Abstract
Pfs230 is a malaria transmission-blocking antigen candidate, expressed on the surface of Plasmodium falciparum gametocytes. A recombinant, his-tagged Pfs230 fragment (Pfs230C1; amino acids 443–731) formed serum-stable particles upon incubation with liposomes containing cobalt-porphyrin-phospholipid (CoPoP). In mice, immunization with Pfs230C1, admixed with the adjuvants Alum, Montanide ISA720 or CoPoP liposomes (also containing synthetic monophosphoryl lipid A; PHAD), resulted in elicitation of IgG antibodies, but only those induced with CoPoP/PHAD or ISA720 strongly reduced parasite transmission. Immunization with micrograms of Pfs230C1 adjuvanted with identical liposomes lacking cobalt (that did not induce particle formation) or Alum was less effective than immunization with nanograms of Pfs230C1 with CoPoP/PHAD. CoPoP/PHAD and ISA720 adjuvants induced antibodies with similar Pfs230C1 avidity but higher IgG2-to-IgG1 ratios than Alum, which likely contributed to enhanced functional activity. Unlike prior work with another transmission-blocking antigen (Pfs25), Pfs230C1 was found to be effectively taken up by antigen-presenting cells without particle formation. The anti-Pfs230C1 IgG response was durable in mice for 250 days following immunization with CoPoP/PHAD, as were antibody avidity and elevated IgG2-to-IgG1 ratios. Immunization of rabbits with 20 µg Pfs230C1 admixed with CoPoP/PHAD elicited antibodies that inhibited parasite transmission. Taken together, these results show that liposomes containing CoPoP and PHAD are an effective vaccine adjuvant platform for recombinant malaria transmission blocking antigens.
Highlights
Malaria is caused by Plasmodium parasites and is transmitted to and from humans by female Anopheles mosquitoes
Cryo-electron microscopy with Pfs230C1 bound to CoPoP/PHAD liposomes showed particles that exhibited
Liposomes, native polyacrylamide gel electrophoresis (PAGE) was Pfs230C1 itself was not large enough to be visualized on the used (Fig. 1a; the full blot is shown in Supplementary Fig. 1). 1.5 μg of Pfs230C1 was loaded into each lane of the gel and subjected to electrophoresis
Summary
Malaria is caused by Plasmodium parasites and is transmitted to and from humans by female Anopheles mosquitoes. Pfs[230] is a transmission-blocking antigen expressed on the surface of gametocytes within human red blood cells, so the host immune responses have potential to be re-boosted by natural infection, unlike some other TBV antigens like Pfs[25], which is expressed only in mosquito hosts[6]. Since red blood cells do not express major histocompatibility complexes on their surface and are not recognized by T cells, the parasite is likely to avoid clearance by the host immune response[8]. An exhaustive study of Pfs[230] fragments spanning the entire protein suggested that only constructs containing the first cysteine motif domain (amino acids 589–730) induce transmission-reducing activity[9]. Insect cellbased production of a recombinant his-tagged N-terminal fragment of Pfs[230] (amino acids 443–731), termed Pfs230C1, which induces transmission-reducing antibodies in mice, has been described previously, and was the antigen used in this study[10]
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