The memory B cell response to influenza vaccination is impaired in older persons

Abstract

Influenza imparts an age-related increase in mortality and morbidity. The most effective countermeasure is vaccination; however, vaccines offer modest protection in older adults. To investigate how ageing impacts the memory B cell response we tracked haemagglutinin specific B cells by indexed flow sorting and single cell RNA sequencing in twenty healthy adults administered the trivalent influenza vaccine. We found age-related skewing in the memory B cell compartment six weeks after vaccination, with younger adults developing haemagglutinin specific memory B cells with an FCRL5+ 'atypical' phenotype, showing evidence of somatic hypermutation and positive selection, which happened to a lesser extent in older persons. We confirmed the germinal center ancestry of these FCRL5+ 'atypical' memory B cells using scRNASeq from fine needle aspirates of influenza responding human lymph nodes and paired blood samples. Together, this study shows that the aged human germinal center reaction and memory B cell response following vaccination is defective.

Mechanisms underpinning poor antibody responses to vaccines in ageing

“…Memory B cell formation, which is another important output of the GC reaction, has also been shown to be impaired in older individuals. A recent study from our lab showed that there is impaired expansion of antigen-specific memory B cells in the peripheral blood of older adults post-influenza immunisation [79] . This age-related impairment in antigen-specific memory B cell formation was also observed after SARS-CoV-2 vaccination with mRNA-based vaccines [80] .…”

“…It has been proposed that ABCs represent a heterogenous population that can include plasma cell precursors, recently activated cells or recirculating memory B cells depending on context [202] , [203] , [204] , [205] . After seasonal influenza vaccination of younger and older people, the formation of haemagglutinin-specific memory B cells, including FCLR5+ atypical B cells, is impaired in older individuals [79] . This is despite the accumulation of ABCs with age, and thus it is likely that the increased frequency of ABCs with age represents the memory B cell pool acquired over the multiple immune challenges throughout the individual's lifetime, and that the formation of new vaccine-responsive ABCs is impaired during ageing.…”

“…As such, older people may be less able to adapt their antibody responses to antigenically distinct epitopes on emerging drifted and shifted strains, rendering them more vulnerable to new strains of influenza virus. The process of GC B cell selection after SHM also seems to be perturbed with age, as evident from a decrease in the replacement/silent ratios in the IgVH genes in activated B cells after influenza vaccination and in GC B cells in the Peyer's patch [ 79 , 209 , 226 ]. This may suggest that apart from B cell-intrinsic defects, extrinsic changes with age, such as those described above in FDCs and Tfh cells, may also contribute to poorer affinity maturation observed in immune responses in aged individuals post-vaccination.…”

“…In aged mice, FDCs have intrinsic defects in activation and expansion, and are impaired in immune complex retention, which contributes to a lower magnitude of the GC response [ 151 , 166 ]. Defects in FDC function and Tfh cell help can contribute to impairments in the positive selection process of GC B cells [ 79 , 209 , 226 ]. Eventually, an impaired GC response results in poor memory B cell [ 79 , 228 ] and long-lived plasma cells formation and reduced vaccine-induced antibody titres in older individuals [ 7 , 12 , 58 , 59 , 74 , 77 ].…”

B Cell Responses against Influenza Viruses: Short-Lived Humoral Immunity against a Life-Long Threat

“…In accordance, older adults are less likely to seroconvert against influenza viruses and generally have lower neutralizing antibody titers than younger adults [ 131 , 132 ]. Moreover, MBCs from elderly subjects are less likely to re-enter into GCs and further affinity mature against drifted variants [ 51 , 133 , 134 , 135 ]. Notably, GC B cells in elderly mice and humans are noted for their reduced expression of activation-induced cytidine deaminase (AID) [ 136 , 137 ], an enzyme critical for somatic hypermutation.…”