The sharpest tool in the shed: question-based clinical development of vaccines to address global health priorities

Abstract

This thesis presents clinical research on vaccine development for global health challenges, with a focus on malaria, Shigella, and COVID-19.

Part I addresses diseases that primarily affect low- and middle-income countries. Chapter 2 reports a clinical trial testing vaccine candidate GA2, a genetically attenuated malaria parasite. Remarkably, a single immunization via mosquito bites protected 9 of 10 volunteers against a controlled human malaria infection. Chapter 3 describes the study protocol for a trial investigating a novel Shigella vaccine combined with an adjuvant to enhance immune responses. Initial testing is conducted in Dutch adults, followed by studies in Zambia.

Part II focuses on vaccine dose optimization during the COVID-19 pandemic. Chapter 4 reviews early clinical studies showing that dose-sparing strategies were initiated by public institutions, not industry. Chapters 5–8 present trials with the mRNA-1273 (Moderna) vaccine, demonstrating that one-fifth intradermal doses are safe and induce robust immune responses for both primary and booster vaccination. Intradermal vaccination also offered a solution for individuals with suspected mRNA vaccine allergy.

Together, these studies advance strategies to make vaccines safer, more efficient, and more accessible worldwide.