Immunopotentiation by Lymph-Node Targeting of a Malaria Transmission-Blocking Nanovaccine

Abstract

A successful malaria transmission blocking vaccine (TBV) requires the induction of a high antibody titer that leads to abrogation of parasite traversal of the mosquito midgut following ingestion of an infectious bloodmeal, thereby blocking the cascade of secondary human infections. Previously, we developed an optimized construct UF6b that elicits an antigen-specific antibody response to a neutralizing epitope of Anopheline alanyl aminopeptidase N (AnAPN1), an evolutionarily conserved pan-malaria mosquito midgut-based TBV target, as well as established a size-controlled lymph node targeting biodegradable nanoparticle delivery system that leads to efficient and durable antigen-specific antibody responses using the model antigen ovalbumin. Herein, we demonstrate that co-delivery of UF6b with the adjuvant CpG oligodeoxynucleotide immunostimulatory sequence (ODN ISS) 1018 using this biodegradable nanoparticle vaccine delivery system generates an AnAPN1-specific immune response that blocks parasite transmission in a standard membrane feeding assay. Importantly, this platform allows for antigen dose-sparing, wherein lower antigen payloads elicit higher-quality antibodies, therefore less antigen-specific IgG is needed for potent transmission-reducing activity. By targeting lymph nodes directly, the resulting immunopotentiation of AnAPN1 suggests that the de facto assumption that high antibody titers are needed for a TBV to be successful needs to be re-examined. This nanovaccine formulation is stable at -20°C storage for at least 3 months, an important consideration for vaccine transport and distribution in regions with poor healthcare infrastructure. Together, these data support further development of this nanovaccine platform for malaria TBVs.

Immunogenicity of PvCyRPA, PvCelTOS and Pvs25 chimeric recombinant protein of Plasmodium vivax in murine model

“…Therefore, we explored three different adjuvants, thus evaluating immunization and recognition of PvRMC-1. The AddaVax adjuvant, characterized as a squalene-based oil-in-water nano-emulsion, is formulated to mimic the Novartis MF59(®) adjuvant, with the activity of eliciting both a Th1 and Th2 response and promoting a faster antibody development in a study involving a malaria Transmission-Blocking Nanovaccine ( 34 ). Studies also describe an expanded response of IgG subtypes ( 35 ) and activity of neutralizing sporozoites ( 36 ); The Stimune® adjuvant, also known as Specol, is an oil-based alternative to Freund’s adjuvant ( 37 ), with high efficacy in promoting a strong and persistent antibody level ( 38 , 39 ), which is a powerful trigger of significant side effects ( 40 ) and is frequently employed in veterinary medicine ( 41 , 42 ); Al(OH)3, the most commonly used chemical as adjuvant ( 43 ), including in malaria studies ( 44 , 45 ), capable to increase the avidity of antibody responses ( 46 – 48 ), performing a higher neutralizing potency of the antibodies ( 49 ).…”

Monoclonal antibodies for malaria prevention

“…To this end, the mosquito midgut protein, AnAPN1, shows considerable promise as a nanoparticle vaccine in animal models that functions by blocking ookinete invasion of the mosquito midgut. [138][139][140] Another interesting approach targets the other side of mosquito transmission: the saliva proteins that are injected with the parasite during probing. These proteins have a myriad of functions, including immunomodulation during normal probing feeding.…”