Future Trials with Hybrid1 Vaccine

Dr. T. Mark DOHERTY

Department of Infectious Disease Immunology, Statens Serum Institut, Denmark

Abstract

This presentation describes some of the recent work by the SSI on their recombinant protein vaccines, with emphasis on the move towards human clinical trials. A summary of results in different animals models is presented, showing the effectiveness of the Hybrid1 molecule as a primary or booster vaccine. A brief description is given of some of the large multi-centre research projects involved in clinical trials of TB vaccines and some of the issues involved in bringing a successful vaccine to market.

Presentation

The EC's commitment to pushing forward work in the area of novel TB vaccines is demonstrated by the fact that the EC has recently provided solid funding for two programs on vaccines for tuberculosis and other diseases prevalent in the developing world. In addition, the EC is not the only sources of funding for TB vaccine development, and these programs are also starting to attract commercial partners, which is a very positive development.

The Hybrid1 Vaccine

The Hybrid1 vaccine that the SSI is currently developing is made up of two immunodominant antigens: Ag85B and ESAT-6. The vaccine has been very immunogenic and effective in all of the species tested so far. Both of these antigens are very broadly recognized in humans, and a surprisingly high number of TB patients and contacts respond to them. This suggests that these antigens are highly expressed during infection or exposure in humans. The following slides refer to work carried out in mice and in the much more sensitive guinea pig model but the vaccine has also been tested in cattle and non-human primates. The Hybrid1 vaccine prolongs survival after infection, to an extent not significantly different from BCG, whereas use of the single antigens is less effective at preventing severe lung pathology and death.

Booster Vaccine

Since many individuals have already been vaccinated with BCG, experiments have also been carried out on boosting vaccines in the mouse and guinea pig models. Mice were vaccinated with PBS (negative control), BCG, or the Hybrid1 vaccine. Nine months later, they were vaccinated again with saline, BCG or the sub-unit vaccine. This resulted in a significant boost in immunogenicity in terms of the IFN-g read out, which lasts a few months after vaccination. The use of two doses of the hybrid results in a very strong IFN-g result, lasting for some months after the booster vaccination. A single dose of Hybrid1 given to previously BCG-vaccinated animals resulted in a significant increase in protection.
A similar experiment was also carried out in the USA by the NIH, using the more sensitive guinea pig model, and a rest period of one year, with 14 to 16 guinea pigs per group. The use of BCG alone protected the animals from death for approximately six months. A booster dose of BCG extended protection slightly more than six months. However, the use of Hybrid1 as a booster vaccine pushed survival times even further out, and was significantly better than BCG alone.

Modes of Administration

The second issue we have addressed relates to the way in which the vaccine is administered. The current recommended practice for tuberculosis vaccination involves administration by injection, in or under the skin. However, originally, tuberculosis vaccination was administered orally. This is now no longer recommended, although there are still some areas of the world where it is administered orally. The issue we addressed was whether we could go back to this oral type of administration. This is of particular interest when the population is HIV positive, where it is very tempting to be able to dispense with needles.
We therefore tested oral vaccination in the mouse model. PBS or the Hybrid1 vaccine was administered subcutaneously, orally or nasally, and followed by a booster. Two subcutaneous doses resulted in a strong IFN-g response in the lungs of these animals. While they gave an immune response, the results of two oral doses were not very encouraging, and the results of two nasal doses were only marginally better. However, a subcutaneous priming vaccination followed by an oral or nasal boost led to dramatic increases in IFN-g levels in the lung. We plan, together with other partners in the MUVAPRED project, to take the nasal vaccination protocol into human trials in the next two years. It would definitely simplify the task of administering vaccines on a large scale, and should improve the safety and reproducibility of delivery. However, this is still very much a technology in its infancy.
The Hybrid1 vaccine appears to be safe and well tolerated. It is effective as a primary vaccine and as a booster vaccine. It is effective when delivered through the skin, nasally or orally.

Future Work

TB-VAC Timeline

We are starting the introduction of this product, and preparing the documentation required as a pre-requisite to any clinical work. We are hoping to start safety trials in 2005, in Europe where we can be relatively sure that healthy, skin-test negative volunteers are not tuberculosis infected. We will then move onto extended safety trials in people who are mycobacterially sensitised, and eventually tuberculosis infected individuals. Only once we are sure that the vaccine is safe, will we move on to working in Africa in 2006/2007. We will also repeat the studies in sensitised individuals, and carry out a larger trial. We have good results with the Hybrid1 vaccine but are trying to see if it can be improved. We have one new vaccine candidate undergoing final testing, which appears to better than Hybrid1. It is thus an ongoing process, and we will not be finished with Phase 1 trials for some time.

MUVAPRED Timeline

This project has a very similar profile and timeline to the TBVAC one. We do not yet have funding to carry out oral vaccine testing in Africa. To this end, we are working intensively with the Ministry of Health in Ethiopia. They are very interested in the project given its potential for cost reduction and increased safety by the removal of the need for needles.

