Towards ending maternal and infant preventable deaths : omics tools to support vaccine development against Plasmodium falciparum malaria and Streptococcus agalactiae disease

Abstract

The United Nations sustainable developmental goal 3 “good health and well-being” includes the aim to significantly reduce global maternal mortality and preventable deaths of newborns and children under 5 years of age until the year 2030. Two major contributors to global maternal and infant morbidity and mortality are Plasmodium falciparum severe malaria and Group B Streptococcus (GBS) invasive disease. The central aspect in the WHO strategy towards the elimination of these two diseases is the development of effective malaria and GBS vaccines. In the case of malaria, the immunization with radiation-attenuated P. falciparum sporozoites (PfSPZ) has been shown to convey protective immunity against controlled human malaria infection (CHMI), making this a promising vaccination approach. However, the molecular mechanisms underlying protective anti-malarial immune responses as well as the reasons for the poor immunogenicity of the PfSPZ vaccine in malaria-experienced individuals compared to malaria-naive volunteers, remain poorly understood. Emerging system analysis approaches, including genome-wide accession of gene expression using RNA-Sequencing (RNA-Seq) provide valuable insight into post-vaccination systemic molecular dynamics and can help to identify immunological correlates of protection. In the case of GBS, multivalent glycoconjugate vaccines, targeting selected GBS capsular polysaccharide types, are currently under clinical trial evaluation. With demonstrated good safety and immunogenicity profiles, the licensure of such vaccines is foreseeable. Large-scale monitoring of vaccine recipients for GBS carriage and assessment of vaccine impact on vaginal colonization, potential serotype replacement and emergence of escape strains will be an important aspect of post-licensure epidemiological studies. Matrix-assisted laser desorption time-of-flight mass spectrometry (MALDI-TOF MS), has emerged as the method of choice for high-throughput microbial species identification in clinical microbiology and has been suggested for strain level typing of bacteria. The overall aims of this thesis therefore included to (i) evaluate the safety and protective efficacy against CHMI of PfSPZ vaccination in Tanzanian volunteers and (ii) elucidate gene expression dynamics in unvaccinated Tanzanian volunteers following CHMI and (iii) to establish a MALDI-TOF MS typing method for GBS for rapid screening of circulating and emerging genotypes. Building on these objectives, the here presented thesis is structured around five manuscripts.