Abstract
The leading malaria vaccine candidate, RTS,S, based on the Plasmodium falciparum circumsporozoite protein (CSP), will likely be the first publicly adopted malaria vaccine. However, this and other subunit vaccines, such as virus-vectored thrombospondin-related adhesive protein (TRAP), provide only intermediate to low levels of protection. In this study, the Plasmodium berghei homologues of antigens CSP and TRAP are combined. TRAP is delivered using adenovirus- and vaccinia virus-based vectors in a prime-boost regime. Initially, CSP is also delivered using these viral vectors; however, a reduction of anti-CSP antibodies is seen when combined with virus-vectored TRAP, and the combination is no more protective than either subunit vaccine alone. Using an adenovirus-CSP prime, protein-CSP boost regime, however, increases anti-CSP antibody titers by an order of magnitude, which is maintained when combined with virus-vectored TRAP. This combination regime using protein CSP provided 100% protection in C57BL/6 mice compared to no protection using virus-vectored TRAP alone and 40% protection using adenovirus-CSP prime and protein-CSP boost alone. This suggests that a combination of CSP and TRAP subunit vaccines could enhance protection against malaria.
Highlights
There are approximately 3.4 billion people at risk of malaria infection, 207 million cases and 627,000 deaths annually [1]
Subunit vaccines, consisting of single or multiple antigens from various stages of the malaria parasite, have been a focus of research development. These include the preerythrocytic-stage antigens circumsporozoite (CS) protein [12] and thrombospondin-related adhesive protein (TRAP) [13], the blood-stage antigens MSP-1 [14, 15], AMA-1 [16], and RH-5 [17], and the Plasmodium vivax antigen Duffy binding protein [18, 19]; the transmission-blocking antigens Pfs25, Pvs25, Pfs230, and Pfs48/45 have been investigated as potential subunit vaccines [20,21,22,23]
The current leading malaria vaccine candidate, RTS,S, is a subunit vaccine undergoing phase III clinical trials in Africa [12]. This vaccine consists of part of the CS protein of Plasmodium falciparum malaria fused to the hepatitis B virus surface antigen (HBsAg) and coexpressed in yeast with HBsAg
Summary
There are approximately 3.4 billion people at risk of malaria infection, 207 million cases and 627,000 deaths annually [1]. The current leading malaria vaccine candidate, RTS,S, is a subunit vaccine undergoing phase III clinical trials in Africa [12]. This vaccine consists of part of the CS protein of Plasmodium falciparum malaria fused to the hepatitis B virus surface antigen (HBsAg) and coexpressed in yeast with HBsAg. The vaccine is administered as a protein-in-adjuvant formulation. Multi-epitope TRAP (ME.TRAP) antigen delivered using virus-vectored vaccines produces very high levels of sterile protection in rodents [29], and in a recent phase IIa clinical trial [27] it was determined that this vaccine in a ChAd63-MVA primeboost regime induced sterile protection in 21% of human volunteers
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