Shared B cell memory to coronaviruses and other pathogens varies in human age groups and tissues - Science

We evaluated convergent antigen-specific antibody genes of similar sequences shared between individuals in pediatric and adult blood, and deceased organ donor tissues.

Adults had higher clone frequencies and greater class-switching in lymphoid tissues than blood, while pediatric blood had abundant class-switched convergent clones.

Consistent with reported serology, pre-pandemic children had class-switched convergent clones to SARS-CoV-2 with weak cross-reactivity to other coronaviruses, while adult blood or tissues showed few such clones.

Humoral immune responses can differ between children and adults, as seen in children utilizing more B cell clones to achieve neutralizing antibody breadth to human immunodeficiency virus 1 (HIV-1) (6).

Whether B cell clones specific for coronaviruses and other pathogens differ between children and adults is unclear.

To study changes in antigen-specific B cell memory over the human lifespan and across tissues, we characterized convergent Ig heavy chain (IGH) repertoires specific to six common pathogens, and two viruses not encountered by the participants, Ebola virus (EBOV) and SARS-CoV-2, in pre-COVID-19 pandemic individuals.

Convergent clones in children and adults were largely mutM/D or CS (Fig. 1A and fig. S1).

In adult blood, convergent clones for Hib, NM, and RSV were predominantly mutM/D clones, whereas PP, TT, and flu clones were predominantly CS (fig. S2A).

Adults over 45 years of age had elevated mutM/D B cell clone frequencies to NM, potentially from exposures preceding widespread NM vaccination (20).

Surprisingly, children had higher frequencies than adults of CS convergent clones for Hib, PP, TT, and RSV (fig. S2B), with mutated IgM or IgD also found in these clones (Fig. 1B).

Convergent clone frequency in children’s blood was not significantly associated with vaccination timing (figs. S3 to S5 and table S3), indicating persistently elevated frequencies.

Flu-specific convergent clone frequencies were comparable in children and adults (Fig. 1A), with age-related increases in IgG SHM potentially due to frequent exposures via vaccination or infection (Fig. 1C) (18).

Children have significantly higher fractions of class-switched convergent clones with mutated IgM/IgD clone members (colored in purple) than adults, (P = 5.08 × 10−32, 6.66 × 10−29, 2.39 × 10−29, 3.45 × 10−34, and 1.71 × 10−41 for Hib, NM, PP, TT, and RSV, respectively, by Wilcoxon–Mann–Whitney (WMW) test).

SHM frequencies of convergent clones expressing IgG or IgA were lower in children than in adults (P = 6.50 × 10−13 and 1.96 × 10−8, respectively, WMW test).

To test whether low frequencies of CS convergent clones in adult blood reflect preferential localization of clones in lymphoid tissues, we analyzed the blood, spleen, mediastinal lymph nodes (MDLN), and mesenteric lymph nodes (MSLN) of eight adult deceased organ donors.

Convergent clones frequencies for Hib, NM, PP, TT, RSV, and flu were higher in adult lymph nodes and spleen than blood (Fig. 2A).

Adult lymph nodes and child blood shared more convergent clones than adult and child blood, showing differing distributions of these clones in children and adults (Fig. 2B and fig. S8, P = 0.0001181, Fisher’s exact test).

However, frequencies of convergent clones for Hib, NM, and PP are similar or higher in lymph nodes than in spleen.

(A) Convergent clone frequencies in adult blood (PBMC), MDLN, MSLN, and spleen.

(B) Convergent antigen-specific IGH in CB and blood of children, healthy adults (Adult* PBMC), deceased organ donors (Donor PBMC), and donor spleen, MSLN and MDLN.

By contrast, convergent clones for SARS-CoV-2 (table S4) were more common in children’s blood.

Adult frequencies of SARS-CoV-2 convergent clones were lower in blood and lymphoid tissues compared to children’s blood, with few CS examples (Fig. 3A and fig. S9).

CS and mutM/D convergent clone frequencies for SARS-CoV-2 are higher in children than adults (P = 1.22 × 10−13 and 0.0089, respectively, WMW test).

Top row: CDR-H3 sequence logos for reported antigen-specific clones; Second row: sequence logos for convergent clones from children (blue indicates a match, cyan indicates sequence differences).

Three convergent clones from five children but no adults in this study had IGH sequences highly similar to SARS-CoV-2 S-binding clones isolated from a pre-pandemic donor that were reported to weakly bind other HCoV spikes (26) (Fig. 3C).

Thus, children’s convergent coronavirus-binding B cells may have greater cross-reactivity compared to those of adults, in addition to having higher frequencies.

We find that in comparison to adults, children have higher frequencies of convergent B cell clones in their blood for pathogens they have encountered.

Notably, pre-pandemic children also had class-switched convergent clones to SARS-CoV-2 and its viral variants, but not EBOV, at higher frequencies than adults.