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This is part of a series of lectures presented by UCSD CFAR…
A few minutes of video microscopy…
This was a study was a collaborative effort between the University of Bamako in Mali, WRAIR, USAID, GSK, and the University of Maryland (Chris Plowe’s group). It was a small safety and immunogenicity study of 60 adults comprised of three arms: half-dose test vaccine, full dose test vaccine and a comparator rabies vaccine. The test vaccine was the AMA-1/ASO2 vaccine which is a lyophilized recombinant protein expressed in E. coli in the ASO2 adjuvant. AMA1 (apical membrane antigen) is a malaria blood stage protein that is expressed in the intraerythrocytic stage of the merozoite and subsequently cleaved before being exported to the merozoite surface. AMA-1, like DBP and the RBLs, thought to be crucial in the invasion of erythrocytes. In this study, a recombinant version of AMA-1 derived from the P. falciparum 3D7 strain called FMP2.1 was used and manufactured under GMP standards. The participants were immunized at Day 0, 30 and 60.
The study measured safety and tolerability and two secondary outcomes: antibody titers at specified times during the study and growth inhibition studies using serum derived from study participants.
The results were that there were minimal adverse events from the–no major adverse events. Among the common solicited adverse events were pain and swelling at the injection site and headache. Common unsolicited adverse events were URI symptoms and headache. The investigators also measured labs such as serum creatinine, liver enzymes and hematocrit and found a few abnormalities but none were clinically relevant.
For the antibody studies, the investigators measured anti-AMA1 IgG and found high baseline titers that peaked around two months for the test vaccines–there was a dose response with the full-dose vaccine eliciting a more robust response. The titers gradually waned over the remaining 300 days of the 360 day follow up.
For the ancillary studies, growth inhibition studies (measuring parasite LDH as the outcome) using pre-immune and Day 72 immune (i.e. 2 weeks after third immunization) serum showed that only serum from the full-dose group inhibited parasite growth significantly–surprisingly (for me at least) the effect was heterologous and inhibited FVO parasites just as well as 3D7.
This was a necessary step in the development of AMA1 as a vaccine candidate. However, this vaccine probably cannot live by itself. I suspect (as well as everyone else in the malaria vaccine world) that one must take all the malaria vaccine candidates based on the recombinant protein model like RTS,S, AMA-1, MSP1, TRAP, etc. and make a multi-antigen, mult-stage, and possibly multi-valent vaccine. The problem, however, is the question of immunodominance and possible interference by having so many antibodies cooking in the same kitchen.
Reference: PLoS ONE. 2008 Jan 23;3(1):e1465
tmt
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
