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Vaccines prevent infectious disease largely by inducing protective neutralizing antibodies against vulnerable epitopes. Several major pathogens have resisted traditional vaccine development, although vulnerable epitopes targeted by neutralizing antibodies have been identified for several such cases. Hence, new vaccine design methods to induce epitope-specific neutralizing antibodies are needed. Here we show, with a neutralization epitope from respiratory syncytial virus, that computational protein design can generate small, thermally and conformationally stable protein scaffolds that accurately mimic the viral epitope structure and induce potent neutralizing antibodies. These scaffolds represent promising leads for the research and development of a human respiratory syncytial virus vaccine needed to protect infants, young children and the elderly. More generally, the results provide proof of principle for epitope-focused and scaffold-based vaccine design, and encourage the evaluation and further development of these strategies for a variety of other vaccine targets, including antigenically highly variable pathogens such as human immunodeficiency virus and influenza.
Vaccination is a proven, safe and cost-effective way to protect against infectious disease1,2, but potentially vaccine-preventable illnesses continue to place a heavy burden on the human population. Data from recent epidemiological studies indicate that in 2010, infectious diseases caused 18.5% of all human deaths and 23% of disability-adjusted life years3,4. This burden could be reduced by broader deployment and use of existing vaccines or by other prevention modalities or treatment regimens. However, for maximal, affordable and sustainable gains in global health, new or improved vaccines are needed for several major pathogens including human immunodeficiency virus (HIV)-1 (ref. 5), malaria6, Mycobacterium tuberculosis7, influenza virus8, dengue virus9 and respiratory syncytial virus (RSV)10. One likely impediment to vaccine development in these cases is the limited set of antigen design or presentation methods available to vaccine engineers. For example, current licensed vaccines in the United States11 derive from strategies that have been available formanyyears: viral vaccines are composed of recombinant virus-like particles or live, live-attenuated or whole inactivated viruses or subunit vaccines, and bacterial vaccines are composed of bacterial surface proteins, detoxified toxins or polysaccharides with or without conjugation to a carrier protein.
Epitope-focused vaccine design is a conceptually appealing but unproven method in which immunogens are designed to elicit protective antibody responses against structural epitopes that are defined by protective antibodies isolated frominfectedpatients or animalmodels12....