Milder COVID-19 in children may be due to higher memory B cells responses to SARS-CoV-2

The importance of durable immunity against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become increasingly evident, particularly as newer strains of the virus emerge, which are sometimes more infectious or partially resistant to neutralization by the antibodies produced by earlier strains.

A new research paper published in the journal Science explores the differences in coronavirus-specific B memory cell repertoires in children versus adults, as well as the functional importance of this discovery.

The study includes blood samples from both young children and adults.

B cell responses

The immune response includes B cells, which generate specific antibodies to engage and neutralize various pathogens, preventing the establishment of active infections. B cells must be activated in order for antibody generation to take place. Activation is dependent on the binding of specific ligands to the B cell receptor (BCR).

The BCR sequence thus determines which antigen it binds to, and in turn the sequence of the antibody produced. The great variety in immunoglobulin (Ig) antibody sequences is possible because of the rearrangement of the variable, diversity, and joining (VDJ) gene segment. The Ig sequences are further driven apart by somatic hypermutation (SHM), as well as class switch recombination (CSR).

Convergent BCRs

When different people are exposed to the same antigen, they may share very similar (convergent) BCRs, indicating that the antigen determines the B cell clone that is selected by activation. Thus, individuals may share a common immunological memory.

Antibody responses differ by age, with children often showing a broader B cell response to HIV-1 than adults and thus a broader spectrum of neutralizing antibodies.

The relatively mild phenotype of SARS-CoV-2 infection in children compared to adults could be due to variations in the distribution of the viral receptors, such as the angiotensin-converting enzyme 2 (ACE2), within the body, as well as changes in immune response with age.

In any case, children typically show lower antibody titers and higher SARS-CoV-2-spike-specific IgG levels compared to anti-N antibodies. This may be why they clear the virus faster and have lower viral loads.

Study aim

The study focused on examining B cell responses against the viral spike change over time and in different tissues. Earlier studies have focused mostly on blood samples.

Lymph nodes, spleen and digestive tract tissues have large numbers of B cells, and high rates of SHM and CSR occur within the immune cells at these sites, sometimes in a tissue-specific manner.

Study details

The samples for the study included cord blood, and samples from children aged 1-3 years, healthy adults 17-87 years, and various tissue samples from eight deceased organ donors.

The children had taken the following vaccinations:

• Haemophilus influenzae type b (Hib)
• Pneumococcus pneumoniae (PP)
• Tetanus toxoid (TT)
• Influenza

Most had probably been exposed to the respiratory syncytial virus (RSV).

The researchers analyzed the common Ig heavy chain (IGH) sequences formed in response to six common pathogens and in two novel pathogens – the Ebola virus (EBOV) and SARS-CoV-2. The presence of convergent BCRs to the latter was tested in samples dating to the pre-pandemic period.

Shared IGH sequences fell into three categories, beginning with BCRs that were unexposed to any antigens, the second containing BCRs exposed but without undergoing class switching, and the third having undergone class switching as well.

Thus, the first subset contained unmutated IgM and IgD, the second mutated IgM and IgD, and the third class-switched B cells. These are represented as unmutM/D, mutM/D, and CS, respectively.

Age-related mutations in IgG

The cord blood samples had the least number of common IGH frequencies, as expected since fetuses are not typically exposed to the above pathogens, or to vaccines expressing such antigens.

In adults and children, most shared clones were related to prior antigen exposure. Thus, mutated clones, with or without class switching from one antibody isotype to another, predominated.

In adults, most mutated clones producing IgM or IgD antibodies, indicative of acute exposure, were correlated with BCRs reactive to Hib, NM and RSV. Class-switched BCRs, seen in a mature immune response, was observed in most clones induced by PP, TT, and influenza viruses.

Surprisingly, in children, B cell clones convergent for Hib, PP, TT, and RSV showed class switching. Convergent clones were found to be persistently high in frequency in children, rather than showing a rise just after vaccination.

