Editors' ChoiceVaccines

Intelligent Vaccine Design: Evolution of a Principle

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Science Translational Medicine  26 Mar 2014:
Vol. 6, Issue 229, pp. 229ec55
DOI: 10.1126/scitranslmed.3009019

Vaccination is the most effective way to protect a host from infectious diseases. However, traditional vaccine development, which involves immunization with natural pathogens or pathogen products, is not effective against many human pathogens, including respiratory syncytial virus (RSV). Indeed, attempts to immunize infants with formalin-inactivated RSV particles did not provide protection but rather led to the exacerbation of disease after subsequent RSV exposure. As a result, no safe vaccine exists for this important pathogen that can cause severe disease in infants and the elderly.

Correia et al. have reported a major breakthrough toward the development of a safe RSV vaccine. The authors used state-of-the-art computational and structural biology approaches to develop artificial protein scaffolds that faithfully mimic a structural epitope in the RSV fusion (F) protein, a target of a clinically used prophylactic RSV antibody. These protein scaffolds were first designed through computational approaches to mimic the folding of the protein backbone around the structural epitope of RSV F. The authors then expressed the artificial protein scaffolds in Escherichia coli and immunized macaques. They observed that a number of protein scaffolds induced antibodies that can recognize the natural RSV F protein and the whole virus. Remarkably, the majority of the immunized macaques mounted neutralizing antibody responses, which were comparable with those that follow natural infection in patients. Neutralizing antibodies produced in macaques targeted the RSV F epitope, but their fine specificities differed from those of the known prophylactic antibody.

Although these epitope-focused immunogens have a long way to go before they can be used as vaccines for human patients, the new data provide a proof of principle that in silico–generated artificial protein scaffolds with a neutralization epitope can induce neutralizing antibody responses against RSV. Because these protein scaffolds share only the structural epitope with RSV particles, immunization with them is unlikely to produce the vaccine-enhanced disease observed with the administration of formalin-inactivated RSV in the 1960s. In addition, artificial protein scaffolds focusing on conserved epitopes might be more potent than natural antigens for eliciting broadly neutralizing antibodies reactive to multiple virus strains, because antibody responses during immunization with natural antigens are often dominated by strain-specific antibodies. Thus, these scaffold immunogens may represent promising, and safe, RSV vaccine candidates. Furthermore, the approach may be applied to improve vaccine designs for antigenically variable viruses such as HIV and influenza.

B. E. Correia et al., Proof of principle for epitope-focused vaccine design. Nature. 507, 201–206 (2014). [Abstract]

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