A Peptide-Based PD1 Antagonist Enhances T-Cell Priming and Efficacy of a Prophylactic Malaria Vaccine and Promotes Survival in a Lethal Malaria Model.

Timothy W Phares,Moriya Tsuji,Amy R Noe,Vinayaka Kotraiah,Michelle N Wykes,Jing Huang,Cecille D Browne,Marc Mansour,Gabriel M Gutierrez,James Pannucci,Peter Buontempo,Deshapriya S Karunarathne

doi:10.3389/fimmu.2020.01377

Abstract

The blockade of programmed cell death-1 (PD1) and its ligand PDL1 has been proven to be a successful immunotherapy against several cancers. Similar to cancer, PD1 contributes to the establishment of several chronic infectious diseases, including malaria. While monoclonal antibodies (mAbs) targeting checkpoint receptors are revolutionary in cancer treatment, the immune-related adverse events (irAEs) may prevent their utilization in prophylactic and therapeutic treatments of infectious diseases. The irAEs are, in part, due to the prolonged half-life of mAbs resulting in prolonged activation of the immune system. As an alternative modality to mAbs, peptides represent a viable option because they possess a shorter pharmacokinetic half-life and offer more formulation and delivery options. Here, we report on a 22-amino acid immunomodulatory peptide, LD01, derived from a Bacillus bacteria. When combined prophylactically with an adenovirus-based or irradiated sporozoite-based malaria vaccine, LD01 significantly enhanced antigen-specific CD8+ T cell expansion. Therapeutically, LD01 treatment of mice infected with a lethal malaria strain resulted in survival that was associated with lower numbers of FOXP3+Tbet+CD4+ regulatory T cells. Taken together, our results demonstrate that LD01 is a potent immunomodulator that acts upon the adaptive immune system to stimulate T cell responses both prophylactically and therapeutically.

Highlights

IntroductionThe world is still without a malaria vaccine capable of establishing a long-lasting anamnestic response
Despite decades of research, the world is still without a malaria vaccine capable of establishing a long-lasting anamnestic response
To demonstrate the ability of LD01 to interfere with programmed death 1 (PD1):PDL1 interaction, the PathHunter PD1 Signaling Bioassay (Eurofins DiscoverX) was performed

Summary

Introduction

The world is still without a malaria vaccine capable of establishing a long-lasting anamnestic response. The parasite’s resistance to traditional vaccinology suggests that the pathogen is actively employing immune suppression mechanisms. Even after years of exposure to high P. falciparum transmission, there is no indication of acquired, sterile immunity to P. falciparum infections, while clinical immunity to blood-stage malaria can be achieved [1]. Enhancing T-Cell Responses in Malaria for parasite transmission via mosquitos. This is in contrast to many viral and bacterial pathogens, which generally induce lifelong immunity after a single exposure [2]. Checkpoint receptors have been implicated in establishing immune exhaustion, not unlike in cancer, during parasitic infection, thereby allowing the parasite to evade immunity [3]. PD1-deficient mice rapidly clear the parasites, unlike infections in wildtype mice [3, 6], supporting PD1-mediated suppression of anti-malarial immunity

Methods

Results

Conclusion