This is the first study to describe serotype-specific Bmem response kinetics over a 12-month period following a 0 + 1 or 1 + 1 infant schedule of PCV10 and PCV13. It is also the first study to evaluate Bmem responses in an LMIC setting as part of a large RCT. We found that Bmem levels peaked at seven days post-vaccination in contrast with IgG levels that peaked at 28 days post-vaccination. Importantly, Bmem levels were similar for both vaccines following a 0 + 1 schedule, but in a 1 + 1 schedule PCV13 induced higher Bmem levels than PCV10. When compared with serotype-specific IgG concentrations, Bmem levels did not wane as rapidly by 12 months post-vaccination with the 1 + 1 schedules for most serotypes.
Very few studies have assessed Bmem responses following a single infant dose of PCV and none of these studies assessed responses at the seven-day post-vaccination timepoint. A study of Kenyan toddlers aged 12–23 months found that a single dose of PCV10 elevated Bmem levels to serotypes 1 and 19F one month post-vaccination. 17 Our previous RCT in Viet Nam found that after a single dose of PCV10 at 18 months of age, Bmem responses to serotypes 1 and 18C remained higher than unvaccinated children at six months post-vaccination. 18 In our current study, the 0 + 1 schedule resulted in stronger Bmem responses for serotypes 1, 6B, and 19A with PCV13 compared to PCV10. We also found that Bmem levels peaked at seven days following a 1 + 1 schedule for both PCV10 and PCV13. The few studies that have examined PCV Bmem responses in infants and young children have only studied the day 28 timepoint post-vaccination due to the feasibility of such studies. Serotype-specific IgG concentrations and opsonophagocytic titres are currently used for licensure of PCVs. There are established IgG correlates of protection for IPD but not for carriage or mucosal diseases including pneumonia. As such, there is a need to identify novel correlates of long-term protection following PCV use, especially for reduced-dose schedules. A three-dose primary PCV schedule without booster has been introduced into many LMICs. This schedule elicits high antibody titres during the first year of life and has led to major reductions in paediatric morbidity and mortality. 22, 23 However, pneumococcal meningitis outbreaks continue to impact older children and adults in the African meningitis belt, 24 which suggests poor achievement of herd immunity. Therefore, high antibody concentrations may not translate to high vaccine efficacy in these settings, 11 which is further compounded by the lower efficacy of PCV in some African settings due to higher carriage rates and force of infection. 25
Correlates of protection based on IgG response also differ between serotypes. Although the use of the 0.35 µg/mL correlate of protection has enabled the introduction of PCVs in many settings, serotype-specific correlates of protection could provide a more accurate prediction of protection against common serotypes. 26 Since antibody concentrations may not be a perfect indication of long-term protection, there is a need to assess Bmem and other novel markers of PCV immunity. We found that Bmem levels were strongest against serotype 1 in the PCV13 0 + 1 and PCV10/13 1 + 1 arms. This is of importance as serotype 1 is a leading cause of pneumococcal meningitis in children living the African meningitis belt. 27 Interestingly, however, the high Bmem levels for serotype 1 with the 0 + 1 schedules did not reflect the results from our opsonophagocytic assays which were low at 28 days post-vaccination. 9
A unique aspect of our study was the head-to-head comparison of Bmem responses following PCV10 and PCV13 as part of a RCT. We observed that PCV13 elicited stronger Bmem levels in the 1 + 1 compared to the 0 + 1 arm for all serotypes. PCV10 elicited similar Bmem levels in the 0 + 1 and 1 + 1 arms, although levels for serotypes 5 and 6B were higher in the 1 + 1 arm. In the PCV13 1 + 1 arm, Bmem levels for all serotypes waned from peak timepoint (12m + 7d) to 12 months post-vaccination (24m), but did not return to baseline levels (12m). A UK study found that a 2 + 1 schedule of PCV13 resulted in elevated Bmem levels for serotypes 1, 4, 9V, 3, and 19A one month post-vaccination, whereas no increases were seen with PCV10. 15 However, Bmem levels waned at 12 months post-vaccination in both arms, apart from serotypes 14 and 19A with PCV10 and serotype 3 with PCV13. Our large RCT was conducted in a setting with high carriage rates and no routine use of PCVs, and showed sustained Bmem levels over time.
