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The WHO had also sought to eradicate the measles virus by 2020. Measles can lead to serious complications, including blindness or fatal meningitis, especially in children younger than five. About 2.6 million people died of measles worldwide every year before the first vaccination became available in 1964. After that, the figures rapidly decreased—until 2016. Unfortunately, since then the illness has once again been gaining ground. In 2019 the WHO sounded the alarm: The number of registered cases of measles had increased by 700 percent in Africa and by about 300 percent in Europe in a single year. Many people who live in poor regions have no access to vaccines, but the spread of measles in rich countries is primarily due to growing skepticism about vaccination. In reaction to these figures, mandatory measles vaccination was introduced in Germany in March 2020.

In the struggle against the novel coronavirus, there are no plans for mandatory vaccination, even though fears about such a mandate are being voiced by vaccination skeptics and believers in conspiracy theories. At the moment the focus is on the search for a suitable vaccine and on the associated hopes for ending the pandemic as soon as possible. “There’s a lot of optimism,” said Professor Klaus Cichutek, the president of the Paul-Ehrlich-Institut (PEI—the Federal Institute for Vaccines and Biomedicines), which is responsible for approving vaccines in Germany, back in August. The initial results of ongoing studies have shown “that some vaccines can actually induce a specific immune reaction in human beings against SARS-CoV-2,” he said.

The new vaccine technologies are based on the classic processes that make use of the memory of our immune system. When it is invaded by a virus or a bacterium, the immune system reacts by forming antibodies. The information about these antibodies remains stored in special white blood cells. If there is a new infection by the same pathogen, these white blood cells can produce these antibodies very quickly and render the intruders harmless.

As a rule, a vaccination actively introduces pathogens into the human body in order to stimulate the immune system to form antibodies. This is usually done by means of an injection into a muscle or subcutaneously. We distinguish between various classes of vaccine. Live vaccines contain viruses or bacteria that have been attenuated to such an extent that they can still reproduce themselves but can no longer cause the disease. The protection afforded by a live vaccine lasts for many years. Examples include the live vaccines against measles, mumps, rubella, and chickenpox.

In inactivated or killed vaccines, the pathogen is first killed, so that it is unable to reproduce itself and cause the disease. In this case the protection gradually decreases and must therefore be regularly renewed with a booster shot. Vaccines of this type protect the recipients from polio, tick-borne encephalitis (TBE), and hepatitis B. Other vaccines, such as those against tetanus, diphtheria, whooping cough, and the flu, only contain components of the pathogen, such as proteins or sugars that are recognized by our immune system. These vaccines also protect recipients for only a limited period of time.

The time to develop traditional vaccines can typically take several years as a general rule. For one thing, large amounts of virus material are required. For another, the large-scale production of a vaccine requires a lot of time and effort. “For example, in the case of inactivated vaccines the pathogens have to be precisely specified under strict safety conditions,” explains PEI President Cichutek. “Next, the strain is produced, cultured in large amounts, and only then inactivated.”

This is why the researchers who are searching for effective protection against the coronavirus as well as diseases such as AIDS and certain types of cancer have been focusing in recent years on completely new candidates: gene-based vaccines that contain not the virus itself but only a blueprint that the human body can use in order to produce exactly that part of the virus that triggers the immune response. For example, in the case of the coronavirus this part could be the “spike protein” on the virus envelope. Serums of this kind can be produced in large amounts relatively quickly, and if the pathogens should mutate the serums can be adapted as necessary.

Vector vaccines are a variant of these innovative vaccines. In vector vaccines, genetic material of the pathogen is inserted into harmless carrier viruses (such as the virus used for measles vaccine or attenuated adenoviruses). Initial vaccines against dengue fever and Ebola have already been approved. And Russia already dashed forward in August and produced a vector serum against Covid-19.

Scientists believe that additional opportunities are offered by vaccines based on nucleic acids, which are the carriers of genetic information inside cells in the form of DNA (deoxyribonucleic acid) and RNA (ribonucleic acid). Because the production of DNA or RNA vaccines requires not the entire virus but only its genetic material, it is much easier and faster than the production of other types of vaccine. Dozens of studies are now being conducted in this area. However, by mid-October no vaccines against Covid-19 had been approved for use on human beings.

