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.
Highlights
Malaria continues to be a persistent threat to the world population with more than 229 million individuals infected worldwide and 409,000 deaths recorded in 2019 [1]
After conjugation with UF6b-SH overnight, the NP size grew to a number average size of 37.13 ± 2.93 nm and became more neutral in charge with a zeta potential of -6.88 ± 0.95 mV, likewise suggesting successful conjugation of the UF6b construct onto PLGA-b-PEG NPs (UF6b-NPs)
Antibodies at the same total IgG concentration from 25UF-0.25C conferred between 62–65% reduction in oocyst intensity in two of the three replicates. These results demonstrate that PLGA-bPEG mediated presentation and delivery of UF6b and CpG cues at experimentally determined optimal dose and antigen:adjuvant ratio to the local draining lymph nodes induces potent transmission-reducing activity against P. falciparum, suggesting that this platform is a promising approach for potentiating further an already promising malaria transmission blocking vaccine (TBV) candidate
Summary
Malaria continues to be a persistent threat to the world population with more than 229 million individuals infected worldwide and 409,000 deaths recorded in 2019 [1]. To focus the immune response to the key T-B epitopes we developed a new, purification tag-free AnAPN1 construct, UF6b, containing two copies of peptides 2-9 connected by a glycine linker [8]. This new construct can be produced at scale and was shown to be highly immunogenic in outbred CD1 mice immunized intramuscularly (i.m.) with UF6b formulated with the human-safe adjuvant Glucopyranosyl Lipid Adjuvant in a liposomal formulation with saponin QS21 (GLA-LSQ), eliciting a focused peptide 9 specific response resulting in potent T-B antibodies [6, 8]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
