Antibody therapies for the prevention and treatment of viral infections

Salazar, Georgina; Zhang, Ningyan; Fu, Tong-Ming; An, Zhiqiang

orne disease, with an estimated 390 million people each year becoming infected. 136 Severe dengue, associated with infection with different strains of the virus, is characterized by vascular permeability, bleeding from mucosa and intestinal tract, dengue shock syndrome, and acute renal failure. 137 In contrast with HCMV where severe symptoms are accompanied by a detectable active phase, 138 dengue symptoms often appear after the peak of viremia; 139 therefore, an antibody applied for passive immunotherapy would have to be used before the onset of symptoms to be early enough to avoid viremia. Another difference between HCMV and dengue is that for HCMV, developing fetuses or infants and people with compromised immune systems are clearly at risk for the development of severe disease. 43 In contrast, there are no clear prognostic indicators for susceptibility to severe dengue virus disease. Such prognostic indicators are necessary due to practical limitations on the number of people who can receive passive immunotherapy. Further, dengue antibodies at subneutralizing concentrations may enhance uptake of dengue virus in a way that dramatically aggravates symptoms (antibodydependent enhancement, ADE). 136 Therefore, the development of vaccines has been the focus for dengue control. So far one vaccine has been approved, but the vaccine (CYD-TDV, Dengvaxia, Sanofi Pasteur) is less than ideal and better dengue vaccines are urgently needed. 140 mAbs against dengue have been generated so their interaction with dengue could be analyzed to identify the virus' best target epitopes, a key first step in vaccine design. A summary of these epitopes and their associated antibodies is presented in several excellent reviews. 136, 141 The epitopes targeted by antibodies most effective at neutralizing dengue virus were grouped into broad classifications based on whether these epitopes were present in a single virion (epitopes on a monomer) or were composed of features on more than one virion (quaternary epitopes). Epitopes on a monomer were further grouped according by region of the dengue virion bound: prM protein, FLE (amino acids [98] [99] [100] [101] [102] [103] [104] [105] [106] [107] [108] [109] [110] [111] [112] [113] , BC loop E protein domain II (amino acids 73,78, and 79), or EDIII. Quaternary epitopes were also sub-divided into EDE epitopes (EDI, EDII, and EDIII); E protein epitopes (monomer EDI, EDI-EDII hinge, and EDIII; intact virion only); and E protein herring-bone epitope (EDI, EDI-EDII hinge, and EDIII). Although no dengue antibody therapeutics have reached the stage of clinical trials, some of Antibody therapies for viral infections G Salazar et al.