Biomarkers for Enhanced Vaccine Immunosafety
Unbiased biomarkers for the prediction of respiratory disease outcomes


Start Date
End Date
IMI1 - Call 3
Grant agreement number

Type of Action: 
RIA (Research and Innovation Action)

IMI Funding
17 408 770
EFPIA in kind
7 999 683
5 522 917
Total Cost
30 931 370


Vaccination is one of the greatest triumphs of modern medicine, and new technologies now allow us to describe in great detail how individuals respond to vaccines at the cellular, genetic and molecular level. The BIOVACSAFE project, the first IMI project on vaccines, carried out a five-year investigation into new ways to identify and better understand the causes of adverse reactions to vaccines at all stages of development, and showed that it is possible to identify signals in the body (biomarkers) that can predict their long-term safety and tolerability. They carried out 14 studies of well-known vaccines in different groups of people and identified new biomarkers of adverse reactions to licensed antiviral vaccines. They have produced a wealth of publicly-available data that can help researchers make decisions about the safety and tolerability of vaccines in development, which will in turn make vaccines more acceptable to people, and potentially even help reduce the number of animals used in research.

Using a vaccine to probe the workings of the immune system

Vaccines work by triggering a mild and localised inflammatory response that will create the right environment to establish immunity against a given disease. However, excessive inflammation can result in serious complications. It is currently difficult to predict when severe inflammation will occur, and this has led to some vaccines being withdrawn from the market. Immediate reactogenicity (side effects) of vaccines, as well as rare or delayed side effects or adverse outcomes might not show up during clinical trials, and identifying safety issues when a vaccine is in late development or after licensing is expensive and causes delays and  - most importantly - exposes populations to unexpected increased risk.

The BIOVACSAFE project was launched right about the time that new technological developments were changing the way scientists can study biological material. Genomics, proteomics and metabolomics and new ways of working with cell components helped the researchers look at vaccines in a new light. BIOVACSAFE wanted to understand whether the reactions, or ‘flags,’ that appeared in the days and weeks after a person has received a vaccination, could accurately predict what would happen to them in the longer term. This knowledge would help accelerate the development of a vaccine by, for example, making decisions more quickly on whether to pursue alternatives.

The project partners used systems vaccinology techniques to carry out their analyses. In systems vaccinology, scientists can evaluate a wide range of different parameters in order to churn out a huge amount of data that are then used to make interpretations about clinical endpoints (symptoms, signs) in an integrated way, as opposed to the more traditional descriptive way. A descriptive reading of data might be that, for example, the number of antibodies have increased; systems vaccinology techniques can demonstrate that the increase correlates, for example, with the expression of certain genes in a predictive way.

Most of the new methodologies are very sensitive, and it was important for the study investigators to be sure that if they find a ‘flag’ that it is indeed indicative of tolerability or reactogenicity. That’s why they chose to study vaccines for which we already know a lot, and for which there is a large clinical database of information on their tolerability and of mild or medium reactogenicity. There were two sites that carried out clinical trials with a limited number of subjects who each received either one of six vaccines or placebo.

The team carried out a deep analysis of a large set of immunological data molecular data to see whether there were signals that could have predicted the reactions that are known to be produced by these vaccines. With this, they were able to come up with a ‘threshold’ of signals that indicate that the vaccine is working.

A question of acceptability

An important question for the BIOVACSAFE project concerned acceptability; in most cases, vaccines are injected into a healthy person, and so questions about vaccine safety and tolerability are tied up with questions about acceptability of the vaccine by people. To what degree do individuals feel that the benefits of the vaccine outweigh unwanted side effects? A mild reaction might not be tolerated by people who are in good health, in many cases. BIOVACSAFE wanted to figure out the minimum required level of reactogenicity that the vaccine produces to induce a response, while also being considered tolerable by a healthy individual.

This is a very important question that is vital for making sure there is adequate uptake of any new vaccine. If ways can be found to reduce even a very mild reaction by dissecting the mechanisms by which they are elicited, while maintaining a good quality of immune response, confidence and acceptability of vaccines can be greatly increased in the future. This is a problem for which the project was able to contribute great insights and new knowledge.

