Association of antibodies to Plasmodium falciparum reticulocyte binding protein homolog 5 with protection from clinical malaria

Abstract

Emerging evidence suggests that antibodies against merozoite proteins involved in Plasmodium falciparum invasion into the red blood cell (RBC) play an important role in clinical immunity to malaria. The protein family of parasite antigens known as P. falciparum reticulocyte binding protein-like homolog (PfRh) is required for RBC invasion. PfRh5 is the only member within the PfRh family that cannot be genetically deleted, suggesting it plays an essential role in parasite survival. This antigen forms a complex with the cysteine-rich P. falciparum Rh5 interacting protein (PfRipr), on the merozoite surface during RBC invasion. The PfRh5 ectodomain sequence and a C-terminal fragment of PfRipr were cloned and expressed in Escherichia coli and baculovirus-infected cells, respectively. Immunization of rabbits with these recombinant proteins induced antibodies able to inhibit growth of various P. falciparum strains. Antibody responses to these proteins were investigated in a treatment–re-infection study conducted in an endemic area of Papua New Guinea (PNG) to determine their contribution to naturally acquired immunity. Antibody titers to PfRh5 but not PfRipr showed strong association with protection against P. falciparum clinical episodes. When associations with time-to-first infection were analyzed, high antibody levels against PfRh5 were also found to be associated with protection from high-density infections but not from re-infection. Together these results indicate that PfRh5 is an important target of protective immunity and constitutes a promising vaccine candidate.

Recent Developments in Malaria Vaccinology

“…Analyses of 290 clinical P. falciparum isolates worldwide by whole genome sequencing revealed that there are only five non-synonymous PfRH5 single nucleotide polymorphisms (SNPs) that are present at frequencies of more than 10% per geographical region (Bustamante et al, 2013;Williams et al, 2012). Consistent with this finding and the ability to raise broadly neutralising antibodies by vaccination, are the observations that PfRH5 may be under extremely limited immune pressure in the context of natural infection (Douglas et al, 2011;Villasis et al, 2012), although when these responses are detected (albeit at very low concentrations) they associate with clinical protection (Chiu et al, 2014;Tran et al, 2014). In addition, attempts to knockout PfRH5 in laboratory parasite strains have failed so far, suggesting that it is essential for erythrocyte invasion (Baum et al, 2009;Hayton et al, 2008), now known to be through its interaction with the erythrocyte surface protein basigin (CD147) (Crosnier et al, 2011).…”

Crystal structure of PfRh5, an essential P. falciparum ligand for invasion of human erythrocytes

“…This is supported by clinical data showing that antibodies to PfRh5 are associated with protection against malaria, indicating that PfRh5 may be a component of acquired protective immunity (Chiu et al, 2014; Tran et al, 2014). …”

Evaluating antidisease immunity to malaria and implications for vaccine design

“…For instance, it was observed that Rh5 responders at baseline were associated with a median 34‐day delay to the first clinical bout of malaria compared with non‐responders 43. This finding was confirmed in independent studies where higher Rh5 antibodies protected against high density parasitaemia, and not against re‐infection 42. Another longitudinal study in Ghana found a significant delay in time to first malaria infection in children with high antibody‐dependent cellular inhibition (ADCI) 76.…”

“…Polymorphic GPI‐anchored antigens [such as anti‐mitochondrial antibodies (AMA)‐1] often induced relatively higher antibody levels compared with conserved antigens (such as the Rhs) 43, 78, 79, 80. Responses also seemed site‐specific, with different levels observed for the same antigen in different sites 42, 43. Overall, in light of this evidence, it may be difficult to determine the right combinations for a multi‐component erythrocytic stage vaccine because humoral responses to various components will differ in magnitude and kinetics, and vary based on the level of exposure 81.…”