Nonetheless, a variety of approaches to enhance subunit vaccine responses, including presentation of epitopes in multimeric format (e.g., virus-like particles, VLPs, or nanoparticles) or use of immunostimulatory adjuvants, have been utilized. Subunit vaccines that consist primarily of peptides or proteins, in contrast, can face limitations with respect to immunogenicity and thus may require multiple immunizations to achieve similar levels of immune response.

In general, inactive or attenuated pathogens can stimulate a robust immune response because they contain both B- and T-cell epitopes presented in a conformation that is relevant to the pathogen. The seasonal influenza vaccine is composed of mixtures of viral strains grown in eggs and then heat inactivated. For example, the smallpox vaccine was first derived by Edward Jenner in 1796 from a related but nonpathogenic strain that only infects cattle (cowpox). The vast majority of vaccines against infectious diseases, the largest class of vaccines, consists of inactivated or live attenuated pathogens.

In immuno-oncology, in particular, it has become clear that activation of antigen-specific T cell responses will become a critical factor for the development of successful immunotherapies against solid tumors. In the cases of both cancer and Alzheimer’s disease (on which we focus here), therapeutic promise via passive immunization provides the underlying rationale that vaccines could be developed to invoke similar protective responses but without the continual need for administration of a therapeutic agent. Nonetheless, the potential to develop vaccines against chronic diseases remains appealing. In fact, immunological dysregulation of self-responses is suspected to be causative for many autoimmune disorders such as rheumatoid arthritis, lupus, and Graves’ disease.

In contrast, vaccines targeting diseases that involve “self” antigens (e.g., cancer or neurodegenerative disease) provide an additional complication in that the immune system suppresses responses to “self” antigens. The major challenges that confront infectious disease vaccines stem from the nature of the epitopes against which the immune response is directed in some cases, immunodominant epitopes arising from natural infection may not be those that are most desirable (e.g., susceptible to neutralization and/or highly conserved). Infectious disease vaccines aim to induce a protective immune response in a naïve host by exposing the immune system to epitopes contained on the pathogen prior to exposure to the infectious agent itself. While peptide vaccines hold substantial promise in the prevention of human disease, many obstacles remain that have hampered their clinical use thus, continued research efforts to address these challenges are warranted. We examine both clinically tested vaccines as well as nascent approaches and explore current challenges and potential remedies.

We discuss factors that contribute to vaccine efficacy and how these parameters may potentially be modulated by design. In this Review, we discuss peptide-based vaccines and their potential in three therapeutic areas: infectious disease, Alzheimer’s disease, and cancer. Subunit vaccines consist of nongenetic components of the infectious agent or disease-related epitope. In addition, the development of vaccines against chronic diseases has attracted considerable interest as an approach to prevent, rather than treat, conditions such as cancer, Alzheimer’s disease, and others. Vaccines have had a profound impact on the management and prevention of infectious disease.

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