In the case of DNA vaccines, the sequence of the desired antigen is inserted into the genetic information of a bacterium. After the bacterium has entered the target cell, this information is read in the cell’s nucleus and the antigen is produced directly inside the cell. Researchers have already been working on these vaccines for many years. Pharmaceutical companies are currently working on DNA vaccines against about 20 diseases including rabies, leukemia, and AIDS. So far, the possibility of foreign DNA being inserted into human genetic information, which in the worst case could lead to increased tumor formation, has not been documented in any studies. “We have spent many long decades investigating a theoretical risk that might be harbored by DNA vaccines, but in fact this risk has never materialized in animal testing or in clinical trials,” said PEI President Cichutek at a press briefing in April 2020 in order to calm any fears.

In order to completely exclude this risk, there is the option to use not the entire DNA of a protein but only its mRNA, or messenger RNA. A protein’s mRNA is basically a copy of its blueprint, which is read out from the DNA. The mRNA transports this blueprint directly to those places in the cell where the desired protein is produced. In other words, it is not incorporated into the cell’s nucleus, and thus it cannot be inserted into the DNA there.

However, in order to unfold its effect the mRNA must first reach the right place inside the human body. “For a long time this was a big problem for scientists, because it is a very unstable construct,” explains Stefan Randl. This is where the lipid nanoparticles from Evonik—ultrafine particles of fats and waxes—once again come into play. “If I were to inject mRNA without having previously formulated it—in other words, without having packaged it inside a protective layer—it would disintegrate in the bloodstream within seconds.”

Evonik produces lipid nanoparticles and complete mRNA serums at a facility in the town of Burnaby near Vancouver, Canada. In 2016 Evonik expanded its portfolio for advanced drug delivery to include the development and production of liposomal formulation technologies by acquiring the local company Transferra Nanosciences. “Vancouver is an epicenter for the development and the production of LNPs,” says Randl. Research on lipid nanoparticles has been conducted there for almost 30 years. “The researchers have already deistered via injection—against diseases such as cancer or amyloidosis, which is triggered by protein deposits in the body and can lead to organ dysfunction. This was the first application of an RNA-based therapy. “Certain combinations of active ingredients, as well as personalized medications, would also be unthinkable without LNPs,” Randl adds. In the future, serums based on lipid nanoparticles could play an important role in the market for vaccines and many therapeutic drug products.

By means of its highly specialized and complex production processes for LNP-based medicines, Evonik develops formulations for pharmaceutical companies in Vancouver from start to finish. “For example, the customer sends us the mRNA, and we then conduct research in order to find out the proportions in which lipids must be mixed with other ingredients,” says Jay Natarajan, the head of research in Burnaby. The tiny lipid particles have to protect the nucleic acids from destructive enzymes and thus enable them to pass through the cell membrane.

“To make sure the mRNA safely reaches its target, the LNPs themselves have to consist of many different lipid and buffer components, so there’s a long list of ingredients,” explains Natarajan. The lipid ingredients are first dissolved using ethanol and combined with the mRNA, which has been dissolved in a buffer solution. This is done using a very rapid micromixing process that creates lipid nanoparticles encapsulating the mRNA just like the layers of an onion. These lipid nanoparticles are then subjected to a downstream purification process to form a final drug product that is ready for clinical trials on humans.

When the particles reach the target cells, they fuse with the cell membrane and release the mRNA into the cell exactly where it is needed. There the information that is required to manufacture the desired protein is read out, and the production of the antigens begins.

As soon as the right formulation for the customer’s mRNA has been determined in Burnaby, serums can be produced in amounts sufficient for reaching Phase I /II of clinical testing. Looking ahead, Evonik is planning future operations that go beyond this stage. The laboratories at the company’s location in Birmingham, Alabama have the capability to produce larger batches. The company has already developed and produced drugs based on bioresorbable polymer microparticles.

Incidentally, the story of the little boy in England had a good ending. Not only did the vaccination make him immune to smallpox—to show his gratitude, the country doctor Edward Jenner later on gave him a cottage to live in with his family. Eventually, this house became the first Jenner Museum.

Photos: Ollanski, Stefan Wildhirt/Evonik, Mohammed Munawar