Murine infection models for vaccine development: the malaria example

Abstract

Vaccines are developed and eventually licensed following consecutive human clinical trials. Malaria is a potential fatal vector-borne infectious disease caused by blood infection of the single-cell eukaryote Plasmodium. Pathogen stage conversion is a hallmark of parasites in general and permits unprecedented vaccine strategies. In the case of malaria, experimental human challenge infections with Plasmodium falciparum sporozoites can be performed under rigorous clinical supervision. This rare opportunity in vaccinology has permitted many small-scale phase II anti-malaria vaccine studies using experimental homologous challenge infections. Demonstration of safety and lasting sterile protection are central endpoints to advance a candidate malaria vaccine approach to phase II field trials. A growing list of antigens as targets for subunit development makes pre-selection and prioritization of vaccine candidates in murine infection models increasingly important. Preclinical assessment in challenge studies with murine Plasmodium species also led to the development of whole organism vaccine approaches. They include live attenuated, metabolically active parasites that educate effector memory T cells to recognize and inactivate developing parasites inside host cells. Here, opportunities from integrating challenge experiments with murine Plasmodium parasites into malaria vaccine development will be discussed.

Figure 1. Clinical development of exemplary malaria vaccine candidates. RTS,S/AS01 (top) is currently the clinically most advanced subunit vaccine candidate. The recombinant proteins are shown as boxes (HbS, hepatitis B surface antigen) and the adjuvant AS01 as a lipid droplet. It was developed in the 80s and consistently protected 40% of adult volunteers against homologous challenge with infected laboratory-reared Anopheles mosquitoes (mosquito symbol). In a subsequent field trial (palm symbol) no protection was afforded in adults. Pictograms represent adults, 5–17 mo old children, and 6 weeks to 3 mo old infants. N/A, not applicable. Irradiated sporozoites (center) were first tested in a murine infection model in the 60s and shown to consistently protect non-human primates and adult volunteers against homologous challenge with infected laboratory-reared Anopheles mosquitoes. Sporozoite infection under chloroquine cover (bottom) was tested in a murine infection model in the 70s and recently shown to elicit robust and lasting protection in adult volunteers against homologous challenge with infected laboratory-reared Anopheles mosquitoes.