4.9.10 Infectious Disease Models

Infectious disease models require appropriately biosafety-contained facilities and are used to evaluate candidate antimicrobial, antiparasitic, antifungal,...

Infectious disease models require appropriately biosafety-contained facilities and are used to evaluate candidate antimicrobial, antiparasitic, antifungal, and antiviral agents under conditions that reproduce genuine host-pathogen interaction, complementing the in-vitro antimicrobial screening described in Phase 3.

Tuberculosis — Mycobacterium tuberculosis Infection Model

Experimental tuberculosis is modelled by aerosol or intravenous infection of mice (or, for studies requiring closer pathological similarity to human cavitary disease, guinea pigs or non-human primates) with a defined, low-dose inoculum of Mycobacterium tuberculosis, performed exclusively within a Biosafety Level 3 containment facility given the organism's human pathogenicity and airborne transmissibility. Disease progression and drug efficacy are assessed through quantitative bacterial colony-forming unit counts recovered from lung and spleen homogenate at defined time points, survival analysis in chronic infection protocols, and histopathological assessment of granuloma formation, the hallmark pathological lesion of tuberculosis. Isoniazid, rifampicin, and other first-line anti-tubercular agents serve as standard reference comparators, and the model is central to evaluating both novel single agents and combination regimens intended to shorten the unusually long (six-month) standard duration of human tuberculosis therapy. The chronic, slow-growing nature of M. tuberculosis necessitates infection studies extending over weeks to months, representing a substantial practical and biosafety commitment relative to most other infectious disease models.

Malaria — Plasmodium berghei Rodent Model

Antimalarial drug evaluation uses rodent-adapted Plasmodium species — most commonly Plasmodium berghei — which productively infect laboratory mice and reproduce the essential erythrocytic life-cycle stage responsible for malarial clinical disease, despite important biological differences from the human-infective Plasmodium falciparum. Mice are infected by intraperitoneal injection of parasitised erythrocytes, and antimalarial efficacy is evaluated using standardised protocols including the 4-day suppressive test (in which the test compound is administered daily for four days beginning on the day of infection, and blood parasitaemia is assessed by microscopic examination of Giemsa-stained thin blood films on day 5), alongside survival time as a chronic efficacy endpoint. Chloroquine and artemisinin-based compounds serve as standard reference antimalarials, with the choice of reference strain (chloroquine-sensitive or chloroquine-resistant P. berghei) selected according to the resistance mechanism under investigation. This model's principal strength is its low cost, rapid turnaround, and extensive historical validation underlying the majority of currently used antimalarial drugs; its principal limitation is the biological divergence between rodent and human-infective Plasmodium species, necessitating eventual confirmation in human-parasite in-vitro systems and clinical trials.

Fungal Infection — Candida albicans Systemic Infection Model

Systemic antifungal efficacy is evaluated using intravenous inoculation of immunocompetent or, for enhanced infection severity, immunosuppressed mice with a defined inoculum of Candida albicans, producing disseminated infection with characteristic fungal burden in the kidneys (the primary target organ in this model), liver, and spleen. Efficacy is assessed through survival analysis over a defined observation period, quantitative fungal colony-forming unit counts recovered from target organ homogenate, and histopathological assessment of tissue fungal invasion and associated inflammatory response. Fluconazole and amphotericin B serve as standard reference antifungal comparators, reflecting the two principal mechanistic classes (azole and polyene) of clinically used systemic antifungal therapy. This model is particularly valuable for evaluating novel antifungal agents intended for invasive candidiasis, a serious and increasingly antifungal-resistant infection of major concern in immunocompromised and critically ill patient populations.

Viral Infection — Influenza Mouse Model

Antiviral drug evaluation for respiratory viral pathogens commonly uses the mouse-adapted influenza A virus model, in which mice are infected intranasally under light anaesthesia with a defined viral inoculum, producing a self-limiting respiratory infection with measurable weight loss, clinical illness scoring, and, at higher inoculum doses, mortality, closely paralleling the clinical course of human influenza. Efficacy of candidate antiviral agents is assessed through survival analysis, body-weight change (a sensitive, non-invasive measure of overall illness severity), lung viral titre (quantified by plaque assay or quantitative PCR from lung homogenate at defined time points), and histopathological assessment of pulmonary inflammation. Oseltamivir, a neuraminidase inhibitor and the current first-line clinical antiviral for influenza, serves as the standard reference comparator. This model's principal strengths are its close mechanistic and clinical parallel to human influenza and its adaptability to evaluating both prophylactic (pre-exposure) and therapeutic (post-exposure) dosing regimens, directly informing the clinical dosing strategy of candidate antivirals.