title: Evaluating impact and effectiveness of the 13-valent pneumococcal conjugate vaccine on Streptococcus pneumoniae vaccine-serotype pneumococcal carriage and population incidence of invasive pneumococcal disease in Blantyre, Malawi
Creators: name: Swarthout, Todd
Publisher: name: University of Liverpool Repository
Year: 2022

description: Background: Streptococcus pneumoniae (pneumococcus) is a leading cause of childhood morbidity and mortality worldwide. The 13-valent pneumococcal conjugate vaccine (PCV13) was introduced to the Malawian infant immunization programme on 12 November 2011. In Malawi, PCV continues to be administered using a 3+0 schedule (doses given at 6, 10, and 14 weeks of age, with no booster dose). This thesis aims to evaluate the impact of PCV13 on pneumococcal carriage and invasive pneumococcal disease (IPD) in Blantyre, Malawi, and to provide evidence to inform national stakeholders on the implementation of impactful vaccination strategies in Malawi. Methods: To evaluate PCV13’s impact on pneumococcal carriage, prospective nasopharyngeal carriage surveys were conducted in Blantyre, between 2015 and 2018, among healthy PCV age-eligible and -ineligible children, as well as HIV-infected adults on antiretroviral therapy (ART). The evaluation of PCV13’s impact on IPD was achieved by leveraging pneumococcal isolates from ongoing laboratory-based surveillance at Queen Elizabeth Central Hospital in Blantyre, including 6 years before and 7 years after the introduction of PCV13. Multiple pneumococcal serotyping methods were implemented and compared using samples from community carriage surveillance in Blantyre, Malawi, with evaluations of concordance between latex agglutination, whole-genome sequencing (WGS) with Pneumococcal Capsular Typing (PneumoCaT) software, and DNA microarray. Results: Despite evidence of reduced vaccine-serotype (VT) carriage over the study period, there is persistently high residual carriage among PCV-vaccinated children (16.1% relative reduction from 19.9%-16.7%), PCV unvaccinated children (40.5%; 26.4%-15.7%), and HIV- infected adults on ART (41.4%; 15.2%-8.9%). A decline in total (VT+non-VT [NVT]) IPD preceded the introduction of PCV13: 19% (incidence rate ratio [IRR], 0.81; 95% confidence interval [CI], 0.74-0.88]; p&lt;0.001) among infants, 14% (IRR, 0.86; 95% CI, 0.80-0.93; p&lt;0.001) among young children, and 8% (IRR, 0.92; 95% CI, 0.83-1.01; p=0.08) among adolescents and adults. Compared with the counterfactually predicted incidence of VT-IPD, the PCV13-associated VT IPD incidence was 38% (95% CI, 37%-40%) lower among infants, 74% (95% CI, 70%-78%) lower among young children, 79% (95% CI, 76%-83%) lower among older children, and 47% (95% CI, 44%-51%) lower among adolescents and adults. Concordance between serotyping methods was high: 90.7% (95% CI, 89.0%-92.2%) between latex and PneumoCaT, 95.2% (95% CI, 93.9%-96.3%) between latex and microarray, and 96.6% (95% CI, 95.5%-97.5%) between microarray and PneumoCaT. However, by detecting additional VT pneumococcus carried at low relative abundance, microarray increased VT detection by 31.5% across all ages compared with conventional latex serotyping. Conclusion: Compared with high-income settings, Blantyre had high residual VT carriage 3.6 to 7.1 years after the introduction of PCV13. Though there were significant declines in IPD before PCV implementation, and though the PCV13-attributable impact on IPD was significant among vaccine age-eligible children 7 years after PCV13’s introduction, indirect effects benefitting unvaccinated infants and adults were more modest. We report high concordance between three serotyping techniques applicable to routine pneumococcal surveillance in this setting. Latex serotyping, which requires the least expertise and fewest resources for field implementation and analysis, accurately identifies VT pneumococcus. However, WGS (which adds population structure) and microarray (which adds multiple serotype carriage) should be considered at regional reference laboratories while investigating the impact of VT carriage (in low relative abundance) on transmission and disease. The PAVE study was initiated in March 2021 to evaluate an alternative World Health Organization–approved three-dose schedule, including a booster dose at 9 months of age. Policy decisions should consider multiple alternative public health strategies for reducing carriage and disease burden, including targeted vaccination outside infant immunization programmes to benefit vulnerable populations. Rigorous evaluation of strategies to augment vaccine-induced control of carriage is required, including alternative schedules and catch-up campaigns.