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A malaria vaccine adjuvant based on recombinant antigen binding to liposomes

Nature Nanotechnology volume 13, pages 1174–1181 (2018)Cite this article

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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.

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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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Authors and Affiliations

  1. Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, NY, USA

    Wei-Chiao Huang, Cuiyan Lin, Kevin A. Carter, Jumin Geng, Xuedan He, Upendra Chitgupi, Jasmin Federizon, Boyang Sun & Jonathan F. Lovell

  2. Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA

    Bingbing Deng, Carole A. Long & Kazutoyo Miura

  3. Department of Anatomy and Cell Biology, McGill University Montreal, Quebec, Canada

    Aida Razi & Joaquin Ortega

  4. Walter Reed Army Institute of Research, Silver Spring, MD, USA

    Sheetij Dutta

  5. PATH’s Malaria Vaccine Initiative, Washington, DC, USA

    C. Richter King & Shwu-Maan Lee

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Contributions

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.

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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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