IC51: a new investigational Japanese encephalitis vaccine

Abstract

Christoph S Klade is a biochemist and immunologist by training. He obtained his PhD from the University of Vienna (Austria) and obtained further training in immunology at the Universities of Berkeley and Stanford (CA, USA). After university, Dr Klade spent over 13 years in industrial R&D. These years included the setting up of technology platforms for identification of both B- and T-cell antigens, discovery research, assay development and validation and close involvement in clinical research. At Intercell AG, he set up the Department of Clinical Immunology, responsible for all immunological monitoring of Intercell’s vaccine trials, including T-cell and serology assays. Recently, data from this department was the basis for successful pivotal Phase III trials in the development of a novel prophylactic vaccine against Japanese encephalitis virus 1. Currently, Dr Klade serves as Vice President of Technology Development/Clinical Immunology at Intercell AG, overlooking functions such as Analytical and Formulation Development, Process Development, External Manufacturing and Clinical Immunology. In addition, Dr Klade has been appointed to lead the codevelopment of the hepatitis C virus therapeutic vaccination program of Intercell and Novartis.

The Japanese encephalitis vaccine, IC51, is one of the leading products of Intercell. In Phase III clinical studies, why did you choose JE-VAX^® as a comparator vaccine and what are the main differences between the two vaccines?

The reason JE-VAX was chosen is because it is the only Japanese encephalitis vaccine that has obtained regulatory approval in the Western World, namely in the USA.

The major differences between our vaccine and JE-VAX are that we are using certified Vero cells to grow the virus, whereas JE-VAX vaccine viruses are grown in mouse brains.

Regarding the vaccine formulation, IC51 is in ready-to-use liquid format, while JE-VAX is lyophilized. IC51 contains aluminum hydroxide, a widely used adjuvant; however, it contains neither stabilizer (porcine gelatin) nor preservative (thimerosal), unlike JE-VAX.

Moreover, we utilize a more convenient two-dose schedule 4 weeks apart for our IC51 vaccine (intramuscularly), while JE-VAX has a three-dose schedule on days 0, 7 and 28 (subcutaneously).

Finally, the vaccine strain we are using is SA14-14-2, which is an attenuated virus, whereas JE-VAX contains Nakayama, a wild-type virus strain.

Results from Phase III studies with IC51 are very promising and serve as the basis of its license application to the US FDA, the European EMEA and the Australian TGA, just to name the three most important ones. Can you highlight the main findings?

The FDA licensure of IC51 will be based on immunogenicity (i.e., noninferiority compared with licensed vaccine). For Japanese encephalitis, the immune correlate of protection is neutralizing antibodies, which can be measured with the plaque reduction neutralization test (PRNT). An indicator of efficacy is that the serum from immunized individuals, when diluted 1:10 or more, still gives a 50% reduction in PRNT. This is a marker that shows a reliable correlation with protection and has been accepted by the WHO.

From our Phase III studies, our vaccine IC51 has demonstrated noninferiority in terms of neutralizing antibody response, and our seroconversion rate and geometric mean antibody titers using IC51 are at least as good as JE-VAX. The long-term safety of IC51 in our trials has been excellent and comparable to placebo. Systemic tolerability was similar between IC51 and JE-VAX, while our vaccine, IC51, might have a more favorable local tolerability than JE-VAX [2].

Given that Japanese encephalitis is mainly prevalent in the Indian subcontinent, China and Southeast Asian countries, and not in the developed world, what do you envisage as the future coverage and impact of IC51?

IC51 has been developed primarily as a traveler’s vaccine in developed countries and for military use. Our targeted populations are primarily adults, adult travelers, expatriates and military personnel. Our partner Novartis will distribute the vaccine to the civilian market in the USA and in Europe, our partner CSL Biotherapies Pty Ltd in Australia and New Zealand while Intercell will deliver the vaccine to the US military itself.

Pediatric indication is the second target that we are working on. We have carried out a Phase II study in Indian children between 1 and 3 years of age (the IC51–221 study from my presentation [2]). We have demonstrated that IC51 shows comparable immune responses at half the adult dose. We are planning further confirmation studies in India and Southeast Asia. Our partner, Biological E in India, will manufacture the vaccine for the Indian market as well as for the neighboring countries. Our aim is to establish the safety and immunogenicity in children 1–17 years of age and to make IC51 available for childhood vaccination in endemic areas.

Regarding the future of vaccines for travelers, besides IC51, what is the status of other vaccines that Intercell are currently developing?

IC51 is the leading vaccine that Intercell will bring to the market, but there is a rich pipeline behind [101]. Through the acquisition of Iomai (see later) we have a vaccine for travelers’ diarrhea, which has successfully passed Phase II trials and will go ahead with Phase III development [3]. Intercell’s therapeutic hepatitis C virus vaccine IC41 is in Phase II trials and is the most advanced therapeutic vaccination approach in the field. A Staphylococcus aureus vaccine, based on our antigen-discovery technology, is being developed in partnership with Merck and is in Phase II trials. Complementing Intercell’s nosocomial (hospital-acquired infections) franchise we are ourselves developing a Pseudomonas aeruginosa vaccine currently in Phase II trials. Our partner Novartis is performing clinical trials in the influenza arena with a vaccine adjuvanted with IC31^®. IC31 is a fully synthetic adjuvant developed by Intercell and has the potential to become the new benchmark for vaccine adjuvants. It is also used in two TB vaccines developed by the Staten Serum Institute, Sanofi Pasteur and the AERAS foundation. Finally, a variety of promising vaccines including one against pneumococci and another against borreliosis are aggressively moved forward to clinical entry.

What is the main advantage of the planned acquisition of Iomai by Intercell in your opinion, in terms of future vaccine development?

The deal creates a leading traveler’s vaccine portfolio by adding to Intercell’s Japanese encephalitis vaccine a needle-free travelers’ diarrhea vaccine from Iomai. Iomai provides a perfect partner and is highly complementary in that it brings in the delivery technology. We believe that we have strong technology in antigens, strong technology in adjuvants and now also in delivery. Furthermore, Intercell will also gain full rights to two additional clinical and three preclinical programs under development, the most advanced being an immunostimulant vaccine patch currently in Phase II trials for pandemic influenza.

Financial & competing interests disclosure

C Klade is an employee of Intercell AG. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.