Design of a stabilized non-glycosylated Pfs48/45 antigen enables a potent malaria transmission-blocking nanoparticle vaccine
Thayne H. Dickey,
Richi Gupta,
Holly McAleese,
Tarik Ouahes,
Sachy Orr-Gonzalez,
Rui Ma,
Olga Muratova,
Nichole D. Salinas,
Jen C. C. Hume,
Lynn E. Lambert,
Patrick E. Duffy,
Niraj H. Tolia
Affiliations
Thayne H. Dickey
Host-Pathogen Interactions and Structural Vaccinology Section, Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH)
Richi Gupta
Host-Pathogen Interactions and Structural Vaccinology Section, Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH)
Holly McAleese
Vaccine Development Unit, Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH)
Tarik Ouahes
Vaccine Development Unit, Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH)
Sachy Orr-Gonzalez
Vaccine Development Unit, Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH)
Rui Ma
Host-Pathogen Interactions and Structural Vaccinology Section, Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH)
Olga Muratova
Vaccine Development Unit, Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH)
Nichole D. Salinas
Host-Pathogen Interactions and Structural Vaccinology Section, Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH)
Jen C. C. Hume
Vaccine Development Unit, Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH)
Lynn E. Lambert
Vaccine Development Unit, Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH)
Patrick E. Duffy
Vaccine Development Unit, Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH)
Niraj H. Tolia
Host-Pathogen Interactions and Structural Vaccinology Section, Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH)
Abstract A malaria vaccine that blocks parasite transmission from human to mosquito would be a powerful method of disrupting the parasite lifecycle and reducing the incidence of disease in humans. Pfs48/45 is a promising antigen in development as a transmission blocking vaccine (TBV) against the deadliest malaria parasite Plasmodium falciparum. The third domain of Pfs48/45 (D3) is an established TBV candidate, but production challenges have hampered development. For example, to date, a non-native N-glycan is required to stabilize the domain when produced in eukaryotic systems. Here, we implement a SPEEDesign computational design and in vitro screening pipeline that retains the potent transmission blocking epitope in Pfs48/45 while creating a stabilized non-glycosylated Pfs48/45 D3 antigen with improved characteristics for vaccine manufacture. This antigen can be genetically fused to a self-assembling single-component nanoparticle, resulting in a vaccine that elicits potent transmission-reducing activity in rodents at low doses. The enhanced Pfs48/45 antigen enables many new and powerful approaches to TBV development, and this antigen design method can be broadly applied towards the design of other vaccine antigens and therapeutics without interfering glycans.
