Interview about vaccine research with PD Dr. Michael Mühlebach
The new coronavirus SARS-CoV-2 still dominates everyday life of many peaople worldwide. Nobody can say yet, when a return to "normality“ will be possible again without risking human lives. Hopes are high that the development of a vaccine will be successful which could protect the world population, or at least particularly vulnerable groups of people, from the new pathogen. The Paul Ehrlich Institute (PEI), the German Federal Institute for Vaccines and Biomedical Drugs, which is responsible for the approval of clinical trials and the evaluation and authorisation of vaccines in Germany, has now approved the first clinical trial of a vaccine against COVID-19 in Germany. The National Research Platform for Zoonoses will discuss the background of laboratory research prior to vaccine development with PD Dr. Michael Mühlebach, researcher at the Paul Ehrlich Institute and member of the Internal Advisory Board of the German Research Platform for Zoonoses.
Note: the interview is translated from German. See the original German version
“Primum, non nocere“, translated: “First, do not harm!“
ZOOP: Dr. Mühlebach, according to a study by Vasilakis et al  the development of vaccines takes apprixmatly 10 years, whereas only around 6% of the candidates make it to the market. What makes vaccines development so time intensive? And why is the failure rate so high?
Mühlebach: The relatively long development times and high failure rates are not a specific characteristic of vaccine development alone, but a tendency that can be observed for all drugs. The core principle is always: "Primum, non nocere", translated: "First (in the sense of highest principle), do not harm! This means that all drugs must show during their development that they do more good than harm, and that any side effects remain within an acceptable range in any case. This holds true for vaccines particularly, which are in principle administered to healthy people, and whose benefit lies in the prevention of disease, i.e. this benefit is not even directly apparent.
For this reason, great care is taken in the development of drugs and in particular vaccines in order to describe the risk-benefit-ratio carefully and to avoid to expose the test candidates to any avoidable risk.
The failure rate is composed of many different factors. A candidate that might have seem promising in an animal model might not work in humans as expected. It might turn out that it is impossible to produce it in the required quantity or quality, some unacceptable risk in regards to side effects might show up during the development process or a candidate is simply not as good as an alternative product, so it would be pointless to continue the development process.
ZOOP: What states does a vaccine need to pass before approval?
Mühlebach: Vaccine development starts with so-called Proof-of-Concept studies in the laboratory. Here a vaccine concept is tested for its ability to protect in a suitable disease model. If this model shows promising data, then a production process for the vaccine candidate must be established that enables the vaccine to be produced in a quality and quantity that allows it to be used on humans at all. Vaccine candidates of the appropriate quality must then show in animal models for toxicology and pharmacology that efficacy, but above all safety, can be expected when used in humans.
These data must then be used to apply for and conduct clinical studies on volunteers, the test persons, step by step. In so-called phase I clinical trials, the main aim is to prove the safety of the vaccines in relatively small numbers of volunteers, including humans. Once the safety expected from the animal models has been confirmed, the next phase II studies will be carried out to determine the immunising effect of the vaccine candidate and the optimal dose, type of immunisation and sequence of any multiple immunisations that may be necessary in humans. In Phase III studies, the vaccine must finally prove its efficacy, meaning that immunisation and the immune responses provoked by it actually protect against the disease. For this purpose, a sufficiently large number of volunteers are usually immunised. After a certain time it is tested whether statistically fewer people are infected or sick in the group of volunteers than have become ill at the same time under the same conditions in a remaining comparable population group. From this, a protective effect can then be deduced and the vaccine can be granted approval if applicable.
The Paul-Ehrlich-Institute – the national authority responsible for vaccines in Germany
ZOOP: Which role does the Paul-Ehrlich-Institute (PEI) play in this whole procedure in Germany?
Mühlebach: The PEI is the national authority responsible for vaccines in Germany. The clinical studies just mentioned, which are necessary for the approval procedures and are to be carried out in Germany, must be approved in advance by our institute on the basis of the requirements. The approval of the vaccines after successful Phase III is now generally carried out within a European framework by the European Commission after evaluation by experts from the PEI and other national drug authorities in committees of the European Medicines Agency EMA. After approval has been granted, the safety and efficacy of the vaccines on the market are continuously monitored at national level within the framework of so-called pharmacovigilance. The PEI is also responsible for this in Germany. In addition, the PEI issues the national batch release permission for each batch.
ZOOP: Can the procedure be accelerated in the event of a global pandemic such as COVID-19?
Mühlebach: In terms of content, it must be ensured that the necessary care is still exercised in the approval and licensing processes. However, in terms of working procedures the processes will be speeded up - for example, when submitting an application for approval of a clinical trial, the applicants do not yet have to submit all documents in full, as is normally the case. Instead, certain data packages are reviewed in advance and any queries regarding these data are clarified while the outstanding data sets are still being collected. This causes work, but saves time in the procedure.
ZOOP: Which criteria does a vacine candidate need to fulfil before it can be approved for a clinical trial in humans?
Mühlebach: The vaccine needs to show some effects in an animal model. Further, preclinical studies must demonstrate the induction of a specific immune response and a good tolerability. In addition, in order to be clinically tested in humans, the vaccine must meet certain defined quality criteria in its manufacture and properties.
