Abstract
Many pathogens use the same immune evasion mechanisms as cancer cells. Patients with chronic infections have elevated levels of checkpoint receptors (e.g., programed cell death 1, PD1) on T cells. Monoclonal antibody (mAb)-based inhibitors to checkpoint receptors have also been shown to enhance T-cell responses in models of chronic infection. Therefore, inhibitors have the potential to act as a vaccine “adjuvant” by facilitating the expansion of vaccine antigen-specific T-cell repertoires. Here, we report the discovery and characterization of a peptide-based class of PD1 checkpoint inhibitors, which have a potent adaptive immunity adjuvant capability for vaccines against infectious diseases. Briefly, after identifying peptides that bind to the recombinant human PD1, we screened for in vitro efficacy in reporter assays and human peripheral blood mononuclear cells (PBMC) readouts. We first found the baseline in vivo performance of the peptides in a standard mouse oncology model that demonstrated equivalent efficacy compared to mAbs against the PD1 checkpoint. Subsequently, two strategies were used to demonstrate the utility of our peptides in infectious disease indications: (1) as a therapeutic in a bacteria-induced lethal sepsis model in which our peptides were found to increase survival with enhanced bacterial clearance and increased macrophage function; and (2) as an adjuvant in combination with a prophylactic malaria vaccine in which our peptides increased T-cell immunogenicity and the protective efficacy of the vaccine. Therefore, our peptides are promising as both a therapeutic agent and a vaccine adjuvant for infectious disease with a potentially safer and more cost-effective target product profile compared to mAbs. These findings are essential for deploying a new immunomodulatory regimen in infectious disease primary and clinical care settings.
Highlights
Vaccinations have successfully provided protection from many life-threatening infectious diseases
As the dominant checkpoint drug modality, Monoclonal antibody (mAb) have several practical drawbacks when combined with vaccine formulations in some disease indications
Most important, are the safety concerns related to severe immunerelated adverse events, which are likely a result of the sustained programmed cell death 1 (PD1) inhibition because of a half-life of 15–20 days and >70% receptor occupancy for months [24, 25, 39,40,41]. While these types of adverse outcomes are often tolerable in an oncology setting, the risk–benefit ratio of potentially trading an autoimmune disease from a checkpoint mAb for the opportunity to protect against infectious diseases domestically and in the developing world is high, especially considering the risk to childhood vaccination strategies [42]
Summary
Vaccinations have successfully provided protection from many life-threatening infectious diseases. [2], as well as viral infections, such as the hepatitis B virus, the human immunodeficiency virus, and influenza [3] Many of these pathogens have evolved strategies to actively downregulate T-cell function by blocking naïve T-cell priming, and eventually exhausting T cells [2]. Overcoming these evasion strategies and boosting T-cell responses toward pathogen-derived vaccine antigens is a novel adjuvant strategy. The checkpoint receptors, such as programmed cell death 1 (PD1), represent a critical link in this pathogen-induced mechanism of immune evasion [4]. PD1 inhibition embodies a critical target for use as a CD8+ T cell-inducing agent that can enhance prophylactic and therapeutic vaccines
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