Pathogen Dose in Animal Models of Hemorrhagic Fever Virus Infections and the Potential Impact on Studies of the Immune Response

Abstract

Viral hemorrhagic fever viruses come from a wide range of virus families and are a significant cause of morbidity and mortality worldwide each year. Animal models of infection with a number of these viruses have contributed to our knowledge of their pathogenesis and have been crucial for the development of therapeutics and vaccines that have been approved for human use. Most of these models use artificially high doses of virus, ensuring lethality in pre-clinical drug development studies. However, this can have a significant effect on the immune response generated. Here I discuss how the dose of antigen or pathogen is a critical determinant of immune responses and suggest that the current study of viruses in animal models should take this into account when developing and studying animal models of disease. This can have implications for determination of immune correlates of protection against disease as well as informing relevant vaccination and therapeutic strategies.

The Biosafety Research Road Map: The Search for Evidence to Support Practices in the Laboratory—Crimean Congo Haemorrhagic Fever Virus and Lassa Virus

“…Animal models are essential in identifying infectious dose rates via various transmission methods, pathogenicity mechanisms, antiviral treatments' effectiveness, and vaccine development. Currently, there is a lack of a clearly defined animal model, agreed on CCHFV strain for use, dose level (infections dose or lethal dose), dose measure (TCID or plaque forming units [PFU]), or mode of inoculation 32 Each of these factors impacts the disease outcome, hence the research results, and subsequently their application to research questions.…”

Livestock and Risk Group 4 Pathogens: Researching Zoonotic Threats to Public Health and Agriculture in Maximum Containment

“…It has also been proposed that over-challenge may also lead to masking the natural susceptibility of animals of interest, because a more robust immune response could prevent disease from occurring, therefore minimizing the perceived risk. 43 , 49 Consideration of social housing of livestock in a maximum containment setting is another critical concern to the study design. The benefits of social housing include both improved animal welfare as well as increased scientific validity, because singly housing social animals may mask the development of pathogen-specific, abnormal behavior.…”

Susceptibility of domestic pigs to experimental infection with ebolaviruses

“…• Challenge dose: "over-challenge" vs "under-challenge"; 43,49,52 • Route of inoculation/exposure: mimicking natural routes of infection, oronasal, use of vectors for inoculation vs intradermal injection, aerosolization studies, etc; 10,53 • Strain or isolate of challenge organism and potential for mutations to alter outcome:…”