Screening of viral-vectored P. falciparum pre-erythrocytic candidate vaccine antigens using chimeric rodent parasites

Abstract

To screen for additional vaccine candidate antigens of Plasmodium pre-erythrocytic stages, fourteen P. falciparum proteins were selected based on expression in sporozoites or their role in establishment of hepatocyte infection. For preclinical evaluation of immunogenicity of these proteins in mice, chimeric P. berghei sporozoites were created that express the P. falciparum proteins in sporozoites as an additional copy gene under control of the uis4 gene promoter. All fourteen chimeric parasites produced sporozoites but sporozoites of eight lines failed to establish a liver infection, indicating a negative impact of these P. falciparum proteins on sporozoite infectivity. Immunogenicity of the other six proteins (SPELD, ETRAMP10.3, SIAP2, SPATR, HT, RPL3) was analyzed by immunization of inbred BALB/c and outbred CD-1 mice with viral-vectored (ChAd63 or ChAdOx1, MVA) vaccines, followed by challenge with chimeric sporozoites. Protective immunogenicity was determined by analyzing parasite liver load and prepatent period of blood stage infection after challenge. Of the six proteins only SPELD immunized mice showed partial protection. We discuss both the low protective immunogenicity of these proteins in the chimeric rodent malaria challenge model and the negative effect on P. berghei sporozoite infectivity of several P. falciparum proteins expressed in the chimeric sporozoites.

Plasmodium sporozoites require the protein B9 to invade hepatocytes

“…Our data are consistent with a recent study showing that chimeric P. berghei sporozoites where the entire PbB9 has been replaced by PfB9 are not infective. 47 Reciprocally, the essential role of B9 in assembling invasion complexes with P36 and P52 could also explain why P. falciparum and P. vivax P36 and P52 failed to compensate for the absence of their counterparts in P. berghei 6 as these proteins may not associate with PbB9 to form functional complexes.…”

Sterile protection and transmission blockade by a multistage anti-malarial vaccine in the pre-clinical study

“…The gene cassettes encoding PfCSP and Pfs25 linked via the hinge sequence, and the fusion protein, were introduced into an m8Δ/AAV vaccine, which enabled it to function as not only a pre-erythrocytic vaccine (PEV) but also a TB vaccine (TBV). In terms of a PEV, the method using transgenic rodent parasites such as PfCSP/Pb has been well established, but achieving complete protection in mice using these vaccines is challenging ( 26 ). In fact, it was necessary for sterile protection against the transgenic parasites to select a specific combination of the vaccines such as RTS,S and R21 along with potent adjuvants because other combinations resulted in only 0%–80% protection ( 27 , 28 ).…”