Other Issues

There is a growing consensus that BCG administration in childhood will offer protection for a period of time from 8 to 15 years. There is also a suggestion that its administration to naïve adults will result in 8 to 10 years of protection from tuberculosis. If BCG really offers protection against tuberculosis, even though its protection does not last, it will be very difficult to stop BCG vaccination of children, from an ethical point of view. We are therefore aiming at a vaccine for adults that supplements rather than replaces BCG.
The question that then arises is, if we administer the vaccine to boost BCG, when should this be done and to whom should it be administered. Previous studies show that, at best, BCG offers about 10 years of protection. An on-going study in Africa was carried out on 500 individuals, using identical recruitment criteria in Ethiopia, Zambia and Gambia. The number of people with BCG scars in Ethiopia was about 1%. This is due to the fact that mothers give birth at home and babies are rarely given BCG vaccinations. There is a significant bulge in TB incidence in the early years, very similar to the pre-vaccination curve shown by Don ENARSON. In Zambia and Gambia, the rate of vaccination is much higher, and the median age of TB patients has moved up. This would suggest that the median age of onset of tuberculosis has moved up by about 10 years in countries that have good vaccination programs. To some extent, this defines our target population: to have a significant impact on tuberculosis in these countries, we need to reach people prior to the onset of TB in a significant percentage of the population.

Ethical Issues - The Paradox of the TB Market

We have faced great difficulties in recent years in interesting commercial partners in developing tuberculosis vaccines. This is starting to change, given that the market for tuberculosis vaccines is one of the largest in the world: about 132 million BCG doses are administered per year. However, this only represents EUR 34 million per year, which is not very attractive to pharmaceutical companies. It will take us a long time to know if the new vaccine will work. In addition, if a vaccine is carried through Phase III trials, the cost of producing, packaging, registering and distributing it world-wide amounts to about EUR 200 million, and the potential pay back is much lower than this.
When designing clinical trials, we have to ask what is ethically acceptable in countries such as Asia or Africa as compared to trials in Europe, for example. The suggestion has thus arisen that the same vaccine could be sold in Europe or Japan for EUR 50, and for EUR 4 in the developing world. This would swell the potential market to about EUR 600 million, which is obviously of interest to pharmaceutical companies.
There is more to tuberculosis vaccine trials than just producing an effective vaccine. If we cannot get all the players on board (scientists, companies, health ministries), no progress will be made. We are hopefully in the process of solving this issue today.

Dr Adrian HILL

You stated that you needed the support of a pharmaceutical company for your work. What is the status of SSI as a manufacturer? Would it not consider manufacturing the vaccine?

Dr Mark DOHERTY

SSI is a government, not for profit organisation. This makes it unlikely that SSI would be involved in large-scale TB vaccine development. However, SSI does manufacture and sell vaccines to support some of its work, such as a polio vaccine. We are one of the few organisations in the world where discussions on vaccine development give equal weight to public health concerns. However, as a government, not for profit organisation we cannot set up large scale commercial collaborations for world-wide vaccine development, and we would need a commercial partner to do this. There may be other options to having a commercial partner, but I do not see any for the moment.

From the floor

Why did the change from oral to skin vaccination occur in the past? How long will immunity last for oral doses?

Dr Mark DOHERTY

The move away from oral vaccination occurred for two reasons. First, the Lubeck incident, where children were accidentally dosed orally with M. tuberculosis instead of BCG, resulting in a large number of deaths, made people suspicious of oral vaccination. The Institute Pasteur had already been vaccinating subcutaneously, and the shift to this method of administration occurred. Second, and more relevantly, BCG is a live vaccine. If it is administered orally it will lead to a higher incidence of suppurative adenitis. The WHO therefore currently recommends subcutaneous vaccination. We do not know how long immunity from oral vaccination will last, although we know from small animal studies that immunity to Hybrid1 vaccination can last for at least two years, and it seems to last at least as long as the immunity from BCG in animal models. We also know that if tuberculosis enters the body primarily through the mouth and nose, starting an immune response in those organs may offer practical benefits.

Dr Adrian HILL

What adjuvants have you been using or plan to use?

Dr Mark DOHERTY

This is a crucial issue. The choice of an effective adjuvant is just as important as the choice of antigen. In these studies, all the subcutaneous vaccinations were carried out with a DDA/MPL combination. While these adjuvants have been tested in humans, their combination has not yet been tested on humans. We are looking at different approaches to this issue. DDA/MPL is not our adjuvant of choice. For oral vaccination, we are using an adjuvant from Chiron. A number of other candidates have performed well in animal models. We would not want to rely on a single effective candidate, and we have tested five possible aduvants, some of which have already been in human trials or are heading toward them.

Brigitte GICQUEL

Many people have used ESAT-6 as a diagnostic test. Using it also as a vaccine could raise problems.

Dr Mark DOHERTY

We are hoping to replace the ESAT-6 component with the new vaccine that is currently in testing. However, before we can do that we need to ensure that it is as or more effective than Hybrid1.