Treatment of Junin Virus‐Infected Guinea Pigs With Immune Serum: Development of Late Neurological Disease

Abstract

Guinea pigs infected with Argentine hemorrhagic fever virus (Junin) were treated with pooled, homologous convalescent sera. Use of 15,000 or 5,000 therapeutic units of immune sera prevented all signs of illness when administered within 24 hr of infection. We could also prevent illness and death in infected guinea pigs as late as 6 days after infection if we used more antisera (30,000 therapeutic units/kg). In some treatment groups, surviving animals developed a late neurological syndrome with prominent rear-limb paralysis. Treated animals typically expressed higher viral titers in the brain than in any other organ. There appeared to be no acute exacerbation of disease by antibody administration. Our data suggest that, after replicating peripherally, Junin virus infects the brain where circulating immunoglobulins may not eliminate viable virus. Subsequent replication of virus in the brain may generate a neurological phase of the illness. Histological examination of brains from guinea pigs in treatment groups favoring the neurological phase of illness showed encephalitis, meningitis, and swollen astrocytes, suggestive of neuronal degeneration. There is likely a delicate balance among presence of virus in the brain, the amount of antibody transported into the central nervous system, and the occurrence of this late neurological aspect of experimental Argentine hemorrhagic fever. Further study of this model may elucidate factors relevant in understanding the continuing problem of the late neurological syndrome seen in some human cases of Argentine hemorrhagic fever treated with immune plasma.

Rescue of a Recombinant Machupo Virus from Cloned cDNAs and In Vivo Characterization in Interferon (αβ/γ) Receptor Double Knockout Mice

“…Studies utilizing "chaired" NHPs reported lethal disease development following intradermal, intramuscular, and intranasal challenge (34)(35)(36). Interestingly, African green monkeys, rhesus macaques, and cynomolgus monkeys developed a lethal late neurological syndrome (LNS), a disease also reported in guinea pig models infected with JUNV (37). A recent publication utilizing mice lacking alpha/beta and gamma interferon receptors (IFN-␣␤/␥ R Ϫ/Ϫ ) characterized an acute model for lethal disease following challenge with JUNV (38), indicating the critical role of the IFN pathway in limiting JUNV infection in mice.…”

Monoclonal antibody therapy for Junin virus infection

“…More recently, favipiravir (T-705), an antiviral approved for use against influenza in Japan and evaluated clinically against Ebola virus in Guinea, was found to provide up to 78% survival in the guinea pig model when treatment was initiated 2 d after infection (8). However, none of these experimental agents have proven as efficacious as immune plasma or convalescent serum, which have been shown to provide 100% protection to guinea pigs when delivered as late as 6 d after infection (9).…”

Expression, Purification, and In Vivo Administration of a Promising Anti-Idiotypic HIV-1 Vaccine

“…The results were consistent with the ones obtained with the crude sera. A reasonable explanation for this rather strong competitive activity is that Ab2/3H6 IgG1 had not been entirely cleared from the guinea pig immune system since the final immunization was 10 days prior to bleeding and the halflife of human IgG is reported to be around 21 days [15]. As a proof of our assumption we precoated plates with the purified IgG fractions of all serum samples including the controls and performed an antihuman c chain specific ELISA.…”