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 3

Genomic characterization of parental strains and hybrid progeny.

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Genomic characterization of parental strains and hybrid progeny. (A) Gen...
(A) Genome-wide SNP-based PCA, using clinical isolates from several geographic regions (circles) and parental strains (larger symbols, diamonds and star). PC2 separates continents, while PC4 separates African isolates by longitude. MAL31 (green) and NF165 (gold) cluster with East African isolates (brown), while HL1209 (red) clusters with those from West Africa (yellow), including NF54 (star). (B) Graphical example of fragment analysis obtained through capillary electrophoresis for the NF54 × MAL31 cross. NF54 fingerprinting reveals 2 unique peaks (gray), and MAL31 parent has 4 unique peaks (blue). AV66, a potential recombinant clone, displays peaks derived from both parental lines. (C) PCA based on whole-genome sequence variants, including 4 parental strains (NF54, star; HL1209, triangle; MAL31, rhombus; NF165, square) and the hybrid clones (each dot represents 1 clone; different colors for each genetic cross). In each case, hybrid clones are intermediate in genetic composition relative to their respective parents. NF54 is shared by all hybrids and is centrally located. (D) Chromosome composition of 8 selected hybrid clones. Short-read, nonhuman whole-genome sequencing was used to infer chromosomal segments contributed by each parent. Contributions from NF54 are shown in beige and from the non-NF54 parental strain in gray. Subtelomeric regions derived from either parent (white) were excluded from the analysis. The unusually large number of inferred crossover events required to generate the genome structure observed in hybrid AVA2, derived from a cross between NF54 and NF165, suggests that this parasite line was not clonal.