Hyperimmune Bovine Colostrum as a Low-Cost, Large-Scale Source of Antibodies with Broad Neutralizing Activity for HIV-1 Envelope with Potential Use in Microbicides

Kramski, Marit; Center, Rob J.; Wheatley, Adam K.; Jacobson, Jonathan; Alexander, Marina R.; Rawlin, Grant; Purcell, Damian F. J.

doi:10.1128/aac.00453-12

Cited by 52 publications

(66 citation statements)

References 66 publications

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“…The optical density at 405 nm was read on a microplate reader (Molecular Devices). For experiments involving antibody binding to antigen at different pH, serial dilutions of mAbs were incubated in PBS at different pHs or simulated vaginal fluid 19 (SVF) for 1 hr at RT and then washed 5× with PBS + 0.05% tween before addition of goat anti-human IgG F(ab′)2 conjugated to alkaline phosphatase secondary. SVF was made with citric acid instead of lactic acid to improve buffering at higher pH levels.…”

Section: Methods/supplementary Informationmentioning

confidence: 99%

“…Cows, however, produce antibodies with HCDR3s that average ~26 amino acids in length with an ultralong subset (10–15% of the repertoire) that can be over 70 amino acids in length 4–6,8,9,16 . Previous work has shown that repeated immunization over multiple years with a non-well-ordered Env trimer in cows can lead to some neutralization breadth in the immunoglobulin-rich colostrum 17–19 , although with relatively low potency. Here, we immunized cows with the well-ordered BG505 trimer, showed the longitudinal development of potent extensive neutralization breadth and demonstrated that antibodies with ultralong HCDR3s are responsible for serum breadth and potency.…”

Section: Main Textmentioning

confidence: 99%

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Rapid elicitation of broadly neutralizing antibodies to HIV by immunization in cows

Sok

Vadnais

et al. 2017

Nature

152

198

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No immunogen to date has reliably elicited broadly neutralizing antibodies (bnAbs) to HIV in humans or animal models. Advances in the design of immunogens (BG505 SOSIP) that antigenically mimic the HIV envelope glycoprotein (Env)1 have improved the elicitation of potent isolate-specific Ab responses in rabbits2 and macaques3, but so far failed to induce bnAbs. One possible contributor to this failure is that the relevant antibody repertoires are poorly suited to target somewhat occluded conserved epitope regions on Env relative to exposed variable epitopes. To test this hypothesis, we immunized four cows with BG505 SOSIP. The antibody repertoire of cows contains long third heavy chain complementary determining regions (HCDR3) with an ultralong subset that can reach over 70 amino acids in length4–9. Remarkably, BG505 SOSIP immunization resulted in rapid elicitation of broad and potent serum antibody responses in all four cows. Longitudinal serum analysis for one cow showed the development of neutralization breadth (20%, n = 117 cross-clade isolates) in 42 days and 96% breadth (n = 117) at 381 days. A monoclonal antibody (mAb) isolated from this cow harbored an ultralong HCDR3 of 60 amino acids and neutralized 72% of cross-clade isolates (n = 117) with a potent median IC50 of 0.028 μg/ml. We note that breadth was elicited with a single trimer immunogen and did not require additional envelope diversity. Immunization of cows may provide an avenue to rapidly generate antibody prophylactics and therapeutics to address disease agents that have evolved to avoid human antibody responses.

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Section: Methods/supplementary Informationmentioning

confidence: 99%

Section: Main Textmentioning

confidence: 99%

Rapid elicitation of broadly neutralizing antibodies to HIV by immunization in cows

Sok

Vadnais

et al. 2017

Nature

152

198

View full text Add to dashboard Cite

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“…Colostrum-derived polyclonal IgG showed broad cross-clade binding and neutralization in cows vaccinated with HIV-1 Env gp140 oligomers in a long duration regimen. 37 Bovine IgG with strong binding to gp140 had robust ADCC function and could mediate HIVspecific killing by human immune cells. 38 HIV neutralization and FccR-mediated cell functions have the potential to provide a rapid and potent response against both cell-free HIV-1 virus and HIV-infected cells, which might be particularly important in Ab-mediated microbicides for prevention of HIV transmission.…”

Section: Opportunities For Combination Hiv Preventionmentioning

confidence: 97%

Biology of Mucosally Transmitted Sexual Infection—Translating the Basic Science into Novel HIV Intervention: A Workshop Summary

