Anthony S. Fauci, MD Director, National Institute of Allergy and Infectious Diseases National Institutes of Health U.S. Department of Health and Human Services A key challenge for vaccinologists is developing vaccines against microbes for which the immune response to natural infection does not adequately control or eliminate the pathogen in question. For many pathogens for which effective vaccines have been developed—including smallpox, measles, and polio—the human immune system can generate a response that clears the infection and confers life-long protection against re-infection. This natural proof-of-concept has led to a fundamental tenet of vaccinology: To develop an effective vaccine, one should mimic natural infection, without causing disease. However, when natural immunity does not adequately protect against a pathogen, vaccines must be designed to induce “unnatural immunity”—that is, an effective immune response that natural infection either does not elicit, or does so poorly. Two well-recognized examples of infections for which natural immunity falls short are HIV and influenza. HIV-infected individuals make some broadly neutralizing antibodies, but they do so weakly and late in the course of infection. It is believed that components of the HIV envelope that must be targeted for viral neutralization are not presented to the immune system during natural infection in a manner that rapidly induces a protective response. The challenge for vaccinologists is to present those components of the viral envelope to the immune system in a form that is recognizable and that will elicit a robust response, much better than the response to natural infection. Similarly, with influenza, despite repeated exposures over one’s lifetime to both influenza infections and vaccines, most people are not protected against all emerging influenza strains. Current vaccines target components on the head of the influenza hemagglutinin spike protein that are readily accessible to the immune system but that constantly evolve and escape from previously induced immune responses. Recently, scientists have identified conserved components on the stem of the hemagglutinin spike that are capable of inducing broadly protective responses, but are shielded from the immune system during natural infection and in response to classic influenza vaccines by other confounding molecules. The challenge now is to present this conserved stem region of the hemagglutinin to the immune system in a way that is structurally unencumbered and that will induce a broadly protective immune response, here again, a response that is even better than the response to natural infection. Thus, with the scientific tools available today, we now can develop vaccines that improve on natural immunity, bringing vaccinology squarely into the 21st century.