Development of safe, cost-effective vaccines is a desirable goal in practically all areas of human and animal health. In the latter field, foot-and-mouth disease (FMD) is paradigmatic of the challenge of designing strategies alternative to the conventional vaccines still used to prevent this highly transmissible, devastating livestock disease (Grubman & Baxt, 2004). Classical FMD vaccines rely on chemically inactivated FMD virus (FMDV) administered with an adjuvant and require about 7 days to induce a protective immunity that requires re-vaccination after 6-12 months to maintain its protective effect (Doel, 2005; Rodriguez & Grubman, 2009). High levels of circulating neutralizing antibodies are considered as the main correlate for FMDV protection, albeit this relationship is not absolute and differences in resistance to virus challenge can be found in animals with similar levels of neutralizing antibodies (McCullough et al., 1992). Duration of the protective immunity is essential in establishing the fitness of any FMD vaccine (Smitsaart & Bergmann, 2017), and boosting at approximately 6 monthly intervals is often required to maintain a protective response in pigs (Cox,

Foot-and-mouth disease virus (FMDV) causes a highly contagious disease of cloven-hoofed animals whose control relies on efficient vaccination. We have reported that dendrimer peptide B2T, with two copies of FMDV B-cell epitope VP1 (136–154) linked through maleimide units to T-cell epitope 3A (21–35)], elicits potent B- and T-cell specific responses and confers solid protection in pigs to type-O FMDV challenge after two doses of peptide. Herein we now show that B2T evokes specific protective immune responses after administration of a single dose of either 2 or 0.5 mg of peptide. High titers of ELISA and neutralizing antibodies against FMDV were detectable at day 15 post-immunization. Likewise, activated T cells and induced IFN-γ response to in vitro recall with FMDV peptides were also detected by the same day. Further, in 70% of B2T-vaccinated pigs, full protection—no clinical signs of disease—was observed upon virus challenge at day 25 post-immunization. These results strengthen the potential of B2T as a safe, cost-effective candidate vaccine conferring adequate protection against FMDV with a single dose. The finding is particularly relevant to emergency scenarios permitting only a single shot immunization.

Vaccines are considered one of the greatest global health achievements, improving the welfare of society by saving lives and substantially reducing the burden of infectious diseases. However, few vaccines are fully effective, for reasons ranging from intrinsic limitations to more contingent shortcomings related, e.g., to cold chain transport, handling and storage. In this context, subunit vaccines where the essential antigenic traits (but not the entire pathogen) are presented in rationally designed fashion have emerged as an attractive alternative to conventional ones. In particular, this includes the option of fully synthetic peptide vaccines able to mimic well-defined B- and T-cell epitopes from the infectious agent and to induce protection against it. Although, in general, linear peptides have been associated to low immunogenicity and partial protection, there are several strategies to address such issues. In this review, we report the progress towards the development of peptide-based vaccines against foot-and-mouth disease (FMD) a highly transmissible, economically devastating animal disease. Starting from preliminary experiments using single linear B-cell epitopes, recent research has led to more complex and successful second-generation vaccines featuring peptide dendrimers containing multiple copies of B- and T-cell epitopes against FMD virus or classical swine fever virus (CSFV). The usefulness of this strategy to prevent other animal and human diseases is discussed.

Multimeric antigen display and high overall valency are increasingly regarded as strategic goals for potent and broadly efficacious synthetic vaccines with potential market prospects. Herein, a modular and versatile approach to multifunctional peptide-based vaccine platforms at multimilligram scale in reasonable yields is reported. Preparation of chemoselectively modified peptide building blocks of medium-to-large size, conjugation of these subunits, and final assembly were achieved by a combination of Michael-type thiol–ene addition and copper­(I)-mediated alkyne–azide cycloaddition. The size and structural complexity of the building blocks required exploration of a further level of orthogonality, namely furan/maleimide Diels–Alder chemistry. After process optimization, a finely tuned, stepwise click approach has emerged as a workable, on-demand strategy to create macromolecular therapeutic vaccine assemblies.

Synthetic dendrimer peptides are a promising strategy to develop new FMD vaccines. A dendrimer peptide, termed B 2 T-3A, which harbors two copies of the major FMDV antigenic B-cell site [VP1 (140-158)], covalently linked to a heterotypic T-cell from the non-structural protein 3A [3A (21-35)], has been shown to protect pigs against viral challenge. Interestingly, the modular design of this dendrimer peptide allows modifications aimed at improving its immunogenicity, such as the replacement of the T-cell epitope moiety. Here, we report that a dendrimer peptide, B 2 T-3D, harboring a T-cell epitope from FMDV 3D protein [3D (56-70)], when inoculated in pigs, elicited consistent levels of neutralizing antibodies and high frequencies of IFN-γ-producing cells upon in vitro recall with the homologous dendrimers, both responses being similar to those evoked by B 2 T-3A. Lymphocytes from B 2 T-3A-immunized pigs were in vitro-stimulated by T-3A peptide and to a lesser extent by B-peptide, while those from B 2 T-3D-immunized animals preferentially recognized the T-3D peptide, suggesting that this epitope is a potent inducer of IFN-γ producing-cells. These results extend the repertoire of T-cell epitopes efficiently recognized by swine lymphocytes and open the possibility of using T-3D to enhance the immunogenicity and the protection conferred by B 2 T-dendrimers.