Article by Stefania Abati, who interviewed with Prof. Massimo Amicosante, Prof. Maurizio Mattei and Prof. Vittorio Colizzi of the University of Rome "Tor Vergata", on the collaboration between Italy and Bulgaria for novel vaccines and diagnostics development for the "International Survey: Bulgaria-Italy" of Novinite.com (Sofia News Agency).

It might seem bizarre to the eyes of most people, but in the 21st century we are still fighting against some of man's oldest enemies: infectious diseases. These are still the leading cause of death accounting for a quarter to a third of estimated deaths worldwide. New and re-emerging infectious diseases are posing a rising global health threat and will continue to complicate global health and security over the next 50 years.

The problem is not only relative to Third World countries, but also affects Europe, where medical infrastructure is reasonably good in every country and modern diagnostic facilities are widely available with reasonable ease.

Most of the seven biggest killers worldwide (including tuberculosis, hepatitis, and, in particular, HIV/AIDS) continue to surge in wide areas of the Mediterranean and Eastern Europe.

Similarly, acute lower respiratory infections, including pneumonia and influenza with the appearance of possible new strains, seem to have peaked at high incidence levels and remain a major cause of illness in Europe.

It is well known that the spread of infectious diseases results from changes in lifestyles, land use patterns, increased trade and travel and inappropriate use of antibiotic drugs as well as from pathogen mutations. The dramatic upsurge in the spread of drug-resistant microbes over the past decade is undermining today's efforts to control infectious diseases.

As diseases once thought to be under control become increasingly resistant to the arsenal of available drugs, the spectrum of incurable infectious diseases looms large. As a consequence, the fight against infectious diseases nowadays still represents one of the major public health problems.

One of the milestones in controlling infectious diseases is the rapid identification of the affected subjects or even more of the healthy subjects carrying the infectious agents. Therefore, effective diagnostic systems are playing a primary role in the strategies for controlling infectious diseases.

However, the most important approach in controlling infectious diseases has been the development of preventive vaccines. The eradication and control of infectious diseases that has been possible in the past centuries involved the large use of vaccines, together with the possibility of access to clean water.

Nevertheless, poverty-related diseases, largely affecting Europe as well, are far from being under control, thus increasing the need to have efficient vaccines available. However, the costs of developing and producing vaccines are incredibly high and only a common effort by scientists and funding agencies, putting together specific experiences in research, development and production, can lead to a reduction of time and costs for the rapid development of new effective vaccines against many infectious diseases.

We are here today discussing this topic with Prof. Massimo Amicosante, Prof. Maurizio Mattei and Prof. Vittorio Colizzi of the University of Rome "Tor Vergata", who for many years have been collaborating with scientists at the National Center for Infectious and Parasitic Diseases (NCIPD) and at the BulBio-NCIPD in Sofia, in order to develop new vaccine strategies and innovative diagnostic systems.

How did the collaboration with your Bulgarian colleagues start?

It is a long story which dates back to the mid-nineties. Ass. Prof. Tatiana Sumerska, who unfortunately passed away a few years ago, formerly working at the NCIPD, spent several working periods in our laboratory at the University of Rome "Tor Vergata", collaborating on immunological aspects of infectious diseases, such as tuberculosis and HIV. She introduced us to other Bulgarian scientists who were very interested in collaborating on these aspects.

But the great boost to our collaboration come after we took part in the scientific evaluation of the large HIV outbreak at the Benghazi Children's Hospital, demonstrating that the five Bulgarian nurses and the Palestinian medical student accused and condemned to death for the spreading of HIV were not guilty at all.

After that, a very close collaboration began (i) in the field of immunological diagnostic tools for tuberculosis with the NCIPD (Ass. Prof. Roumiana Markova, Ass. Prof. Maria Nikolova, Prof. Hristo Taskov and Acad. Prof. Bogdan Petrunov) and (ii) for co-formulated vaccine development with the BulBio-NCIPD (Prof. Plamen Nenkov).

Moreover, the collaboration also involved general public health strategies in the field of infectious diseases with active participation in and coordination of EU PHARE Twinning projects (Prof. Todor Kantardjiev, Dr. Stefan Panaiotov), with active collaboration in two EU-7FP Programmes and in a large number of other scientific collaborations among different groups at the NCIPD.

