Development of <i>Plasmodium</i>‐specific liver‐resident memory CD8<sup>+</sup> T cells after heat‐killed sporozoite immunization in mice

Ghilas, Sonia; Enders, Matthias H.; May, Rose; Holz, Lauren E.; Fernandez‐Ruiz, Daniel; Cozijnsen, Anton; Mollard, Vanessa; Cockburn, Ian A.; McFadden, Geoffrey I.; Heath, William R.; Beattie, Lynette

doi:10.1002/eji.202048757

Cited by 7 publications

(3 citation statements)

References 51 publications

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“…immunogenicity, of SPZ-based vaccines. Our findings extend the work that has previously established the feasibility of improving SPZ immunogenicity via the traditional adjuvanting method of administering a mixture of SPZ and adjuvant ( 27 – 30 ). Specifically, we found that chemically augmented SPZ-SAS(CL307) can be stably formed and show considerably boosted immunogenicity in vitro , with 35-fold increases in IL-6 production by macrophages compared to unadulterated SPZ.…”

Section: Discussionsupporting

confidence: 87%

Chemically augmented malaria sporozoites display an altered immunogenic profile

Duszenko,

van Schuijlenburg,

Chevalley-Maurel

et al. 2023

Front. Immunol.

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Despite promising results in malaria-naïve individuals, whole sporozoite (SPZ) vaccine efficacy in malaria-endemic settings has been suboptimal. Vaccine hypo-responsiveness due to previous malaria exposure has been posited as responsible, indicating the need for SPZ vaccines of increased immunogenicity. To this end, we here demonstrate a proof-of-concept for altering SPZ immunogenicity, where supramolecular chemistry enables chemical augmentation of the parasite surface with a TLR7 agonist-based adjuvant (SPZ-SAS(CL307)). In vitro, SPZ-SAS(CL307) remained well recognized by immune cells and induced a 35-fold increase in the production of pro-inflammatory IL-6 (p < 0.001). More promisingly, immunization of mice with SPZ-SAS(CL307) yielded improved SPZ-specific IFN-γ production in liver-derived NK cells (percentage IFN-γ+ cells 11.1 ± 1.8 vs. 9.4 ± 1.5%, p < 0.05), CD4+ T cells (4.7 ± 4.3 vs. 1.8 ± 0.7%, p < 0.05) and CD8+ T cells (3.6 ± 1.4 vs. 2.5 ± 0.9%, p < 0.05). These findings demonstrate the potential of using chemical augmentation strategies to enhance the immunogenicity of SPZ-based malaria vaccines.

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Section: Discussionsupporting

confidence: 87%

Chemically augmented malaria sporozoites display an altered immunogenic profile

Duszenko,

van Schuijlenburg,

Chevalley-Maurel

et al. 2023

Front. Immunol.

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“…A prior study evaluated HK-spz immunization in C57Bl/6 mice previously adoptively transferred with parasite-specific PbT-1 cells. Unadjuvanted HK-spz conferred no sterile protection in such mice, and the addition of a-GalCer protected only one of eight mice, 49 suggesting that viable spz are critical for protection. RAS have limited intrahepatic development but do actively invade hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

Cryopreserved Sporozoites with and without the Glycolipid Adjuvant 7DW8-5 Protect in Prime-and-Trap Malaria Vaccination

Watson

Shears

Matsubara

et al. 2022

The American Journal of Tropical Medicine and Hygiene

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Repeated intravenous (IV) administration of radiation-attenuated sporozoite (RAS) vaccines induces Plasmodium-specific CD8+ liver-resident 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 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 Pyspz challenge 112 days after vaccination. Additionally, when the glycolipid adjuvant 7DW8-5 was coadministered with cryo-RAS, 7DW8-5 permitted the dose of cryo-RAS to be reduced 4-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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“…Finally, we asked whether active spz motility in the skin and during liver invasion was critical for protection for ULV ID-RAS + 7DW8-5. Non-motile, heat-killed spz (HK-spz) cannot actively migrate, do not invade hepatocytes, and do not achieve sterile protection against IV-spz challenge in mice 20 , 52 . Similarly, here we found that mice trapped with IV- or ID- HK-spz + / − 7DW8-5 did not provide significant protection against spz challenge (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Ultra-low volume intradermal administration of radiation-attenuated sporozoites with the glycolipid adjuvant 7DW8-5 completely protects mice against malaria

Watson,

Shears,

Kalata

et al. 2024

Sci Rep

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Radiation-attenuated sporozoite (RAS) vaccines can completely prevent blood stage Plasmodium infection by inducing liver-resident memory CD8+ T cells to target parasites in the liver. Such T cells can be induced by ‘Prime-and-trap’ vaccination, which here combines DNA priming against the P. yoelii circumsporozoite protein (CSP) with a subsequent intravenous (IV) dose of liver-homing RAS to “trap” the activated and expanding T cells in the liver. Prime-and-trap confers durable protection in mice, and efforts are underway to translate this vaccine strategy to the clinic. However, it is unclear whether the RAS trapping dose must be strictly administered by the IV route. Here we show that intradermal (ID) RAS administration can be as effective as IV administration if RAS are co-administrated with the glycolipid adjuvant 7DW8-5 in an ultra-low inoculation volume. In mice, the co-administration of RAS and 7DW8-5 in ultra-low ID volumes (2.5 µL) was completely protective and dose sparing compared to standard volumes (10–50 µL) and induced protective levels of CSP-specific CD8+ T cells in the liver. Our finding that adjuvants and ultra-low volumes are required for ID RAS efficacy may explain why prior reports about higher volumes of unadjuvanted ID RAS proved less effective than IV RAS. The ID route may offer significant translational advantages over the IV route and could improve sporozoite vaccine development.

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Development of Plasmodium‐specific liver‐resident memory CD8⁺ T cells after heat‐killed sporozoite immunization in mice

Cited by 7 publications

References 51 publications

Chemically augmented malaria sporozoites display an altered immunogenic profile

Chemically augmented malaria sporozoites display an altered immunogenic profile

Cryopreserved Sporozoites with and without the Glycolipid Adjuvant 7DW8-5 Protect in Prime-and-Trap Malaria Vaccination

Ultra-low volume intradermal administration of radiation-attenuated sporozoites with the glycolipid adjuvant 7DW8-5 completely protects mice against malaria

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Development of Plasmodium‐specific liver‐resident memory CD8+ T cells after heat‐killed sporozoite immunization in mice

Cited by 7 publications

References 51 publications

Chemically augmented malaria sporozoites display an altered immunogenic profile

Chemically augmented malaria sporozoites display an altered immunogenic profile

Cryopreserved Sporozoites with and without the Glycolipid Adjuvant 7DW8-5 Protect in Prime-and-Trap Malaria Vaccination

Ultra-low volume intradermal administration of radiation-attenuated sporozoites with the glycolipid adjuvant 7DW8-5 completely protects mice against malaria

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Development of Plasmodium‐specific liver‐resident memory CD8⁺ T cells after heat‐killed sporozoite immunization in mice