- ABSTRACT.
- INTRODUCTION
- MATERIALS AND METHODS
- Mice.
- DNA vaccination by gene gun.
- Freshly-dissected spz vaccination and challenge.
- Cryopreserved spz vaccination and challenge.
- Glycolipid adjuvant preparation.
- Mouse plasma ELISA.
- CD1d depletion.
- Liver burden reverse transcription polymerase chain reaction (RT-PCR).
- Liver lymphocyte isolation and flow cytometry.
- Statistics.
- RESULTS
- DNA prime and Py fresh- or cryo-RAS trap leads to substantial parasite liver burden.
- Py fresh- or cryo-RAS trap induce comparable levels of PyCSP-specific liver CD8+ Trm cells.
- DNA priming followed by cryo-RAS trap protects mice against Py spz challenge 4–6 weeks post-vaccination.
- Py cryo-RAS trapping can be dose de-escalated by the co-administration of glycolipid adjuvant 7DW8-5.
- DISCUSSION
- ACKNOWLEDGMENTS
- References
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Cryopreserved Sporozoites with and without the Glycolipid Adjuvant 7DW8-5 Protect in Prime-and-Trap Malaria Vaccination
ABSTRACT.
Repeated intravenous (IV) administration of radiation-attenuated sporozoite (RAS) vaccines induces Plasmodium-specific CD8+ liver-resident memory T (Trm) cells in mice and achieves sterile protection against challenge. Our heterologous “prime-and-trap” vaccine strategy was previously shown to simplify and improve upon RAS vaccination. Prime-and-trap vaccination combines epidermal priming by DNA-encoded circumsporozoite protein (CSP) antigen followed by a single IV dose of freshly dissected RAS (fresh-RAS) to direct and trap activated and expanding CD8+ T cells in the liver. Prime-and-trap vaccination protects mice against wild-type sporozoite (spz) challenge. Assessment of prime-and-trap vaccines in nonhuman primate (NHP) models and/or humans would be greatly enabled if fresh-RAS could be replaced by cryopreserved RAS (cryo-RAS). Here, we investigated if fresh-RAS could be replaced with cryo-RAS for prime-and-trap vaccination in BALB/cj mice. Despite a reduction in spz vaccine liver burden following cryo-RAS administration compared with fresh-RAS, cryo-RAS induced a similar level of Plasmodium yoelii (Py) CSP-specific CD8+ liver Trm cells and completely protected mice against Py spz challenge 112 days after vaccination. Additionally, when the glycolipid adjuvant 7DW8-5 was co-administered with cryo-RAS, 7DW8-5 permitted the dose of cryo-RAS to be reduced four-fold while still achieving high rates of sterile protection. In summary, cryo-RAS with and without 7DW8-5 were compatible with prime-and-trap malaria vaccination in a mouse model, which may accelerate the pathway for this vaccine strategy to move to NHPs and humans.
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Author Notes
Financial support: This research was supported by NIH grant 1R01AI141857 to S. C. M. and NIH Diversity Supplement funding to F. N. W.
Disclosures: S. C. M. filed a patent application on selected aspects of the prime-and-trap concept through the University of Washington. S. C. M. has equity in a startup company (Sound Vaccines, Inc.) that is negotiating with the University of Washington for rights to this intellectual property. The relationship between the authors and Sound Vaccines, Inc., has been reviewed by the University of Washington and complies with all University and State of Washington policies on such activities. S. C., B. K. L. S., and S. L. H. are paid employees of Sanaria Inc. M. T., S. C., and S. L. H. are inventors on two patents related to 7DW8-5 and Plasmodium SPZ, both of which are assigned in part to Sanaria Inc.—(1) Title: Pharmaceutical Compositions Comprising Attenuated Sporozoites and Glycolipid Adjuvants. Inventors: Chakravarty, Hoffman, and Tsuji. Date of Filing: October 28, 2013, Date of Issue: March 8, 2016. US Patent Issue Number: 9,278,125. (2) Title: Pharmaceutical Compositions Comprising Attenuated Sporozoites and Glycolipid Adjuvants (methods of use). Inventors: Chakravarty, Hoffman, and Tsuji. Date of Filing: February 18, 2016, Date of Issue: May 9, 2017. US Patent Issue Number: 9,642,909. M. T. is also an inventor of four patients related to 7DW8-5, all of which are assigned to Rockefeller University. (1) Glycolipids and analogues thereof as antigens for NK T cells. Date of Issue: May 19, 2009. US Patent Issue Number: 7,534,434. (2) Glycolipids and analogues thereof as antigens for NK T cells. Date of Issue: April 12, 2011. US Patent Issue Number: 7,923,013. (3) Glycolipids and analogues thereof as antigens for NK T cells. Date of Issue: April 24, 2012. US Patent Issue Number: 8,163,290 B2. (4) Glycolipids and analogues thereof as antigens for NK T cells. Date of Issue: November 19, 2013. US Patent Issue Number: 8,586,051. The other authors have no financial conflicts of interest.
Authors’ addresses: Felicia Watson, Graduate Program in Pathobiology, Department of Global Health, University of Washington, Seattle, WA, Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, and Center for Emerging and Re-Emerging Infectious Diseases (CERID), University of Washington, Seattle, WA, E-mail: fewatson@uw.edu. Melanie Shears, Jokichi Matsubara, Anya Kalata, Annette Seilie, Irene Cruz Talavera, and Tayla Olsen, Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, and Center for Emerging and Re-Emerging Infectious Diseases (CERID), University of Washington, Seattle, WA, E-mails: mshears@uw.edu, jokichi.matsubara@gmail.com, kalata@uw.edu, amseilie@uw.edu, ict@uw.edu, and taylao@uw.edu. Moriya Tsuji, Aaron Diamond AIDS Research Center, Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY, E-mail: mt3432@cumc.columbia.edu. Sumana Chakravarty, B. Kim Lee Sim, and Stephen Hoffman, Sanaria Inc., Rockville, MD, E-mails: schakravarty@sanaria.com, ksim@sanaria.com, and slhoffman@sanaria.com. Sean Murphy, Graduate Program in Pathobiology, Department of Global Health, University of Washington, Seattle, WA, Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, Center for Emerging and Re-Emerging Infectious Diseases (CERID), University of Washington, Seattle, WA, Department of Microbiology, University of Washington, Seattle, WA, and Washington National Primate Research Center, University of Washington, Seattle, WA, E-mail: murphysc@uw.edu.