ADITEC: Joining Forces for Next-Generation Vaccines

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Science Translational Medicine  04 Apr 2012:
Vol. 4, Issue 128, pp. 128cm4
DOI: 10.1126/scitranslmed.3003826


Scientists sit poised at a singular moment in the history of vaccine research. Genomics and systems biology have fueled advances in our understanding of human immunology. Together with adjuvant development and structure-based design of immunogens, these next-generation technologies are transforming the field of vaccinology and shaping the future of medicine. However, the sophisticated science behind the development of modern vaccines and the resulting knotty ethical issues have become so complex that scientists and policy-makers need a new model for vaccine research. The European Commission–sponsored Advanced Immunization Technologies project—ADITEC—brings together some of the leading laboratories in the field to tackle the problems that no lab can tackle in isolation.


Vaccines rank as one of the most important achievements of mankind. Together with hygiene and clean water, vaccines have eliminated diseases that once killed millions of people every year. But vaccines can do more to address many of the needs of modern society, such as the controlling of costly established and emerging infections in the growing aging population and in residents of low-income countries (1). The tackling of some of the challenges of modern society—which include pandemic and seasonal influenza, human immunodeficiency virus (HIV) infection, tuberculosis, malaria, and the paucity of therapeutic vaccines—requires a change in the mindset on how to conceive new effective vaccines and, consequently, the development of creative technologies that aid in the design of vaccines in the 21st century.

Furthermore, modern vaccine development also requires new knowledge—both broadly applicable and pathogen-specific—that illuminates the molecular mechanisms of human immunity, pathogen biology, and host-pathogen interactions. Diverse expertise and a spirit of collaboration are needed to meet these myriad challenges. Here, we describe how the European Commission–sponsored Advanced Immunization Technologies project—ADITEC—plans to unite willing participants in a quest to develop modern vaccines (table S1).

The ADITEC project ( is a 30 M€ High Impact Project (HIP) project funded by the European Commission that gathers 42 participants (table S2, full list) from 12 European counties and the United States, 22 academic and research institutions, 13 small and medium enterprises, two large industries, nonprofit entities [Sclavo Vaccines Association (SVA), Novartis Vaccines Institute for Global Health (NVGH), Seattle Biomedical Research Institute (SBRI), and Infectious Disease Research Institute (IDRI)], and agencies such as the World Health Organization (WHO) to confront a challenge that none of the individual laboratories could take on in isolation: accelerate the development of new tools and concepts needed for vaccine development and vaccination strategies. The project is coordinated by the nonprofit organization SVA, which, having vaccine development as a mission, guarantees the long-term commitment and sustainability of this initiative beyond the duration of ADITEC itself.

Challenges and opportunities. The majority of the vaccines available today have been developed empirically, using killed or attenuated pathogenic microbes, without fully understanding the physiological mechanisms behind the resulting vaccine’s protective abilities. Modern vaccinology has many outstanding scientific questions about: (i) the characteristics and functions of powerful immunogens; (ii) the mechanistic nature of protective immune responses; (iii) how one can change the quality of an existing immune response; (iv) mechanisms of the developing and aging human immune systems; and (v) the nature and functions of host factors that influence susceptibility to and protection from disease.

Powerful new tools that can aid scientists in addressing these crucial questions are: (i) an enhanced ability to study human immunology (2); (ii) the use of affordable genomic and systems biology techniques to identify new genomic, epigenomic, gene expression, proteomic, and metabolomic signatures that define the nature of protective immune responses and permit patient stratification in clinical trials (3); and (iii) the ability to develop molecularly defined adjuvants that strengthen the immune response to vaccines by known mechanisms (4). Indeed, scientists now possess the unprecedented power to isolate many human monoclonal antibodies to common and rare epitopes, determine intricate crystal structures of antibody-antigen complexes (5), and engage in structure-based design of synthetic or recombinant immunogens that induce broadly protective immunity (6). Clearly, one group cannot master all of the new technologies and knowledge, compile diverse patient data, carry out the necessary clinical trials, and research and make new vaccine policy. ADITEC seeks to improve vaccine research outcomes in the context of a group that is more than the sum of its parts (Fig. 1).