It is hypothesised that Bmem may be a more useful marker of long-term protection as their levels do not significantly wane over time as seen with antibody concentrations. Existing data from adult challenge studies have shown the relationship between Bmem and carriage, but whether this is also seen in infants is not known. 13, 28 Our study was able to compare waning of Bmem levels and IgG concentrations over time following vaccination in the 1 + 1 schedules. We found that for all serotypes, the extent of Bmem waning from peak timepoint to 12 months post-vaccination was not as pronounced as seen with IgG concentrations, and that Bmem levels remained detectable and did not return to baseline levels at 12 months post-vaccination. Our previous study in Viet Nam found that serotype-specific Bmem responses to a single dose of PCV10 persisted up to at least six months post-vaccination. 18 In our current study, Bmem responses had increased by 24 months of age in the 0 + 1 PCV schedules.
Our study found that Bmem levels generally peaked at seven days, before decreasing by 28 days, then increasing by 12 months post-vaccination. The increase at 12 months post-vaccination may suggest an immune response to carriage, which may have boosted Bmem levels by 24 months of age, particularly in the 0 + 1 groups. Although vaccine-type carriage decreased between 12 and 24 months of age in our RCT, both Bmem and IgG levels increased between these two timepoints. 9 We observed similar patterns of waning and subsequent elevation as a serosurveillance study from Malawi, which found that serotype-specific IgG concentrations waned in the nine months following a PCV13 3 + 0 schedule, but with subsequent elevation to five years of age. 29 It is likely that overall exposure to pneumococci during this period may not have been detected by our carriage outcomes as only two timepoints (18m and 24m) were measured. The elevated levels of Bmem and IgG at 24 months may have resulted from both vaccine response and boosting through carriage. However, while the 0 + 1 PCV schedules were immunogenic, they may not be sufficient to prevent carriage acquisition compared to the 1 + 1 PCV schedules.
The introduction of PCV programs has led to a decline in vaccine-type pneumococcal carriage in many settings. 30 However, global coverage of the WHO-recommended three-dose PCV schedule was low even prior to the COVID-19 pandemic, with an estimated coverage of 48% in 2019. 31 There is an even lower coverage in the Southeast Asian (23%) and Western Pacific (14%) regions, 31 where there is a high burden of pneumococcal disease. 32 Single-dose PCV schedules may be useful for catch-up campaigns in low-coverage settings or in humanitarian settings that face multiple barriers to immunisation. In this context, our data provides new insights into the long-term immunity and potential protection induced following a single dose of PCV.
Transitions to reduced-dose schedules require the maintenance of herd immunity through the control of vaccine-type carriage. The recent transition to a 1 + 1 PCV13 schedule in the UK was followed by an increase in IPD incidence in children aged 2–5 years, although overall incidence including adults, and differences in breakthrough and vaccine failure rates between the 1 + 1 and 2 + 1 schedules, were not significantly different pre- and post-transition. 8 The increase in IPD incidence was attributed primarily to serotype 3, but also 19F, 19A, and 4. While the immunological correlates of protection for IPD are defined, these are known to vary by serotype and are not available for pneumococcal carriage, which is a prerequisite for IPD. Early markers of pneumococcal immunity, such as Bmem responses, could be integrated with carriage data for association analysis. This could identify whether Bmem levels in the month following vaccination may be a more reliable marker of long-term protection against vaccine-type carriage acquisition or density at a later timepoint. There are also very few studies using flow cytometry to assess Bmem responses following PCV administration in infants. We are currently conducting studies using PBMCs from this RCT, focusing on a high dimensional spectral flow cytometry assay to measure serotype-specific Bmem levels and their correlation with nasopharyngeal carriage acquisition by five years of age.
The main limitation of this analysis was that a different set of participants were tested for Bmem levels at each timepoint. Due to ethical considerations, we could not collect the larger-volume blood samples required for these tests from the same participant at all study visits. However, baseline characteristics of participants were similar across the four vaccine arms and all between-group comparisons were made at individual timepoints. We also could not measure all serotypes in PCV10/13 due to limited number of PBMCs, but to our knowledge, this study represents the most comprehensive range of serotypes examined in any PCV study.
In conclusion, this study reports serotype-specific Bmem responses for 0 + 1 and 1 + 1 reduced-dose schedules of PCV10 and PCV13. Compared with IgG concentrations, Bmem levels waned to a lesser degree from peak timepoint to 12 months post-vaccination. There is a need to study the use of Bmem and other novel markers of long-term protection against pneumococcal carriage and disease, especially in LMICs and ideally from RCTs. Integrating Bmem data with carriage data could shed light on whether Bmem responses shortly after vaccination can help predict carriage acquisition at a later timepoint. This information is crucial in the current era where reduced-dose schedules are being considered by LMICs to improve access to pneumococcal vaccines and protect infants at high risk of disease.