Purcell

Cunningham

Turville³

et al. 2012

AIDS Research and Human Retroviruses

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A group of over 200 international scientists came together on April 15 in Sydney, Australia just before the 2012 International Microbicides Conference as a part of a workshop to address the basic concepts and factors that modulate HIV infection at the mucosal surface. The meeting focused on defining the interaction between virus, prevailing host physiology, microbiota, and innate and adaptive immune responses and how they combine to impact the outcome at the moment of potential viral transmission. Speakers examined the biology of HIV entry during transmission, innate and natural antiviral mechanisms at the mucosa, microbicide efficacy, pharmacokinetic, and pharmacodynamics, animal models, and opportunities for combining HIV prevention strategies. Other viral infection models both in vivo and in vitro were considered for the insights they provided into HIV transmission events. The workshop raised important questions that we need to answer to further our basic understanding of host and viral factors influencing HIV transmission to inform the development of novel prevention strategies.

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“…These antibodies include specificities that bind the highly conserved CD4bs on HIV Env trimmers and compete with the VRC01 mAb selected for analysis in the AMP trial and related BrNAbs, like b12 [40]. Heydarchi et al showed that bovine antibodies from vaccinated cow, not only bind to CD4bs but also can neutralize HIV infectivity through this region [41]. In addition, they showed that vaccination of the cows with oligomeric AD8 gp140 could induce the antibody response against the SOS-IP gp140 Env, which is the antigen with the closest structure to the functional Env protein [41].…”

Section: Anti-hiv/aids Activity Of Bovine Colostrummentioning

confidence: 99%

“…Heydarchi et al showed that bovine antibodies from vaccinated cow, not only bind to CD4bs but also can neutralize HIV infectivity through this region [41]. In addition, they showed that vaccination of the cows with oligomeric AD8 gp140 could induce the antibody response against the SOS-IP gp140 Env, which is the antigen with the closest structure to the functional Env protein [41]. In another study, IgG from hyper immune bovine colostrum from Env gp140 trimer vaccinated cows showed anti-HIV Antibody-Dependent Cellular Cytotoxicity (ADCC) activity.…”

Section: Anti-hiv/aids Activity Of Bovine Colostrummentioning

confidence: 99%

Broad Neutralizing Antibodies to HIV Env and Other Complex Viral Antigens from Vaccinated Cows

Heydarchi¹,

Quiroz²,

Purcell³

2016

J Vaccines Vaccin

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The idea of using antibodies to restrain HIV viral replication has been a growing interest since many years ago. HIV-patient serum with elite virus-neutralizing breadth has led to the preparation of broadly neutralizing antibodies (BrNAbs) with long and highly mutated CDRH3 domains that can neutralize a broad array of viral strains and prevent transmission in animal models. Recent advances have resulted in the discovery of BrNAbs that are more potent and can neutralize many HIV-1 subtypes. However, elicitation of these antibodies in infected individuals usually requires a long time of antigen exposure. Though BrNAbs are shown to be successful either therapeutically or prophylactically against HIV-1, production of these antibodies in bulk, commercial-sized batches are expensive and non-affordable particularly for poor countries. Therefore, more durable preventative or therapeutic strategies are required. Immunization of the cows with HIV Env is shown to be capable of producing 20 kg purified anti-HIV-1 BrNAbs and this amount could be sufficient for 2 million × 10 mg doses for formulation and pre-clinical testing as an HIV microbicide. In addition, bovine immunoglobulins typically have variable third heavy complementarity determining regions (CDRH3) that may potentially facilitate access to antigenic epitopes that are very difficult for other species to engage. Thus, cows could be engaged to elicit anti-HIV antibodies with the features of human BrNAbs and bovine colostrum could be a promising and cheap resource for the development of combination microbicides.

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Hyperimmune Bovine Colostrum as a Low-Cost, Large-Scale Source of Antibodies with Broad Neutralizing Activity for HIV-1 Envelope with Potential Use in Microbicides

Cited by 52 publications

References 66 publications

Rapid elicitation of broadly neutralizing antibodies to HIV by immunization in cows

Rapid elicitation of broadly neutralizing antibodies to HIV by immunization in cows

Biology of Mucosally Transmitted Sexual Infection—Translating the Basic Science into Novel HIV Intervention: A Workshop Summary

Broad Neutralizing Antibodies to HIV Env and Other Complex Viral Antigens from Vaccinated Cows

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