Herd immunity: hyperimmune globulins for the 21st century
Authors: Sarah TC Elliott, David B Weiner
Journal: The Lancet Infectious Diseases (2018)

Recent headlines, including outbreaks of Ebola virus disease in urban west Africa, the intercontinental transmission of Middle East respiratory syndrome virus (MERS) from the Arabian Peninsula to South Korea, and the emergence of Zika virus as a fetal neurotoxic agent, highlight the global threat posed by emerging infectious diseases in an increasingly connected world. In use since the late 1800s, convalescent blood products are some of the oldest instruments in the expanding toolbox of immune therapies for infectious disease. Passive transfer of convalescent human sera has been investigated for protection against coronaviruses (severe acute respiratory syndrome), arenaviruses (Lassa, Junin), filoviruses (Ebola, Marburg), and pandemic influenza viruses (H5N1, H1N1).1Marano G Vaglio S Pupella S et al.Convalescent plasma: new evidence for an old therapeutic tool?.Blood Transfus. 2016; 14: 152-157PubMed Google Scholar However, positive findings have not been substantiated by controlled trials. Few immunoglobulins are licensed for infectious disease and passive transfer is not without some attendant risks (appendix). Heterologous equine and ovine immune globulins can induce hypersensitivity; Fab and F(ab')2, which have shorter in-vivo half-lives, lessen hypersensitivity, suggesting this hypersensitivity is largely mediated by foreign FC. Although human IgG is desirable, the risk of transmitting unidentified pathogens and costly donor screening protocols are barriers to use of fractionated human immune plasma products. For example, clinical studies of anti-MERS intravenous immunoglobulin reported difficulty identifying human plasma donors because of low neutralising titres in convalescent patients and the generally short-lived nature of neutralising antibody responses after coronavirus infection.2Arabi YM Hajeer AH Luke T et al.Feasibility of using convalescent plasma immunotherapy for MERS-CoV infection, Saudi Arabia.Emerg Infect Dis. 2016; 22: 1554-1561Crossref PubMed Scopus (178) Google Scholar In The Lancet Infectious Diseases, John Beigel and colleagues report results from a first-in-human phase 1 clinical trial of the safety and tolerability of SAB-301, a fully human polyclonal IgG developed from plasma of transchromosomic cattle immunised with MERS spike protein nanoparticles.3Beigel JH Voell J Kumar P et al.Safety and tolerability of a novel, polyclonal human anti-MERS coronavirus antibody: a phase 1 randomised, double-blind, single-dose-escalation study.Lancet Infect Dis. 2018; (published online Jan 9.)http://dx.doi.org/10.1016/S1473-3099(18)30002-1Summary Full Text Full Text PDF PubMed Scopus (96) Google Scholar The transchromosomic cattle used to produce SAB-301 were developed over the course of a decade in a remarkable feat of genetic engineering (figure). In research studies, multiple vaccine platforms have generated antigen-specific human IgG in transchromosomic cattle. Hyperimmunisation of transchromosomic cattle with anthrax protective antigen yields human neutralising antibodies that protect mice against anthrax challenge.4Kuroiwa Y Kasinathan P Sathiyaseelan T et al.Antigen-specific human polyclonal antibodies from hyperimmunized cattle.Nat Biotechnol. 2009; 27: 173-181Crossref PubMed Scopus (106) Google Scholar Additionally, DNA vaccination yields human neutralising antibodies with demonstrated efficacy after passive transfer to rodent models of Ebola virus and hantavirus infection.5Bounds CE Kwilas SA Kuehne AI et al.Human polyclonal antibodies produced through dna vaccination of transchromosomal cattle provide mice with post-exposure protection against lethal Zaire and Sudan Ebolaviruses.PLoS One. 2015; 10: e0137786Crossref PubMed Scopus (22) Google Scholar, 6Hooper JW Brocato RL Kwilas SA et al.DNA vaccine-derived human IgG produced in transchromosomal bovines protect in lethal models of hantavirus pulmonary syndrome.Sci Transl Med. 2014; 6: 264ra162Crossref PubMed Scopus (49) Google Scholar Immunisation with recombinant nanoparticles used in the production of SAB-301 or with gamma-irradiated whole-killed virions induced anti-MERS neutralising human IgG in transchromosomic cattle, which reportedly reduce lung viral load in a non-lethal murine MERS challenge.7Luke T Wu H Zhao J et al.Human polyclonal immunoglobulin G from transchromosomic bovines inhibits MERS-CoV in vivo.Sci Transl Med. 2016; 8: 326ra21Crossref PubMed Scopus (99) Google Scholar In their study, Beigel and colleagues show