Successful Phase I Clinical Trial of spi-VECTM Oral Hepatitis B Vaccine Paves the Way for Phase II Efficacy Trial

WOKINGHAM, England -- Microscience is announcing further significant results from a Phase I clinical study of its spi-VECTM oral immunotherapeutic vaccine designed for the treatment of subjects chronically infected with the hepatitis B virus (HBV). The trial met its primary objectives and successfully demonstrated safety and immunogenicity, supporting the vaccines continued development as a therapeutic for chronic HBV carriers.

A Phase I, open-label, dose-escalating study was performed in 30 healthy adult volunteers to evaluate the safety and immunogenicity of a candidate oral immunotherapy given on two occasions, 56 days apart.

The primary aim of the study was to assess safety and to determine the cellular immune responses against hepatitis B core antigen (HBcAg) raised by two dose levels of this novel vaccine. It is known that a cellular immune response is critical for an immunotherapy to be effective against this life-threatening infection.

The vaccine was shown to be safe and well tolerated. The immunological data have demonstrated that all subjects mounted a T-cell proliferative response to both the HBcAg and to groups of peptides representing the whole sequence of HBcAg, indicating that the antigen had been successfully delivered to the immune system in all subjects. In addition, 95 percent of responders in the high dose group elicited a Th1-biased response characterised by the secretion of gamma interferon and the absence of IL-5 secretion by stimulated T-cells. Th1 responses are known to play an important role in the promotion of viral clearance in chronic hepatitis B. The excellent safety profile and the powerful immunological data generated in this Phase I study support the further development of this important immunotherapeutic vaccine.

Rod Richards, chief executive officer, commented: There are some 350 million carriers of chronic hepatitis B carriers worldwide, accounting for one million deaths per year and current treatments offer only limited efficacy. These results are very exciting as they demonstrate that the spi-VECTM-based vaccine stimulates the appropriate type of immune response required to promote clearance of the hepatitis B virus in chronic carriers.  Having successfully demonstrated in this study both the immunogenicity of this oral hepatitis B vaccine and a favorable safety profile, we are now planning a Phase II program in subjects chronically infected with the virus. The vaccine could also pave the way for the development of a new generation of immunotherapeutic vaccines, using spi-VECTM technology, targeting a range of chronic viral diseases.

These results, together with those recently announced using Microsciences spi-VECTM ETEC travelers diarrhea vaccine, exemplify the potential of the platform and demonstrate its utility in two key disease indications. Microscience is also harnessing the spi-VECTM platform technology to develop other new oral vaccines to protect against typhoid and anthrax.

About Hepatitis B

Most people who become infected with hepatitis B will clear the infection, however, in 2 percent to 10 percent of infected adults the immune system fails to clear the virus and these subjects consequently become carriers of the virus. In children, the number that become carriers after infection is much higher. The consequences of carrying the virus can be devastating; these patients are at high risk of developing chronic liver disease such as cirrhosis and primary liver cancer.

The group of chronically infected patients most at risk of developing liver disease are those in which viral replication can be detected. Currently available therapies for this patient population consist mainly of alpha-Interferon and antiviral drugs. Their efficacy is limited and long-term use is problematic due to either safety concerns or the development of resistant forms of the virus. Microscience believes there is a clear need for a new treatment for chronically infected patients with active viral replication to prevent development of liver disease and reduce transmission of the virus.

About spi-VECTM

The spi-VECTM vaccine consists of a harmless Salmonella bacterium that has been modified to carry the hepatitis B core antigen. The Salmonella bacterium then acts as a vehicle to deliver the antigen directly to cells of the immune system resulting in effective antigen presentation with resultant strong immune responses.

Immunotherapy against HBV that is able to induce interferon gamma production from CD4+ Th1 cells and intra-hepatic CD8+ T cells in chronic carriers may promote clearance of the virus. Therefore administration of HBcAg using a vector system such as spi-VEC that expresses the antigen intracellularly, followed by processing and correct display of peptides to the immune system, may be effective in generating a sustained Th1 response, strong enough to promote clearance of virus-infected cells.

Rationale for use of Hepatitis B core antigen

The nucleocapsid (core) of HBV is a particle made up of multiple copies of a single 21 kDa polypeptide subunit encoded by the hepatitis B core gene.  In chronic carriers HBcAg is not found circulating in the blood, and hence, the virus minimizes the exposure of this antigen to the patients immune system. The intact hepatitis B core structures are highly immunogenic, eliciting much stronger humoral and cellular responses than vaccines containing hepatitis B surface antigens. The immunogenicity of HBcAg is well reported in the literature from various animal models and is expected to translate to an advantage over surface antigen preparations in terms of the magnitude of the immune response elicited in chronic carriers.

There are several lines of evidence to suggest that the HBcAg is more likely than surface antigen preparations to induce the type of immune response that may result in viral clearance in chronic carriers, or reduce viral load to prevent the sequelae of chronic infection. In acute hepatitis a strong Th1 response against HBcAg appears mandatory to prevent chronicity of infection and initiate the process of clearance.

Patients that clear the virus during the acute phase of infection mount a potent CD4+ Th1 and CD8+ T-cell response against a range of epitopes from all structural and non-structural hepatitis B viral proteins. However, the HBcAg appears to be the most important immune target to prevent chronic infection and initiate the process of viral clearance. In individuals who become chronic carriers, the CD4+ Th1 and CD8+ responses are weaker, recognise a narrower repertoire of epitopes and a Th2 response predominates. There is evidence to suggest that a CD4+ Th1 response and/or CD8+ T cell response against HBcAg are important to initiate and maintain viral clearance in chronic carriers. Moreover, in chronically infected patients who have episodes of acute exacerbation of the disease, a strong Th1 response to HBcAg is observed, that on occasions can lead to seroconversion or that is associated with a favorable outcome in patients administered exogenously produced interferon. Several studies have also been performed in animal models demonstrating the potential of HBcAg as an immunotherapy for clearance of chronic hepatitis B infection.

Another line of evidence comes from a study looking at bone marrow transplantation from hepatitis B virus immune subjects to chronic carrier recipients. Bone marrow from donors with antibodies to HBsAg and HBeAg or HBsAg antigen alone were transferred to chronic carrier recipients. Clearance of S antigen in the recipients was seen with bone marrow from donors with antibodies to S and HBeAg but not with donors who had antibody to S antigen alone. The donors who cleared the S antigen showed a specific Th1 response to hepatitis B cores.

SOURCE: Microscience Ltd