Broad and potent neutralizing human antibodies to tick-borne flaviviruses protect mice from disease

Abstract

Tick-borne encephalitis virus (TBEV) is an emerging human pathogen that causes potentially fatal disease with no specific treatment. Mouse monoclonal antibodies are protective against TBEV, but little is known about the human antibody response to infection. Here, we report on the human neutralizing antibody response to TBEV in a cohort of infected and vaccinated individuals. Expanded clones of memory B cells expressed closely related anti-envelope domain III (EDIII) antibodies in both groups of volunteers. However, the most potent neutralizing antibodies, with IC50s below 1 ng/ml, were found only in individuals who recovered from natural infection. These antibodies also neutralized other tick-borne flaviviruses, including Langat, louping ill, Omsk hemorrhagic fever, Kyasanur forest disease, and Powassan viruses. Structural analysis revealed a conserved epitope near the lateral ridge of EDIII adjoining the EDI–EDIII hinge region. Prophylactic or early therapeutic antibody administration was effective at low doses in mice that were lethally infected with TBEV.

A Virus-Like Particle-Based Vaccine Candidate against the Tick-Borne Powassan Virus Induces Neutralizing Antibodies in a Mouse Model

“…A subset of cross-reacting monoclonal antibodies protected against POWV, Langat virus (LGTV), and TBEV infection in a mouse model. In another study, broadly neutralizing antibodies against tick-borne flavivirus were discovered in humans after TBEV infection [34]. The antibodies were able to bind the TBEV EDIII domain and exert broad neutralization activity against multiple tick-borne flaviviruses, including…”

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

“…It is believed that the lateral ridge of the D3 domain of glycoprotein E is the main receptor binding site on the surface of the TBEV virion (reviewed in Mandl CW, 2005 and Kellman EM et al, 2018). This supported by the fact that the majority of highly neutralizing and protective mice-derived monoclonal antibodies and some human-derived antibodies against flaviviruses are directed to this region of the D3 domain (Roehrig JT, 2003; Oliphant T et al, 2005; Sánchez MD et al, 2005; Dai L et al, 2016; Agudelo M et al, 2021). Since the ch14D5 antibody recognizes the epitope located on the lateral ridge of the D3 domain, we assume that one of the major mechanisms of the antiviral action of this antibody is blocking the binding of the virion to cellular receptors.…”

“…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). Comparison of the structure determined in this study with these structures showed that the epitope of the ch14D5 antibody is adjacent and partially overlap with other epitopes, but it is not identical to them.…”

“…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).…”

“…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). These antibodies are virus-neutralizing and bind adjacent epitopes on the lateral ridge of the D3 domain of glycoprotein E. This region is believed to interact with cell receptors and mediate virus binding, supported by the fact that the most potent virus-neutralizing mouse antibodies against various flaviviruses bind this ridge (Mandl CW, 2005; Kellman EM et al, 2018).…”