Engineering transgenic P. Falciparum to propagate in mice: Artificial human chromosome multivalent vaccines for malaria and other parasites

Terry Spithill

Research output: Contribution to journalArticle

Abstract

The creation of a mouse model for propagating P. falciparum would dramatically enhance vaccine discovery by allowing a high-throughput genomic approach to validatesingle or, importantly, multivalent vaccines in the well established murine system. Given the difficulty of evaluating vaccines in primates, this may be the only effective way totest novel candidates such as the 3200 hypothetical sequences found in the malaria genome, many of which contain signal and Pexel motifs and are thus good candidates to be expressed on the merozoite surface or exported into the red blood cell membrane: any one of these proteins could be a superior vaccine candidate. Recent studies have highlighted the potential of hypothetical sequences as vaccine candidates. Support for adapting P. falciparum to grow in mice includes one early success and in vitro data. There is considerable functionalconservation between P. falciparum and mouse malaria at the level of vaccine efficacy i.e. functionally conserved domains in P. falciparum that cross-protect mice against murine malarias. Key molecules such as MSP1 and AMA1 of P. falciparum can be complemented with orthologous molecules from murinemalaria species. MSP1-transgenic P. falciparum parasites have been shown to grow in human red blood cells and AMA1 transgenic P. falciparum invade mouse red blood cells in vitro, showing that invasion of murine RBC is potentially feasible. The challenge is to determine the minimal number of key orthologues that are required to be engineered to allow the full blood stage cycle to be established in mice. Candidates include molecules on the merozoite surface required for RBC invasion, molecules involved in catabolism of mouse haemoglobin and molecules such as the bir/cir/yir gene family involved in modification of the RBC membrane. A focused campaign to produce a mouse-adapted transgenic P. falciparum strain should be a high priority if we are to fully exploit the malaria genome for a cross-protective,strain-transcending human vaccine. A major challenge in developing vaccines for parasitic diseases is to be able to deliver multiple vaccine molecules in children in a single dose. For example, an effective bloodstage malaria vaccine may involve over 15 sequences or allelic variants of key sequences (1). The practical costs of engineering more than 15 vaccines is a major barrier to malaria vaccine investment and has necessitated the focus of funding into three molecules: MSP1, AMA1, MSP2. Bivalent and trivalent protein combination vaccines are being evaluated for malaria but even vaccines of this complexity have limitations, e.g. the trivalent combination B vaccine elicited partial protection in children with breakthrough infection by an allelic variant of MSP2. A novel alternative is to use human artificial chromosome technology to deliver multiple antigens from multiple parasites in a single vaccine priming vehicle. Such chromosomes have been developed for gene therapy but could be adapted to engineer expression of antigens for a variety of parasitic diseases, circumventing the need to clone, express and deliver each antigen separately. A whole chromosome vaccine will be stably inherited in target cells such as fibroblasts or haemopoietic cells, allowing ongoing priming of the immune system: responses will be boosted by natural infection. The challenge will be to develop needle-lessdelivery of the vaccines in young children.
Original languageEnglish
Pages (from-to)235-269
Number of pages35
JournalParasite Immunology
Volume28
Issue number6
DOIs
Publication statusPublished - Jun 2006

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