Targeting AMR via the lymphatic system

Matthew Siggins

Dr Matthew Siggins 
Postdoctoral Research Associate 
Imperial College London, Department of Medicine (UK)

Collaborators:

Professor Shiranee Sriskandan, Imperial College London, Department of Medicine (UK)
Professor Adam Finn, University of Bristol, Bristol Children’s Vaccine Centre (UK)

Summary

Antimicrobial resistance (AMR) represents a significant problem to health, particularly in low- and middle-income countries (LMIC). Vaccines are proven in combating AMR and reducing deaths from drug-resistant infections. However, irrespective of a multitude of antigen candidates and the development of novel adjuvants, efficacious vaccines that provide one-dose, broad and long-lived immunity remain elusive for many important AMR bacterial pathogens. 

Advances in vaccine immunology have revealed that strong and lasting humoral and cell-mediated immunity is generated following sustained delivery of high levels of vaccine antigens to lymph nodes. Investigators have tried to achieve targeting of lymph nodes through use of hydrophilic nanoparticles. However, the properties that ensure efficient lymphatic delivery also hinder internalisation by antigen presenting cells within lymph nodes, meaning that these particles are poorly retained, hampering immunogenicity and causing systemic toxicity. 

Recently, we demonstrated that Streptococcus pyogenes exhibits tropism for lymph nodes due to its hyaluronan capsule. We propose engineering the harmless probiotic bacterium Lactococcus lactis to express hyaluronan capsule and vaccine antigens against AMR bacteria to serve as a lymphatic-homing vaccine vector that persists in lymph nodes to provide sustained delivery of vaccine antigens in situ. 

The project will assess the persistence and antigen production of our recombinant vaccine vector within lymph nodes and compare generated immune response with traditional vaccine approaches. These proof of concept murine studies represent an important first step for an approach that could deliver a flexible, low-cost vaccine vectors that can be manufactured in LMIC countries and provide long-lived humoral and cellular immunity.