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Oncolytic Newcastle disease virus (NDV) might be a promising new therapeutic agent for the treatment of pancreatic cancer. We evaluated recombinant NDVs (rNDVs) expressing interferon (rNDV-hIFNβ-F0) or an IFN antagonistic protein (rNDV-NS1-F0), as well as rNDV with increased virulence (rNDV-F3aa) for oncolytic efficacy in human pancreatic adenocarcinoma cells. Expression of additional proteins did not hamper virus replication or cytotoxic effects on itself. However, expression of interferon, but not NS1, resulted in loss of multicycle replication. Conversely, increasing the virulence (rNDV-F3aa) resulted in enhanced replication of the virus. Type I interferon was produced in high amounts by all tumor cells inoculated with rNDV-hIFNβ-F0, while inoculation with rNDV-NS1-F0 resulted in a complete block of interferon production in most cells. Inoculation of human pancreatic adenocarcinoma cells with rNDV-F3aa caused markedly more cytotoxicity compared to rNDV-F0, while inoculation with rNDV-hIFNβ-F0 and rNDV-NS1-F0 induced cytotoxic effects comparable to those induced by the parental rNDV-F0. Evaluation in vivo using mice bearing subcutaneous pancreatic cancer xenografts revealed that only intratumoral injection with rNDV-F3aa resulted in regression of tumors. We conclude that although lentogenic rNDVs harboring proteins that modulate the type I interferon pathway proteins do have an oncolytic effect, a more virulent mesogenic rNDV might be needed to improve oncolytic efficacy.

Newcastle disease virus (NDV) is an avian paramyxovirus with oncolytic potential. Detailed preclinical information regarding the safety of oncolytic NDV is scarce. In this study, we evaluated the toxicity, biodistribution and shedding of intravenously injected oncolytic NDVs in non-human primates (Macaca fascicularis). Two animals were injected with escalating doses of a non-recombinant vaccine strain, a recombinant lentogenic strain or a recombinant mesogenic strain. To study transmission, naive animals were co-housed with the injected animals. Injection with NDV did not lead to severe illness in the animals or abnormalities in hematologic or biochemistry measurements. Injected animals shed low amounts of virus, but this did not lead to seroconversion of the contact animals. Postmortem evaluation demonstrated no pathological changes or evidence of virus replication. This study demonstrates that NDV generated in embryonated chicken eggs is safe for intravenous administration to non-human primates. In addition, our study confirmed results from a previous report that naïve primate and human sera are able to neutralize egg-generated NDV. We discuss the implications of these results for our study and the use of NDV for virotherapy.

Although avian paramyxovirus type 1 is known to cause mild transient conjunctivitis in human beings, there are two recent reports of fatal respiratory disease in immunocompromised human patients infected with the pigeon lineage of the virus (PPMV-1). In order to evaluate the potential of PPMV-1 to cause respiratory tract disease, we inoculated a PPMV-1 isolate (hPPMV-1/Netherlands/579/2003) from an immunocompromised human patient into three healthy cynomolgus macaques (Macaca fascicularis) and examined them by clinical, virological, and pathological assays. In all three macaques, PPMV-1 replication was restricted to the respiratory tract and caused pulmonary consolidation affecting up to 30% of the lung surface. Both alveolar and bronchiolar epithelial cells expressed viral antigen, which co-localized with areas of diffuse alveolar damage. The results of this study demonstrate that PPMV-1 is a primary respiratory pathogen in cynomolgus macaques, and support the conclusion that PPMV-1 may cause fatal respiratory disease in immunocompromised human patients.

Avoiding overloading the healthcare system remains a central issue during the COVID-19 pandemic. The logic of preventing such overload situations is intuitive since the level and quality of critical care is a function of the available capacity to provide it. Where this capacity is no longer available due to a surge in admissions, patient outcomes will invariably deteriorate in the long run, which ultimately leads to disproportionate mortality. In this paper, we study the three worst affected regions in Italy, the Netherlands, and Germany during the first COVID-19 wave in the spring of 2020. We report on quantitative analyses that show how mortality rises non-linearly as the proportion of COVID-19 patients in the ICU increases. We identify changes to the patient-staff ratio, increasing exhaustion and infection levels amongst staff, as well as equipment shortages as likely causes driving this rise in mortality. We explore these findings further with interviews of key stakeholders in the respective healthcare systems. Our results demonstrate that the common approach of managing COVID-19 surges by stretching ICU capacity in hotspot regions may be detrimental to patient outcomes. Instead, we posit that transferring patients proactively out of developing hotspots to less affected regions, well before high ICU workload situations emerge, will improve patient outcomes.

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