Alarm at the Checkpoint
Which vaccines strengthen the human immune system? Expert teams at Charité and Freie Universität search for answers.
Dec 10, 2018
Fall is vaccination season. To many people, refreshing their protection from flu on an annual basis is a matter of course. Others refuse all protective immunizations on principle because they believe the potential risks outweigh the benefits.
The arguments are generally not rationally based, but the consequences of not vaccinating are very real indeed – and, all too often, even fatal. In 2017, a wave of influenza infections claimed nearly 1,000 lives in Germany alone. And according to the World Health Organization (WHO), measles – a disease the WHO has committed to eradicate – kills 400 children around the world every day.
It has been proven that vaccinations offer protection not only to the person who is vaccinated directly, but also to others around him or her (those who have not been vaccinated) because those who have received the shot cannot transmit the disease. The principle of “active immunization” traces back to Edward Jenner, an English physician and scientist. He discovered in 1796 that farm workers who had contracted cowpox, a harmless disease, were immune to infection with smallpox, which was often fatal. After that, many successful vaccines were developed to combat diseases such as diphtheria, tetanus, and polio.
“Live” vaccines like those given for smallpox – which has been considered eradicated worldwide since 1980 – are based on similar but greatly weakened viruses or bacteria. The alternative is “inactivated” vaccines, in which the pathogen has been killed by heat or other methods, or “subunit” vaccines, which contain only part of the virus that causes the disease. They are considered to be even lower in risk, but they do need to be refreshed frequently.
“In most cases, satisfactory immunization is not achieved at all until the patient has been vaccinated three times – that’s true of the hepatitis vaccine, for example,” says Professor Leif Erik Sander, an infectious disease specialist and pneumologist at Charité – Universitätsmedizin Berlin, the joint medical school of Freie Universität and Humboldt-Universität zu Berlin.
It was not until the development of additives known as adjuvants, such as the aluminum salts that are a frequent target of criticism from anti-vaccine activists, that inactivated vaccines provided acceptable immunization at all. A single dose of live measles or rubella vaccine, on the other hand, protects more than 95 percent of those who receive it, and the protection typically lasts a lifetime.
But why do live vaccines trigger much stronger, longer-lasting immune responses? “If the body’s immune system recognizes invaders as dead, all it does is activate a sort of economy program. By contrast, pathogens that still contain RNA molecules are taken much more seriously.” Sander was able to demonstrate this using mice several years ago. Just recently, his team succeeded in explaining the difference at the molecular level as well. To do this, the researchers infected human cells in vitro and then looked for receptors that can recognize RNA. They found what they were looking for in the phagosomes of phagocytes, a special kind of cell.
“Inside these cell organelles, substances that are foreign to the body, such as pathogens, are typically broken down and inactivated. Certain components of pathogens are also presented on the surface of the cell as antigens, so they trigger what is known as the adaptive immune response, which is ultimately responsible for the protection provided by a vaccination.”
Forming lasting antibodies requires certain helper cells, but they don’t come into the picture until a certain “checkpoint” in the phagosome – Toll-like receptor 8 (TLR8) – sounds the alarm. And that, in turn, is only activated by live pathogens, or more precisely their RNA. Special chemical substances transmit the message, which then prompts formation of follicular helper cells, which help to form effective antibodies and eliminate the intruder.
Sander’s team continued its research in cooperation with veterinary medicine researchers from Freie Universität, using pigs from breeding facilities that receive routine immunizations. One group was given a live vaccine for Salmonella, while the other received a vaccine that had been inactivated using heat. Animal pathology professor Achim Gruber and Kristina Dietert, who holds a doctorate in veterinary medicine, used microscopic tissue analysis to study the effects of various vaccine types and examined the immune responses mediated by TLR8.
Two immunologists, Professor Suanne Hartmann and Friederike Ebner, who holds a doctorate in veterinary medicine, isolated certain defense cells from the animals’ blood and spleen and worked with colleagues from Charité – Universitätsmedizin Berlin to establish the first in vitro test to show the presence of follicular helper cells in pigs.
The findings from Sander’s lab, where the team worked with human cells, were confirmed to impressive effect in the pigs. The infectious disease specialists will now use this knowledge to give inactivated vaccines more power. Their goal is to develop innovative adjuvants that trigger the same alarm at the TLR8 checkpoint as the RNA of living pathogens would.
“RNA itself might be too unstable for this purpose, so we are looking for small molecules that look similar to nucleic acid components.” Several promising candidates have already been identified. Now that the mechanism of action has been decoded, another question arises in the context of increasing antibiotic resistance: whether it might be possible to ramp up the activity level of the human immune system in general. That might be done before the winter, for example, to help ward off a whole range of pathogens.
As a pneumologist, Sander is thinking of bacterial infections in particular: “Patients with breathing difficulties like asthma or cystic fibrosis suffer recurring infections.” An immunity boost like this would be desirable in veterinary medicine as well. Having something like that could dramatically reduce the use of antibiotics in livestock operations, and thus also in people.
Another subject Sander is working on is adjuvant immune therapies. “We’re wondering whether there are immunostimulants that we can give to patients to give their immune system an additional boost when they have an infection, perhaps even prophylactically.” Initial tests have already been performed, administering immunostimulants to patients via the airways following a difficult surgery to prevent subsequent pneumonia.
Sander firmly believes the knowing how the most effective vaccines work will open whole new doors in many areas. “Live vaccines are still the best way to develop an effective vaccine quickly in the case of epidemics like Ebola, but in the long term, we do want to move away from them.” In cooperation with the Robert Koch Institute and other partners, the researchers from Charité are also working to advance scientists’ understanding of the standard measles vaccine toward that aim.
The hope is that this will lead to even more effective, safer vaccines in the future. Maybe that would cause vaccine skeptics will reconsider their stance.