Serbia’s Institute of Virology, Vaccines, and Sera “Torlak” has been producing vaccines for national and global use since the 1930s. Its roster is impressive, and at one point or another included vaccines against cholera, diarrheal disease, diphtheria, influenza, pertussis, polio, tetanus, tuberculosis, and typhus. Torlak vaccines have been exported to 110 different countries around the world and included in World Health Organization (WHO) and United Nations Children’s Fund programs. Torlak is no novice when it comes to vaccine production.
Vaccine clinical trials, however, are a different story.
“Clinical trials are very new to us,” says Dr. Vera Stoilljkovic, Managing Director at Torlak. “This is not something we have had to do in the past. We have a long, strong history in vaccine production, but this was never a part of it.”
Vaccine study and development through the years
Torlak thoroughly evaluates and confirms the safety and effectiveness of all its products, but in its nearly 90 years in existence, had never conducted a complex clinical study in human volunteers; it hadn’t needed to. When Torlak began operations in the early 20th century, it was producing existing vaccines using established methods. These products had spent years on the market accumulating proven safety and effectiveness data, therefore, new clinical trials were not needed. Certainly Torlak tested all of its product for safety and effectiveness regardless, but those studies could be done in a different manner than the complex clinical studies in human volunteers required for new vaccines or new development methods.
For instance, Torlak conducted field tests of its vaccines. Polio is a prime example—in 1960 Torlak carried out a field study to examine seroconversion (the time period during which a specific antibody develops and becomes detectable in the blood) with Dr. Albert Bruce Sabin’s original polio vaccine as compared to the polio vaccine produced by Torlak. In 1960, 400 children between 6 months and 8 years of age were given the Sabin vaccine and in 1961, 400 children between 6 months and 19 years of age were given the Torlak vaccine; study results showed both vaccines to be nearly identical in terms of seroconversion, proving the effectiveness of Torlak’s vaccine. Torlak continued to intensively study the vaccine over the next 15 years, examining the duration of protection it offered, the appropriate dosage, and the most effective vaccination schedule.
In 1963, Torlak conducted similar field studies on its original seasonal influenza vaccine. Several thousand soldiers volunteered to participate in a study that examined the vaccine’s ability to prompt a sufficient immune response—a necessary step before bringing the vaccine to market.
“It was a very interesting position to be in—to be producing for decades and suddenly have to learn how to conduct a trial.”— Dr. Vera Stoilljkovic, managing director, Torlak
Eventually, though, regulatory requirements for influenza vaccine production changed, and Torlak found itself in need of updated equipment and updated development processes. In 2005, Torlak ceased influenza vaccine production and the country was forced to turn to foreign vaccine manufacturers. This isn’t an ideal situation, particularly for low- and middle-income countries that may struggle to access imported vaccines—if they can afford them at all. The global 2009 A/H1N1 influenza pandemic is a painful example: worldwide vaccine shortages left many low-resource countries waiting months—years, even—for lifesaving vaccines.
Serbia wasn’t satisfied to wait, though. With the support of Serbia’s Ministry of Health, Torlak made early efforts to improve influenza vaccine development—purchasing new equipment, updating its laboratory and manufacturing processes—but it was in 2009, when WHO recruited Serbia to participate in the Global Action Plan for Influenza Vaccines (a comprehensive strategy to reduce the global shortage of influenza vaccines) that progress truly began to accelerate. And with it came the need to conduct clinical studies in human volunteers.
“It was a very interesting position to be in—to be producing for decades and suddenly have to learn how to conduct a trial,” Dr. Stoilljkovic says.
Dr. Vera Stoilljkovic, Torlak managing director, is confident that Torlak’s increased influenza vaccine development and manufacturing capacity will help protect not only Serbia, but the entire Balkan region. Photo: PATH/Katie Regan
A 'catastrophic' influenza problem
Influenza vaccine was no random choice. Seasonal influenza is a dangerous, sometimes fatal respiratory infection; pandemic influenza is a global threat with the potential to kill millions. And it will strike, sooner or later. The best weapon in the fight is a well-established seasonal vaccine production process. Sustainable seasonal influenza vaccine production helps a country to ensure pandemic preparedness because it maintains manufacturing capacity on an ongoing basis.
This is particularly important in a country like Serbia, where vaccination rates are low. Very low. Only 2 percent of the population receives a seasonal influenza vaccination every year. And only 10 percent of Serbian doctors and nurses do.