Advances in -omics technologies and systems biology along with an expanded focus on clinical immunology provide an opportunity to address vaccine-related scientific questions directly in human patients rather than relying on animal models, which are often irrelevant artificial surrogates of human diseases. For example, researchers have mostly used mice as a model system for studying the immune response to the influenza virus that causes pandemic and seasonal disease in humans. However, the influenza virus does not naturally infect mice, and the protective immunity observed in mice that are artificially infected with influenza does not correlate with protection in humans. So by studying influenza in mice, we can publish many scientific papers, but in fact, we learn very little about mechanisms of immunity that protect humans from viral disease. Similar examples can be made for other human pathogens such as HIV, Mycobacterium tuberculosis, Plasmodium falciparum and vivax, hepatitis B and C viruses, salmonella, shigella, and meningococcus.

With the ability to characterize the immune response directly in human patients comes the capacity to investigate—at the molecular, cellular, tissue, and systems levels—how the human immune system responds to infection and immunization and then to use the information to design new or improved vaccines. Today, in addition to the antibody response, scientists can assess the number, quality, and kinetics of activation of B and T cells that are specific for an immunogen; functionally characterize the entire cellular repertoire of the immune response; and detect changes in the gene expression and cytokine profiles of peripheral blood mononuclear cells (PBMCs) induced by, or determine which specific immune-cell subsets are activated by, an infecting organism or a vaccine. A second level of investigation might focus on how all of these parameters are influenced by, vaccine formulations, adjuvants, and delivery systems or by host factors such as a patient’s age, gender, comorbidities, or medications. Such data can be analyzed through systems biology approaches to define macromolecular signatures that predict disease susceptibility and level of protection in response to a vaccine.

Studies in human subjects are expected to yield new findings and raise new questions about fundamental mechanisms of immune responses that can then be studied in well-designed mouse models that mimic the relevant aspects of human physiology. For instance, a knockout mouse can be designed to permit dissection of a specific signaling pathway that is modulated by a particular adjuvant. A new term—coclinical—has been coined for the new vaccinology, in which we no longer follow the old paradigm of performing all preclinical studies in mice before moving into humans but rather, study humans and mice in parallel or start from observations in humans and then move back into mice for mechanistic studies (7). Within ADITEC, we plan to fully apply these coclinical concepts. Systems biology approaches will be used to study existing and experimental vaccines in patient-characterization studies and in clinical trials to investigate the effects of various vaccine components (adjuvants, vectors, formulations, delivery devices, routes of immunization, homologous, and heterologous prime–boost schedules) and host factors. Animal models will be used to complement human studies and to select new immunization technologies to be advanced to the clinic.

The outcome of the new knowledge acquired by this multidisciplinary coordinated approach is expected to accelerate clinical development of new vaccines. The conventional “linear” approach of development tends to test single constructs first in animals and then in humans. The new paradigm is a “parallel” approach to vaccine development, in which participants in ADITEC will test many constructs at the same time (even coclinically, in humans and in animals). The resulting information will be analyzed with the goal of selecting the most promising candidates for further development, reducing the risk of failure by abandoning less promising candidates at the very early stages before large amounts of resources have been invested (7).


The power of the organization became clear during the project’s kick-off meeting in October 2011. Participants suddenly realized that the most sophisticated tools that are often a dream for many laboratories, such as those for systems biology studies and human genetics research, constitute valuable resources available to every participant. The aim of the ADITEC project is to produce the knowledge necessary to develop powerful new immunization technologies for the next generation of human vaccines. This goal requires a multidisciplinary approach in which diverse and complementary scientific disciplines and technologies converge. To realize its goals, the project is structured around two major components: (i) the human immune response to vaccination studied through next-generation methodologies and (ii) the development of advanced immunization technologies. These two components are strictly interlinked, and each benefits from the activities of the other (Fig. 1).

Fig. 1. The ADITEC strategy.

Shown is a schematic representation of basic concepts of the ADITEC project. Human immunology, studied in the clinic and supported with systems biology tools and investigations, will be used to study the impact of new technologies, including vaccine adjuvants, formulations, and delivery systems. Animal models will be used in parallel to support the study and validation of mechanisms of human immunology.


