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ALL TOGETHER NOW

Vaccines rank as one of the most impor-tant 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 mod-ern society, such as the controlling of costly established and emerging infections in the growing aging population and in residents of low-income countries (1). � e tackling of some of the challenges of modern soci-ety—which include pandemic and seasonal in� uenza, human immunode� ciency virus (HIV) infection, tuberculosis, malaria, and the paucity of therapeutic vaccines—requires a change in the mindset on how to conceive new e� ective vaccines and, consequently, the development of creative technologies that aid in the design of vaccines in the 21st century.

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

� e ADITEC project (http://www.aditecproject.eu) is a 30 M€ High Impact Project (HIP) project funded by the Euro-pean Commission that gathers 42 partici-pants (table S2, full list) from 12 European counties and the United States, 22 academ-ic and research institutions, 13 small and medium enterprises, two large industries, nonpro� t entities [Sclavo Vaccines Associ-ation (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 Organi-

zation (WHO) to confront a challenge that none of the individual laboratories could take on in isolation: accelerate the devel-opment of new tools and concepts needed for vaccine development and vaccination strategies. � e project is coordinated by the nonpro� t 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. � e ma-jority of the vaccines available today have been developed empirically, using killed or attenuated pathogenic microbes, with-out fully understanding the physiological mechanisms behind the resulting vaccine’s protective abilities. Modern vaccinology has many outstanding scienti� c questionsabout: (i) the characteristics and func-tions 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 ag-ing human immune systems; and (v) the nature and functions of host factors that in� uence susceptibility to and protection from disease.

Powerful new tools that can aid scien-tists in addressing these crucial questions are: (i) an enhanced ability to study human immunology (2); (ii) the use of a� ordable genomic and systems biology techniques

P O L I C Y

ADITEC: Joining Forces for Next-Generation Vaccines

Rino Rappuoli1,2* and Donata Medaglini2,3

*Corresponding author. E-mail: rino.rappuoli@novartis.com

1Novartis Vaccines and Diagnostics, 53100 Siena, Italy. 2Sclavo Vaccines Association, 53100 Siena, Italy. 3De-partment of Biotechnology, University of Siena, 53100 Siena, Italy.

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 � eld 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 Com-mission–sponsored Advanced Immunization Technologies project—ADITEC—brings together some of the leading laboratories in the � eld to tackle the problems that no lab can tackle in isolation.

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.

New concepts New toolsHuman immunology

New concepts

Advanced immunization

technologies

Animal models

In vitro models

Adjuvants, formulations,

vectors, delivery devices

Advanced immunization

technologies

GMP

Analysis of the

immune response

Systems biology

Bioinformatics

Patient characterization

Clinical studies

Phase 1 clinical trials

New vaccines

Toxicology

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“ ”to identify new genomic, epigenomic, gene expression, proteomic, and metabolomic signatures that de� ne the nature of protec-tive immune responses and permit patient strati� cation in clinical trials (3); and (iii) the ability to develop molecularly de� ned adjuvants that strengthen the immune re-sponse to vaccines by known mechanisms (4). Indeed, scientists now possess the un-precedented 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 allof 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).

VACCINOLOGY’S RENAISSANCE

Advances in -omics technologies and sys-tems biology along with an expanded focus on clinical immunology provide an oppor-tunity to address vaccine-related scienti� c questions directly in human patients rather than relying on animal models, which are o� en irrelevant arti� cial surrogates of hu-man diseases. For example, researchers have mostly used mice as a model system for studying the immune response to the in� uenza virus that causes pandemic and seasonal disease in humans. However, the in� uenza virus does not naturally infect mice, and the protective immunity observed in mice that are arti� cially infected with in-� uenza does not correlate with protection in humans. So by studying in� uenza in mice, we can publish many scienti� c 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, My-cobacterium tuberculosis, Plasmodium falci-parum and vivax, hepatitis B and C viruses, salmonella, shigella, and meningococcus.

With the ability to characterize the im-mune response directly in human patients comes the capacity to investigate—at the molecular, cellular, tissue, and systems lev-

els—how the human immune system re-sponds 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 activa-tion of B and T cells that are speci� c for an immunogen; functionally characterize the entire cellular repertoire of the immune re-sponse; and detect changes in the gene ex-pression and cytokine pro� les of peripheral blood mononuclear cells (PBMCs) induced by, or determine which speci� c 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 in� uenced by, vaccine formulations, adjuvants, and delivery sys-tems or by host factors such as a patient’s age, gender, comorbidities, or medications. Such data can be analyzed through systemsbiology approaches to de� ne macromolec-ular signatures that predict disease suscep-tibility and level of protection in response to a vaccine.

Studies in human subjects are expected to yield new � ndings and raise new ques-tions 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 speci� c signaling pathway that is modulated by a particular adjuvant. A new term—coclini-cal—has been coined for the new vaccin-ology, 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 par-allel or start from observations in humans and then move back into mice for mecha-nistic 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 e� ects 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 ad-vanced to the clinic.

