Pan-African hybridization of PfSPZ increases antigenic diversity and replicative capacity for malaria vaccine design
Lucia Pazzagli, Bethany Jenkins, Ankit Dwivedi, Asha Patil, Yonas Abebe, Tales V. Pascini, Urvashi Rai, Priya Gupta, Nastaran Rezakhani, Chakshu Gandhi, Yiwei Yang, Sudhir Kumar, Mohd Kamil, Gigliola Zanghí, Manuel Llinás, Stephen L. Hoffman, Joana C. Silva, Ashley M. Vaughan, B. Kim Lee Sim
Lucia Pazzagli, Bethany Jenkins, Ankit Dwivedi, Asha Patil, Yonas Abebe, Tales V. Pascini, Urvashi Rai, Priya Gupta, Nastaran Rezakhani, Chakshu Gandhi, Yiwei Yang, Sudhir Kumar, Mohd Kamil, Gigliola Zanghí, Manuel Llinás, Stephen L. Hoffman, Joana C. Silva, Ashley M. Vaughan, B. Kim Lee Sim
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Research Article Immunology Infectious disease

Pan-African hybridization of PfSPZ increases antigenic diversity and replicative capacity for malaria vaccine design

Abstract

Plasmodium falciparum sporozoite (PfSPZ) vaccines, composed of aseptic, purified, live parasites that arrest during or just after liver-stage development, show excellent safety and efficacy in humans. They can induce complete protection against Pf infection, mediated primarily by cellular immune responses against parasite antigens expressed in hepatocytes. Current PfSPZ vaccines rely on the West African PfNF54 parasite, which uniquely produces high numbers of PfSPZ in mosquitoes, facilitating manufacturing efficiency. However, PfNF54 has relatively low hepatocyte infectivity, limiting potency. We created hybrid pan-African Pf strains by genetically crossing PfNF54 with East African Pf strains. The hybrid, AV27, was selected for development based on balanced contribution of parental genomes, high PfSPZ production, and high liver-stage infectivity. As compared with NF54-based PfSPZ vaccines, we expect AV27-based vaccines will have greater and broader efficacy at lower doses due to higher liver-stage infectivity and inclusion of unique East African CD8+ T cell epitopes.

Authors

Lucia Pazzagli, Bethany Jenkins, Ankit Dwivedi, Asha Patil, Yonas Abebe, Tales V. Pascini, Urvashi Rai, Priya Gupta, Nastaran Rezakhani, Chakshu Gandhi, Yiwei Yang, Sudhir Kumar, Mohd Kamil, Gigliola Zanghí, Manuel Llinás, Stephen L. Hoffman, Joana C. Silva, Ashley M. Vaughan, B. Kim Lee Sim

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Figure 2

Liver-stage infectivity and growth of Pf NF54, MAL31, and HL1209 in the human liver–chimeric FRG NOD huHep mouse.

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Liver-stage infectivity and growth of Pf NF54, MAL31, and HL1209 in the ...
(A) MAL31 and HL1209 sporozoites exhibit increased liver infectivity compared with NF54. Cryopreserved MAL31 or HL1209 sporozoites were co-inoculated with NF54mCherry sporozoites, and liver-stage infection was assessed on day 6 by immunofluorescence analysis of at least 100 parasites. Individual FRG NOD huHep mice were injected with 2 × 106 cryopreserved NF54mCherry sporozoites (red) together with 2 × 106 MAL31 (purple), HL1209 (gold), or NF54 (gray) sporozoites. Each column represents a single mouse (M1–M3), with colors indicating the proportion of parasites detected across 2 independent liver lobes (± SD). Absolute parasite counts are provided in Supplemental Table 2. (B) MAL31, NF54, and NF54mCherry liver stages show similar sizes, whereas HL1209 liver stages are significantly larger. Each point represents an individual parasite (purple, red, and gray: n = 20; gold: n = 56); gray bars denote median values. Statistical significance was determined by 1-way ANOVA (****P < 0.0001). (C) Liver-stage parasites of MAL31 and HL1209 display nuclear morphology (DAPI, DNA, blue), apicoplast organization (ACP, green), and parasitophorous vacuole membrane expression (EXP1, magenta) comparable to NF54 and NF54mCherry (mCherry, red). Day 6 liver sections (50 μm) were stained with antibodies against ACP, EXP1, and mCherry. Scale bars: 10 μm.