Innovation Against Infection

With over 800 companies in its network, the Infection Innovation Consortium: iiCON led by Liverpool School of Tropical Medicine, with partners Unilever, LifeArc, Evotec, the University of Liverpool, Infex Therapeutics, and Liverpool University Hospitals NHS Foundation Trust is helping pioneer infection innovation by providing companies with access to world-leading infectious disease research facilities and expertise across 11 specialist R&D platforms. These platforms are co-developed and operated by iiCON’s industrial, academic, and clinical partners. Recognizing that the incidence of gonorrhea is increasing worldwide – and the need to accelerate therapeutic drug discovery, iiCON’s specialist organoids platform, led by LSTM , will be used to establish a Neisseria gonorrhea organoid infection model.

Organoid models are still a relatively new technology – currently with no standardized protocols governing the generation and characterization of these tissues. Through direct comparison of organoid infection models against established methods of assessment, the aim is to facilitate widespread adoption of this technology and integration into regulatory approval pathways, thereby supporting the development of new interventions targeting a variety of infectious diseases. 

To find out more, we spoke with iiCON Founding Director Janet Hemingway and Shaun Pennington, leader of the Organoids Platform and a senior research associate and laboratory lead for drug discovery at the Liverpool School of Tropical Medicine (LSTM).

How big a problem is the increasing risk of gonorrhea transmission?
 

In 2020, there were approximately 82 million new cases of gonorrhea among adolescents and adults globally – this makes gonorrhea the second most prevalent bacterial infection in the world. In men, infection can cause localized pain and result in infertility. In women, infection can cause both of these symptoms, as well as ectopic pregnancy and an increased risk of HIV transmission. In newborns, gonococcal conjunctivitis can lead to corneal damage and, in extreme cases, blindness. The financial costs of these complications are very high for both individuals and healthcare systems. 

Gonorrhea has been and continues to be curable when treated with antibiotics. However, antimicrobial resistance to gonorrhea has increased over the past 50 years, impacting the efficacy of medicines such as tetracyclines, macrolides (including azithromycin), sulphonamides and trimethoprim combinations and, more recently, quinolones. In many countries, ciprofloxacin resistance is exceedingly high, azithromycin resistance is increasing, and resistance or decreased susceptibility to cefixime and ceftriaxone continue to emerge.

The emergence of different forms of resistance is often followed by a rapid spread of the disease. This is not a problem exclusive to low and middle income populations, as recent treatment failures have also been seen in higher income countries. Of all sexually transmitted infections, gonorrhea is the most antibiotic-resistant.

Are there any other barriers to treatment?
 

Gonorrhea infections can be asymptomatic, especially in women, which means that individuals may not be aware they are infected. Co-infection, alongside HIV and chlamydia, is common, which can complicate treatment. 

There are currently no robust and predictable intracellular models of infection that can be used to study N. gonorrhoeae infection, and animal models are limited. To develop new treatments, we need models that can help us to understand pathogenesis and assess treatment activity. 

The stigma associated with STI diagnosis is also a significant barrier to treatment. Industry may be able to develop new, single-dose treatments, but unless efforts are made to remove the stigma, many of the complications associated with infection will continue to cause suffering.

Which demographic is most at risk?
 

It is widely accepted that a range of socioeconomic factors can contribute towards an increased risk of infection, including a lack of healthcare and education. Due to the nature of transmission, infections most commonly occur in sexually active individuals; those who practice unprotected sex, those who have sex with multiple partners, and men who have sex with men are all considered to be at increased risk of infection. 

Of the cases identified in 2020, the most affected are adolescents and adults aged 15–49 years worldwide, with a global incident rate of 19 per 1,000 women and 23 per 1,000 men. Most cases were in the WHO African Region and the Western Pacific Region (1).

What challenges are you likely to face during this project?
 

N. gonorrhoeae is well-adapted to its ecological niche. Developing a representative intracellular model will require use of a selection of host-cell types with varied growth requirements. For the model to be representative of circulating organisms, we will need to study several in parallel to ensure broad coverage.

For new treatments to be approved for clinical use, we need to demonstrate that they have activity against the organisms inside human cells. Unfortunately, the organism can move freely between the intracellular and extracellular compartments, which makes it difficult to quantify activity in either compartment. 

How much data is required to tackle the Gonorrhea problem?
 

A huge amount of data will be required. Currently, the industry doesn’t even have the models required to generate the data! We are at the very early stages of this highly innovative program, which involves working at the vanguard of a new approach to testing treatments in human tissues – helping to address a significant challenge and unlock industry innovation. 

This pathway involves creating new human tissue models. We will then need to undertake extensive validation work to ensure we have a responsive, reproducible model before we begin working with industry partners to start the commercialization process, which will see the model being used for treatment testing.

What might new potential treatments look like?
 

The model that iiCON is developing is agnostic, so it would be relevant to a variety of potential treatments developed by industry – small molecules, host-directed immunomodulatory compounds, and monoclonal antibody therapies could all have utility against N. gonorrhoeae.

This collaboration will respond to industry activity – creating a robust, quick, and effective model for industry to test new treatments in human tissues. This would support industry innovation and address a significant gap in current provision. Because we are developing an agnostic model, it will be able to respond to and test all potential treatment forms – so as industry solutions evolve, our platform will remain a viable model for treatment testing in human tissues.