Novel mucosal adjuvant, mastoparan-7, improves cocaine vaccine efficacy

Ashley St. John is an Associate Professor at Duke-NUS Medical School and PI of the Laboratory of Immunity and Immune Pathology in the Programme in Emerging Infectious Diseases. She also holds appointments in the Department of Microbiology, National University of Singapore, Pathology Department, Duke University and SingHealth Duke-NUS Global Health Institute.

Dr St. John received her BS in Applied Biology from the Georgia Institute of Technology in 2004 and PhD in Immunology from Duke University in 2010 before completing her post-doctoral training at Duke-NUS in 2014. She is an expert in viral immunology, with a focus on immunity to vector-borne pathogens such as dengue and Zika viruses. She also has an interest in immune responses to respiratory viral pathogens such as respiratory syncytial virus and SARS-CoV-2. Her lab works on developing novel vaccination strategies, diagnostics, and therapeutics for infectious and allergic diseases.

The Abraham laboratory is interested in developing innovative approaches for curbing microbial infections through the study of the molecular interactions occurring between pathogenic bacteria and prominent immune and epithelial cells. We believe that there is a significant amount of crosstalk occurring between bacteria and host cells during infection and that the outcome of this interaction dictates both how quickly the infection is cleared and the severity of the pathology associated with the infection. We also believe that through deciphering this crosstalk we should be able to selectively promote certain beneficial interactions while abrogating the harmful ones.

There are two major research areas being pursued in this laboratory. The first involves elucidating the role of mast cells in modulating immune responses to microbes.  Our studies have revealed that mast cells play a key sentinel role and upon bacterial or viral infection, modulate both innate and adaptive immune responses through the release of immunomodulatory molecules borne in granules. Our current investigations are centered on elucidating the molecular and cellular aspects of how mast cells mediate their immunomodulatory role. We are also examining several mast cell-targeted strategies to boost immunity to infections as well as reduce any pathological consequences of infection.

The second area of research investigates cross-talk between distinct infectious agents such as Uropathogenic E. coli, Salmonella typhimurium and Yersinia pestis and the immune system. We have recognized that different pathogens possess distinct mechanisms to evade or coopt one or more immune cells to establish infection. We have also unraveled novel intracellular innate host defense activities including expulsion of whole bacteria from infected epithelial cells, a feat mediated by immune recognition molecules and the cellular trafficking system.

Cumulatively, our studies should facilitate the design of innovative strategies to combat pathogens that selectively potentiate the host’s immune response without evoking some of its harmful side effects.

Areas of Research Interest:

Our laboratory studies methods to induce and regulate antigen-specific immune responses at the mucosal surfaces of the host. The mucosal tissues and surfaces are often the first site of contact with infectious agents, a common location of life-threatening cancers and in constant contact with environmental antigens. A better understanding of factors that control the induction and regulation of mucosal immune responses may aid the development of vaccines and treatments for infectious agents such as HIV and agents of bioterrorism, cancers and environmental allergies.

Research interests in the Staats’ lab currently focus on:

1. DISCOVERING AND DEVELOPING NOVEL MUCOSAL ADJUVANTS AND THEIR MECHANISM OF ACTION

Adjuvants are substances commonly added to vaccines that enhance the induction of protective immune responses to the vaccine antigen. We have been successful at identifying substances with mucosal adjuvant activity such as the pro-inflammatory cytokine interleukin 1α/β (IL-1α/β). IL-1α/β provides effective nasal adjuvant activity in mice, rabbits and non-human primates. Recent studies performed in collaboration with Dr. Soman Abraham have determined that the chemical mast cell activator compound 48/80 provides effective nasal adjuvant activity in mice and rabbits. Recent funding in the laboratory supported the discovery of small molecule mast cell activators with vaccine adjuvant activity.   Current funding in the laboratory supports the discovery of IL-1 receptor agonists (small molecules, peptides, aptamers)  that exhibit vaccine adjuvant activity.

2. OPTIMIZING NASAL IMMUNIZATION TO MAXIMIZE VACCINE IMMUNOGENICITY

Nasal immunization studies in mice have demonstrated the ability of nasal immunization to induce protective immune responses equal to those induced by a vaccine delivered with a needle. However, when nasal immunization is performed in rabbits or non-human primates, animals with a nasal cavity structure/anatomy that closely resembles the human nasal cavity, nasal immunization is often not as effective as immunization delivered with a needle. Studies in our lab have demonstrated that an increased nasal residence time in rabbits correlates with increased vaccine immunogenicity. Studies are being performed to develop vaccine delivery techniques and vaccine formulations that maximize nasal residence time and therefore, the immunogenicity of the vaccine.  Nasal immunization studies performed in rabbits and non-human primates are performed to optimize nasal vaccine methods that may be tested in humans in the future.

3. EVALUATING FACTORS THAT INFLUENCE THE INDUCTION OF FOOD ALLERGY AND DEVELOPING NOVEL MUCOSAL TREATMENTS FOR FOOD ALLERGY

The number of individuals with food allergy in steadily increasing in developed countries. The administration of food allergens via mucosal routes, a procedure known as “mucosal immunotherapy”, has provided encouraging results suggesting that mucosal immunotherapy is able to modify the host anti-food allergen response to reduce the severity of allergic responses. A recent avenue of research in the laboratory is to 1) develop novel mucosal immunotherapy formulations to treat existing food allergy and 2) evaluate the influence of environmental factors on the induction and severity of food allergies.