A broad panel of adjuvants, live vaccine vectors, formulations, and delivery devices are available to all participants in the consortium (Fig. 2) and will be tested, compared, selected, and optimized by using common prototype vaccine antigens. These preclinical studies will give rise to new concepts in vaccinology and modern tools for vaccine development and testing, which will generate innovative vaccine candidates to be tested in phase I clinical trials (table S3). These trials will focus on the application of technology developed within the project that represents a paradigm-changing advance likely to improve medical care.

Fig. 2. Immunization technologies.

Schematic representation of immunization technologies (antigens, adjuvants, and vectors) investigated within ADITEC. Model antigens that have been selected for study are hemoagglutinin from influenza strain H1N1 A/California/09 and the H56 fusion protein, which consists of Ag85B, ESAT6, and Rv2660c from Mycobacterium tuberculosis. Adjuvants studied in ADITEC will include MF59 (oil-in-water emulsion of squalene); IC31 (cationic polyaminoacid KLK and oligodeoxynucleotide ODN1a); virosomes; GLA-SE (glucopyranosyl lipid adjuvant-stable emulsion); CAF (liposome-based cationic adjuvant formulations); CTB-CpG (CpG oligodeoxynucleotides conjugated to the nontoxic B subunit of cholera toxin); BCG (bacille Calmette-Geurin vaccine for TB).


Thus, the scientific and technical objectives of the project can be summarized as follows: (i) development of advanced immunization technologies to be advanced to the clinic; (ii) assessment of host factors’ impact on successful immunization through coordinated preclinical, clinical, and population-based studies to identify optimal immunization strategies for specific target groups; (iii) development of concepts and tools to address regulatory and standardization guidance for new immunization technologies; and (iv) creation of European training curricula for translational immunology and vaccinology.

Through this effort, ADITEC offers the opportunity to create synergies and promote cross fertilization among divergent research disciplines. Interdisciplinary collaborations have the potential to fill knowledge gaps that are inhibiting the discovery of new effective and safe immunization technologies.


In order to address diverse scientific questions and make tools available to all participants in the consortium, the ADITEC project has selected a matrix management structure, a format often used by industry to manage large interdisciplinary projects. Under this structure, each of the scientific activities is integrated in a matrix of “horizontal” themes and “vertical” experimental approaches (Fig. 3).

Each activity in the project is managed by two independent coordinators, one for each theme (adjuvants, vectors, routes and devices, prime-boost, host factors, and system biology) and one for each of the scientific approaches (technologies, animal models, and human immunology). This management system ensures that all activities performed within the context of the 42 ADITEC partners are focused to reach the project goals. At the same time, this is a management structure without walls that allows each component of the team to access all of the tools and competencies that are available within the project. In contrast to most other organizational structures, matrix management functions within a dual-authority system, in which each participant reports to two independent project managers. This type of coordination helps to avoid the drift toward individualistic or conservative approaches that often afflict large multipartner projects. Last, the overall coordination structure is supported by an internal steering committee, an external advisory board, and a project-ethics review board.

Fig. 3.

The matrix. ADITEC’s research activities are organized and carried out in 14 work packages (WPs). Each WP is managed by two independent coordinators, one for each tool and one for each scientific theme.



As always, powerful new technologies will raise policy questions that must be addressed if the new findings are to be useful to society. To avoid surprises later on, many of these questions should be tackled upfront, in close collaboration with stakeholders and regulatory agencies. Some of the key questions are the nature of informed consent and the ethical and regulatory pathways for innovative vaccines and adjuvants.

Informed consent. To fully capture the power of modern technology, subjects that are enrolled in an ADITEC study may have their genomes sequenced. Researchers may request permission to clone vaccine-specific B and T cells, derive monoclonal antibodies from immunoglobulin gene sequences of study participants, and derive vaccine-specific T cell receptor repertoires from the gene sequence of various T cells. When thinking about patient consent, scientists should also anticipate new questions that will be generated by the studies. Obtaining open-ended informed consent, while maintaining the confidentiality of the individuals in the studies, will require sophisticated technical solutions and appropriate communication and education strategies.

