Use of a small molecule integrin activator as a systemically administered vaccine adjuvant in controlling Chagas disease

Nandadeva Lokugamage,Upendra Marathi,Darren G Woodside,Jeffrey K Actor,Nisha Jain Garg,Navin D Warier,Peter Vanderslice,Robert V Market,Shen-An Hwang,Imran H Chowdhury,Sayadeth Khounlo,Ronald J Biediger

doi:10.1038/s41541-021-00378-5

Abstract

The development of suitable safe adjuvants to enhance appropriate antigen-driven immune responses remains a challenge. Here we describe the adjuvant properties of a small molecule activator of the integrins αLβ2 and α4β1, named 7HP349, which can be safely delivered systemically independent of antigen. 7HP349 directly activates integrin cell adhesion receptors crucial for the generation of an immune response. When delivered systemically in a model of Chagas disease following immunization with a DNA subunit vaccine encoding candidate T. cruzi antigens, TcG2 and TcG4, 7HP349 enhanced the vaccine efficacy in both prophylactic and therapeutic settings. In a prophylactic setting, mice immunized with 7HP349 adjuvanted vaccine exhibited significantly improved control of acute parasite burden in cardiac and skeletal muscle as compared to vaccination alone. When administered with vaccine therapeutically, parasite burden was again decreased, with the greatest adjuvant effect of 7HP349 being noted in skeletal muscle. In both settings, adjuvantation with 7HP349 was effective in decreasing pathological inflammatory infiltrate, improving the integrity of tissue, and controlling tissue fibrosis in the heart and skeletal muscle of acutely and chronically infected Chagas mice. The positive effects correlated with increased splenic frequencies of CD8+T effector cells and an increase in the production of IFN-γ and cytolytic molecules (perforin and granzyme) by the CD4+ and CD8+ effector and central memory subsets in response to challenge infection. This demonstrates that 7HP349 can serve as a systemically administered adjuvant to enhance T cell-mediated immune responses to vaccines. This approach could be applied to numerous vaccines with no reformulation of existing stockpiles.

Highlights

Vaccines have proven to be one of the most effective treatments for preventing life-threatening infectious diseases
Prophylactic efficacy was evaluated against the acute parasitemic phase (Fig. 2c), and therapeutic efficacy was determine whether a structural analog of THI0019 could enhance evaluated against the chronic phase of parasite persistence and integrin-dependent cell adhesion, we tested 7HP349 in standard tissue pathology (Fig. 2d)
We evaluated the potential of a small molecule activator of the integrins α4β1 and αLβ2 to serve as a vaccine adjuvant, when administered systemically separate from the vaccine antigen

Summary

Introduction

Vaccines have proven to be one of the most effective treatments for preventing life-threatening infectious diseases. Adjuvants are required to enhance the effectiveness of most vaccines, conventional adjuvants have limited effectiveness in high-risk subjects such as children and the elderly, and economic, safety and tolerability issues have hindered research into new adjuvants[2,3]. This is highlighted by the fact that the only FDA-approved adjuvant for many decades was aluminum salts (e.g., Alum)[1]. As the immune response has become better understood, approaches to finely target specific receptors and mediators to enhance antigen presentation, T cell co-stimulation, and Th1 vs. Th2 cytokines production, are being evaluated[4]

Methods

Results

Conclusion