Vectored antibody gene delivery protects against Plasmodium falciparum sporozoite challenge in mice
Malaria caused by Plasmodium falciparum kills nearly one million children each year and imposes crippling economic burdens on families and nations worldwide. No licensed vaccine exists, but infection can be prevented by antibodies against the circumsporozoite protein (CSP), the major surface protein of sporozoites, the form of the parasite injected by mosquitoes. We have used vectored immunoprophylaxis (VIP), an adeno-associated virus-based technology, to introduce preformed antibody genes encoding anti-P. falciparum CSP mAb into mice. VIP vector-transduced mice exhibited long-lived mAb expression at up to 1,200 µg/mL in serum, and up to 70% were protected from both i.v. and mosquito bite challenge with transgenic Plasmodium berghei rodent sporozoites that incorporate the P. falciparum target of the mAb in their CSP. Serum antibody levels and protection from mosquito bite challenge were dependent on the dose of the VIP vector. All individual mice expressing CSP-specific mAb 2A10 at 1 mg/mL or more were completely protected, suggesting that in this model system, exceeding that threshold results in consistent sterile protection. Our results demonstrate the potential of VIP as a path toward the elusive goal of immunization against malaria.
© 2014 National Academy of Sciences. PNAS Early Edition; edited by Louis H. Miller, National Institutes of Health, Rockville, MD, and approved July 15, 2014 (received for review April 22, 2014). Published ahead of print August 11, 2014. The authors thank Dr. Christine Zink and Dr. Nathan Pate for performing gross mouse pathology, Dr. Victoria Baxter for invaluable assistance with mice, and Dr. Alan Scott, Dr. Diane Griffin, Dr. Richard Markham, and Dr. David Sullivan for critical comments on the manuscript. This research was supported by a Johns Hopkins Malaria Research Institute pilot grant (to G.K.). C.D. is a recipient of a Bloomberg School of Public Health Sommer Scholarship. A.B.B. was supported by the National Institute of Allergy and Infectious Disease (NIAID) Career Transition Award 1K22AI102769. D.B. was supported by the National Institutes of Health (HHSN266200500035C) through a contract from the NIAID and by the Joint Center for Translational Medicine. F.Z. was supported by National Institutes of Health (NIH) Grant R01AI044375. D.A.E. and C.D. were supported by NIH Grant T32 AI007417. Author contributions: C.D., A.B.B., F.Z., and G.K. designed research; C.D. and D.A.E. performed research; A.B.B., F.Z., and D.B. contributed new reagents/analytic tools; C.D., A.B.B., D.A.E., F.Z., D.B., and G.K. analyzed data; and C.D., A.B.B., and G.K. wrote the paper. The authors declare no conflict of interest. This article is a PNAS Direct Submission. This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1407362111/-/DCSupplemental.
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