Therapeutic alphavirus cross-reactive E1 human antibodies inhibit viral egress

Exposing cryptic epitopes on the Venezuelan equine encephalitis virus E1 glycoprotein prior to treatment with alphavirus cross-reactive monoclonal antibody allows blockage of replication early in infection

“…MAb 1A4B-6 was also found to inhibit virus egress at high concentrations 6 h PI. Since the assay to determine inhibition of viral egress relied on detection of infectious virus that may or may not have been inhibited by residual antibody in the culture medium, we are unable to conclusively say 1A4B-6 inhibited VEEV egress; however, others have shown that broadly alphavirus cross-reactive MAbs recognizing similar epitopes on the fusion loop do not inhibit viral egress in vitro ( Williamson et al, 2021 ).…”

“…Potent neutralizing MAbs specific to the E2 glycoprotein of VEEV, EEEV and WEEV have been shown to protect in mouse models ( Burke et al, 2018 ; Hunt et al, 2011 ; Kim et al, 2019 ). Non-neutralizing antibodies may also confer protection after lethal alphavirus challenge, and this protection may be inhibiting viral egress from the infected cell and facilitating monocyte-dependent antibody effector functions ( Boere et al, 1983 ; Kim et al, 2021 ; Parker et al, 2010 ; Rulker et al, 2012 ; Schmaljohn et al, 1982 ; Williamson et al, 2021 ).…”

“…Antibodies can neutralize viruses by several mechanisms, including prevention of viral particle attachment to cells, which can occur through virus aggregation or at the cell receptor-virus protein interface, prevention of virus envelope-cell endosomal membrane fusion, or by impeding virus egress from the infected cell. The potency of a MAb to neutralize virus by any of these mechanisms is dependent upon the virus-specific epitope involved in MAb binding and the accessible antibody-binding sites on the virion or infected cell-surface, which may be impacted by temperature and/or other reaction conditions such as changes in pH or exposure to reducing agents ( Fong et al, 2014 ; Lok et al, 2008 ; Meyer et al, 1992 ; Schmaljohn et al, 1983 ; Sevvana and Kuhn, 2020 ; Williamson et al, 2021 ; Zhou et al, 2020 ).…”

“… Fox et al (2015) also showed that broadly cross-reactive MAbs recognizing an epitope on the B domain of the alphavirus E2 protein elicited broad alphavirus protection in vivo . Even though the E1 protein elicits mostly non-neutralizing cross-reactive MAbs, these MAbs may still confer protection in vivo ( Boere et al, 1983 ; Burke et al, 2018 ; Kim et al, 2021 ; Rico et al, 2016 ; Schmaljohn et al, 1982 ; Williamson et al, 2021 ). This protection has been associated with MAb interactions with “cryptic” E1 epitopes not accessible on the mature virion surface.…”

Peptide and protein alphavirus antigens for broad spectrum vaccine design

“…Other recent studies have indicated that some mAbs can protect against both WEEV and EEEV in murine aerosol challenge [9]. Further, mAbs to the highly conserved fusion loop of E1 (which lies below the B-region of the E2 protein in the intact virus) have cross-neutralizing activity [39], confirming that diverse AV have a similar mechanisms of cell entry. Humans infected with EEEV can produce antibodies that also limit infection with VEEV or CHIKV [39], while those infected with CHIKV can produce antibodies that protect against multiple alphaviruses [40].…”