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.
Yes. Um. Well. I have just heard a lecture by the redoubtable Marc van Regenmortel (disclosure: my former mentor) pointing out how this strategy is highly UNLIKELY to be "the" way of generating antigens that are likely to be good immunogens – and I was convinced.
Um, he said. And…the MHvR arguments still stand, I think: why should something that supposedly looks like the thing that supposedly elicited a strongly neutralising antibody, elicit a strongly neutralising antibody?
OK, it apparently did here – but as a general rule? Do we KNOW what "good" neutralising epitopes look like in 3D? Because linear epitopes are really just an approximation to what real epitopes are, and epitopes are in fact just those things that BIND antibodies – NOT necessarily what ELICITS them.
Damn, I’m sounding like Marc – must be catching!
But seriously: antibodies are the membrane receptors of B cells; they are generated by random recombinations, and then selected by adventitiously binding another molecule that is not self; they are then further selected by repeated rounds of binding, while undergoing random mutations affecting their hypervariable regions, while weak binders are selected AGAINST by Tregs.
And end up both with higher affinity, and more broad binding to related "epitopes" as a result.
Incredibly hard to duplicate as general phenomenon, I would surmise.
See on www.nature.com