Three asymptomatic animal infection models of hemorrhagic fever with renal syndrome caused by hantaviruses

Abstract

Hantaan virus (HTNV) and Puumala virus (PUUV) are rodent-borne hantaviruses that are the primary causes of hemorrhagic fever with renal syndrome (HFRS) in Europe and Asia. The development of well characterized animal models of HTNV and PUUV infection is critical for the evaluation and the potential licensure of HFRS vaccines and therapeutics. In this study we present three animal models of HTNV infection (hamster, ferret and marmoset), and two animal models of PUUV infection (hamster, ferret). Infection of hamsters with a ~3 times the infectious dose 99% (ID 99 ) of HTNV by the intramuscular and ~1 ID 99 of HTNV by the intranasal route leads to a persistent asymptomatic infection, characterized by sporadic viremia and high levels of viral genome in the lung, brain and kidney. In contrast, infection of hamsters with ~2 ID 99 of PUUV by the intramuscular or ~1 ID 99 of PUUV by the intranasal route leads to seroconversion with no detectable viremia, and a transient detection of viral genome. Infection of ferrets with a high dose of either HTNV or PUUV by the intramuscular route leads to seroconversion and gradual weight loss, though kidney function remained unimpaired and serum viremia and viral dissemination to organs was not detected. In marmosets a 1,000 PFU HTNV intramuscular challenge led to robust seroconversion and neutralizing antibody production. Similarly to the ferret model of HTNV infection, no renal impairment, serum viremia or viral dissemination to organs was detected in marmosets. This is the first report of hantavirus infection in ferrets and marmosets.

Anti-HFRS Human IgG Produced in Transchromosomic Bovines Has Potent Hantavirus Neutralizing Activity and Is Protective in Animal Models

“…As no disease models for HTNV and PUUV infections exist, infection models have been characterized and are used for testing vaccines and neutralizing antibodies, with sterile immunity used as a measure of protection from infection (Hooper et al, 1999(Hooper et al, , 2001aBrocato et al, 2013;Witkowski et al, 2017;Perley et al, 2019). Administration of low levels of SAB-159 and SAB-159P are sufficient to protect from infection, with serum neutralizing antibody titers at >100 PsVNA 50 required to protect >90% of hamsters from infection against low-dose HTNV or PUUV challenges.…”

“…The HTNV/ and PUUV/hamster infection models can be considered more rigorous models as the antiviral must prevent infection, as these viruses do not cause disease in hamsters. While viremia is not detected until Day 10 in the 10 PFU HTNV/hamster model and is undetectable in the 1,000 PFU PUUV/hamster model (Perley et al, 2019), treatment with SAB-159 or SAB-159P within 3 days is necessary to prevent infection as measured by seroconversion ( Figures 5B,C). This is similar to a previous study showing the MAb HCO2 is protective and can eliminate viremia in an HFRS model when administered 4 days post infection (Liang et al, 1996).…”

“…Hantaan virus is highly infectious in Syrian hamsters (ID 50 = 1.5 PFU) but does not cause disease (Perley et al, 2019). The hamster model was used to evaluate the capacity of SAB-159 to protect against infection.…”

“…Like Syrian hamsters, marmosets can be infected with HTNV as measured by seroconversion but do not develop disease (Perley et al, 2019). Specifically, an intramuscular injection of 1,000 PFU of HTNV resulted in high anti-N by ELISA and high neutralizing antibody titers 30 days after challenge.…”

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

“…Syrian hamsters have been used as a model for hantavirus infections, and this is one of the standard lethal models of Andes virus infection [ 154 , 155 ]. Infection of hamsters with Puumala, Dobrava, Seoul, or Hantaan viruses results in viral replication and animals do not show signs of disease [ 154 , 156 ]. These models have been used to test the immunogenicity and efficacy of vaccines and immune serum against infection [ 156 , 157 , 158 , 159 ].…”