Studying the protective efficacy of radiation-attenuated Plasmodium sporozoites as anti-infective malaria vaccine during concurrent infection with Mycobacterium tuberculosis

• Applicant: Dr. Bianca Schneider
• Subject Area: Parasitology and Biology of Tropical Infectious Disease Pathogens ; Immunology
• Term: from 2015 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 272316421

Malaria remains one of the main threats to mankind. A major goal in malaria research is the development of new vaccines. It has been known for more than 40 years that immunization with radiation attenuated sporozoites (RAS) confers sterile protection against subsequent Plasmodium challenge in mouse and man. Studies in mice have elucidated a leading role for CD8+ T cells in protection against liver-stage Plasmodium infection upon RAS immunization. Moreover, extremely high numbers of memory CD8+ T cells are required to provide sterilizing protection. It has been proposed that a high antigen load is needed to progress from short- to long-term protection and that the persistence of a memory T cell response depends at least in part on the persistence of an antigen-depot in the liver.Immune responses to other pathogens can interfere with vaccine-induced memory T cell responses and thus, with the ability to respond adequately to Plasmodium infections. In areas where malaria is endemic, many people are exposed to Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (Tb). In a murine co-infection model we found that the initial occurrence of parasites in the blood (prepatency) following P. berghei sporozoite transmission was delayed in animals pre-infected with Mtb, indicating impaired liver stage development when Mtb is concurrent. This suggests that unspecific immune activation can influence sporozoite numbers in the liver. Moreover, we have preliminary data indicating that protection against wild type sporozoite challenge upon vaccination with genetically attenuated parasites is partially abrogated when Mtb is concurrent. Interestingly, a significant impact of BCG vaccination on RAS-mediated protection against malaria infection has been demonstrated already more than 30 years ago. Together, these studies bring us to our research hypothesis that Mtb infection causes modulation of the immunological environment and impedes plasmodial liver-stage mediated protection. Given the high prevalence of Tb in malaria endemic areas, this would have major implications on whole-sporozoite vaccination approaches. RAS immunization still represents the gold standard for induction of sterile protection and has moved to clinical trials. The goal of this grant proposal is to use our co-infection model to investigate how the protective efficacy of RAS immunization is modulated in the context of concurrent Mtb. Specifically we will study the impact of Mtb infection on RAS-induced short and long-term memory responses. Moreover, we will compare short- and long-term protection by wild type challenge at different time points after immunization in Mtb infected and non-infected animals. We will further investigate adaptive responses post challenge to find out if vaccine-induced responses can be boosted during Mtb co-infection. The results of our study may have important implications for future human studies and will contribute significantly to the field.

• DFG Programme: Research Grants