The importance of the immunodominant CD8+ T cell epitope ofPlasmodium bergheicircumsporozoite protein in parasite- and vaccine-induced protection

Abstract

21The circumsporozoite protein (CSP) builds up the surface coat of sporozoites and is the leading 22 malaria pre-erythrocytic-stage vaccine candidate. CSP has been shown to induce robust CD8+ 23 T cell responses that are capable of eliminating developing parasites in hepatocytes resulting 24 in protective immunity. In this study, we characterised the importance of the immunodominant 25 CSP-derived epitope, SYIPSAEKI, of Plasmodium berghei in both sporozoite-and vaccine-26 induced protection in murine infection models. In BALB/c mice, where SYIPSAEKI is efficiently 27 presented in the context of the major histocompatibility complex class I (MHC-I) molecule H-28 2-K d , we established that epitope-specific CD8+ T cell responses contribute to parasite killing 29 following sporozoite immunisation. Yet, sterile protection was achieved in the absence of this 30 epitope substantiating the concept that other antigens can be sufficient for parasite-induced 31 protective immunity. Furthermore, we demonstrated that SYIPSAEKI-specific CD8+ T cell 32 responses elicited by viral-vectored CSP-expressing vaccines effectively targeted parasites in 33 hepatocytes. The resulting sterile protection strictly relied on the expression of SYIPSAEKI. In 34 C57BL/6 mice, which are unable to present the immunodominant epitope, CSP-based 35 vaccines did not confer complete protection, despite the induction of high levels of CSP-36 specific antibodies. These findings underscore the significance of CSP in protection against 37 malaria pre-erythrocytic stages and demonstrate that a significant proportion of the protection 38 against the parasite is mediated by CD8+ T cells specific for the immunodominant CSP-derived 39 epitope. 40 41 3 INTRODUCTION 42 Malaria is caused by a protozoan parasite of the genus Plasmodium and remains a major 43 global health challenge in tropical and subtropical countries (1). A vaccine that diminishes the 44 burden of disease and prevents malaria transmission remains a decisive goal for malaria 45 elimination programmes. As a gold standard in malaria vaccination, multiple immunisations of 46 g-radiation-attenuated Plasmodium sporozoites (RAS) can completely protect against wild-47 type (WT) sporozoite challenge (2-4). This parasite-induced protection targets the developing 48 exo-erythrocytic forms in hepatocytes, also called liver stages, and completely abrogates blood 49 stage infection. Antibodies and T cells have been implicated as important mechanisms of 50 protection (5), and CD8+ T cells are the prime mediators of cell-mediated protective immunity, 51 as exemplified in murine (6, 7) and non-human primate (8) infection models. 52 53 The circumsporozoite protein (CSP), the major surface coat protein of the malaria sporozoite, 54 has been at the forefront of vaccination studies -being the basis of RTS,S/AS01, the most 55 progressed malaria vaccine candidate to date (9). Immunisation of BALB/c mice 56 with Plasmodium berghei (Pb) or P. yoelii (Py) RAS evokes immunodominant major 57 histocompatibility complex cla...

Mosquito bites and stages specific antibody responses againstPlasmodium falciparumin southern Ghana

“…CC-BY 4.0 International license perpetuity. It is made available under a preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in The copyright holder for this this version posted November 4, 2022. ; https://doi.org/10.1101/2022.11.03.514987 doi: bioRxiv preprint cell-mediated and antibody immune responses in the host [4,5]. Immune responses generated by a host against this parasite stage prevents the establishment of an infection within the liver [6].…”

“…Sporozoites are the first parasite stage to be encountered by the human host and initiate an infection. The surface of sporozoites has antigens including the circumsporozoite protein (PfCSP) that induces cell-mediated and antibody immune responses in the host [4, 5]. Immune responses generated by a host against this parasite stage prevents the establishment of an infection within the liver [6].…”