Innate Immune Activation Restricts Priming and Protective Efficacy of the Radiation-Attenuated Pfspz Malaria Vaccine

Senkpeil, Leetah; Bhardwaj, Jyoti; Little, Morgan R.; Holla, Prasida; Upadhye, Aditi; Swanson, Phillip A.; Wiegand, Ryan E.; Macklin, Michael D.; Bi, Kevin; Flynn, Barbara J.; Yamamoto, Ayako; Gaskin, Erik L.; Sather, D. Noah; Oblak, Adrian L.; Simpson, Edward; Gao, Hongyu; Haining, W. Nicholas; Yates, Kathleen B.; Liu, Xiaowen; Otieno, Kephas; Kariuki, Simon; Xuei, Xiaoling; Liu, Yunlong; Polidoro, Rafael B.; Hoffman, Stephen L.; Oneko, Martina; Steinhardt, Laura C.; Schmidt, Nathan W.; Seder, Robert A.; Tran, Tuan M.

doi:10.2139/ssrn.3946574

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“…It is speculated that an effective liver innate immune response is responsible for protection in this particular animal and subsequently suppresses the formation of local sporozoite-specific T cell responses in the liver. This hypothesis is supported by recent observations; (1) innate immune responses involving type I IFN signaling in infected liver cells can control liver-stage infection [ 17 ]; (2) type I IFN signaling in the liver can dampen the response of antigen-specific CD8 + T cells in the liver [ 27 ]; and (3) stimulation of innate immune response can confer protection against liver-stage infection but reduces priming of antigen-specific CD8 + T cells in mice immunized with radiation-attenuated sporozoites [ 28 ].This hypothesis opens avenues for further research into the intricate interplay between innate and adaptive immunity in the context of malaria liver-stage infection.…”

Section: Discussionmentioning

confidence: 99%

Superior protection in a relapsing Plasmodium cynomolgi rhesus macaque model by a chemoprophylaxis with sporozoite immunization regimen with atovaquone-proguanil followed by primaquine

Yongvanitchit,

Kum-Arb,

Limsalakpetch

et al. 2024

Malar J

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Background To gain a deeper understanding of protective immunity against relapsing malaria, this study examined sporozoite-specific T cell responses induced by a chemoprophylaxis with sporozoite (CPS) immunization in a relapsing Plasmodium cynomolgi rhesus macaque model. Methods The animals received three CPS immunizations with P. cynomolgi sporozoites, administered by mosquito bite, while under two anti-malarial drug regimens. Group 1 (n = 6) received artesunate/chloroquine (AS/CQ) followed by a radical cure with CQ plus primaquine (PQ). Group 2 (n = 6) received atovaquone-proguanil (AP) followed by PQ. After the final immunization, the animals were challenged with intravenous injection of 104P. cynomolgi sporozoites, the dose that induced reliable infection and relapse rate. These animals, along with control animals (n = 6), were monitored for primary infection and subsequent relapses. Immunogenicity blood draws were done after each of the three CPS session, before and after the challenge, with liver, spleen and bone marrow sampling and analysis done after the challenge. Results Group 2 animals demonstrated superior protection, with two achieving protection and two experiencing partial protection, while only one animal in group 1 had partial protection. These animals displayed high sporozoite-specific IFN-γ T cell responses in the liver, spleen, and bone marrow after the challenge with one protected animal having the highest frequency of IFN-γ+ CD8+, IFN-γ+ CD4+, and IFN-γ+ γδ T cells in the liver. Partially protected animals also demonstrated a relatively high frequency of IFN-γ+ CD8+, IFN-γ+ CD4+, and IFN-γ+ γδ T cells in the liver. It is important to highlight that the second animal in group 2, which experienced protection, exhibited deficient sporozoite-specific T cell responses in the liver while displaying average to high T cell responses in the spleen and bone marrow. Conclusions This research supports the notion that local liver T cell immunity plays a crucial role in defending against liver-stage infection. Nevertheless, there is an instance where protection occurs independently of T cell responses in the liver, suggesting the involvement of the liver's innate immunity. The relapsing P. cynomolgi rhesus macaque model holds promise for informing the development of vaccines against relapsing P. vivax.

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Section: Discussionmentioning

confidence: 99%