Post-exposure administration of chimeric antibody protects mice against European, Siberian, and Far-Eastern subtypes of tick-borne encephalitis virus

Abstract

Tick-borne encephalitis virus (TBEV) is the most important tick-transmitted pathogen. It belongs to the Flaviviridae family and causes severe human neuroinfections. In this study, protective efficacy of the chimeric antibody chFVN145 was examined in mice infected with strains belonging to the Far-Eastern, European, and Siberian subtypes of TBEV, and the antibody showed clear therapeutic efficacy when it was administered once one, two, or three days after infection. The efficacy was independent of the TBEV strain used to infect the mice; however, the survival rate of the mice was dependent on the dose of TBEV and of the antibody. No enhancement of TBEV infection was observed when the mice were treated with non-protective doses of chFVN145. Using a panel of recombinant fragments of the TBEV glycoprotein E, the neutralizing epitope for chFVN145 was localized in domain III of the TBEV glycoprotein E, in a region between amino acid residues 301 and 359. In addition, three potential sites responsible for binding with chFVN145 were determined using peptide phage display libraries, and 3D modeling demonstrated that the sites do not contact the fusion loop and, hence, their binding with chFVN145 does not result in increased attachment of TBEV to target cells.

Structural insights into tick-borne encephalitis virus neutralization and animal protection by a therapeutic antibody

“…In the case of the ch14D5 antibody, it was shown that it is able to bind to the D3 domain at a reduced pH value (pH 4.8, which is even more acidic than pH ~ 5.0 inside of late endosomes) almost as strongly as at physiological pH 7.2 (FigureS6). Our hypothesis that the ch14D5 antibody can block infection at the post-attachment step is in good agreement with the fact that this antibody, as well as the related chFVN145 antibody, did not induce ADE in in vivo experiments(Baykov IK et al, 2014;Matveev AL et al, 2019). At the moment, experimental structures are only available for three antibodies against TBEV: 19/1786 (Fuzik T et al, 2018), Mab 4.2 (Yang X et al, 2019) and T025 (Agudelo M et al, 2021).…”

“…These factors also affect whether a particular antibody is prone to cause undesirable antibody-mediated enhancement (AME) of infection or not (Pierson TC et al, 2007;Pierson TC et al, 2008;Dowd KA et al, 2011). Several neutralizing or protective monoclonal antibodies have previously been described against TBEV (Guirakhoo F et al, 1989;Mandl CW et al, 1989;Holzmann H et al, 1995;Tsekhanovskaya NA et al, 1993;Levanov LN et al, 2010;Kiermayr S. et al, 2009;Matveev AL et al, 2019;Agudelo M et al, 2021). However, the 3D structures of the antigen-antibody complex have only been published for three of them: 19/1786, Mab 4.2 and T025 (Niedrig M et al 1994;Fuzik T et al, 2018;Jiang W et al, 1994;Yang X et al, 2019;Agudelo M et al, 2021).…”

Computational and Rational Design of Single-Chain Antibody against Tick-Borne Encephalitis Virus for Modifying Its Specificity

“…Recombinant antibodies are one of the promising types of medicines against flaviviruses, TBEV in particular [ 15 , 22 , 23 , 24 ]. Several antibodies against TBEV have been obtained [ 43 , 44 , 45 , 46 ].…”

“…Recombinant antibodies are promising medicines against flaviviruses, including TBEV [ 15 , 22 , 23 , 24 ]. The chimeric antibody ch14D5 has been previously constructed and characterized [ 22 ].…”

Tick-Borne Encephalitis Virus: A Quest for Better Vaccines against a Virus on the Rise

“…A more recent study investigating TBEV neutralization in vitro and in mice by treatment with intravenous immunoglobulins containing high amount of TBEV-specific neutralizing antibodies supports these findings since no ADE was observed by the application of cross-reactive or virus-specific antibodies at different neutralization levels [ 148 ]. In vivo investigations in mice with sub-neutralizing concentrations of a chimeric antibody against EDIII containing the constant regions of human IgGκ (chFVN145), proposed as post-exposure treatment, also showed no indications of ADE for the three main TBEV subtypes [ 149 ]. Additionally, in vivo and in vitro studies addressing the potential effect of TBEV-specific immunity on ZIKV infection suggested that humoral immunity against TBEV is unlikely to contribute to enhancement of ZIKV-induced pathogenesis in humans [ 150 ].…”