Infectivity of Plasmodium falciparum sporozoites determines emerging parasitemia in infected volunteers

Abstract

Malaria sporozoites must first undergo intrahepatic development before a pathogenic blood-stage infection is established. The success of infection depends on host and parasite factors. In healthy human volunteers undergoing controlled human malaria infection (CHMI), we directly compared three clinical isolates for their ability to infect primary human hepatocytes in vitro and to drive the production of blood-stage parasites in vivo. Our data show a correlation between the efficiency of strain-specific sporozoite invasion of human hepatocytes and the dynamics of patent parasitemia in study subjects, highlighting intrinsic differences in infectivity among isolates from distinct geographical locales. The observed heterogeneity in infectivity among strains underscores the value of assessing the protective efficacy of candidate malaria vaccines against heterologous strains in the CHMI model.

Strains used in whole organism Plasmodium falciparum vaccine trials differ in genome structure, sequence, and immunogenic potential

“…The identification of sequence variants (both SNPs and indels) within transcriptional regulators, such as the AP2 family, may assist in the study of different growth phenotypes in these strains. NF166.C8 and NF135.C10 merozoites enter the bloodstream several days earlier than those of NF54 [14], suggesting that NF54 may develop more slowly in hepatocytes than do the other two strains. Therefore, Fig.…”

“…To determine the likely position of each non-reference contig on the 3D7 reference genome, MUMmer's show-tiling program was used with relaxed settings (-g 100000 -v 50 -i 50) to align contigs to 3D7 chromosomes (top). 3D7 nuclear chromosomes [1][2][3][4][5][6][7][8][9][10][11][12][13][14] are shown in gray, arranged from smallest to largest, along with organelle genomes (M = mitochondrion, A = apicoplast). Contigs from each PfSPZ assembly (NF54: black, 7G8: green, NF166.C8: orange, NF135.C10: hot pink) are shown aligned to their best 3D7 match.…”

“…However, depending on the immunization regimen, sterile protection can be significantly lower (8-83%) against heterologous CHMI using the 7G8 Brazilian clone [7,8], and against infection in malaria-endemic regions with intense seasonal malaria transmission (29% and 52% by proportional and time to event analysis, respectively) [9]. Heterologous CHMI in chemoprophylaxis with sporozoites trials, in which immunization is by infected mosquito bite of individuals undergoing malaria chemoprophylaxis, have been conducted with NF135.C10 from Cambodia [13] and NF166.C8 from Guinea [14], and have had lower efficacy than against homologous CHMI [15,16]. One explanation for the lower efficacy seen against heterologous P. falciparum strains is the extensive genetic diversity in this parasite species, which is particularly high in genes encoding antigens [17] and which combined with low vaccine efficacy against non-vaccine alleles [18][19][20] reduces overall protective efficacy and complicates the design of broadly efficacious vaccines [21,22].…”

“…Indeed, NF54 and 3D7 have several reported phenotypic differences when grown in culture, including the variable ability to produce gametocytes [26]. In addition, 7G8, NF166.C8, and NF135.C10 have not been rigorously compared to each other or to NF54 to confirm that they are adequate heterologous strains, even though they do appear to have distinct infectivity phenotypes when used as CHMI strains [14,16]. While the entire sporozoite likely offers multiple immunological targets, no high-confidence correlates of protection currently exist.…”

Current Challenges in the Identification of Pre-Erythrocytic Malaria Vaccine Candidate Antigens

“…Recently, new P. falciparum clinical isolates NF135 and NF166 were identified by Sauerwein, that present a significantly higher infectivity on human primary hepatocytes in vitro, around 3%, and showed faster egress to the blood compared to NF54, which correlated directly with the magnitude of the first wave of bloodstage parasites to emerge from the liver in vivo, and correlated inversely with the pre-patent period in controlled human malaria infection (CHMI) subjects (71).…”