Vaccines have been instrumental in reducing morbidity and mortality from infectious diseases and improving quality of life for over 3 centuries [1]. From inception through to most of the 20th century, vaccine development was mostly empiric, relying primarily on trial and error 1, 2, 3. In 1986, the highly purified hepatitis B recombinant surface antigen vaccine was the first genetically engineered vaccine to receive regulatory approval, heralding the application of molecular biology to the science of vaccine development (vaccinology). Since then, vaccine concepts, candidates, and platforms have continued to evolve utilizing genomics, systems biology, immune profiling, and other modern molecular tools. The ultimate objective is to produce vaccines with improved effectiveness and reduced reactogenicity.

In a Controlled Human Infection Model (CHIM), a well-characterized pathogen is deliberately administered to healthy adult volunteers who are closely monitored for development of intentional infection and disease [4]. This deliberate and calculated exposure ensures a controlled and acceptable safety profile otherwise unattainable via natural infection. The core principles of such experimental infection include ethics, safety, and scientific value that collectively encompass healthy participant eligibility, a pathogenic agent amenable to treatment and/or typically causing self-limiting infection, alongside a disease epidemiology that warrants further study in search of therapeutic and preventative interventions [5]. While intentional exposure and infection of healthy adults has been in practice by researchers for almost a century, what was learned from such experiments in earlier years was somewhat limited 6, 7. For the most part, researchers were only able to observe and study the clinical course and outcome, occasionally with and without therapeutic intervention, lacking in-depth understanding of the underlying mechanisms occurring at the cellular level, the real arena for immunological functions and pathogenesis of infectious disease.

With the advent of modern molecular biology, there have been numerous advances in microbiology and cell biology, which collectively advanced the study of infectious disease pathology and immunology. Benefits of combining molecular biology and CHIMs include down selection of vaccine and therapeutic regimens, product development, as well as capacity to expedite assessment and licensure of novel and reformulated products. This article reviews vaccinology in the context of modern molecular biology techniques and explores how CHIMs can further enhance the advances already achieved.