� e outcome of the new knowledge ac-quired by this multidisciplinary coordinated approach is expected to accelerate clinical de-C

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Antigens

Adjuvants

Vaccine vectors

Influenza

HA

TB H56

MF59

IC31

GLA-SE

CAF

CTB-CpG

Virosomes

PLA

nanoparticles

Salmonella

Adenovirus

BCG

Lentivirus

Arenavirus

CpG ODN

Streptococcus

gordonii

Ag85B ESAT6 rv2660

+ +

++

+

+

CTB

ODN1a

KLK

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 in-fl uenza 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 (cat-ionic polyaminoacid KLK and oligodeoxynucleo-tide 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).

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velopment of new vaccines. � e conventional “linear” approach of development tends to test single constructs � rst in animals and then in humans. � e new paradigm is a “par-allel” approach to vaccine development, in which participants in ADITEC will test many constructs at the same time (even coclinical-ly, in humans and in animals). � e 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 can-didates at the very early stages before large amounts of resources have been invested (7).

ADITEC’S AMBITIONS

� e power of the organization became clear during the project’s kick-o� meeting in Octo-ber 2011. Participants suddenly realized that the most sophisticated tools that are o� en a dream for many laboratories, such as those for systems biology studies and human ge-netics research, constitute valuable resources available to every participant. � e aim of the ADITEC project is to produce the knowledge necessary to develop powerful new immuni-zation technologies for the next generation of

human vaccines. � is goal requires a multi-disciplinary approach in which diverse and complementary scienti� c disciplines and technologies converge. To realize its goals, the project is structured around two major com-ponents: (i) the human immune response to vaccination studied through next-generation methodologies and (ii) the development of advanced immunization technologies. � ese two components are strictly interlinked, and each bene� ts from the activities of the other (Fig. 1).

A broad panel of adjuvants, live vaccine vectors, formulations, and delivery devices are available to all participants in the consor-tium (Fig. 2) and will be tested, compared, selected, and optimized by using common prototype vaccine antigens. � ese preclini-cal 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). � ese trials will focus on the application of technology developed within the project that represents a paradigm-changing advance likely to im-prove medical care.

� us, the scienti� c and technical objec-tives of the project can be summarized as follows: (i) development of advanced im-munization technologies to be advanced to the clinic; (ii) assessment of host factors’impact on successful immunization through coordinated preclinical, clinical, and pop-ulation-based studies to identify optimal immunization strategies for speci� c target groups; (iii) development of concepts and tools to address regulatory and standard-ization guidance for new immunization technologies; and (iv) creation of European training curricula for translational immu-nology and vaccinology.

� rough this e� ort, ADITEC o� ers the opportunity to create synergies and promote cross fertilization among divergent research disciplines. Interdisciplinary collaborations have the potential to � ll knowledge gaps that are inhibiting the discovery of new e� ective and safe immunization technologies.

MATRIX MANAGEMENT

In order to address diverse scienti� c ques-tions and make tools available to all par-ticipants in the consortium, the ADITEC C

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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 scientifi c theme.

Technology Advanced animal models Human immunology

Adjuvants

Vectors

Routes and

devices

Prime-boost

Host factors

Systems

biology

WP1

WP2

WP3

WP4

Discovery, development,

mechanism of action

Construction and

mechanism of action

Formulation and

delivery devices

Routes of immunization

(mucosal and systemic)

WP5

WP6

Prime-boost

Efficacy and safety

WP10

WP13

Human immune response to adjuvant

Phase 1- new adjuvant

WP11 Clinical testing of novel

routes of immunization

WP10 Human immune response

to prime-boost schedule

WP14 Human genetics, gender

pathological conditions

WP13 Phase 1- new vector

WP7 Early life and aging

WP5

WP6

Prime-boost

Efficacy and safety

WP7 Early life and aging

WP5

WP6

Prime-boost

Efficacy and safety

WP7 Early life and aging

WP5 Comparative studies

WP7 Early life and aging

WP6 Efficacy and safety

WP1 WP1 Adjuvants

mechanismsof action

WP6 WP10, WP11, WP12, WP13 and WP7

Clinical studies

Efficacy and safety

WP8

WP9

Molecular signatures of immunity, immunogenicity, and safety

Systems biology applied to immunization

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“ ”project has selected a matrix management structure, a format o� en used by industry to manage large interdisciplinary projects. Under this structure, each of the scienti� c activities is integrated in a matrix of “hori-zontal” 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 sys-tem biology) and one for each of the sci-enti� c approaches (technologies, animal models, and human immunology). � is management system ensures that all activi-ties 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 ac-cess all of the tools and competencies that are available within the project. In contrast to most other organizational structures, ma-trix management functions within a dual-authority system, in which each participant reports to two independent project manag-ers. � is type of coordination helps to avoid the dri� toward individualistic or conserva-tive approaches that o� en a� ict large mul-tipartner projects. Last, the overall coordi-nation structure is supported by an internal steering committee, an external advisory board, and a project-ethics review board.

