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

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.

A Peptide-Based Checkpoint Immunomodulator Alleviates Immune Dysfunction in Murine Polymicrobial Sepsis

“…Furthermore, peptide-based immunomodulators offer more formulation and delivery options, and have better tissue penetration and rapid synthetic manufacturing (31)(32)(33)(34). We recently reported that LD01, a 22-amino acid peptide derived from a Bacillus bacteria, antagonized PD-1, enhanced antigen-specific CD8 T-cell expansion, and promoted the survival of mice in a lethal malaria model (35).…”

Bridging Computational Vaccinology and Vaccine Development Through Systematic Identification, Characterization, and Downselection of Conserved and Variable Circumsporozoite Protein CD4 T Cell Epitopes From Diverse Plasmodium falciparum Strains

“…In this regard, we have recently demonstrated that when a peptide-based PD1 antagonist is prophylactically-combined with an adenovirus-based or irradiated sporozoitebased malaria vaccination, antigen-specific CD8 T cell expansion is enhanced (48). Additionally, with the same peptide-based PD1 antagonist, we found that therapeutic treatment of mice infected with a lethal malaria strain resulted in survival that was associated with lower numbers of Treg cells (48). When taken together with the data suggesting poor immune response to malaria infection is partially due to Treg cell activation and that interference in regulation of immune checkpoint proteins can lead to chronic malaria disease (24)(25)(26), we posit the need for minimizing epitopes cross-conserved with the human proteome and the inclusion of mechanisms to boost immune response through modulation of checkpoint proteins such as PD1 in best practice PfCSP vaccine development strategies.…”

“…Further, as programmed cell death (PD1) expression in Treg cells is indispensable for their suppressive functions ( 46 ) and PD1 upregulation upon naïve T cell activation plays a regulatory role in naïve-to-effector T cell differentiation ( 47 ), modulation of PD1 signaling may increase vaccine induced, antigen-specific responses. In this regard, we have recently demonstrated that when a peptide-based PD1 antagonist is prophylactically-combined with an adenovirus-based or irradiated sporozoite-based malaria vaccination, antigen-specific CD8 T cell expansion is enhanced ( 48 ). Additionally, with the same peptide-based PD1 antagonist, we found that therapeutic treatment of mice infected with a lethal malaria strain resulted in survival that was associated with lower numbers of Treg cells ( 48 ).…”

Viral delivery of a peptide-based immunomodulator enhances T cell priming during vaccination

“…In the current study, we report on LD10, an active, 18-amino acid derivative of our previously reported peptide ( Phares et al, 2020 ). In vitro , LD10 demonstrated greater potency at impairing PD-1 receptor signaling relative to LD01.…”

“…In non-human primates, immunization with an SIV Gag adenovirus-based vaccine in combination with an anti-PD-1 monoclonal antibody (mAb) significantly elevated peak Gag-specific T cell responses ( Finnefrock et al, 2009 ). Further, we recently showed that antagonizing the PD-1 receptor during prophylactic immunization with an adenovirus-based or radiation-attenuated sporozoite-based malaria vaccine significantly enhanced the number of antigen-specific CD8 + T cells ( Kotraiah et al, 2020 ; Phares et al, 2020 ). These observations suggest that PD-1 modulation may be a critical T cell-focused immunomodulator capable of enhancing T cell expansion and differentiation, resulting in increased numbers and functionality of effector and memory T cells.…”