“Regardless of an acute situation, potential long-term consequences require special consideration.“
ZOOP: When developing a vaccine, are potential long-term consequences also being investigated and how to treat such a risk in view of an acute outbreak of a disease when time is of the essence?
Mühlebach: Regardless of an acute situation, potential long-term consequences require special consideration. This is not a risk that is specific to vaccines, but has to be considered in the development of drugs in general, and every effort is being made to minimise this risk with chronic toxicity studies. However, neither these studies nor clinical trials can fully map long-term effects that last for several months or that occur at a very low frequency. For this reason, vaccines, like all other drugs, are also monitored after their approval as part of the above-mentioned pharmacovigilance and the risk potential is constantly re-evaluated to the current status, especially when adverse reaction reports are received, which in the worst case can result in a withdrawal of the approval. However, it is extremely rare for such consequences to become evident, also due to the tried and tested mechanisms for approval.
ZOOP: How can a suitable animal model for testing a vaccines be found and can a vaccine be tested in humans before having been evaluated in animals first?
Mühlebach: The animal model should be as comparable as possible to humans. This means that it should respond to the vaccine candidate in such a way that the reaction in the animal model allows the best possible conclusions to be drawn about human reactions. However, it is usually not possible to test vaccine candidates in humans without data on safety and efficacy directly from the animal model, because of the responsibility towards the test persons.
“Human medicine can profit from veterinary medicine in multiple aspects regarding vaccine development.“
ZOOP: How much can verterinary and human medicine work together and learn from each other in vaccine development?
Mühlebach: Human medicine can profit from veterinary medicine in multiple aspects regarding vaccine development. On the one hand, in the identification or development of a suitable animal model, since this should also depict the interaction between patient - immune system - pathogen as similar as possible to humans.
On the other hand, certain vaccine concepts are possibly already established in veterinary medicine and can be transferred to human medicine to a limited extent. It is possible that vaccines against related pathogens already exist in veterinary medicine and conclusions can be drawn about the vaccine to be developed for humans. For example, in contrast to human medicine, there is already a vaccine against a somewhat more closely related corona virus for cats, from whose side effect profile one can possibly learn something for the risk assessment of the COVID-19 vaccine to be developed. The concept of vaccine platform technologies had also been established in veterinary medicine for much longer than in human medicine.
After all, COVID-19 is also a zoonosis, i.e. the pathogen, SARS-CoV-2, originally comes from an animal host. In the case of zoonoses, veterinary and human medicine can prepare for the development of appropriate vaccines by early identification of pathogens occurring in the animal kingdom.
ZOOP: Are the requirements for vaccine approval the same in all countries of the world?
Mühlebach: At the European level the requirements for vaccine approval are indeed the same and are defined in European law. In addition, as already mentioned, novel vaccines are mainly approved for the whole of Europe by the European Commission (for certain groups of vaccines, this route is exclusively intended). There are still some differences in the requirements for vaccine approval on a global level, but there is a recognisable effort, for example in WHO bodies, to harmonise the requirements within the framework of the exchange between the relevant authorities and the development of WHO guidelines.
ZOOP: The vaccine candidate against COVID-19 of the German biotechnology company BioNTech is a so-called RNA-vaccine. What exactly is that?
Mühlebach: RNA is a nucleid acid and serves in biology among other things universally as a construction plan for proteins. An RNA vaccine introduces the building instructions for protein structures of the pathogens into the human body against which the body is to develop effective immune responses, so-called antigens. Each vaccinated person then produces these proteins himself, presents them to his/her immune system and causes it to develop protective immune responses against these pathogen proteins.
ZOOP: What other vaccine types exist?
Mühlebach: There are pathogen-specific vaccines, which can be roughly divided into inactivated vaccines, i.e. killed pathogens, subunit or conjugate vaccines, i.e. purified or recombinant pathogen proteins, possibly conjugated to an immunostimulating carrier substance, and live-attenuated vaccine strains. The latter are attenuated variants of the pathogen (e.g. in mumps or measles vaccines) or closely related pathogens (e.g. in smallpox vaccines) which, although they no longer cause illness in healthy people, can stimulate their immune system very efficiently. New vaccine types are DNA, RNA and vector vaccines.
And then there are the vaccine platform technologies, on the basis of which not only a vaccine specific for one pathogen can be developed, but which can serve as a basis for the development of vaccines against different pathogens.
Fig. 1: Overview of different vaccines types
Vaccine platforms can significantly facilitate the balancing of risk-benefit-profiles
ZOOP: What is a “vaccine platform“?
Mühlebach: A vaccine platform is a system on the basis of which certain proteins or other structures of any pathogen can be presented to the immune system in such a way that a protective immune response against the selected pathogen is triggered in vaccinated persons.
As in the case discussed above, this can be a suitably modified construction manual for the corresponding harmless antigens of the pathogen directly in the form of RNA. However, these can also be modified, attenuated pathogens that efficiently transport this construction manual as non-proliferating vectors. Finally, some proven vaccines such as measles or smallpox vaccine viruses are genetically modified in such a way that they also carry the construction manual for foreign antigens. This means that the immune system is not only presented with the measles or smallpox antigens, but also with the structures of the new pathogen against which the vaccination is actually intended.
