How can vaccines be manipulated to redirect optimal immune responses to where they are most needed?

Attempting to understand bacterial immunity also informs another focus of the lab: defining mechanisms of vaccine-mediated immunity, particularly against enteric pathogens like Salmonella. For pathogens such as this, it would be desirable to direct immune cells to the intestines where they can target the bacteria at their initial entry point, but it is unclear how this might be achieved. While it is known that vaccines given via traditional routes, i.e. intramuscularly, can protect against many infectious diseases, it is less clear how changing routes or vaccine make-up can affect immune cell migration or phenotype. Does immunizing in skin direct a different response compared to immunizing via another route? Does the type of adjuvant change the predominant immune response from antibody-dominated to one that is more cell-mediated? We are investigating these questions using different types of vaccine adjuvants and immunization routes combined with pMHCII tetramers. Our ultimate goal is to be able to imprint an anatomical “zip code” for the correct type of cells against a particular pathogen based purely on vaccine design.

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Associate Professor

James McLachlan

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Laboratory Research Supervisor

Vicki Immethun

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PhD Candidate

Jaikin Harrell

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PhD Candidate

Shaina D'Souza

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PhD Student

Vanessa Limbert

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PhD Student

Louay Bachnak

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PhD Student

Juniper Rosen

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MD/PhD Student

Rebecca Horowitz

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Undergraduate Student

Alyse Diamond

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Undergraduate Student

Claire Callahan

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Undergraduate Student

Suey Diep

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Pathogens (Basel, Switzerland) · 2024-06-18

Control of Persistent Salmonella Infection Relies on Constant Thymic Output Despite Increased Peripheral Antigen-Specific T Cell Immunity.

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Pathogens (Basel, Switzerland) · 2024-06-18

An Outer Membrane Vesicle-Adjuvanted Oral Vaccine Protects Against Lethal, Oral Salmonella Infection.

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Frontiers in cellular and infection microbiology · 2024-06-18

Salmonella Biofilm Formation, Chronic Infection, and Immunity Within the Intestine and Hepatobiliary Tract.

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Pharmaceutics · 2024-06-18

Bacterial-Derived Outer Membrane Vesicles are Potent Adjuvants that Drive Humoral and Cellular Immune Responses.

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Journal of immunology (Baltimore, Md. : 1950) · 2024-06-18

SARS-CoV-2 Antibody Response Is Associated with Age and Body Mass Index in Convalescent Outpatients.

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Infection and immunity · 2024-06-18

Vaccination with a single CD4 T cell peptide epitope from a Salmonella type III-secreted effector protein provides protection against lethal infection.

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Immunology letters · 2024-06-18

Salmonella infection: Interplay between the bacteria and host immune system.

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Infection and immunity · 2024-06-18

Salmonella Persistence and Host Immunity Are Dictated by the Anatomical Microenvironment.

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Mucosal immunology · 2024-06-18

Adjuvant selection regulates gut migration and phenotypic diversity of antigen-specific CD4(+) T cells following parenteral immunization.

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NIAID ·

Using parenteral combination adjuvants to induce pan-mucosal cellular and humoral immunity

Most pathogens enter the body at mucosal surfaces, yet, to date, the majority of licensed vaccines are injected parenterally, predominantly intramuscularly. While excellent at eliciting systemic immunity, they do not always induce the required mucosal immune responses. This highlights a gap in our understanding of how non-mucosal immunization might be manipulated to elicit mucosal immune responses and how such knowledge could be exploited to create better vaccines against mucosal pathogens. Defining the role that adjuvants play in this response is key to developing such vaccines; however, the mechanisms that dictate adjuvant driven mucosal antibody and cellular immune responses are not well understood. Our published work and preliminary experiments using major histocompatibility complex class I (MHCI) and II (MHCII) and B cell tetramers to examine mucosal immune responses after intradermal immunization with a novel detoxified bacterial ADP- ribosylating enterotoxin, called dmLT, demonstrate that we can retarget the endogenous T and B cell immune responses to the lung, intestinal mucosa, and female reproductive tract (FRT). When dmLT is combined with a safe, bacterial-derived outer membrane vesicle (OMV) adjuvant, CD4 T cell numbers and vaccine-specific antibodies and B cells are even further increased. Simultaneously, OMV adjuvant induces significant expansion of vaccine-specific CD8 T cells. Furthermore, immunization with dmLT- or OMV-adjuvanted vaccines elicits protection against bacterial infections in the lung and gut. These results lead us to hypothesize that intradermal immunization with combined dmLT plus OMVs will drive antigen-specific B cells and T cells to the mucosa and enhance vaccine protection against mucosal pathogens. We propose to: 1) determine how intradermal immunization with dmLT combined with OMV adjuvant directs 1) T cells and 2) B cells to mucosal tissue and whether these cells are bona fide tissue resident memory cells. In parallel, we will 3) examine if immunization with dmLT-OMV adjuvanted vaccines is protective against mucosal viral and bacterial infections in the lung, gut and FRT. This investigation will provide novel insights into how adjuvants regulate immunity at the mucosa and allow us to guide the response in favor of pathogen elimination.