Article

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: 4.65). 09/2001; 75(16):7470-80. DOI: 10.1128/JVI.75.16.7470-7480.2001
Source: PubMed

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 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.

Download full-text

Full-text

Available from: Regina Hofmann-Lehmann, Apr 07, 2014
1 Follower
 · 
187 Views
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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.
    Plant Molecular Biology 09/2012; 80(4-5):477-88. DOI:10.1007/s11103-012-9962-6 · 4.07 Impact Factor
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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.
    Frontiers in Immunology 07/2012; 3:215. DOI:10.3389/fimmu.2012.00215
  • Source
    • "It is widely believed that such a vaccine would require the induction of both virus-specific CD8+ T cells and neutralizing antibodies (nAbs) (Letvin et al., 2002; Mascola, 2003). Evidence for the role of nAbs comes from studies with non-human primates which have confirmed the protective capacity of passively transferred nAbs (Baba et al., 2000; Hofmann-Lehmann et al., 2001; Mascola et al., 1999, 2000; Parren et al., 2001; Veazey et al., 2003) and from recent data showing that, in some HIV-infected individuals, monoclonal nAbs can reduce the rate of viral rebound following a structured treatment interruption (Trkola et al., 2005). Despite considerable effort, there has been little progress in creating a vaccine capable of eliciting nAbs, most likely due to difficulties in designing an immunogen that sufficiently resembles the native Env trimer (Garber et al., 2004). "
    [Show abstract] [Hide abstract]
    ABSTRACT: This study aimed to characterize genetic features of HIV-1 subtype C envelope glycoproteins capable of eliciting cross-reactive neutralizing antibodies during natural infections. The gp160 sequences were determined for 36 HIV-1 subtype C isolates (donor viruses) from infected individuals residing in Malawi, Zimbabwe, Zambia and South Africa, whose sera displayed a range of cross-neutralizing activities against a panel of 5 subtype C and 5 subtype B viruses (panel viruses). Hierarchical clustering analysis of neutralization data of the panel viruses predicted phylogenetic relationships between subtype B and C panel viruses, suggesting some subtype-specific neutralization determinants. A similar comparison of subtype C donor viruses showed no significant correlation; however of three donor sequence pairs resolvable by phylogenetic analysis, two were also associated within the neutralization clustering dendrogram, suggesting that closely related viruses may elicit antibodies targeting common neutralization determinants. Significantly, viruses that had shorter V1-V4 loops induced antibodies that showed more neutralization breadth against the subtype C panel viruses (p=0.0135). This study indicates that that some structural features of envelope, such as shorter variable loops, may facilitate the elicitation of cross-reactive neutralizing antibodies in natural infections. Collectively these data provide some insights into design features of an envelope immunogen aimed at inducing neutralizing antibodies.
    Virology 12/2007; 368(1):172-81. DOI:10.1016/j.virol.2007.06.013 · 3.28 Impact Factor
Show more