Vaccines have provided some of the greatest successes in the history of medicine, including the eradication of smallpox, the near eradication of polio, and the prevention of considerable morbidity and mortality from numerous infectious diseases each year. However, past strategies for vaccine development are unlikely to succeed in the future against major global diseases such as AIDS, tuberculosis, and malaria. For such diseases, the correlates of protection are poorly defined, and the pathogens evade immune detection and/or exhibit extensive genetic variability. Limitations of animal models to predict human immune responses to vaccines, coupled with low success rates for vaccine development compared with biopharmaceuticals, suggest that new paradigms must be implemented for accelerating vaccine development.

Accelerating next-generation vaccine development. Recent advances in vaccine discovery and immune monitoring will enable new human immunology–based clinical research studies to address major gaps in knowledge of vaccine-induced human immune responses and thereby accelerate development of next-generation vaccines.

Recent technological advances in molecular genetics, molecular and cellular immunology, structural biology, bioinformatics, computational biology, nanotechnology, formulation methods, and systems biology are ushering in a new era of vaccine discovery. For example, genomic-based antigen discovery is being exploited for the design of vaccines against multiple bacterial pathogens. Similarly, interrogation of the memory B cell and antibody repertoires from virus-infected subjects has led to the identification of broadly neutralizing antibodies against HIV, influenza, and other viruses, which are now being exploited as tools to design highly conserved epitope-based vaccines. Advances in adjuvant and vector delivery technologies are providing novel approaches for immune potentiation of vaccines, offering new strategies for improving vaccine response rates in neonates and the elderly. However, translation of these advances into vaccines remains impeded by major gaps in our knowledge of human immune responses, including methods to focus immune responses on subdominant protective epitopes, to elicit long-term memory responses, and to drive antibody maturation processes. These gaps can now be addressed given the technological advances described, including the development of approaches to analyze immune responses at the single-cell and systems levels.

Successful development of vaccines against the major global diseases for which vaccines do not currently exist would be transformational for public health, with huge benefits across society. To accelerate next-generation vaccine development, we propose that new human immunology–based clinical research initiatives be established, with the goal of elucidating and more effectively generating vaccine-induced protective immune responses. Collectively, such a "Human Vaccines Project" holds the potential to greatly accelerate the development of next-generation vaccines against major global killers such as AIDS, tuberculosis, malaria, and other infectious diseases; enable more successful vaccine development against allergies, autoimmune diseases, and cancers; and provide a foundation for vaccine development against new and emerging diseases.