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Close-up medical syringe with a vaccine.
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On the Trail of New Vaccines

Several research groups at Helmholtz Munich are working on innovative vaccines. Two of them are about to clear a crucial hurdle before approval - fighting the Epstein-Barr virus and Hepatitis B. But how do researchers develop a vaccine?

Several research groups at Helmholtz Munich are working on innovative vaccines. Two of them are about to clear a crucial hurdle before approval. But how do researchers develop a vaccine?

"The Epstein-Barr virus is extremely complex"

The process that culminates in a spectacular world of innovation begins with a complicated balancing act. Prof. Dr. Wolfgang Hammerschmidt, a renowned expert on the Epstein-Barr virus, is considering what a vaccine against this insidious disease might look like. "We didn't want to use a live vaccine that contains the virus in small doses because the virus can trigger various types of cancer," he explains. Therefore, he and his research group decdided for a different approach: they developed so-called virus-like particles - a kind of perfect copy of the pathogen that trains the human immune system to fight off the virus.

The resulting vaccine is now set to enter clinical trials after the first test runs to produce the virus-like particles - the crucial phase before final approval as a drug. If all goes well, the new vaccine will become another chapter in Helmholtz Munich's success story: the next proof of how basic research can directly benefit patients and how findings from the labs can be translated into concrete therapies for diseases.

Wolfgang Hammerschmidt and his team chose an approach that no one had tried before him. “The Epstein-Barr virus is extremely complex. It consists of about 60 viral proteins, and we don't know which combination of them provides the best target for the immune response,” he says. By comparison, the Coronavirus has only four viral proteins, making its structure less complex. “We wanted to pull the teeth out of the virus without changing its protein combinations,” Hammerschmidt explains. With his team, he therefore recreated the structure in the virus-like particles as accurately as possible, including many viral proteins.

"This is high-level biotechnology. And the first time globally that a vaccine candidate has been based on such complex virus-like particles."

Prof. Dr. Wolfgang Hammerschmidt, Head of the Helmholtz Munich Gene Vectors Research Group

Fighting Kissing Disease

Epstein-Barr virus is a common herpes virus, but it can be insidious. Typically, people are exposed to the virus as infants or young children, and it then settles in the body without causing disease. However, if initial contact occurs at a later age usually during puberty - the consequences can be severe. Pfeiffer's glandular fever, which then often develops, triggers weeks of fever and can even lead to an exhaustion syndrome lasting months. "Kissing disease" is the colloquial name for glandular fever because it is transmitted by droplet infection during kissing, which is why it is particularly common among adolescents. The viruses are even suspected of provoking an exaggerated immune response, thus playing a role in the development of Multiple Sclerosis, an autoimmune disease affecting the brain and spinal cord. The vaccine that Wolfgang Hammerschmidt and his team are developing is intended to prevent all these consequences - and this is becoming increasingly urgent: In Germany, the number of patients with Multiple Sclerosis, but also with glandular fever, continues to rise. This is probably because infants and young children are less likely to encounter the virus as a result of hygiene measures. Infection during puberty is much more dangerous and can trigger these two diseases.

A Possible Rescue for Chronic Hepatitis B

Almost 300 million humans carry the hepatitis B virus as a ticking time bomb – often since birth. Prof. Dr. Ulrike Protzer is working on an eagerly awaited therapeutic vaccination and is at a crucial stage: testing the vaccine in the first humans in a clinical trial. The vaccine is designed to cure patients with chronic hepatitis B. Ulrike Protzer still remembers the moment a co-worker ran into her office. She had just come from the lab, where she cares for the mice carrying the virus. "She was very excited and shouted, 'The immune system has eliminated the virus!’ and we all felt we had taken a decisive step forward," says the virology professor who conducts research at Helmholtz Munich. She and her team are developing a vaccine that is, in fact, more an immunotherapy and is eagerly awaited by many people affected by the hepatitis B virus around the world - and it has one special feature: It is a therapeutic vaccine that is administered when someone is already sick. For Ulrike Protzer, the start of clinical trials is an important highlight in her fight against the virus. TherVacB is the name of the vaccine she has developed, which will first be tested in Germany and then in a Europe-wide consortium.

The initial situation: As protection against hepatitis B, a vaccine is administered to newborns in Germany as part of their childhood vaccinations. However, those who are not vaccinated or who inherit the virus from their mother can become seriously ill: Hepatitis B causes liver cirrhosis and liver cancer, and around 820,000 people worldwide die every year as a result of this infection. So far, no drug cures the disease.

But why are Ulrike Protzer and her team focusing on a therapeutic vaccine? “There are therapies that have a direct antiviral effect,” she explains. These drugs inhibit viral replication, but the hepatitis B virus cleverly deposits its survival form in the nucleus of infected cells. There it lies, waiting for years, and as soon as the drug is discontinued, the virus starts replicating all over again. And the cancer risk remains. In her search for a therapy that completely cures the virus, Ulrike Protzer is therefore relying on the principle of therapeutic vaccination: The vaccine is intended to activate the body's immune system to specifically target viral antigens so that it can combat the pathogen - and eliminate it from the body once and for all.

In this video, Ulrike Protzer explains the difference between a protective vaccination and a therapeutic vaccination.

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A Construction Kit for Vaccine Researchers

Working on such a vaccine is like systematically searching for the right composition for years. “At the beginning, you must identify your targets: the question is, against which parts of the virus we want to induce an immune response,” says Ulrike Protzer. “Ideally, a vaccine targets not only one specific antigen but several antigens simultaneously so that the virus cannot evade the immune response.” Her vaccine is designed to target not only the envelope protein but also the capsid and the inner proteins. The goal is to have all hepatitis B virus variants covered worldwide, from Africa to China to Europe. “We first select the appropriate components, for example, nanoparticles consisting of viral structural proteins, with or without adjuvants, and then various vaccine vectors, systematically compare them, and then combine them,” Ulrike Protzer explains the approach.

The way she and her colleagues proceed compares to working on a construction kit: They look for precisely those parts that fit the intended location. Instead of playful ease, however, it is a highly complex research endeavor: The experts have been working on the puzzle for many years, and in that time, they have filed several patents because they have repeatedly discovered completely new methods and combinations. Ulrike Protzer realized she had made important progress when she presented her results to colleagues caring for patients: “They were deeply impressed and willing to support us in clinical development.”

Navigating the transition from the research laboratory to the clinical approval stage for a complex vaccine proved challenging for the small team. Production according to Good Manufacturing Practice (GMP) guidelines at contract manufacturers for each vaccine component required simultaneously scaling up production, developing a comprehensive catalog of quality control tests according to the European Pharmacopoeia, and implementing a stability program. Each required step must be closely monitored and involves uncertainties. This is what makes vaccine development so unpredictable. Unforeseen obstacles added to the complexity, including resource and material shortages due to the COVID-19 pandemic. The team persisted, always being aware of millions of chronic hepatitis B patients desperately waiting for a cure option. Despite countless setbacks, their dedication, adaptability, and resilience were pivotal in navigating the complicated path of vaccine development. This ultimately led to the successful start of clinical trials.

Now, to translate the promising results to humans, Ulrike Protzer and her team are preparing the clinical trial phase. "We are very grateful to our clinical partners for supporting us in this final, decisive step with such commitment and for taking over responsibility for the clinical trial," says a delighted Ulrike Protzer. If the clinical trials are successful, her novel vaccine against chronic hepatitis B will be ready for approval in a few years' time.

“This is unquestionably a special moment in our lives as researchers.”

Prof. Dr. Ulrike Protzer, Director at the Helmholtz Munich Institute of Virology

Latest update: March 2024.