Since influenza is an annual and seasonal infection, the convergent flu-specific SHM-positive IgG BCR response showed an age-dependent rise. B cell clones were equivalent in frequency in adults and children.

In those over 45 years of age, NM-elicited mutated B cell clones were higher in frequency, probably because they were exposed at much higher levels before NM vaccines became common.

Enrichment of convergent BCRs in lymphoid tissue

The lower frequency of convergent class-switched clones in adult blood could be since these clones are accumulated in lymphoid tissues. This was confirmed by examination of various tissues from deceased organ donors. B cell clones appeared to expand more in lymphoid tissues and spleen and less frequently moved out of these sites.

Different clones were dominant in different tissues. Moreover, the total extent of SHM in a clone was linked to the number of tissues occupied by it. This indicates that as a clone is exposed to more antigens, it becomes dominant in more tissues.

Therefore, in adults, lymphoid tissue in the spleen and lymph nodes showed higher convergent clone frequencies for the six commonly encountered antigens, elicited either by vaccination or natural infection, compared to blood. Shared convergent clones were more likely to be found when adult lymphoid tissue was compared to blood samples from children, rather than a comparison of clones in blood samples from children and adults.

B cells bearing bacterial lipopolysaccharide (LPS)-specific receptors are enriched in the spleen. This means that patients who have undergone spleen removal are at higher risk of infection by such bacteria.

However, convergent clones for Hib, NM, and PP were found at comparable or higher frequencies in lymph nodes compared to the spleen. Also, since B cells are more abundant in lymph nodes than the spleen, the latter is not the only location where these are found.

Notably, the IGH of these convergent polysaccharide-specific clones are usually IgM and IgD, indicating acute exposure, with a few CS clones for PP are found in splenic and lymph node tissue.

Therefore, bacterial LPS antigens elicit memory B cells in multiple lymphoid tissues and of multiple isotypes.

Convergent SARS-CoV-2 clones in children

The finding that blood samples from children dating from before the pandemic also contained SARS-CoV-2 antibodies has attracted much attention, as these could potentially account for the milder phenotype in children. The current study shows that a majority of convergent clones for this virus result from prior antigen exposure, showing SHM, and sometimes CS as well.

Adults showed lower frequencies of these clones in blood and lymphoid tissue, and CS was less likely to be found.

The IGH sequence similarity of convergent B cell clones from several children in this study to pre-pandemic SARS-CoV-2 binding clones indicates a higher frequency of these coronavirus binding clones in children relative to adults.

Of 17 SARS-CoV-2 spike and spike domain binders identified by the researchers, four inhibited more than 90% of virus-receptor binding. Moreover, three monoclonal antibodies from child samples, and one from an adult, showed the most significant binding affinity for different viral variants, including B.1.1.7, B.1.351, and P.1.

The monoclonal antibodies expressed in this study reacted weakly to endemic human coronaviruses, though higher in children than in adults.

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

What are the implications?

The study implies that coronavirus-specific B cell repertoires are different in adults and children.

The immune exposures occurring in childhood are responsible for shaping the pool of memory B cells that defines future responses. The study shows that children have higher frequencies of convergent B cell clones against antigens that they have already encountered.  

For instance, children had higher frequencies of class-switched convergent clones to SARS-CoV-2 and its variants compared to adults.

Pre-existing B cell responses to earlier human coronaviruses could induce cross-reactive antibodies to the novel coronavirus during the current pandemic. If these clones are highest in frequency in childhood, it could explain why they have milder disease following SARS-CoV-2 infection compared to adults.

“These findings suggest that encounters with coronaviruses in early life may produce cross-reactive memory B cell populations that contribute to divergent COVID-19 susceptibilities.”

It is crucial to examine how cross-reactive memory B cell clones produce primary immune responses to related, though different viruses. This would help produce more effective vaccines against COVID-19 as well as future pathogens.

Source

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.