Peptide-based vaccines, although promising, have several drawbacks. First, a particular peptide may not bind to all the MHC molecules present in the population. Because humans are highly polymorphic in the MHC, a large panel of protective peptides would be needed for coverage of most individuals. Second, some direct exchange of short peptides on MHC molecules can occur without physiological antigen processing. If the required antigenic peptides load directly onto MHC molecules on cells other than dendritic cells, this may induce tolerance in T cells rather than stimulating immunity. Third, exogenous proteins and peptides delivered by a synthetic vaccine are efficiently processed for presentation by MHC class II molecules, but require ‘cross-presentation’ in specific types of dendritic cells to be loaded onto MHC class I molecules (see Section 6-5). Directing peptide-based vaccines to such cells may enhance vaccine efficacy.
Recent peptide-based vaccines have already shown promise in human clinical trials. Patients with established vulvar intraepithelial neoplasia, an early form of vulvar cancer caused by human papilloma virus (HPV), were treated with a vaccine consisting of long peptides covering the entire length of two oncoproteins of HPV-16—E6 and E7—and delivered in an oil-in-water emulsion as adjuvant. By using very long peptides, around 100 amino acids in length, multiple candidate peptide epitopes can be delivered that may also be presented by different MHC alleles. These peptides seem to be too long for direct exchange with peptides on cell surfaces and require processing by dendritic cells in order to be loaded onto MHC class I molecules. This vaccine induced complete clinical remission in one-quarter of the patients, and about half of the treated patients showed significant clinical responses that correlated with in vitro evidence of enhanced cell-mediated immunity.
16-29 Adjuvants are important for enhancing the immunogenicity of vaccines, but few are approved for use in humans.
Vaccines based on peptides or purified proteins require additional components to mimic how real infections activate immunity. Such components of a vaccine are known as adjuvants, which are defined as substances that enhance the immunogenicity of antigens (see Appendix I, Section A-41). For example, tetanus toxoid is not immunogenic in the absence of adjuvants, and so tetanus toxoid vaccines contain inorganic aluminum salts (alum) in the form of noncrystalline gels that bind polyvalently to the toxoid by ionic interactions. Pertussis toxin has adjuvant properties in its own right and, when given mixed as a toxoid with tetanus and diphtheria toxoids, not only protects against whooping cough but also acts as an additional adjuvant for the other two toxoids. This mixture makes up the DTP triple vaccine given to infants in the first year of life.
The antigenic components and adjuvants in a vaccine are not approved for use on their own; they are approved only in the context of the specific vaccine in which they are formulated. At present, alum is the only adjuvant that is approved by the FDA in the United States for use in marketed human vaccines, although some other adjuvant–vaccine combinations are undergoing clinical trials. Alum is the common name for certain inorganic aluminum salts, of which aluminum hydroxide and aluminum phosphate are most frequently used as adjuvants. In Europe, in addition to the alum adjuvants, an oil (squalene)-in-water emulsion called MF-59 is used as an adjuvant in a formulation of influenza vaccine and is undergoing evaluation in clinical trials. As we described in Section 3-9, alum seems to act as an adjuvant by stimulating one of the innate immune system’s bacterial sensor mechanisms, NLRP3, thus activating the inflammasome and the inflammatory reactions that are a prerequisite for an effective adaptive immune response.