Abstract
Development of effective malaria vaccines requires delivery platforms to enhance the immunogenicity and efficacy of the target antigens. This is particularly challenging for transmission-blocking malaria vaccines (TBVs), and specifically for those based on the Pfs25 antigen, that need to elicit very high antibody titers to stop the parasite development in the mosquito host and its transmission. Presenting antigens to the immune system on virus-like particles (VLPs) is an efficient way to improve the quantity and quality of the immune response generated. Here we introduce for the first time a new VLP vaccine platform, based on the well-established hepatitis B surface antigen (HBsAg) fused to the SpyCatcher protein, so that the antigen of interest, linked to the SpyTag peptide, can be easily displayed on it (Plug-and-Display technology). As little as 10% of the SpyCatcher::HBsAg VLPs decorated with Pfs25::SpyTag (molar ratio) induces a higher antibody response and transmission-reducing activity in mice compared to the soluble protein, with 50 and 90% of the VLP coupled to the antigen further enhancing the response. Importantly, using this carrier that is a vaccine antigen itself could be beneficial, as we show that anti-HBsAg IgG antibodies are induced without interfering with the Pfs25-specific immune response generated. Furthermore, pre-existing anti-HBsAg immunity does not affect the antigen-specific response to Pfs25::SpyTag-SpyCatcher::HBsAg, suggesting that these VLPs can have a broad use as a vaccine platform.
Highlights
In 2017, there were 219 million estimated cases of malaria worldwide, with 435,000 associated deaths [1]
We previously showed that Pfs25::SpyTag-SpyCatcher::AP205 virus-like particles (VLPs) are immunogenic, and elicit in mice increased quantity of anti-Pfs25 IgG antibodies and higher transmissionreducing activity compared to the soluble protein [23]
We demonstrate that the antigen-specific immune response induced in BALB/c mice when using SpyCatcher::hepatitis B surface antigen (HBsAg) as carrier is comparable to that induced by SpyCatcher::AP205VLPs (Figure 2)
Summary
In 2017, there were 219 million estimated cases of malaria worldwide, with 435,000 associated deaths [1]. One of the most clinically advanced TBV candidate antigens against Plasmodium falciparum is Pfs, a 25 kDa protein expressed on the surface of zygotes and ookinetes in the mosquito midgut [5] Antibodies against this protein exhibit transmissionreducing activity (TRA, % inhibition in mean oocyst count per mosquito), as well as transmission-blocking activity (TBA, % inhibition in prevalence of infected mosquitoes) in pre-clinical studies; high antibody titers against Pfs are required in humans for an effective TRA [6], which have not been yet successfully achieved and represents the major limitation in developing an effective Pfs25-based TBV. Fusion of the Catcher protein to a VLP and of its partner Tag peptide to the antigen of choice allows easy decoration of the carrier with the selected antigen, enabling specific orientation of the target antigen [20,21,22]
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