-19: a higher level of ILC seemed to protect against severe disease.
  • In children with COVID disease, ILC (not T cells) also decreased, while in MIS-C both ILC and T cells decreased.
  • Blood ILCs produced amphiregulin, a protein implicated in disease tolerance



  • ILCs decrease morbidity and mortality associated with SARS-CoV-2 infection,
  • Lower ILC abundance accounts for increased COVID-19 severity with age and in males


Ep 191-10: Neeland in Nat Comm find reduced circulating monocytes, natural killer cells and dendritic cells, but increased proportion of activated neutrophils  during acute phase of COVID in children.  Activated neutrophils were also observed in exposed uninfected children and adults.


→  These findings are interpreted as evidence of “redistribution”: these innate cells may disappear from the circulation to concentrate in the site of infection.   Presence of immune and inflammatory cells in broncho-alveolar lavage has been shown in adult (but not pediatric) COVID patients.



Ep 191-11:  Carl Pierce et al in JCI Insight Feb 2021 provide direct evidence of more vigorous anti-viral and inflammatory response at the nasopharyngeal mucosa in children versus adults: besides confirming higher IL17-A and IFN-gamma (just like in blood see Ep 191-6) they now show also higher type 1 IFN and higher IL1beta and IL-18 at the mucosal site

Remarkable, levels of IgG and IgA antibodies were similar in children and adults.


Ep 191-12:  A very elegant paper by Loske in Nature Biotechnology showing that the nasal mucosa in children is “pre-activated” for antiviral responses, because of higher basal expression of “RNA sensors” such as MDA5 and RIG-I in epithelial cells, macrophages and dendritic cells  (amongst other differences, such as presence of specialized CD8 T cells).


This is a groundbreaking paper, because it goes beyond associations and strongly suggests that the airway immune cells of children are primed for virus sensing, resulting in a stronger early innate antiviral response to SARS-CoV-2 infection than in adults.



Ep 191-13: Buccioli and Meyts in Curr Op Pediatrics review the severity of 649 COVID in pediatric (and some adult) patients with various inborn errors of immunity (IEI).  An overview is shown in Table 1 p. 649. 

  • The overall case fatality rate (CFR) is 9 %, which is rather high, but nevertheless the authors stare that IEI per se is NOT an independent risk factor. It is clearly dependent on the IEI type
  • Closer analysis shows that three conditions contribute most to enhanced risk:
    • Severe combined immune deficiency (in both T and B cells and not corrected by hematopoietic stem cell transplantation) CFR = 54 %
    • Good syndrome (thymoma with hypogammaglobulinemia)  CFR = 43 %
    • Inborn errors of type 1 IFN pathway or auto-antibodies to type 1 IFN (the latter in often in the context of auto-immune polyendocrine syndrome-1) are an important risk factor for severe disease (up to 10 % of all critical COVID-19 cases).
    • In 23 of 649 patients, hyper-inflammatory syndromes such as multisystem-inflammatory system (MSC) or hemophagocytic lymphohistiocytosis (HLH)


Ep 191-14: Sealy and Hurwitz review some of the data on cross-reactivity:

  • In SARS-CoV-2-unexposed humans, cross-reactive serum antibodies were identified toward nucleocapsid (N) and the spike subunit S2.  Those S2-specific antibodies were in some cases associated with neutralization
  • SARS-CoV-2-unexposed humans rarely exhibited antibody responses to the SARS-CoV-2 spike subunit S1, and when naïve mice were immunized with adjuvanted S1 from either SARS-CoV-2 or common cold HCoVs, S1-specific antibodies were poorly cross-reactive.
  • Cross-reactive T cells, like antibodies, were present in humans prior to SARS-CoV-2 exposures and increased following SARS-CoV-2 infections

It remains unclear whether these cross-reactive Ab or T cells are associated with some level of protection or exacerbation.

Besides studies in animals, also well-controlled challenge experiments in humans with different level of cross-reactive T and B cells may clarify their role.


General conclusions

  1. Cross-reactivity between Common Cold CoV and SARS-CoV-2 is clearly present at the level of both T cells and antibodies, but responses are lower and more focused on more conserved parts of nucleoprotein and S2. 
  2. Cross-reactivity is present both in adults and children, with different characteristics. The question whether this type of pre-existing immunity has a (protective or exacerbating) effect on SARS-CoV-2 infection is not settled. Human challenge experiments may provide more insight, but can they be done safely?
  3. To explain the very clear difference in clinical course between children and adults, difference  in innate immunity is the most likely explanation today: the respiratory mucosa of children is better equipped at the molecular level to sense RNA viruses and to quickly produce type-1 interferon (and subsequently activate interferon-stimulated genes.
  4. It is possible, but not yet clearly established that other innate factors, such as innate lymphocytes (ILC), monocytes, neutrophils, tolerogenic myeloid cells …  have also a role in protection against disease in children.