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

Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Journal of Virology (Impact Factor: 4.44). 09/2001; 75(16):7470-80. DOI: 10.1128/JVI.75.16.7470-7480.2001
Source: PubMed


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 that mimics intrapartum mucosal virus exposure (T. W. Baba et al., AIDS Res. Hum. Retroviruses 10:351-357, 1994). Using this model, neonates were protected from mucosal SHIV-vpu(+) challenge by pre- and postnatal treatment with a combination of three human neutralizing monoclonal antibodies (MAbs), F105, 2G12, and 2F5 (Baba et al., Nat. Med. 6:200-206, 2000). 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.

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Available from: Regina Hofmann-Lehmann, Apr 07, 2014
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    • "Novel anti-HIV-1 monoclonal antibodies (mAbs) capable of neutralizing a broad spectrum of HIV-1 isolates have recently been isolated [21-24] and could be useful tools for passive immunization or for the design of active immunization strategies to prevent MTCT. A protective role of broadly-neutralizing antibodies in breast milk HIV-1 acquisition has been established in non-human primates studies, as passive infusion of broadly-neutralizing mAbs protected neonatal rhesus monkeys against oral challenge with a simian-human immunodeficiency virus [25,26]. However, previous studies have indicated that viruses transmitted during breastfeeding are typically resistant to neutralization by maternal autologous plasma and broadly-neutralizing antibodies [11,27-29]. "
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    ABSTRACT: Background Breastfeeding is a leading cause of infant HIV-1 infection in the developing world, yet only a minority of infants exposed to HIV-1 via breastfeeding become infected. As a genetic bottleneck severely restricts the number of postnatally-transmitted variants, genetic or phenotypic properties of the virus Envelope (Env) could be important for the establishment of infant infection. We examined the efficiency of virologic functions required for initiation of infection in the gastrointestinal tract and the neutralization sensitivity of HIV-1 Env variants isolated from milk of three postnatally-transmitting mothers (n=13 viruses), five clinically-matched nontransmitting mothers (n=16 viruses), and seven postnatally-infected infants (n = 7 postnatally-transmitted/founder (T/F) viruses). Results There was no difference in the efficiency of epithelial cell interactions between Env virus variants from the breast milk of transmitting and nontransmitting mothers. Moreover, there was similar efficiency of DC-mediated trans-infection, CCR5-usage, target cell fusion, and infectivity between HIV-1 Env-pseudoviruses from nontransmitting mothers and postnatal T/F viruses. Milk Env-pseudoviruses were generally sensitive to neutralization by autologous maternal plasma and resistant to breast milk neutralization. Infant T/F Env-pseudoviruses were equally sensitive to neutralization by broadly-neutralizing monoclonal and polyclonal antibodies as compared to nontransmitted breast milk Env variants. Conclusion Postnatally-T/F Env variants do not appear to possess a superior ability to interact with and cross a mucosal barrier or an exceptional resistance to neutralization that define their capability to initiate infection across the infant gastrointestinal tract in the setting of preexisting maternal antibodies.
    Full-text · Article · Jan 2013 · Retrovirology
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    • "The inclusion of 2F5 in a broadly-accessible microbicide entails the use of a large-scale production platform because effective prevention is likely to require the administration of up to 5 mg of the active pharmaceutical ingredient twice weekly per individual, which equates to 5,000 kg of antibody per year per 10 million women (Shattock and Moore 2003). This far exceeds the capacity of current CHO-based infrastructure, and even if the capacity were available the costs would be prohibitive (Hofmann-Lehmann et al. 2001; Stiegler et al. 2002). Plants offer a more cost-effective and scalable manufacturing platform that could be used to produce mAbs locally (Ma et al. 2003; Ramessar et al. 2008a). "
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    ABSTRACT: Monoclonal antibodies (mAbs) that neutralize human immunodeficiency virus (HIV) can be used as microbicides to help prevent the spread of HIV in human populations. As an industry standard, HIV-neutralizing mAbs are produced as recombinant proteins in mammalian cells, but the high manufacturing costs and limited capacity reduce the ability of target populations in developing countries to gain access to these potentially life-saving medicines. Plants offer a more cost-effective and deployable production platform because they can be grown inexpensively and on a large scale in the region where the products are required. Here we show that the maize-derived HIV-neutralizing mAb 2F5 is assembled correctly in planta and binds to its antigen with the same affinity as 2F5 produced in mammalian cells. Although 2F5 has been produced at high levels in non-plant platforms, the yield in maize seeds is lower than previously achieved with another HIV-neutralizing mAb, 2G12. This suggests that the intrinsic properties of the antibody (e.g. sensitivity to specific proteases) and the environment provided by the production host (e.g. the relative abundance of different proteases, potential transgene silencing) may combine to limit the accumulation of some antibodies on a case-by-case basis.
    Full-text · Article · Sep 2012 · Plant Molecular Biology
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    • "Even at a relatively low antibody dose, b12 and 2G12 conferred protection in a repeat challenge model (Hessell et al., 2009a,b). Passive immunizations with antibodies b12, 2G12, and 2F5 also protected newborn macaques from oral SHIV challenge (Baba et al., 2000; Hofmann-Lehmann et al., 2001). Furthermore, vector mediated delivery of genes expressing broadly neutralizing antibodies in a humanized mouse model conferred protection against subsequent high dose viral challenges (Johnson et al., 2009; Balazs et al., 2012). "
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    ABSTRACT: The recent surge of research into new broadly neutralizing antibodies in HIV-1 infection has recharged the field of HIV-1 vaccinology. In this review we discuss the currently known broadly neutralizing antibodies and focus on factors that may shape these antibodies in natural infection. We further discuss the role of these antibodies in the clinical course of the infection and consider immunological obstacles in inducing broadly neutralizing antibodies with a vaccine.
    Full-text · Article · Jul 2012 · Frontiers in Immunology
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