Vaccine-elicited receptor-binding site antibodies neutralize two New World hemorrhagic fever arenaviruses

Lars E Clark,Donald D Raymond,Ana M Briggiler,Selma Mahmutovic,John T Manning,Sundaresh Shankar,Takaaki Koma,Slobodan Paessler,Jonathan Abraham,Kai W Wucherpfennig,Delia A Enria,Silvana C Levis,Taleen Dilanyan

doi:10.1038/s41467-018-04271-z

Abstract

While five arenaviruses cause human hemorrhagic fevers in the Western Hemisphere, only Junin virus (JUNV) has a vaccine. The GP1 subunit of their envelope glycoprotein binds transferrin receptor 1 (TfR1) using a surface that substantially varies in sequence among the viruses. As such, receptor-mimicking antibodies described to date are type-specific and lack the usual breadth associated with this mode of neutralization. Here we isolate, from the blood of a recipient of the live attenuated JUNV vaccine, two antibodies that cross-neutralize Machupo virus with varying efficiency. Structures of GP1–Fab complexes explain the basis for efficient cross-neutralization, which involves avoiding receptor mimicry and targeting a conserved epitope within the receptor-binding site (RBS). The viral RBS, despite its extensive sequence diversity, is therefore a target for cross-reactive antibodies with activity against New World arenaviruses of public health concern.

Highlights

We purified polyclonal immunoglobulins (IgG) from CR1 plasma using protein G affinity chromatography and found negligible binding to Junin virus (JUNV) GP1 by ELISA and negligible neutralizing activity against JUNV pseudotypes, as compared to polyclonal IgG purified from the plasma of an Argentine hemorrhagic fever (AHF) survivor known to have high-titer neutralizing activity (Fig. 1a, b)
In non-human primates immunized with Candid #1, low or undetectable antibody levels prior to JUNV challenge can be boosted by JUNV infection, resulting in protection.[24]
Could in part explain why transfusion of survivor immune plasma is highly effective against JUNV.[14]

Summary

Introduction

From the blood of a recipient of the live attenuated JUNV vaccine, two antibodies that cross-neutralize. S everal groups of enveloped RNA viruses cause human hemorrhagic fevers with high case fatality rates and most lack vaccines or effective countermeasures. This underscores a critical point of vulnerability in public health. Old World arenaviruses that cause human viral hemorrhagic fevers.[1] Junin (JUNV), Machupo (MACV), Guanarito (GTOV), Sabiá (SBAV), and Chapare (CHPV) are arenaviruses that cause human viral hemorrhagic fevers in the New World.[1] They are usually transmitted from rodents to humans.[3] Clinical features of infection include hemorrhagic signs, shock, and seizures. The case fatality rate of infection ranges from 15 to 30%.3 New World arenaviruses pose an emerging threat in the North America; Whitewater Arroyo virus (WWAV) was tentatively implicated in three deaths in California from 1999 to 2000.4

Methods

Results

Conclusion