Glycosylated nanoparticle-based PfCSP vaccine confers long-lasting antibody responses and sterile protection in mouse malaria model

Abstract

The development of an effective and durable vaccine remains a central goal in the fight against malaria. Circumsporozoite protein (CSP) is the major surface protein of sporozoites and the target of the only licensed Plasmodium falciparum (Pf) malaria vaccine, RTS,S/AS01. However, vaccine efficacy is low and short-lived, highlighting the need for a second-generation vaccine with superior efficacy and durability. Here, we report a Helicobacter pylori apoferritin-based nanoparticle immunogen that elicits strong B cell responses against PfCSP epitopes that are targeted by the most potent human monoclonal antibodies. Glycan engineering of the scaffold and fusion of an exogenous T cell epitope enhanced the anti-PfCSP B cell response eliciting strong, long-lived and protective humoral immunity in mice. Our study highlights the power of rational vaccine design to generate a highly efficacious second-generation anti-infective malaria vaccine candidate and provides the basis for its further development.

Molecular and functional properties of human Plasmodium falciparum CSP C‐terminus antibodies

“…Inclusion of linear peptide epitopes rather than the complete C‐CSP may be sufficient to provide efficient T cell help without inducing non‐protective humoral responses (Wahl et al , 2022 ). Alternatively, non‐PfCSP T cell epitopes could substitute for the loss of T cell help and promote affinity maturation of the PfCSP‐specific response (Ludwig et al , 2023 ).…”

“…Anopheles gambiae 7b mosquitoes, an immunocompromised transgenic mosquito line derived from the G3 laboratory strain, were used for the production of transgenic P. berghei sporozoites expressing PfCSP and the reporter fluorescence protein mCherry (PbPfCSP(mCherry), Ludwig et al , 2023 ). Briefly, female CD1 mice (7–12‐weeks‐old) and female C57BL/6J mice (8‐weeks‐old) were bred in the MPIIB Experimental Animal Facility (Marienfelde, Berlin), housed in a pathogen‐free animal facility in accordance with the German Animal Protection Law (§8 Tierschutzgesetz) and approved by the Landesamt für Gesundheit und Soziales (LAGeSo), Berlin, Germany (project numbers 368/12 and H0335/17).…”

“…Plasmodium berghei PbPfCSP(mCherry) (Ludwig et al , 2023 ) sporozoites were isolated from mosquito salivary glands 18 dpi in HC‐04 complete medium, incubated for 30 min on ice in siliconized tubes with the indicated concentrations of mAbs (150,000 sporozoites in total volume of 100 μl 1% FCS/PBS). Sporozoites were washed with 1.5 ml of 1% FCS/PBS by centrifugation at 9,300 g for 4 min at 4°C.…”

“…Mice were randomly assigned to different groups. After 20 h, mice were exposed to the bites of three PbPfCSP(mCherry) salivary gland‐infected mosquitoes as described elsewhere (Ludwig et al , 2023 ). Briefly, PbPfCSP(mCherry)‐infected mosquitoes were put to sleep on ice at 17 dpi and selected for mCherry signal in the salivary glands under a fluorescence stereo microscope (Leica, M205 FA).…”

Target-agnostic identification of human antibodies toPlasmodium falciparumsexual forms reveals cross stage recognition of glutamate-rich repeats

“…This strong B cell activation, presumably mediated through the cross-linking of multiple BCRs at the B cell surface (53), has been suggested to limit affinity maturation in germinal centers, potentially due to early exit of B cells, favouring the elicitation of short-term low-affinity Abs to CSP over durable high-affinity responses, thus leading to suboptimal protective responses (54). However, this phenomenon may potentially be altered with the development of cross-reactive responses against repeats of slightly different content (55) (56) (57). Whether such insights extend to other anti-repeats Ab responses in general and anti-glutamate rich repeats in particular remains largely unexplored.…”