Regulatory pathways. Testing of new immunogens, adjuvants, and immunization regimens requires the development and standardization of new regulatory pathways. For example, the sequences of genes that encode immunogens and their expression levels often change within pathogens isolated from different patients, different geographical areas, and at different times. Thus, we will need assays that assess how the variations in gene sequences and levels of expression change the protection power of each vaccine component. Validation of these assays will require close collaboration with the scientific community and regulatory agencies.

Another key question is how to assess the effects of new adjuvants and immunogens. We have very little knowledge about what clinical measures should be performed in a study to evaluate the short- and long-term effects of a vaccine’s various components. The ADITEC project intends to develop signatures of both protection and safety defined by systems biology approaches. Validation of these signatures in multiple patient cohorts—for example, of various ages and with different genetic backgrounds—and acceptance of their validity by regulatory agencies and the public will be a challenge that the project needs to address.

In order to anticipate such issues, ADITEC has a subgroup that will tackle regulatory challenges specific to the implementation of vaccine technologies expected to have substantial public health impact. An ethics review board will also act as an independent consultant body for ethical issues raised by the project’s research.

ADITEC will also focus on standardization challenges specific to the implementation of new technologies as applied to immunization and develop an enabling framework to support standardization by interacting with relevant actors in the field. For example, in partnership with WHO, ADITEC will develop systematic methodologies to build on existing regulatory, standardization, and assay-development expertises and provide a resource for product developers. The expertises available from WHO and the National Institute for Biological Standards and Control (a centre of the Health Protection Agency) will aid ADITEC members to facilitate the establishment of coherent and clear advice that reflects current regulatory thinking at early stages of product, assay, vaccine, or device development.


Also part of ADITEC’s mandate is to contribute to the development of the next generation of scientists in the field of vaccinology. An internationally recognized multilevel training program will be developed with the following aims: (i) contribute to the dissemination of knowledge in the field of translational immunology and vaccinology; (ii) improve and disseminate advanced research skills developed within the project; and (iii) promote mobility and exchanges between academia and industry/SMEs, in synergy with relevant existing training schemes and support structures.

This training platform will comprise three major components: (i) training at a Master’s level built on postgraduate courses in vaccinology and pharmaceutical clinical development; (ii) professional-level training organized in part as an ADITEC-adapted advanced course of vaccinology (ADVAC); and (iii) focused training modules in adjuvant and vaccine formulation.


We believe that ADITEC can address important scientific questions in modern vaccinology and provide an infrastructure for researching fundamental aspects of vaccination and human immunity. However, to achieve a dramatic change in the way vaccines are understood and developed will require joining forces with other similar efforts. For instance, the U.S. National Institutes of Health (NIH) has initiated a human immunology program that involves six American organizations. Three of the partners in ADITEC are also part of the NIH network, and this cross fertilization will allow the exchange of information and identification of areas of potential synergy and duplication. Similarly, the Bill and Melinda Gates Foundation (BMGF) funds many studies in areas of research related to those that will be promoted within ADITEC. To evaluate possible synergies, exchange tools and knowledge, and avoid duplications, representatives of the BMGF were invited to the ADITEC kick-off meeting. In theory, any lab can join ADITEC to access the intellectual and practical resources available in the project, and any funding agency can fund projects that go deeper or broader than what ADITEC can do.

Through the ADITEC project, the European Commission is providing the scientific community with a remarkable opportunity for uniting competencies toward a common goal: to design and develop next-generation vaccines.



Table S1. Key ADITEC data

Table S2. List of ADITEC participants

Table S3. ADITEC clinical trials

References and Notes

  1. Acknowledgments: The authors acknowledge the contribution of the ADITEC participants. Funding sources: The ADITEC Project is funded by the European Union, Seventh Framework Programme, Grant Agreement 280873. Competing interests: R.R. is a full-time employee of Novartis Vaccines and Diagnostics and the project coordinator for ADITEC; D.M. is a full-time employee of the University of Siena and the scientific coordinator for ADITEC.
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