INO-4212 SynCon® vaccine and dMAb targeting Ebola
MilestoneReport phase I data 1Q 2016
Inovio is developing a DNA immunotherapy designed to provide broad protective antibody and therapeutic T cell responses against multiple strains of Ebola virus, including the strains responsible for the 2014 outbreak. Inovio is also advancing a therapeutic DNA-based monoclonal antibody product dMAb™ against the same virus.
Under a $45M grant from the Defense Advanced Research Projects Agency (DARPA), Inovio advanced a DNA-based immunotherapy against Ebola into a phase I study in the second quarter of 2015. Inovio is also conducting preclinical development of its dMAb™ products under this grant.
According to the Centers for Disease Control (CDC, April 15, 2015), more than 10,714 people died in the 2014 outbreak and least 14,874 had been infected (laboratory confirmed cases). There is no vaccine or standard of care treatment for people infected with the Ebola virus.
INO-4212 Ebola vaccine & dMAb
Inovio was selected by DARPA to lead a collaborative team (with Medimmune, GeneOne Life Sciences, VGXI, Inc, University of Pennsylvania, Emory University, and Vanderbilt University) to develop multiple treatment and prevention approaches against Ebola, including Inovio’s therapeutic DNA-based monoclonal antibody and DNA-based immunotherapy products.
Inovio is testing its DNA immunotherapy against multiple strains of the Ebola virus, including the strains responsible for the 2014 outbreak, in a phase I clinical trial. This initial trial will evaluate the safety, tolerability and immunogenicity of Inovio's Ebola immunotherapy (INO-4212) in five groups of healthy subjects (approximately 75) receiving INO-4212 and its components (INO-4201 and INO-4202) alone or in combination with INO-9012, delivered into muscle or skin using Inovio's proprietary electroporation delivery technology.
Inovio also intends to conduct preclinical studies with is dMAb technology.
INO-4212 SynCon® Ebola immunotherapy
This initial trial evaluated INO-4212 in five groups of healthy subjects. INO-4212 consists of two optimized SynCon® DNA plasmids coding for the Ebola glycoprotein antigen from circulating Ebola strains from 1975 - 2014. These plasmids were tested separately and together in muscle and skin in five study arms, one including Inovio’s DNA-based IL-12 immune activator. Of 69 evaluated subjects, 64 (92.7%) seroconverted and mounted a strong antibody response to the Ebola glycoprotein antigen following the three dose immunization regimen; 48 subjects (69.6%) seroconverted after only two doses.
Significantly, in the study arm using intradermal (skin) administration, 13 of 13 evaluable subjects (100%) generated antigen-specific antibody responses after only two doses and all remained seropositive after three immunizations. Similarly, in the study arm receiving the vaccine with intramuscular administration in combination with plasmid IL-12, 12 of 13 evaluable subjects (92.3%) demonstrated strong antibody responses after only two immunizations and 13 of 13 (100%) produced strong antibody responses after three immunizations.
The Ebola glycoprotein specific geometric mean antibody titers measured in the five cohorts ranged from over 2,000 to greater than 46,000. Significantly, a majority of vaccinated subjects in each of the five cohorts produced strong Ebola antigen specific T-cell responses as measured by interferon gamma ELISpot analysis.
To date INO-4212 has been well tolerated and has not demonstrated systemic serious adverse effects, such as fever, joint pain, and low white blood cell counts, reported in association with some viral vector based Ebola vaccines currently in development. Moreover, unlike the viral vectored vaccines which must be kept frozen, INO-4212 was formulated in a solution which was kept refrigerated (2-8 C).
The Ebola virus has been described as one of the most virulent viral diseases known to man with lethality rates approaching 90%. It is capable of causing death within two to twenty-one days of exposure and there is currently no approved vaccine or therapeutic treatment.
Ebola was first discovered in 1976 when simultaneous outbreaks occurred in Sudan and the Democratic Republic of Congo. It is caused by infection with a virus of the family Filoviridae. There are currently five identified Ebola virus species, four of which cause disease in humans: Zaire, Sudan, Taï Forest (formerly known as Côte d’Ivoire), Bundibugyo, and Reston (Reston virus has caused disease in nonhuman primates only). According to the World Health Organization (WHO) the 2014 outbreak in West Africa, the largest outbreak since the virus’s first appearance, was a result of the Zaire species.
Though some uncertainty remains, researchers believe the Ebola virus originates in fruit bats and human infection emerges from close contact with the blood, secretions, organs or bodily fluids of infected animals such as fruit bats, chimpanzees, gorillas, monkeys, and forest antelope. An outbreak can occur in humans when a person comes in contact with the blood, secretions, organs or bodily fluids of an infected individual and with surfaces or materials that contain the contaminated fluids of an infected person, such as bedding and clothing; however, it can only do so when a person is experiencing active symptoms.
Once a person is infected with Ebola, the virus spreads from the initial site of infection to the lymph nodes (through the lymphatic system) as well as to the liver and spleen (through the blood). Here, the virus infects healthy immune cells and causes death of a gross number of killer T cells. This reduction in T cells allows the virus to replicate uncontrollably and often leads to multi-organ infection and failure, which can lead to death.
According to the Centers for Disease Control (CDC, April 15, 2015), more than 10,714 people died in the 2014 outbreak and least 14,874 had been infected (laboratory confirmed cases). There is currently no proven treatment for Ebola.
Like all viruses, the Ebola virus mutated during the outbreak of the 2014 epidemic. It’s possible that changes in the viral genome of the Ebola virus could make it more infectious in nature, leading to a higher number of incidences and deaths in future outbreaks. Using its SynCon® technology, Inovio’s DNA immunotherapy is encoded for a consensus envelope glycoprotein derived from multiple Ebola virus isolates. These consensus immunogens will induce cross reactive cellular and antibody responses against various Ebola viruses, thus providing broad protection against multiple species of Ebola.