The advantage of the vaccine platforms is that the development of pathogen-specific vaccines is usually much more complicated or less efficient and thus relatively lengthy. Roughly speaking, the more similar a vaccine is to an actual pathogen, the stronger and more effective the immune response will be. However, if the vaccine is not weakened enough, it may have too high a risk of side effects. Finding the balance between efficacy and safety is therefore a great challenge when dealing with a newly emerging pathogen. This should generally facilitated with a vaccine platform, as the carrier technology is much better known than for an emerging pathogen and therefore the balancing of the benefit-risk profile is much easier, which should speed up development.
ZOOP: Why do some vaccines have to be administered several times, while some are given only once?
Mühlebach: On the one hand, this depends on the pathogen against which you immunise, the immune responses that you need to achieve in order for them to provide reliable protection (including broad protection), and the vaccine properties themselves. Let's take the following example: The measles vaccine already mentioned is a live-attenuated strain of the pathogen that has a very stimulating effect on the immune system and produces extremely long-lasting protective immune responses. Therefore, once successfully immunized, people are usually protected for the rest of their lives.
Nevertheless, people should be vaccinated against measles twice in the meantime. Why? It is known that approximately 85% of those vaccinated respond to the vaccine with a single immunisation - 15% remain unprotected. However, since a significantly higher proportion of immune people in a society, known as "herd immunity", is necessary for successful suppression of measles due to the high infection rate of measles overall, this very well tolerated vaccine now needs to be administered twice in order to achieve individual protection and high herd immunity with greater probability.
With other vaccines, it is known that the immunity of vaccinated individuals decreases over time, or that more than one immunization is necessary to achieve the required immune responses. In such cases, booster vaccinations and multiple vaccinations may be necessary and are determined on the basis of the data from the studies required for approval.
ZOOP: Is it an advantage in vaccine development if a vaccine against a related pathogen already exists, or do you need to start from scratch every time?
Mühlebach: In my view, it is an advantage if there are already effective vaccines available for related pathogens, as this makes it possible to assess what risks can be expected and which immune responses are necessary to develop a safe and effective vaccine. After all, the relationship between pathogens is often reflected in similar biological principles. The principles identified for the related pathogen can then be transferred. However, the individual differences between the pathogens must also be taken into account. Even if pathogens are related to each other, they are not completely identical. Thus, on the one hand, vaccine development does not necessarily always start from scratch, as one knows the rough direction of development, which has already proven itself in a similar case. On the other hand, all development steps and principles must be confirmed in detail for the new pathogen as well. So you can better estimate what you have to do, but then you have to do it again for each pathogen.
Fig. 2: PD Dr. Michael Mühlebach is Head of the department "Product Testing of Immunological Veterinary Medicinal Products" of the Department of Veterinary Medicine and head of the research group "Oncolytic Measles Virus and Vaccine Vectors" at the Paul-Ehrlich-Institute. Further, he contributes his expertise as a member of the Internal Advisory Board of the Zoonoses Platform.
“HIV is a warning example that shows how difficult it can be to develop a vaccine against a pathogen […]“
ZOOP: Can a vaccine be developed against any pathogen? What conditions must be met?
Mühlebach: To say in general terms that it is possible to develop a vaccine against any pathogen is very difficult. In this respect HIV is a warning example that shows how difficult it can be to develop a vaccine against a pathogen against which humans do not develop protective immune responses under normal circumstances. In the best case, the immune responses of people who have successfully survived a disease can be used to identify so-called protective correlates. These are immune responses that are associated with recovery and thus protection against the pathogen and protect against a renewed infection with the same pathogen. If these immune responses can also be generated with a vaccine, the vaccinated persons are protected.
If it is now not possible to derive protective correlates from the "natural" course of infection, it becomes more difficult. However, there is also a hopeful counter-example: rabies infection is untreated and at a certain point, despite treatment, almost invariably fatal. Nevertheless, the successful vaccine against rabies was developed at a very early stage, since effective antibodies against the rabies virus can protect very well in an early phase of the infection, as is now known.
ZOOP: What structures and external conditions do you think are needed to ensure rapid and efficient vaccine development worldwide?
Mühlebach: In my personal opinion, the rapid and efficient worldwide development of a usable vaccine depends not only on the promotion of the relevant research projects, but also on a high degree of networking, open exchange of information, and a high degree of cooperation between all parties involved, be it academic research, industrial development or the regulatory authorities, so that the knowledge gained at the various points is made available to all parties involved as quickly as possible and thus benefits all projects.
This requires a high degree of cooperation and the will to do so on all sides. However, the insights gained so far make me optimistic that this will actually happen at international level.
ZOOP: Thank you very much for the interview, Dr. Mühlebach.
Interview: Dr. Dana Thal for the German Research Platform for Zoonoses
1. Vasilakis, N., et al., Risk in Vaccine Research and Development Quantified. PLoS ONE, 2013. 8(3).