Brian Grimberg, a member of Chris King’s group at Case Western, published a paper in PLoS Medicine last month which found that antibodies directed against Region II of Plasmodium vivax Duffy Binding Protein (PvDBP-RII), the binding domain of DBP, inhibited erythrocyte invasion by the parasite in in vitro invasion assays. The significance is two fold. First, this paper supports Duffy Binding Protein as the leading P. vivax vaccine candidate by showing that humans exposed to P. vivax in the endemic setting of Papua New Guinea can produce inhibitory antibodies against DBP. These results were comparable to antibodies induced in rabbits that were vaccinated with recombinant PvRBP-RII. Second, Grimberg et al. used short-term P. vivax cultures derived from human volunteers to perform a P. vivax invasion-inhibition assay.Previous studies on the inhibitory function of P. vivax antibodies used ex vivo P. vivax cultures derived from squirrel monkeys. I suspect from now on, pre-clinical studies on P. vivax blood stage candidate antigens must not only show the ability of antibodies to thwart the interaction between the parasite recombinant protein and it’s erythrocyte receptor, but also the ability of anti-parasite antibodies to inhibit invasion in these type of short term cultures derived from human isolates. In other words, this paper raises the bar for future pre-clinical work up of putatuve blood-stage vaccine candidates.The other subplot of this paper is whether or not PvDBP is ready for clinical trials. This is addressed in the accompanying Perspectives article in PLoS by James Beeson and Brendan Crabb (both from the Walter and Eliza Hall Institute of Medical Research in Australia). We still do not know the interactions of the other antibodies produced in a P. vivax infection that may reduce the effectiveness of any anti-PvDBP antibodies induced by vaccination. Nor do we know if anti-PvDBP antibody titers are suitable correlates of protection. Ongoing PvDBP studies in animal challenge models have been underway and hope to shed some light. However, most studies have been done using a PvDBP-RII recombinant protein derived from the Sal I strain, and more global extrapolations of efficacy may be limited because of regional polymorphisms in the RII region among various isolates may exist. As Beeson and Crabb point out, a suitable adjuvant needs to be evaluated before any Phase II efficacy trial can be initiated.

Link to papers:

Grimberg et al. PLoS Med. 2007 Dec; 4(12):e337

Beeson and Crabbe. PLoS Med. 2007 Dec; 4(12):e35

tmt