ETHICAL AND REGULATORY

CHALLENGES

As always, powerful new technologies will raise policy questions that must be ad-dressed if the new � ndings are to be use-ful to society. To avoid surprises later on, many of these questions should be tackled upfront, in close collaboration with stake-holders and regulatory agencies. Some of the key questions are the nature of in-formed consent and the ethical and regula-tory 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-speci� c B and T cells, derive monoclonal antibodies from immunoglobulin gene se-quences of study participants, and derive vaccine-speci� c T cell receptor repertoires from the gene sequence of various T cells. When thinking about patient consent, sci-entists should also anticipate new ques-

tions that will be generated by the studies. Obtaining open-ended informed consent, while maintaining the con� dentiality of the individuals in the studies, will require sophisticated technical solutions and ap-propriate communication and education strategies.

Regulatory pathways. Testing of new im-munogens, adjuvants, and immunization regimens requires the development and standardization of new regulatory path-ways. For example, the sequences of genes that encode immunogens and their expres-sion levels o� en change within pathogens isolated from di� erent patients, di� erent geographical areas, and at di� erent times. � us, 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 scienti� c community and regula-tory agencies.

Another key question is how to as-sess the e� ects of new adjuvants and im-munogens. We have very little knowledge about what clinical measures should be performed in a study to evaluate the short- and long-term e� ects of a vaccine’s various components. � e ADITEC project intends to develop signatures of both protection and safety de� ned by systems biology ap-proaches. Validation of these signatures in multiple patient cohorts—for example, of various ages and with di� erent genetic backgrounds—and acceptance of their va-lidity 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 speci� c to the imple-mentation of vaccine technologies expect-ed to have substantial public health impact. An ethics review board will also act as an independent consultant body for ethical is-sues raised by the project’s research.

ADITEC will also focus on standard-ization challenges speci� c to the imple-mentation of new technologies as applied to immunization and develop an enabling framework to support standardization by interacting with relevant actors in the � eld. For example, in partnership with WHO, ADITEC will develop systematic meth-odologies to build on existing regulatory, standardization, and assay-development expertises and provide a resource for prod-uct developers. � e 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 estab-lishment of coherent and clear advice that re� ects current regulatory thinking at early stages of product, assay, vaccine, or device development.

TRAINING FOR THE FUTURE

Also part of ADITEC’s mandate is to con-tribute to the development of the next generation of scientists in the � eld of vac-cinology. An internationally recognized multilevel training program will be devel-oped with the following aims: (i) contrib-ute to the dissemination of knowledge in the � eld 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 indus-try/SMEs, in synergy with relevant existing training schemes and support structures.

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

PART OF A LARGER GLOBAL SYSTEM

We believe that ADITEC can address im-portant scienti� c questions in modern vac-cinology and provide an infrastructure for researching fundamental aspects of vac-cination and human immunity. However, to achieve a dramatic change in the way vaccines are understood and developed will require joining forces with other simi-lar e� orts. For instance, the U.S. National Institutes of Health (NIH) has initiated a human immunology program that involves six American organizations. � ree of the partners in ADITEC are also part of the NIH network, and this cross fertilization will allow the exchange of information and identi� cation of areas of potential synergy and duplication. Similarly, the Interna-tional AIDS Vaccine Initiative (IAVI) and the Bill and Melinda Gates Foundation (BMGF) funds many studies in areas of re-search related to those that will be promot-ed within ADITEC. To evaluate possible synergies, exchange tools and knowledge, and avoid duplications, representatives of

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“ ”the BMGF were invited to the ADITEC kick-o� 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 proj-ects that go deeper or broader than what ADITEC can do alone.

� rough the ADITEC project, the Eu-ropean Commission is providing the scien-ti� c community with a remarkable oppor-tunity for uniting competencies toward a common goal: to design and develop next-generation vaccines.

SUPPLEMENTARY MATERIALShttp://stm.sciencemag.org/content/4/128/128cm4/suppl/

DC1

Tables

Table S1. Key ADITEC data

Table S2. List of ADITEC participants

Table S3. ADITEC clinical trials

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Acknowledgments: The authors acknowledge the contri-

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ADITEC Project is funded by the European Union, Seventh

Framework Programme, Grant Agreement 280873. Com-

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Citation: R. Rappuoli, D. Medaglini, ADITEC: Joining forces

for next-generation vaccines. Sci. Transl. Med. 4, 128cm4

(2012).

10.1126/scitranslmed.3003826

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DOI: 10.1126/scitranslmed.3003826, 128cm4128cm4.4Sci Transl Med

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