Fighting fire with fire: using non-pathogenic viruses to control unrelated infections


Unmet medical needs

Worldwide more than 250 million people are chronically infected by HBV that causes close to 900,000 deaths every year. Current nucleos(t)ide analogue (NA) therapy is not curative, it merely suppresses viral replication. Most patients require lifelong treatment. NA treatment does not eliminate the risk of hepatocellular carcinoma (HCC), thus 80 million people may die from HCC. Long‐term use of NAs is associated with toxicity, noncompliance, viral resistance, and unsustainable cost implications.

Between 2%–8% of the 150 to 170 million people living with chronic HCV infections are thought to be coinfected with HBV. Reactivation of HBV in these patients is an identified safety concern by the FDA who issued a black box warning that all HCV patients who are going to be treated with DAA agents must first undergo HBV panel testing.

Much of the world is still overwhelmed with COVID-19 infections giving the virus a chance to replicate and mutate. An evolutionary competition in SARS-CoV-2 might evolve to evade immunity. Interventions that can be administered early during the course of infection at an outpatient setting to prevent disease progression and longer-term complications are urgently needed. It is essential to reduce hospital consumption, liberate precious hospital resources and reduce morbidity, and mortality.



Exploitation of viral interference by SIT platform technology

Continuous oral administration of the dsRNA IBDV vector boosts the endogenous innate IFN response. In sharp contrast to systemic IFN-therapy, which is associated with severe toxicity, no serious side effects were observed during IBDV therapy. The reason for this is that systemic IFN therapy induces widespread signaling because type I and II IFN receptors are found on most cell types. Viruses, in contrast, have very restricted cellular and host tropism. The particular cytokine induction profile of IBDV maximizes antiviral action with minimal side effects, thus opening the therapeutic window (Fig. 1, 2).

Reproducible manufacture of homogeneous IBDV drug substance that satisfies both FDA and EMA regulatory requirements could not be met by conventional virus production. An attenuated IBDV vaccine strain was, therefore, cloned into cDNA plasmids ensuring easily reproducible production of a reverse engineered virus R903/78 and all relevant preclinical studies were repeated with the new R903/78 drug candidate. The safety of the R903/78 drug candidate was tested in 15 stage IV cancer patients (including colon, stomach, pancreatic, breast, ovarian, prostate, bladder, head & neck cancers, glioblastoma, melanoma, myeloma) who were resistant to all conventional therapy. Even very high doses of R903/78 virus (10^9 IU/dose, which is 1000-fold higher that the lowest effective dose) were associated with only mild flu-like side effects.

Fig1: Rationale: Superinfection with a harmless virus to induce innate antiviral host defense.


Fig2: In vitro efficacy study of R903/78; IBDV induce expression of interferons.