Postnatal Passive Immunization of Neonatal Macaques with a Triple Combination of Human Monoclonal Antibodies against Oral Simian-Human Immunodeficiency Virus Challenge

Abstract

To develop prophylaxis against mother-to-child human immunodeficiency virus (HIV) transmission, we established a simian-human immunodeficiency virus (SHIV) infection model in neonatal macaques. In the present study, we used this MAb combination only postnatally, thereby significantly reducing the quantity of antibodies necessary and rendering their potential use in humans more practical. We protected two neonates with this regimen against oral SHIV-vpu ؉ challenge, while four untreated control animals became persistently infected. Thus, synergistic MAbs protect when used as immunoprophylaxis without the prenatal dose. We then determined in vitro the optimal MAb combination against the more pathogenic SHIV89.6P, a chimeric virus encoding env of the primary HIV89.6. Remarkably, the most potent combination included IgG1b12, which alone does not neutralize SHIV89.6P. We administered the combination of MAbs IgG1b12, 2F5, and 2G12 postnatally to four neonates. One of the four infants remained uninfected after oral challenge with SHIV89.6P, and two infants had no or a delayed CD4 ؉ T-cell decline. In contrast, all control animals had dramatic drops in their CD4 ؉ T cells by 2 weeks postexposure. We conclude that our triple MAb combination partially protected against mucosal challenge with the highly pathogenic SHIV89.6P. Thus, combination immunoprophylaxis with passively administered synergistic human MAbs may play a role in the clinical prevention of mother-to-infant transmission of HIV type 1.

Potent, Persistent Induction and Modulation of Cellular Immune Responses in Rhesus Macaques Primed with Ad5hr-Simian Immunodeficiency Virus (SIV) env/rev , gag , and/or nef Vaccines and Boosted with SIV gp120

“…However, concerns have arisen about the reliance on vaccines directed solely to limited CTL epitopes, since viral escape from CTL occurs frequently (42) and can lead to AIDS progression (5). It has also been shown that passive immunization with potent, neutralizing human monoclonal antibodies can prevent infection from pathogenic SHIV in primates (3,22,27,38,39,44). Therefore, a vaccine that can induce broad, potent cellular and humoral immune responses would not only be highly desirable but also more likely to exhibit improved protective efficacy against a virulent SIV challenge.…”

The V1V2 Domain and an N-Linked Glycosylation Site in the V3 Loop of the HIV-1 Envelope Glycoprotein Modulate Neutralization Sensitivity to the Human Broadly Neutralizing Antibody 2G12

“…Recently, Gray et al have shown that the absence of the Asn residue at position 295 in most subtype C viruses contributed to this resistance but was not the only determinant involved, suggesting structural differences between subtype C and other HIV subtypes (13). In vivo, when passively administered to macaques, 2G12 used alone or in combination with other monoclonal antibodies protects the animals against simian-human immunodeficiency virus (SHIV) challenge even at relatively low concentrations (14,15,21). Recently, delivery of 2G12 by gene therapy in humanized mice was shown to significantly reduce the replication of HIV in vivo (16).…”

Cost-effective production of a vaginal protein microbicide to prevent HIV transmission

“…The 2G12, 2F5 and 4E10 antibodies have been produced in Chinese hamster ovary (CHO) cells for prophylactic (13) and therapeutic (14) use, but the limitations of this platform (including high cost, low capacity, low scalability, and safety issues) (15) mean that large-scale production for use in developing countries is unfeasible (16). Among the alternative systems available for biopharmaceutical manufacture, only plants provide the scalability and economy required to meet the anticipated demand for such products in the HIV-endemic regions of Africa and Asia at a price the market can bear (17)(18)(19)(20).…”