Inovio Pharmaceuticals, Inc., a company revolutionizing vaccines to prevent and treat today's cancers and challenging infectious diseases, has tested multiple synthetic vaccine constructs for cytomegalovirus (CMV) which induced robust T cells in mice, demonstrating the potential for a SynCon DNA vaccine to treat this virus that causes infant death and congenital abnormalities, is associated with cerebral palsy and brain tumours, and is the most common viral infection in organ transplant recipients.
CMV is also associated with numerous inflammatory diseases and cancers, and is implicated in hypertension, a major risk factor for cardiovascular diseases.
Results from this preclinical study appear in the peer-reviewed journal,Human Vaccines & Immunotherapeutics, in an article entitled, "Vaccination with synthetic constructs expressing cytomegalovirus immunogens is highly T cell immunogenic in mice."
The genetic complexity of CMV has inhibited the advancement of vaccines for this disease. In this study, DNA vaccine constructs targeting multiple novel CMV antigens were created using Inovio's SynCon vaccine platform. These SynCon constructs were administered via Inovio's proprietary electroporation-based delivery technology. The vaccine constructs were observed to induce strong and broad CD8+ and CD4+ T cells in an animal model. These findings are vital given the important role T cells play in clearing infection by killing cells that harbor the virus. This is especially crucial in protecting against diseases in different populations such as organ transplant patients that are at high risk from CMV infection.
Dr J Joseph Kim, Inovio's president and CEO, said, "Our SynCon platform has again generated synthetic vaccine candidates that show promise for providing a treatment where there is none. With recent human data showing the powerful killing effect of T cells generated by our therapeutic vaccine for HPV and HPV associated cervical dysplasia and cancer, we look forward to providing Inovio's answer to CMV, a medical problem that has yet to see a vaccine or cure despite 50 years of research.”
Inovio researchers first investigated a novel panel of ten CMV immunogens comprised of mainly surface-associated proteins based on promising prior clinical and preclinical data that had been previously shown to be important for inducing cellular immune responses in CMV infection. To maximize the potential for broadly-reactive immunity, Inovio researchers created SynCon vaccines for each of the target proteins based on amino acid consensus sequences from multiple variant CMV clinical strains, and excluded those from potentially divergent, highly passaged lab-adapted strains. The researchers adopted the same strategy as was shown previously to enhance protective immune responses against divergent strains of influenza and HIV. The designed target sequences were further genetically optimized at the nucleic acid level.
Researchers observed that vaccination with each CMV construct was highly T cell immunogenic in preclinical proof-of-concept mice studies, generating robust and broad T cell responses as extensively analyzed by the T cell ELISPOT assay. Each antigen produced responses against at least four and as many as 28 different regions of the antigen and, importantly, responses from both CD8+ and CD4+ T cells were observed. This increased diversity and magnitude of cellular responses may be critical for effectively mitigating CMV infection and disease in the transplantation setting.
These data demonstrate that Inovio's next-generation SynCon DNA vaccine technology is effective at inducing CD8+ T cell responses specific to CMV, in contrast to prior strategies that induced mainly CD4+-dominant responses. Additionally, a majority of epitopes identified for the gB, gH, and gL antigens also contained HLAs that have previously been reported to contribute to the suppression of viremia and amelioration of disease. In summary, the elicitation, identification, and characterization of extensive T cell responses driven by Inovio's CMV SynCon constructs will provide an important tool for guiding clinical development of a CMV vaccine. Further ongoing work will determine how many of the 10 antigens will be selected and taken further for clinical development as well as assess the induction of antibody responses to prevent CMV infection.
Cytomegalovirus (CMV) is a member of the herpes family of viruses that spreads from one person to another through the transfer of body fluids. CMV causes a wide variety of infection and illness in healthy adults, in those with compromised immune systems (such as HIV patients), and in pregnant women who can pass the infection to their unborn child (congenital CMV). It is the most common viral infection in solid organ transplant recipients and is considered a causative factor in certain cancers, inflammatory diseases, and cardiovascular/pulmonary diseases. CMV infects over 95 per cent of people in some developing countries. In the US, 50 – 80 per cent of people become infected with CMV by the time they are 40 years old. CMV is the most common viral infection that infants are born with in the United States. The US Institute of Medicine and US National Vaccine Programme offices have ranked CMV with the highest priority in terms of potential healthcare dollar savings and improvement in "quality adjusted life years." Although healthy people usually have few symptoms at the time of initial infection, after infection the virus remains in a latent state in the body for the rest of a person's life. The virus can then be transmitted and cause infection through organ donation, or latent virus can become reactivated and cause symptomatic disease.