António M. Mendes 1 , Marta Machado 1 , Nataniel Gonçalves-Rosa 1 , Isaie J. Reuling 2 , Lander Foquet 3 , 4 , Cláudia Marques 1 , Ahmed M. Salman 5 , 6 , Annie S. P. Yang 2 , Kara A. Moser 7 , Ankit Dwivedi 7 , Cornelus C. Hermsen 2 , Belén Jiménez-Díaz 8 , Sara Viera 8 , Jorge M. Santos 1 , 12 , Inês Albuquerque 1 , Sangeeta N. Bhatia 9 , John Bial 10 , Iñigo Angulo-Barturen 8 , Joana C. Silva 7 , 11 , Geert Leroux-Roels 3 , Chris J. Janse 5 , Shahid M. Khan 5 , Maria M. Mota 1 , Robert W. Sauerwein 2 , Miguel Prudêncio , 1
24 August 2018
There is a pressing need for safe and highly effective Plasmodium falciparum ( Pf) malaria vaccines. The circumsporozoite protein (CS), expressed on sporozoites and during early hepatic stages, is a leading target vaccine candidate, but clinical efficacy has been modest so far. Conversely, whole-sporozoite (WSp) vaccines have consistently shown high levels of sterilizing immunity and constitute a promising approach to effective immunization against malaria. Here, we describe a novel WSp malaria vaccine that employs transgenic sporozoites of rodent P. berghei ( Pb) parasites as cross-species immunizing agents and as platforms for expression and delivery of PfCS ( PbVac). We show that both wild-type Pb and PbVac sporozoites unabatedly infect and develop in human hepatocytes while unable to establish an infection in human red blood cells. In a rabbit model, similarly susceptible to Pb hepatic but not blood infection, we show that PbVac elicits cross-species cellular immune responses, as well as PfCS-specific antibodies that efficiently inhibit Pf sporozoite liver invasion in human hepatocytes and in mice with humanized livers. Thus, PbVac is safe and induces functional immune responses in preclinical studies, warranting clinical testing and development.
A genetically engineered parasite, related to malaria-causing Plasmodium falciparum, excels as a vaccine in preclinical tests. A team led by Miguel Prudêncio, of the University of Lisbon, Portugal, developed a genetically altered vaccine candidate based on Plasmodium berghei, which is pathogenic to rodents but, in humans, fails to progress from a harmless, transient liver infection to causing full, blood-borne malaria. The candidate expresses a human form of ‘circumsporozoite protein,’ a known antigen, and is designed to provoke a more comprehensive immune response as it presents a whole pathogen to the host. In preclinical tests, the candidate generated antibodies able to neutralize infection in human hepatocytes and also provoked a cellular immune response in rabbits. The team’s candidate proved safe and efficacious, warranting further trials and clinical testing.