Memory B Cell Activation Induced by Pertussis Booster Vaccination in Four Age Groups of Three Countries

Abstract

Background: Immunogenicity of acellular pertussis (aP) vaccines is conventionally assessed by measuring antibody responses but antibody concentrations wane quickly after vaccination. Memory B cells, however, are critical in sustaining long-term protection and therefore may be an important factor when assessing pertussis immunity after vaccination.

Aim: We studied pertussis specific memory B cell (re)activation induced by an aP booster vaccination in four different age groups within three countries.

Materials and methods: From a phase IV longitudinal interventional study, 268 participants across Finland, the Netherlands and the United Kingdom were included and received a 3-component pertussis booster vaccine: children (7-10y, n=53), adolescents (11-15y, n=66), young adults (20-34y, n=74), and older adults (60-70y, n=75). Memory B cells at baseline, day 28, and 1 year post-vaccination were measured by a pertussis toxin (Ptx), filamentous haemagglutinin (FHA), and pertactin (Prn) specific ELISpot assay. Antibody results measured previously were available for comparison. Furthermore, study participants were distributed into groups based on their baseline memory B cell frequencies, vaccine responses were monitored between these groups.

Results: Geometric mean (GM) memory B cell frequencies for pertussis antigens at baseline were low. At 28 days post-vaccination, these frequencies increased within each age group and were still elevated one year post-booster compared to baseline. Highest frequencies at day 28 were found within adolescents (GM: 5, 21, and 13, for Ptx, FHA and Prn, respectively) and lowest within older adults (GM: 2, 9, and 3, respectively). Moderate to strong correlations between memory B cell frequencies at day 28 and antibody concentrations at day 28 and 1 year were observed for Prn. Memory B cell frequencies > 1 per 100,000 PBMCs at baseline were associated with significantly higher memory responses after 28 days and 1 year.

Conclusions: An aP booster vaccine (re)activated memory B cells in all age groups. Still elevated memory B cell frequencies after one year indicates enhanced immunological memory. However, antigen specific memory B cell activation seems weaker in older adults, which might reflect immunosenescence. Furthermore, the presence of circulating memory B cells at baseline positively affects memory B cell responses. This study was registered at www.clinicaltrialsregister.eu: No. 2016-003678-42.

Keywords: pertussis; adolescents; adults; children; longitudinal; memory B cells; older adults; vaccination.

Figure 1

Flow diagram BERT-study.

Figure 2

Individual memory B cell frequencies in four age groups. Bmems, memory B cell frequencies; PBMCs, peripheral blood mononuclear cells; D0, day 0 (baseline); D28, day 28 post-vaccination; Y1, 1 year post-vaccination. Memory B cell frequencies specific for (A) pertussis toxin; (B) filamentous haemagglutinin; and (C) pertactin. Presented in truncated violin plots. Corresponding geometric mean frequencies and 95% confidence interval are presented in Table 2 .

Figure 3

Geometric mean memory B cell frequencies per priming vaccination background with 95% confidence intervals. Significances were calculated using a linear mixed model on the log10 transformed data taking the longitudinal structure into account. Bmems, memory B cell frequencies; PBMCs, peripheral blood mononuclear cells. Memory B cell frequencies in adolescents from the Netherlands and Finland together (aP priming n=22, wP priming n=18) specific for (A) pertussis toxin; (B) filamentous haemagglutinin; and (C) pertactin. Observed differences between the aP and wP primed cohorts did not reach significance.

Figure 4

Correlations between memory B cell frequencies and antibody concentrations presented as heatmaps per antigen for all participants together based on Pearsons’ correlation on the log10 transformed memory B cell frequencies and antibody concentrations. Ptx: pertussis toxin; FHA, filamentous haemagglutinin; Prn, pertactin; Bmem, memory B cell frequencies; Abs, antibody concentrations; D0: day 0 (baseline); D28, day 28 post-vaccination; Y1, 1 year post-vaccination. Correlations for (A) pertussis toxin; (B) filamentous haemagglutinin; and (C) pertactin.

Figure 5

Memory B cell responses to different antigens based on a defined frequency cut-off of > 1 memory B cell/100,000 PBMCs. Bmems: memory B cell frequencies; PBMCs, peripheral blood mononuclear cells. Geometric mean memory B cell frequencies with 95% confidence intervals for the combined age groups distributed into two groups based on baseline memory B cell frequencies for (A) pertussis toxin; (B) filamentous haemagglutinin; and (C) pertactin. Corresponding antibody geometric mean concentrations for the two groups for (D) pertussis toxin, (E) filamentous haemagglutinin; and (F) pertactin. Number and proportion of participants in the group with frequencies ≤ 1 memory B cell/100,000 PBMCs can be viewed in Table 3 . *p < 0.001; **p = 0.003.