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.
Project outcomes
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 hypothesised that engineering a harmless probiotic bacterium such as Lactococcus lactis to express hyaluronan capsule and vaccine proteins could serve as a lymphatic-homing vaccine vector that persists in lymph nodes to provide sustained delivery of vaccine antigens in situ. An additional advantage of this strategy is that the low cost and ease of both development and production would allow LMIC to take a lead in vaccine manufacture.
Our BactiVac Catalyst Pump-Priming award funding allowed us to genetically modify L. lactis to express hyaluronan, as well as fluorescent proteins. Using a mouse model, we discovered that expression of this hyaluronan coat allowed L. lactis to persist inside the body longer than control L. lactis (which did not express hyaluronan), this enhanced persistence could be important for generating stronger immune responses. Importantly for safety, hyaluronan expression did not permit L. lactis to invade and drive infection, and the mice remained healthy as the vaccine vector was cleared over time.
As hypothesised, hyaluronan expression also directed lymph node-homing, with counts of hyaluronan expressing vaccine vector in lymph nodes significantly increased compared to control L. lactis vectors. While the COVID-19 pandemic has, for now, delayed experiments assessing whether lymph node-homing drives better immune responses; these proof of concept murine studies represent an important first step. The hyaluronan expressing bacterial vaccine vector approach could deliver flexible, low-cost vaccine vectors that can be manufactured in LMIC countries and might be capable of generating longer-lived humoral and cellular immunity.