that human participants who received infusion of SAB-301 developed anti-MERS neutralising antibody titres that correlated with serum SAB-301 concentrations. These titres were achieved without clinically significant hypersensitivity or adverse events at infusion rates below current intravenous immunoglobulin guidelines. The SAB-301 terminal elimination half-life appears to be within range of a typical human antibody. SAB-301 is enriched in human IgG1κ, which could exhibit important in-vivo effector-mediated functions in addition to demonstrated in-vitro neutralising capability.8Bournazos S Ravetch J V Fcγ receptor pathways during active and passive immunization.Immunol Rev. 2015; 268: 88-103Crossref PubMed Scopus (104) Google Scholar The effect of bovine processes on SAB-301 human IgG development is unclear. Comparative immunology of human beings and cattle point to several key innate immune factors—namely, anatomical (eg, a primary lymphoid organ in the bovine intestine referred to as an ileal Peyer's patch9Yasudaa M Jenne CN Kennedy LJ Reynolds JD The sheep and cattle Peyer's patch as a site of B-cell development.Vet Res. 2006; 37: 401-415Crossref PubMed Scopus (80) Google Scholar), cellular (eg, abundant bovine circulatory γδ T cells with unique capabilities10Telfer JC Baldwin CL Bovine gamma delta T cells and the function of gamma delta T cell specific WC1 co-receptors.Cell Immunol. 2015; 296: 76-86Crossref PubMed Scopus (40) Google Scholar), and molecular (eg, bovine pattern recognition receptor function11Jungi TW Farhat K Burgener IA Werling D Toll-like receptors in domestic animals.Cell Tissue Res. 2011; 343: 107-120Crossref PubMed Scopus (59) Google Scholar) factors, which could lead to distinct adaptive immunity. Post-translational modifications, including glycosylation,4Kuroiwa Y Kasinathan P Sathiyaseelan T et al.Antigen-specific human polyclonal antibodies from hyperimmunized cattle.Nat Biotechnol. 2009; 27: 173-181Crossref PubMed Scopus (106) Google Scholar could lead to dissimilar effector functions between transchromosomic IgG and human IgG, and will require additional work to be understood. Transchromosomic cattle reportedly make 150–600 g of human IgG per animal per month,7Luke T Wu H Zhao J et al.Human polyclonal immunoglobulin G from transchromosomic bovines inhibits MERS-CoV in vivo.Sci Transl Med. 2016; 8: 326ra21Crossref PubMed Scopus (99) Google Scholar thus more than 6500 cows would be needed to produce an immediate 50 mg/kg dose of unfractionated human IgG for one million adults. Potent, functional, antigen-specific antibody generation through optimised vaccination protocols will be crucial for environmental and economic feasibility of this platform. The therapeutic and protective efficacy of SAB-301 in human infection or lethal animal challenge has not been reported, underscoring that this is an early technology requiring further clinical investigation. Vitality in the field of antibodies deployed against infectious diseases is supported by the concomitant rise in systems for rapid delivery of rigorously selected and highly potent monoclonal antibodies as proteins, DNA, or RNA, as well as vectored delivery. Additional technologies addressing the need for sustainable, potent antibody therapies include engineered bispecific antibodies and half-life extension modifications. The study of transchromosomic cattle with the ability to produce polyclonal antibody responses against emergent pathogens advances a platform worthy of further consideration, possibly in outbreak situations as well as for protection of at-risk populations. DBW or his laboratory have received grant funding for industry collaborations, and DBW has received speaking honoraria or fees for consulting and board service, including serving on scientific committees and boards of directors; remuneration includes direct payments or stock or stock options; DBW also reports potential conflicts of interest with Inovio, Merck, Pfizer, Janssen, VGXI, MedImmune, and Bill & Melinda Gates Foundation. STCE declares no competing interests Download .pdf (.11 MB) Help with pdf files Supplementary appendix Safety and tolerability of a novel, polyclonal human anti-MERS coronavirus antibody produced from transchromosomic cattle: a phase 1 randomised, double-blind, single-dose-escalation studySingle infusions of SAB-301 up to 50 mg/kg appear to be safe and well tolerated in healthy participants. Human immunoglobulin derived from transchromosomic cattle could offer a new platform technology to produce fully human polyclonal IgG antibodies for other medical conditions. Full-Text PDF