Broad and potently neutralizing monoclonal antibodies isolated from human survivors of New World hantavirus infection

Abstract

SUMMARY New World hantaviruses (NWHs) are endemic in North and South America and cause hantavirus cardiopulmonary syndrome (HCPS), with a case fatality rate of up to 40%. Knowledge of the natural humoral immune response to NWH infection is limited. Here, we describe human monoclonal antibodies (mAbs) isolated from individuals previously infected with Sin Nombre virus (SNV) or Andes virus (ANDV). Most SNV-reactive antibodies show broad recognition and cross-neutralization of both New and Old World hantaviruses, while many ANDV-reactive antibodies show activity for ANDV only. mAbs ANDV-44 and SNV-53 compete for binding to a distinct site on the ANDV surface glycoprotein and show potently neutralizing activity to New and Old World hantaviruses. Four mAbs show therapeutic efficacy at clinically relevant doses in hamsters. These studies reveal a convergent and potently neutralizing human antibody response to NWHs and suggest therapeutic potential for human mAbs against HCPS.

Human antibody recognizing a quaternary epitope in the Puumala virus glycoprotein provides broad protection against orthohantaviruses

“…S9B). Together, these results indicate that many of our nAbs selected for neutralization potency and breadth directly interfere with Gn/Gc-dependent viral membrane fusion, as also observed for previously isolated nAbs ( 26 ), suggesting that they act by targeting one or more steps in the membrane fusion reaction, including Gn:Gc dissociation, and Gc target membrane insertion and homotrimerization.…”

“…In addition, two recent studies have isolated spike-specific mAbs from ANDV- and/or SNV-experienced HCPS-convalescent donors and identified several that could protect Syrian hamsters from lethal ANDV challenge ( 26 , 27 ). Most of the protective lead mAbs in these reports recognized and/or neutralized Gn/Gc in a virus-specific manner, and Engdahl and colleagues ( 26 ) described several nAbs isolated from SNV-experienced donors with activity against members of both Old World and New World clades (hereafter, cross-clade activity; see Fig. 1A).…”

The Input of Structural Vaccinology in the Search for Vaccines against Bunyaviruses

“…Currently, the most promising candidate vaccines are based on multivalent DNA vaccines containing the M segment of one to four hantaviruses (two of them are in phase I/II clinical trials) [ 30 ]. However, although serologic studies in humans and immunization trials in animals using these multivalent DNA vaccines may have confirmed a certain degree of cross-neutralization across the hantavirus species, this cross-neutralizing activity appears to display high variability, notably depending on the viruses used in the candidate vaccine [ 31 , 32 ].…”

“…Engdahl and colleagues began to decipher the molecular determinants of this variability, providing hints for how to overcome it. Using a panel of 20 mAbs from three donors previously infected with Sin Nombre virus (SNV) and 16 mAbs from one donor previously infected with ANDV, they showed that the variation in the breadth of the humoral response was linked to the different viral glycoproteins targeted by the mAbs: most of the broadly-reactive mAbs recognized Gc whereas the virus-specific mAbs targeted Gn [ 31 ]. This correlation was also observed in murine mAbs derived from B cells of immunized mice [ 22 ].…”

“…Interestingly, Engdahl et al isolated two mAbs which were potent neutralizers of both New and Old World viruses [ 31 ]. Binding experiments to either Gn- or Gc-soluble proteins revealed that none of them recognized Gn nor Gc alone, suggesting that the epitopes recognized by these two mAbs are formed or accessible only in the quaternary spike structure.…”