Medicinal Chemistry and Methodological Advances in the Development of Peptide-Based Vaccines

Sabatino, David A.

doi:10.1021/acs.jmedchem.0c00848

Cited by 20 publications

(14 citation statements)

References 104 publications

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“…Peptide-based vaccines have several advantages over the recombinant protein-based vaccines, such as ease of manufacture, ease of characterization and ease of incorporation into a multivalent vaccine. More than 600 clinical trials with peptide antigens have been performed as of 2020 24 . On the other hand, disadvantages of peptide-based vaccines include that they provide a limited number of epitopes, they have difficulty to faithfully represent three-dimensional protein antigen structures, and they tend to have low immunogenicity.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, disadvantages of peptide-based vaccines include that they provide a limited number of epitopes, they have difficulty to faithfully represent three-dimensional protein antigen structures, and they tend to have low immunogenicity. 24 Two other notable studies have suggested that peptide-based P. falciparum TBVs may be able to induce functional antibodies in rodents, one being a PfHAP2 peptide (18 aa) 25 and the other being a Pfs47 peptide (58 aa) 26 . To be confident of our own initial results (Fig.…”

Section: Discussionmentioning

confidence: 99%

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Elucidating functional epitopes within the N-terminal region of malaria transmission blocking vaccine antigen Pfs230

et al. 2022

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Pfs230 is a leading malaria transmission blocking vaccine (TBV) candidate. Comprising 3135 amino acids (aa), the large size of Pfs230 necessitates the use of sub-fragments as vaccine immunogens. Therefore, determination of which regions induce functional antibody responses is essential. We previously reported that of 27 sub-fragments spanning the entire molecule, only five induced functional antibodies. A “functional” antibody is defined herein as one that inhibits Plasmodium falciparum parasite development in mosquitoes in a standard membrane-feeding assay (SMFA). These five sub-fragments were found within the aa 443–1274 range, and all contained aa 543–730. Here, we further pinpoint the location of epitopes within Pfs230 that are recognized by functional antibodies using antibody depletion and enrichment techniques. Functional epitopes were not found within the aa 918–1274 region. Within aa 443–917, further analysis showed the existence of functional epitopes not only within the aa 543–730 region but also outside of it. Affinity-purified antibodies using a synthetic peptide matching aa 543–588 showed activity in the SMFA. Immunization with a synthetic peptide comprising this segment, formulated either as a carrier-protein conjugate vaccine or with a liposomal vaccine adjuvant system, induced antibodies in mice that were functional in the SMFA. These findings provide key insights for Pfs230-based vaccine design and establish the feasibility for the use of synthetic peptide antigens for a malaria TBV.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Elucidating functional epitopes within the N-terminal region of malaria transmission blocking vaccine antigen Pfs230

et al. 2022

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“…Peptide-based vaccines are attractive and timely alternatives to traditional vaccines [ 169 ]. Strategies to improve their low immunogenicity have given rise to plausible candidates against human infectious diseases and cancer, some of them at advanced stages of clinical trials [ 170 , 171 ]. Veterinary medicine must obviously join the trend of novel safer, versatile vaccines to overcome the shortcomings of conventional ones.…”

Section: Discussionmentioning

confidence: 99%

Peptide-Based Vaccines: Foot-and-Mouth Disease Virus, a Paradigm in Animal Health

et al. 2021

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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.

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“…The high customisability of peptides, coupled with detailed structural analyses of epitope-antibody interactions, means that peptides can be constrained into their antibody-bound conformation. Furthermore, the presentation of a relatively small immunogenic portion of a protein reduces the likelihood of introducing potentially distracting epitopes, and so decreases undesired antigenic load [ 53 ].…”

Section: Discussionmentioning

confidence: 99%

Guiding the Immune Response to a Conserved Epitope in MSP2, an Intrinsically Disordered Malaria Vaccine Candidate

et al. 2021

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The malaria vaccine candidate merozoite surface protein 2 (MSP2) has shown promise in clinical trials and is in part responsible for a reduction in parasite densities. However, strain-specific reductions in parasitaemia suggested that polymorphic regions of MSP2 are immuno-dominant. One strategy to bypass the hurdle of strain-specificity is to bias the immune response towards the conserved regions. Two mouse monoclonal antibodies, 4D11 and 9H4, recognise the conserved C-terminal region of MSP2. Although they bind overlapping epitopes, 4D11 reacts more strongly with native MSP2, suggesting that its epitope is more accessible on the parasite surface. In this study, a structure-based vaccine design approach was applied to the intrinsically disordered antigen, MSP2, using a crystal structure of 4D11 Fv in complex with its minimal binding epitope. Molecular dynamics simulations and surface plasmon resonance informed the design of a series of constrained peptides that mimicked the 4D11-bound epitope structure. These peptides were conjugated to keyhole limpet hemocyanin and used to immunise mice, with high to moderate antibody titres being generated in all groups. The specificities of antibody responses revealed that a single point mutation can focus the antibody response towards a more favourable epitope. This structure-based approach to peptide vaccine design may be useful not only for MSP2-based malaria vaccines, but also for other intrinsically disordered antigens.

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Medicinal Chemistry and Methodological Advances in the Development of Peptide-Based Vaccines

Cited by 20 publications

References 104 publications

Elucidating functional epitopes within the N-terminal region of malaria transmission blocking vaccine antigen Pfs230

Elucidating functional epitopes within the N-terminal region of malaria transmission blocking vaccine antigen Pfs230

Peptide-Based Vaccines: Foot-and-Mouth Disease Virus, a Paradigm in Animal Health

Guiding the Immune Response to a Conserved Epitope in MSP2, an Intrinsically Disordered Malaria Vaccine Candidate

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