Vaccines have had a profound impact on the management and prevention of infectious disease. 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. Subunit vaccines consist of nongenetic components of the infectious agent or disease-related epitope. In this Review, we discuss peptide-based vaccines and their potential in three therapeutic areas: infectious disease, Alzheimer’s disease, and cancer. We discuss factors that contribute to vaccine efficacy and how these parameters may potentially be modulated by design. We examine both clinically tested vaccines as well as nascent approaches and explore current challenges and potential remedies. 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.

Treating Ebola with a Trojan horse: The recent major Ebola virus outbreak in West Africa high-lighted the need for effective therapeutics against this and other filoviruses. Neutralizing ebolaviruses with antibodies is a challenge because the viruses bind their entry receptor, NPC1, inside the cell within endosomes rather than on the cell surface. Furthermore, enzymes in endosomes cleave the Ebola virus surface glycoprotein (GP) to reveal its receptor binding site. Wec et al. now report a bispecific antibody strategy targeting all known ebolaviruses that overcomes this problem (see the Perspective by Labrijn and Parren). They coupled an antibody specific for a conserved, surface-exposed epitope of GP to antibodies that recognize either NPC1 or the NPC1 binding site on GP. Treating mice therapeutically with these antibodies allowed them to survive otherwise lethal ebolavirus infection. Science , this issue p. 350 ; see also p. 284

Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes persistent arthritis in a subset of human patients. We report the isolation and functional characterization of monoclonal antibodies (mAbs) from two patients infected with CHIKV in the Dominican Republic. Single B cell sorting yielded a panel of 46 human mAbs of diverse germline lineages that targeted epitopes within the E1 or E2 glycoproteins. MAbs that recognized either E1 or E2 proteins exhibited neutralizing activity. Viral escape mutations localized the binding epitopes for two E1 mAbs to sites within domain I or the linker between domains I and III; and for two E2 mAbs between the β-connector region and the B-domain. Two of the E2-specific mAbs conferred protection in vivo in a stringent lethal challenge mouse model of CHIKV infection, whereas the E1 mAbs did not. These results provide insight into human antibody response to CHIKV and identify candidate mAbs for therapeutic intervention. Chikungunya virus (CHIKV) is a globally emerging virus that can cause significant disease, including a prolonged and painful arthritis. The virus is spread by mosquitoes that circulate in many regions of the world including the United States. Currently, there are no available vaccines or therapies to treat CHIKV infection. In this report, we identified and characterized a large panel of antibodies against CHIKV from two donors that contracted the viral infection in the Dominican Republic. These antibodies target a number of different regions of the membrane proteins that coat the surface of the virus, and many can inhibit the ability of CHIKV to infect cells. Two of the antibodies were shown to protect mice from a lethal dose of CHIKV. These antibodies have therapeutic potential, and provide insight into the human immune response that may facilitate vaccine development.

Ebola virus (EboV) and Marburg virus (MarV) (filoviruses) are the causative agents of severe hemorrhagic fever. Infection begins with uptake of particles into cellular endosomes, where the viral envelope glycoprotein (GP) catalyzes fusion between the viral and host cell membranes. This fusion event is thought to involve conformational rearrangements of the transmembrane subunit (GP2) of the envelope spike that ultimately result in formation of a six-helix bundle by the N- and C-terminal heptad repeat (NHR and CHR, respectively) regions of GP2. Infection by other viruses employing similar viral entry mechanisms (such as HIV-1 and severe acute respiratory syndrome coronavirus) can be inhibited with synthetic peptides corresponding to the native CHR sequence ("C-peptides"). However, previously reported EboV C-peptides have shown weak or insignificant antiviral activity. To determine whether the activity of a C-peptide could be improved by increasing its intracellular concentration, we prepared an EboV C-peptide conjugated to the arginine-rich sequence from HIV-1 Tat, which is known to accumulate in endosomes. We found that this peptide specifically inhibited viral entry mediated by filovirus GP proteins and infection by authentic filoviruses. We determined that antiviral activity was dependent on both the Tat sequence and the native EboV CHR sequence. Mechanistic studies suggested that the peptide acts by blocking a membrane fusion intermediate.