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A malaria vaccine adjuvant based on recombinant antigen binding to liposomes

Subjects

Abstract

Pfs25 is a malaria transmission-blocking vaccine antigen candidate, but its apparently limited immunogenicity in humans has hindered clinical development. Here, we show that recombinant, polyhistidine-tagged (his-tagged) Pfs25 can be mixed at the time of immunization with pre-formed liposomes containing cobalt porphyrin–phospholipid, resulting in spontaneous nanoliposome antigen particleization (SNAP). Antigens are stably presented in uniformly orientated display via his-tag insertion in the cobalt porphyrin–phospholipid bilayer, without covalent modification or disruption of antigen conformation. SNAP immunization of mice and rabbits is well tolerated with minimal local reactogenicity, and results in orders-of-magnitude higher functional antibody generation compared with other ‘mix-and-inject’ adjuvants. Serum-stable antigen binding during transit to draining lymph nodes leads to enhanced antigen uptake by phagocytic antigen-presenting cells, with subsequent generation of long-lived, antigen-specific plasma cells. Seamless multiplexing with four additional his-tagged Plasmodium falciparum polypeptides induces strong and balanced antibody production, illustrating the simplicity of developing multistage particulate vaccines with SNAP immunization.

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Fig. 1: SNAP with his-tagged Pfs25.
Fig. 2: Pfs25 SNAP immunization in mice and rabbits.
Fig. 3: Mechanistic insights into SNAP immunization.
Fig. 4: Durability of the anti-Pfs25 IgG response with SNAP immunization.
Fig. 5: Immunization potency and local reactogenicity of SNAP compared with other adjuvants (all mixed before injection).
Fig. 6: Multiplexed SNAP with P. falciparum antigens.

Data availability

All raw data are available upon request.

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Acknowledgements

This study was supported by PATH’s Malaria Vaccine Initiative, and grants from the National Institutes of Health (R21AI122964 and DP5OD017898) and the intramural programme of the National Institute of Allergy and Infectious Diseases/NIH. The authors acknowledge assistance from G. Mlambo and A. Tripathi with immunofluorescence assays, and input from C. Alving and A. Birkett.

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W.-C.H., C.R.K., S.-M.L. and J.F.L conceived the project. W.-C.H., K.M., S.-M.L. and J.F.L. designed most of the experiments. W.-C.H. and J.F.L. wrote the manuscript. W.-C.H., C.L. and J.G. performed the animal experiments. W.-C.H., C.L., B.D., C.A.L. and K.M. performed and interpreted the ELISA and SMFA experiments. A.R. and J.O. performed transmission electron cryomicroscopy. W.-C.H., K.A.C., C.L., X.H. and B.S. produced and characterized the liposomes. X.H. performed the splenocyte studies. U.C. and W.-C.H. produced fluorescently labelled antigens. J.F. performed the circular dichroism studies. S.D. and S.-M.L. produced the antigens.

Corresponding author

Correspondence to Jonathan F. Lovell.

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Competing interests

W.-C.H., C.R.K., S.-M.L., J.G. and J.F.L are named inventors on a patent application describing this technology. All other authors declare no competing financial interests.

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Huang, WC., Deng, B., Lin, C. et al. A malaria vaccine adjuvant based on recombinant antigen binding to liposomes. Nature Nanotech 13, 1174–1181 (2018). https://doi.org/10.1038/s41565-018-0271-3

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