Immunofocusing the Humoral Response to the AnAPN1 Malaria Transmission-Blocking Vaccine Antigen Potentiates Efficacy

Nicole Bender

Authors:  Nicole Bender, Prachi Khare, Borja Lopez-Gutierrez, Vincent Nyasembe, Timothy Hamerly, Rhoel Dinglasan

Faculty Mentor:  Rhoel Dinglasan

College:  College of Veterinary Medicine

Abstract

Malaria is a devastating vector-borne disease caused by parasites of the genus Plasmodium, which causes roughly 435,000 deaths a year, predominantly children under the age of five in sub-Saharan Africa. Malarial parasites have a complex life-cycle requiring development in their mosquito vector of the genus Anopheles. Despite progress over the past decade towards malaria eradication, progress has stalled, and novel approaches to eradication are needed. Transmission-blocking vaccines work by preventing the development of malarial parasites within the mosquito vector, thereby blocking transmission. Antibodies raised against the mosquito midgut protein Anopheline Alanyl aminopeptidase N (AnAPN1) in animals have been shown to block ookinete stage parasites from traversing the mosquito midgut epithelium, blocking transmission. By solving the crystal structure of AnAPN1, important transmission-blocking (T-B) epitopes (peptides 7 and 9) and a decoy epitope (peptide 1) were found. To immunofocus the humoral response to these epitopes and increase T-B activity, a dimer was constructed lacking the decoy epitope and containing the key T-B epitopes. Here, we evaluated this new AnAPN1 immunogen with a human safe adjuvant, GLA-LSQ, in a mouse model and found it to be highly immunogenic and able to immunofocus the immune response to peptide 9, resulting in potent T-B capability.

Poster Pitch

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Poster

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Michael V. Bowie
Michael V. Bowie (@guest_238)
1 year ago

Very good poster presentation. The research seems highly promising, what are your expectations when transferring this from the mouse model to humans?

Nicole Bender
Nicole Bender (@guest_482)
1 year ago

Hi Michael, thank you, and that is a great question! So we actually have just recently completed a long term immunization study (a little over 1 year) in non-human primates which are a much closer model to humans. We tried to emulate a boosting regimen that would be similar to one that humans would receive, and we found that UF6 wasn’t quite as highly immunogenic as it is in mice, but it certainly elicited a response and that response was specific to peptide 9. Further studies will be done to better characterize the immune response we generated and to see if we can optimize out vaccine antigen further before moving to clinical trials.

Nirali Pathak
Nirali Pathak (@guest_642)
1 year ago

Hi Nicole! I enjoyed listening to your presentation. What do you think will be some future implications from the results of your project? Will this work the same way in humans as it did in mice?

Michael V. Bowie
Michael V. Bowie (@guest_1198)
1 year ago

This is amazing. These organisms have a way of avoiding the immune system. It could be that another epitope is important in humans and that like in your early experiment, a decoy epitope is being used to focus the immune response. In other words, the antigen in mice may fold different when place in the blood of primates, thus exposing a decoy epitope and protecting the actual part of the protein important for ligation.

Nicole Bender
Nicole Bender (@guest_1240)
1 year ago

Hi Nirali, thank you! The goal with this project is to develop a transmission blocking vaccine (TBV) that works against all species of malarial parasites. An interesting aspect of TBVs is that they provide herd immunity almost instantaneously. Ideally this would be used in a concerted approach against malaria, so that combined with other vaccines that provide personal protection and with measures against mosquitoes a community will see a significantly reduced burden of malaria.

We recently completed a long term immunization study (a little over 1 year) in non-human primates which are a much closer model to humans. We tried to emulate a boosting regimen that would be similar to one that humans would receive, and we found that UF6 wasn’t quite as highly immunogenic as it is in mice, but it certainly elicited a response and that response was specific to peptide 9. Further studies will be done to better characterize the immune response we generated and to see if we can optimize out vaccine antigen further before moving to clinical trials.

Nicole Bender
Nicole Bender (@guest_1742)
1 year ago

Hi Dr. Bowie, we certainly noticed a decoy epitope in mice, peptide 1, and removed it from our vaccine design. If I understand you correctly, you’re suggesting that there is another decoy epitope in our new construct that elicited a high response in mice, then when injected into the non-human primates the protein has a different structure that hides the key epitopes? Interesting. We have considered that UF6 may fold a bit differently and therefore peptide 7 may be hidden from the immune system, but you bring up another good concept I had not thought about before.