At the same time, another BIOVACSAFE group were using the same vaccines in animal models in order to make sure that the signals obtained in humans were paralleled in animal models. The real value of using the animal models in parallel (as opposed to one after the other, as in traditional vaccine development) was that, paradoxically, by making sure that the animal models are more predictive of long-term effects, the number of animals used in research can ultimately be reduced, a sensitive issue for many Europeans.

What’s next

BIOVACSAFE was the first step towards this new generation of vaccines. The techniques tested in the project, though they are not routine, they are being used more and more. Similar omics techniques like those used in BIOVACSAFE are being applied in the development of the new COVID-19 vaccines. The larger the population receiving the vaccine, the higher the chance that concomitant episodes  - episodes not associated with the vaccine - might occur, and the project partners are watching the outcomes of those vaccination campaigns closely. The project has established this expertise in Europe, which makes Europe more competitive in this regard.

Achievements & News

BIOVACSAFE clinical studies get underway
April 2013

The vaccine safety project BIOVACSAFE has started a series of clinical studies that will pave the way for novel tests to predict the safety of new vaccines.### Vaccine safety is of paramount importance; and although vaccines are widely recognised as one of the most effective public health interventions available, concerns about vaccine safety may lead some people to hesitate about having themselves and/or their children vaccinated. Vaccines are thought to work by triggering a mild and localised inflammatory response that will create the appropriate environment to establish immunity against the disease in question. However, excessive inflammation can result in serious complications. Currently, it is hard to predict when severe inflammation will occur, and this has led to some vaccines being withdrawn from the market. In BIOVACSAFE, researchers are using licensed vaccines to identify biological markers (biomarkers) that can predict beneficial and harmful responses to a vaccine. One study that is currently underway is a 'training' study, in which the licensed hepatitis B vaccine, Engerix B, is being evaluated. This vaccine was selected because it is a good representative of a particular class of vaccines and is used in a particular target group. In this study, participants receive two immunisations six months apart. For each immunisation, participants will have to spend a week at the study centre, during which physiological parameters (such as temperature, heart rate and blood pressure) and immunological parameters are investigated in detail. The data from this study will then be used to identify potential biomarkers. Ultimately, the objective is to develop novel tests using biomarkers identified in such studies. These tests can then be integrated into vaccine development programmes to identify new vaccine candidates with the best safety profiles.

Participants Show participants on map

EFPIA companies
  • Glaxosmithkline Biologicals SA, Rixensart, Belgium
  • Glaxosmithkline Vaccines SRL, Siena, Italy
  • Islensk Erfdagreining Ehf, Reykjavik, Iceland
  • Sanofi Pasteur SA, Lyon, France
Universities, research organisations, public bodies, non-profit groups
  • Cdisc Europe Foundation Fondation, Brussels, Belgium
  • Chalmers Tekniska Hogskola AB, Goeteborg, Sweden
  • Commissariat A L Energie Atomique Et Aux Energies Alternatives, Paris, France
  • Department of Health, Leeds, United Kingdom
  • Goeteborgs Universitet, Gothenburg, Sweden
  • Imperial College Of Science Technology And Medicine, London, United Kingdom
  • Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften Ev, Munich, Germany
  • St George'S Hospital Medical School, London, United Kingdom
  • Statens Serum Institut, Copenhagen S, Denmark
  • Universita Degli Studi Di Siena, Siena, Italy
  • Universiteit Gent, Gent, Belgium
  • Universiteit Utrecht, Utrecht, Netherlands
  • University Of Surrey, Guildford, United Kingdom
Small and medium-sized enterprises (SMEs)
  • ImmunArray Ltd, Rehovot, Israel
  • Vismederi SRL, Siena, Italy
Third parties
  • Universitair Ziekenhuis Gent, Gent, Belgium
Project coordinator
Giuseppe Del Giudice
GlaxoSmithKline Vaccines Srl
Managing entity
David Lewis
The University Of Surrey