Last but not least, thanks to the Italian Law n. 84 of 2001 for the development of the Balkan area and with the direct support of the Italian Institute for Foreign Trade (ICE)-Sofia Office, we performed a number of technology-transfer and training activities. One of the most successful projects was BIOVAX2006.

Among these collaboration activities, which one is at the moment most promising and advanced?

The most advanced and promising is undoubtedly the anti-Hepatitis-B and anti-tuberculosis co-formulated vaccine. These are two vaccines which have already been available for years and which are administered to children at different times.

Together with the colleagues at the BulBio-NCIPD, the NCIPD and the Center for Biotechnology of Havana (Cuba), we have recently finished the preclinical study and the phase I study in humans, demonstrating the safety of delivering these two products together.

Furthermore, we observed a strong and probably long-lasting immune response against the anti-Hepatitis-B vaccine that usually requires more than 2-3 recalls with a normal vaccination. We are going to evaluate this effect now in a large phase II study in newborns.

The very important aspect of this approach is to use the adjuvant (collaborative) effect of the anti-tuberculosis vaccine, usually administered at childbirth, on the other co-delivered product. If this is going to be successful, this strategy might open the possibility to co-deliver, together with the anti-tuberculosis vaccine, a lot of vaccines given during the first year of life.

This "first day vaccination" strategy might have a strong impact on the early protection of children against many infectious diseases. Further, it opens the possibility of co-formulation of new vaccine products, including HIV, an aspect we are working on although we are still in a screening phase.

What is the role of the Bulgarian collaborators in this approach?

First of all, Bulgaria has a long story in vaccine production. BulBio-NCIPD is one of the four world producers of the anti-tuberculous vaccine, Mycobacterium bovis var. BCG (usually indicated simply as BCG).

Over the past decades, the Italian vaccine industry has undergone reduction. Therefore, we do not have the availability on our territory of this kind of expertise regarding the production and use of live vaccines.

The collaboration with the colleagues at BulBio-NCIPD is pivotal for the production and regulatory aspects of vaccine co-formulation. Iin addition to this, the experts in immunology at the NCIPD are bringing all their expertise and positive impact in the evaluation of the co-formulated vaccine in the trials we are conducting.

On the other side, what is the Italian expertise that has been brought to Bulgaria?

We have a long experience in the identification of the portion of the infectious agents that are responsible for the induction of the immune response in humans, the part that technically we name antigens and in general in measuring the immune response and finding markers which are related with the protection from infectious agents.

Together with this, in the last 10 years we have also invested considerably in the transfer of technology, in carrying out pre- and clinical studies and in generating animal models for studying infectious diseases.

Specifically, we have created in Bulgaria a small biotech company, ProxAgen Ltd., for carrying out collaborative studies with the Bulgarian partners and bringing some of the most innovative technology and technical platforms that we have developed in the past years (namely a bio-computer approach in the identification of the important part of the infectious agents for the immune system).

Thanks to large databases of genomic information on infectious agents, at ProxAgen Ltd. we are able rapidly to identify a large number of potential antigens in bacteria and viruses within days. This represents a unique tool that is at the basis of the development of modern diagnostic systems and vaccines for infectious diseases.

What are the prospects for your work in Bulgaria and for the collaboration with the Bulgarian scientists?

With regard to the co-formulated vaccine that we have under evaluation at the moment, we are now starting - together with scientists in Burkina Faso - the so-called phase II trial to demonstrate the potential of the vaccine in humans. Within two years we should be able to have some results and move on to a proper industrial plan for the co-formulation.

After that, with the experience developed with this first co-formulation, we would like to move to a wider co-formulated vaccine covering not only Hepatitis B and tuberculosis at childbirth, but also including tetanous, diphtheria, pertussis and Haemophilus influenzae type B.

The current data in scientific literature indicate that newborns do not have an immature immune system: it only needs to be properly stimulated to respond promptly. The co-formulation with BCG is aimed at doing this.

For the diagnostic studies on tuberculosis we are running at the moment, we should be able to realize within two to three years a test that can identify subjects who risk developing active diseases after exposure.

In a nutshell, the past 10 years of collaboration between Italian and Bulgarian Institutions have truly paved the way to the achievement of important results in the control of infectious diseases.

Results that are not far away, but "just around the corner", with just a few more years of work.

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