“Our vaccination coverage rates are catastrophic,” says Dr. Stoilljkovic. “We are aware we need to raise them. It will be a challenge—there are a lot of struggles to overcome in Serbia—but we are confident that Torlak’s vaccine will help us begin to move in the right direction.”
Low influenza vaccination rates aren’t isolated to Serbia—they are endemic to southeastern Europe, and made worse by the fact there is no influenza vaccine manufacturing capacity anywhere within the Balkan region. A Torlak influenza vaccine could potentially turn around vaccination rates for the surrounding countries, as well.
Clinical trial confidence
Torlak developed a seasonal trivalent inactivated influenza vaccine candidate, and, with the support of its partners, ushered it through two rigorous clinical studies designed to test safety and ability to induce an immune response. PATH, in cooperation with the Biomedical Advanced Research and Development Authority, within the US Department of Health and Human Services, provided technical assistance to Torlak throughout the experience, assisting in everything from preparing documentation to facilitating communication among trial partners to organizing trainings and offering input on study protocols.
The studies didn’t just advance Torlak’s clinical skills, though; they established clinical trial capacity at a number of sites in and around Belgrade and trained several area medical professionals to act as principal investigators (PIs)—leaders responsible for overseeing clinical trial functions. Like Torlak, none of the PIs had ever been involved in vaccine clinical trials and had to undergo extensive training; but these are transferable skills that can be taken outside of the influenza world—a valuable asset.
“This vaccine is important not just to Serbia but to Southeastern Europe ... There is a strong need.”— Dr. Vera Stoilljkovic, managing director, Torlak
Ultimately, these studies weren’t just about creating a single vaccine; they marked a turning point in Serbia’s vaccine development history, and opened so many doors into the future.
“This was not just Serbia’s first influenza vaccine trial—it was Serbia’s first vaccine clinical trial of any kind,” Dr. Stoilljkovic says. “Now we know the requirements and the best practices, and we could do this again for other vaccines. The PIs could do this again with other, non-Torlak products. We have all reached a new level of education.”
The future of influenza prevention
Torlak’s vaccine candidate performed well during clinical development and is on track to be submitted for licensure in 2019. Once licensed, it can be made available to the Serbian public, and, eventually, to the entire region.
“This vaccine is important not just to Serbia but to Southeastern Europe,” says Dr. Stoilljkovic. “The neighboring countries stopped production, so the market is open. We have the opportunity and there is a strong need.”
Though Serbia has made great strides toward protecting itself from influenza, it is important to remember the work is not yet done. Torlak’s vaccine shows much promise but manufacturing capacity is not yet at the level it needs to be to protect the country—let alone the region—in the case of a pandemic. However, Torlak’s experience and expertise has grown substantially and staff are confident the day will come when capacity is no longer a concern.
In the interim, Serbia is looking forward to improving its influenza education campaigns and priming the public for influenza vaccine introduction. One of the most critical steps will be educating health care workers about the seriousness of influenza.
“Here in our region, influenza is treated like a common cold. Education about the disease and the benefits of the vaccine have been lacking, especially among health care workers,” says Dr. Stoilljkovic. “It is hard to be an advocate for something you don’t know anything about.”
She hopes that will change in the near future; in an effort to improve coverage rates and promote vaccine acceptability, it will soon be a requirement that Serbian health care workers be vaccinated against influenza.
It is just one more example of growth within Serbia’s vaccine culture. And it is evolving quickly, no doubt a result of Torlak’s unique position as an experienced, trusted vaccine manufacturer, yet one that—until recently—had never conducted a clinical study. As a result of Torlak demonstrating not only skill, but leadership. No longer does Torlak lack vaccine clinical trial knowledge. No longer will Serbia be vulnerable to the ravages of influenza.
“We have the network, we have the communication, we have the labs, we have the system for surveillance, and we have the production,” Dr. Stoilljkovic says. “If the pandemic comes, we will be ready.”
Read the entire series
- Defending the world from influenza: As a nine-year project to build vaccine development capacity worldwide comes to an end, PATH and partners reflect on how far we’ve come.
- From Vietnam to the world: How PATH helped ready locally-made influenza vaccine for global use
- A decade of development: What does it take to build an influenza vaccine from scratch?
- Duty and pride: A vaccine clinical trial through the eyes of a volunteer
- Vietnam’s vaccine champion: Why Dr. Le Van Be fights influenza
- The power of local: Can a domestically produced vaccine increase uptake?
