Passive immunization with anti-dengue virus (DENV) immune serum globulin (ISG) or monoclonal antibodies (Mabs) may serve to supplement or replace vaccination for short-term dengue immune prophylaxis. In the present study， we sought to establish proof-of-concept by evaluating several DENV-neutralizing antibodies for their ability to protect rhesus macaques against viremia following live virus challenge， including human anti-dengue ISG， and a human Mab (Mab11/wt) and its genetically engineered variant (Mab11/mutFc) that is unable to bind to cells with Fc gamma receptors (FcγR) and potentiate antibody-dependent enhancement (ADE). In the first experiment， groups of animals received ISG or Mab11/wt at low d... More
Passive immunization with anti-dengue virus (DENV) immune serum globulin (ISG) or monoclonal antibodies (Mabs) may serve to supplement or replace vaccination for short-term dengue immune prophylaxis. In the present study， we sought to establish proof-of-concept by evaluating several DENV-neutralizing antibodies for their ability to protect rhesus macaques against viremia following live virus challenge， including human anti-dengue ISG， and a human Mab (Mab11/wt) and its genetically engineered variant (Mab11/mutFc) that is unable to bind to cells with Fc gamma receptors (FcγR) and potentiate antibody-dependent enhancement (ADE). In the first experiment， groups of animals received ISG or Mab11/wt at low doses (3-10 mg/kg) or a saline control followed by challenge with DENV-2 at day 10 or 30. After passive immunization， only low-titered circulating virus-neutralizing antibody titers were measured in both groups， which were undetectable by day 30. After challenge at day 10， a reduction in viremia duration compared with the control was seen only in the ISG group (75%). However， after a day 30 challenge， no reduction in viremia was observed in both immunized groups. In a second experiment to test the effect of higher antibody doses on short-term protection， groups received either ISG， Mab11/wt， Mab11/mutFc (each at 25 mg/kg) or saline followed by challenge with DENV-2 on day 10. Increased virus-neutralizing antibody titers were detected in all groups at day 5 postinjection， with geometric mean titers (GMTs) of 464 (ISG)， 313 (Mab11/wt)， and 309 (Mab11/mutFc). After challenge， there was complete protection against viremia in the group that received ISG， and a reduction in viremia duration of 89% and 83% in groups that received Mab11/wt and Mab11/mutFc， respectively. An in vitro ADE assay in Fcγ receptor-bearing K562 cells with sera collected immediately before challenge showed increased DENV-2 infection levels in the presence of both ISG and Mab11/wt， which peaked at a serum dilution of 1:90， but not in Mab11/mutFc containing sera. The results suggest that antibody prophylaxis for dengue might be beneficial in eliminating or reducing viral loads thereby minimizing disease progression. Our results also suggest that blocking FcγR interactions through Mab11 Fc engineering may further prevent ADE.
