Plasmodium falciparum 7G8 challenge provides conservative prediction of efficacy of PfNF54-based PfSPZ Vaccine in Africa

Abstract

Controlled human malaria infection (CHMI) has supported Plasmodium falciparum (Pf) malaria vaccine development by providing preliminary estimates of vaccine efficacy (VE). Because CHMIs generally use Pf strains similar to vaccine strains, VE against antigenically heterogeneous Pf in the field has been required to establish VE. We increased the stringency of CHMI by selecting a Brazilian isolate, Pf7G8, which is genetically distant from the West African parasite (PfNF54) in our PfSPZ vaccines. Using two regimens to identically immunize US and Malian adults, VE over 24 weeks in the field was as good as or better than VE against CHMI at 24 weeks in the US. To explain this finding, here we quantify differences in the genome, proteome, and predicted CD8 T cell epitopes of PfNF54 relative to 704 Pf isolates from Africa and Pf7G8. We show that Pf7G8 is more distant from PfNF54 than any African isolates tested. We propose VE against Pf7G8 CHMI for providing pivotal data for malaria vaccine licensure for travelers to Africa, and potentially for endemic populations, because the genetic distance of Pf7G8 from the Pf vaccine strain makes it a stringent surrogate for Pf parasites in Africa.

Fig. 1. Pairwise genetic distance of 704 Pf African isolates and of Pf7G8 to NF54, the Pf strain in PfSPZ Vaccine.

Histogram shows the proportion of 137,585 variable sites that differ between Pf isolates from West (yellow), Central (orange), and East (brown) Africa and NF54 (X-axis). The Y-axis represents the count of isolates for each genetic distance. For improved visualization, a Gaussian kernel density plot is overlaid on the histograms (shaded). The increasing genetic distance, from West to East, of African isolates to NF54 is expected, since NF54 is thought to originate from West Africa. The pairwise genetic distance between NF54 and the Brazilian clone 7G8 (blue) is larger than the distance of any African isolate and NF54.

Fig. 2. Principal component analysis (PCA) of African and South American clinical malaria samples, as well as PfNF54 and Pf7G8.

The analysis includes samples from West Africa (Mali, Guinea, and Burkina Faso; n = 234), Central Africa (Cameroon and the Democratic Republic of the Congo; n = 229), and East Africa (Kenya, Tanzania, Malawi, and Madagascar; n = 241), as well as from two South American countries (Brazil, n = 23; French Guiana, n-34) near the collection site of Pf7G8, in the Brazilian Amazon. The first PC (PC1) differentiates S. American (blue) from African strains. PC2 separates samples from the three regions in the African continent, where there is a clear differentiation between E. African (brown), Central African (orange), and W Africa (yellow). Some samples collected in Central African countries present the genomic signature of West Africa, as shown by the clustering of some orange samples with yellow samples, suggesting parasite migration through the vector or the human host. PfNF54 (black triangle) is clearly nested among W African samples, while Pf7G8 (blue diamond) clusters with those from S. America.

Fig. 3. Pairwise distance in non-synonymous sites of 704 Pf African isolates and of Pf7G8 to PfNF54.

a Distance estimated across 54,853 variable, non-synonymous sites across the Pf proteome. b Distance estimated for 43,607 variable, non-synonymous sites that fall on predicted CD8⁺ T cell epitopes predicted to bind to one or more of the 26 HLA alleles analyzed. Legend as in Fig. 1. Again, the pairwise proteome difference between NF54 and the Brazilian clone Pf7G8 is larger than the distance of any African isolate to PfNF54, both across all variable non-synonymous sites (5.11%) and only in those that fall on predicted epitopes (5.27%).