Isolation of a Potently Neutralizing and Protective Human Monoclonal Antibody Targeting Yellow Fever Virus

Abstract

Yellow fever virus (YFV) is a mosquito-borne virus that occasionally causes outbreaks of severe infection and disease in South America and sub-Saharan Africa. There are very effective live-attenuated (weakened) yellow fever virus vaccines, but recent problems with their production and distribution have left many people in affected areas vulnerable.

Monoclonal Antibodies and Flaviviruses: a Possible Option?

“…To reach this goal, a deeper comprehension of the biological details of flavivirus replication is certainly needed, together with a better understanding of the immune response elicited. The development of the mAbs described by Doyle et al ( 3 ) absolutely goes in this direction, and this and other similar studies may further contribute to the identification of protective epitopes possibly targeted by other non-mAb-based therapeutic approaches and useful in the development of novel prophylactic strategies.…”

“…Under this perspective, it is therefore very encouraging what is reported by Doyle et al ( 3 ) about the development of a cross-strain-reacting fully human monoclonal antibody (mAb) (YFV-136) directed against the YFV envelope (E) protein, that is, the viral structure mediating both viral attachment and subsequent membrane fusion. YFV-136 is endowed with potent neutralizing activity (50% inhibitory concentration [IC 50 ] of <10 ng/mL) in both pre- and postattachment in vitro neutralization assays, showing its interference with the E-mediated membrane fusion step of the viral entry phase.…”

“…This is possible after a second contact with YFV (as well as with other flaviviruses), especially in the case of nonneutralizing antibodies but also in the case of low titers of neutralizing antibodies. Very honestly, Doyle et al ( 3 ) report that at “lower antibody concentrations,” a “modest enhancement” of in vitro infectivity was observed. However, it would certainly have been interesting to know precisely how low that “lower concentration” was.…”

“…Finally, the interesting paper by Doyle et al ( 3 ) also gives the opportunity to speculate on a more general level about the possibility of selecting mAbs (as well as other types of molecules with possible neutralizing activity) that not only are cross-reactive against different YFV strains but also have “cross-flavivirus”-neutralizing potential ( 7 ). This is extremely intriguing, especially considering that “novel” flaviviruses have been emerging in the last decades (i.e., Zika virus [ZIKV], Japanese encephalitis virus [JEV], tick-borne encephalitis virus [TBEV], and Usutu virus [USUV]) and that even more are expected to make their appearance in the future ( 8 ).…”

Therapeutic neutralizing monoclonal antibody administration protects against lethal Yellow Fever infection

“…In intensive care units, general medical support is the clinical standard ( 13 ). mAbs are increasingly being used to treat a variety of infectious diseases, and there is precedent that mAbs are effective against viruses that generate very high plasma viral concentrations and cause mortality rates similar to YFV, including Ebola ( 14–16 ). Here we report on two different mAbs that prevent death in a highly pathogenic non-human primate YFV challenge model.…”