A humanized IgG but not IgM antibody is effective in prophylaxis and therapy of yellow fever infection in an AG129/17D-204 peripheral challenge mouse model

Abstract

Yellow fever virus (YFV), a member of the genus Flavivirus, is a mosquito-borne virus found in tropical regions of Africa and South America that causes severe hepatic disease and death in humans. Despite the availability of effective vaccines, YFV is responsible for an estimated 200,000 cases and 30,000 deaths annually. There are currently no prophylactic or therapeutic strategies approved for use in human YFV infections. Furthermore, implementation of YFV17D-204 vaccination campaigns has become problematic due to an increase in reported post-vaccinal adverse events. We have created human/murine chimeric MAbs of a YFV-reactive murine monoclonal antibody (mMAb), 2C9, that was previously shown to protect mice from lethal YFV infection and to have therapeutic activity. The new chimeric (c)MAbs were constructed by fusion of the m2C9 IgG gene variable regions with the constant regions of human IgG and IgM and expressed in Sp2 murine myelomas. The 2C9 cMAbs (2C9-cIgG and 2C9-cIgM) reacted with 17D-204 vaccine strain in an enzyme-linked immunosorbent assay and neutralized virus in vitro similarly to the parent m2C9. Both m2C9 and 2C9-cIgG when administered prophylactically 24 hours prior to infection protected AG129 mice from peripheral 17D-204 challenge at antibody concentrations ≥ 1.27 μg/mouse; however, the 2C9-cIgM did not protect even at a dose of 127 μg/mouse. The 17D-204 infection of AG129 mice is otherwise uniformly lethal. While the m2C9 was shown previously to be therapeutically effective in YFV-infected BALB/c mice at day 4 post-infection, the m2C9 and 2C9-cIgG demonstrated therapeutic activity only when administered 1 day post-infection in 17D-204-infected AG129 mice.

Questions regarding the safety and duration of immunity following live yellow fever vaccination

“…Indeed, area-under-the-curve (AUC) analysis showed that there was no reduction in the peak or duration of viremia and there was no evidence that YFV-17D-specific T cells reduced disease symptoms after infection (reviewed in [34]). In contrast, passive transfer of YFV-specific immune serum provides protective immunity against lethal YFV infection in mice [28,35,36], hamsters [37], and rhesus macaques [35]. Together, these studies indicate that neutralizing antibodies are both necessary and sufficient for protection against yellow fever [33].…”

Current trends in West Nile virus vaccine development

“…Although cellular immunity plays an important role in clearing primary WNV infection [5-9], memory CD8 + T cells are dispensable if high levels of antiviral antibody are present [7] and vaccine-induced memory T cells may not play a substantial role in controlling flavivirus infection in humans [10]. Moreover, a number of studies using passive immunization have shown that transfer of neutralizing antibodies to naïve animals is sufficient for protection against lethal WNV infection [11-15]. Accordingly, neutralizing antibody titers are generally correlated with protection against disease for licensed flavivirus vaccines.…”

Humanized monoclonal antibody 2C9-cIgG has enhanced efficacy for yellow fever prophylaxis and therapy in an immunocompetent animal model

“…We recently developed a murine model of disease in mouse strain AG129, which is deficient in α/β- and γ-interferon receptors, peripherally challenged with YF 17D-204 vaccine (Thibodeaux et al, 2012a) and used this model system for evaluation of 2C9-cIgG (Thibodeaux et al, 2012b). Although AG129 mice lack a functional interferon response, they provide a useful model for initial proof of concept studies.…”