Journal
JOURNAL OF VIROLOGY
Volume 81, Issue 23, Pages 12766-12774Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/JVI.01420-07
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Funding
- Intramural NIH HHS Funding Source: Medline
- NCRR NIH HHS [P41 RR001081, P41 RR-01081] Funding Source: Medline
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The chimpanzee monoclonal antibody (MAb) 5H2 is specific for dengue virus type 4 (DENV-4) and neutralizes the virus at a high titer in vitro. The epitope detected by the antibody was mapped by sequencing neutralization escape variants of the virus. One variant contained a Lys(174)-Glu substitution and another contained a Pro(176)-Leu substitution in domain I of the DENV-4 envelope protein (E). These mutations reduced binding affinity for the antibody 18- to >100-fold. Humanized immunoglobulin G (IgG) 5112, originally produced from an expression vector, has been shown to be a variant containing a nine-amino-acid deletion in the Fc region which completely ablates antibody-dependent enhancement of DENV replication in vitro. The variant MAb, termed IgG 5H2 AD, is particularly attractive for exploring its protective capacity in vivo. Passive transfer of IgG 5H2 Delta D at 20 mu g/mouse afforded 50% protection of suckling mice against challenge with 25 50% lethal doses of mouse neurovirulent DENV-4 strain H241. Passive transfer of antibody to monkeys was conducted to demonstrate proof of concept for protection against DENV challenge. Monkeys that received 2 mg/kg of body weight of IgG 5H2 AD were completely protected against 100 50% monkey infectious doses (MID,,) of DENV-4, as indicated by the absence of viremia and seroconversion. A DENV-4 escape mutant that contained a Lys(174)-Glu substitution identical to that found in vitro was isolated from monkeys challenged with 10(6) MID50 of DENV-4. This substitution was also present in all naturally occurring isolates belonging to DENV-4 genotype III. These studies have important implications for possible antibody-mediated prevention of DENV infection.
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