DNA vaccine–derived human IgG produced in transchromosomal bovines protect in lethal models of hantavirus pulmonary syndrome

Abstract

Polyclonal immunoglobulin-based medical products have been used successfully to treat diseases caused by viruses for more than a century. We demonstrate the use of DNA vaccine technology and transchromosomal bovines (TcBs) to produce fully human polyclonal immunoglobulins (IgG) with potent antiviral neutralizing activity. Specifically, two hantavirus DNA vaccines [Andes virus (ANDV) DNA vaccine and Sin Nombre virus (SNV) DNA vaccine] were used to produce a candidate immunoglobulin product for the prevention and treatment of hantavirus pulmonary syndrome (HPS). A needle-free jet injection device was used to vaccinate TcB, and high-titer neutralizing antibodies (titers >1000) against both viruses were produced within 1 month. Plasma collected at day 10 after the fourth vaccination was used to produce purified α-HPS TcB human IgG. Treatment with 20,000 neutralizing antibody units (NAU)/kg starting 5 days after challenge with ANDV protected seven of eight animals, whereas zero of eight animals treated with the same dose of normal TcB human IgG survived. Likewise, treatment with 20,000 NAU/kg starting 5 days after challenge with SNV protected immunocompromised hamsters from lethal HPS, protecting five of eight animals. Our findings that the α-HPS TcB human IgG is capable of protecting in animal models of lethal HPS when administered after exposure provides proof of concept that this approach can be used to develop candidate next-generation polyclonal immunoglobulin-based medical products without the need for human donors, despeciation protocols, or inactivated/attenuated vaccine antigen.

Knowledge, attitudes, and practices regarding hantavirus disease and acceptance of a vaccine trial in rural communities of southern Chile

“…A phase I clinical trial of a DNA HTNV and/or Puumala (PUUV) vaccine showed that they were safe and immunogenic, 20 and a DNA vaccine for HCPS, including Sin Nombre virus (SNV) and ANDV M segments, was immunogenic in non-human primates and produced human IgG NAbs following vaccination of transchromosomal bovines. 12,21 The sporadic presentation of the disease and low incidence suggest that it is exceedingly unlikely that vaccine efficacy studies would be feasible in humans. Strategies for future licensing of an ANDV vaccine in Chile will probably require an approach in which immunogenicity and safety are demonstrated in population at risk of the disease, and efficacy is demonstrated through studies proving passive protective immunity by sera from vaccinated subjects in an animal model using the framework of the "animal rule" of the US Food and Drug Administration.…”

“…[10][11][12] In humans, high titers of NAbs against SNV at hospital admission are associated with reduced mortality. 13 An open study in Chile of treatment of HCPS by passive transfusion of anti-ANDV immune serum was promising, but the open study design prevented analysis of efficacy.…”

Human polyclonal immunoglobulin G from transchromosomic bovines inhibits MERS-CoV in vivo

“…Alternative methods to produce passive immunotherapy without the limitations of animal/human IgGs and monoclonal antibody therapeutics would be beneficial. Tc bovines offer a possible production platform to rapidly produce fully human, polyclonal, and polypathogen IgG in large quantities for the prevention and treatment of human diseases (35,36). Because polyclonal antibodies target multiple epitopes, viral escape leading to a pathogenic virus is more difficult.…”

“…Viruses that escape from a single antibody may still maintain high fitness, whereas escape from multiple antibodies has been shown to lead to reduced fitness in vitro and in vivo. Experimental high-titer Tc hIgGs have shown in vivo protection and/or in vitro neutralization against bivalent hantavirus (Andes and Sin Nombre viruses) (35), bivalent Ebolavirus (Zaire and Sudan viruses) (34), and trivalent seasonal influenza A viruses (pH1N1, H3N2, type B), trivalent alphaviruses (Venezuelan, eastern, and western equine encephalitis viruses), and tetravalent dengue viruses 1 to 4 are also under evaluation. We have shown that the WKVV and SPNV vaccines are highly immunogenic in Tc bovines, and the resulting anti-MERS-CoV Tc hIgG are potent in vitro and in transduced mice.…”

Immunoinformatics Predication and Modelling of a Cocktail of B- and T-cells Epitopes from Envelope Glycoprotein and Nucleocapsid Proteins of Sin Nombre Virus

“…One of these diseases is HCPS especially caused by SNV. Despite SNV is not transmitted from person-to-person; SNV is highly pathogenic (case fatality rate 30 to 50%) [44] regardless of age, [45] health status, [46] or access to advanced medical care, and was responsible for the 2012 Yosemite National Park outbreak [21,47]. The absence of effective vaccines, post exposure prophylactics, or therapeutics to prevent HCPS caused by SNV participated in the worry experienced by about 270,000 Yosemite visitors who got notice of possible exposure [46].…”