The key starting point for design of peptide vaccines is the choice of epitopes that stimulate humoral and/or T cell immunity. There are several ways of identifying the epitopes.

In addition to epitopes capable of stimulating B cells, CD4⁺ and CD8⁺ T cells, peptide vaccines need strong adjuvants to stimulate innate immunity. Rossi et al. describe results with vaccines based on cell penetrating peptide carrying HPV or ovalbumin (OVA) T cell epitopes combined with stimulator of interferon gamma gene agonist (STINGa) as an adjuvant to elicit a potent innate inflammatory response. This strategy stimulated both CD8⁺ and Th1 CD4⁺ T cell responses while inhibiting Treg response. The vaccine was effective in prolonging survival in TC-1 tumour inoculated mice.

Calzas et al. describe a vaccine formulation containing weak but conserved antigens from influenza virus combined with a nanoring comprising elements from respiratory syncytial virus. This ‘nanoring’ stimulates innate immunity - possibly through TLR5. The vaccine is given via the mucosal route and induced strong humoral and cellular immune responses. The vaccine protected mice (but not chickens) from viral challenge.

Three of the above articles involved clinical studies. Two of these addressed HPV infection and both show the importance of T cell immunity in recovery and viral clearance. Shibata et al. describe one case in detail emerging from the Phase I clinical trial of their peptide vaccine (PepCan). The patient, who had a high-grade cervical squamous intraepithelial lesion, received four doses of the peptide vaccine at 4-weeks’ interval. While Treg and Th2 cytokine levels remained unchanged, Th1 cytokine levels were enhanced significantly. At twelve weeks (end of the follow-up), the intraepithelial lesion had completely disappeared, potentially due to this enhanced T cell response. Moreover, using single cell sequencing, the authors showed specific CD3⁺ T cell clonal expansion both systemically and at the lesion site.

In the second HPV-related clinical cohort study, Zhang et al. followed up 131 HPV16-infected patients for 12 months and found that HPV specific T cell immunity is important for the viral clearance.

In the final clinical trial report, Chen et al. investigated the safety and immunogenicity of a neoantigen-based vaccine in seven pancreatic cancer patients. The authors showed that the vaccine was safe and induced both CD4⁺ and CD8⁺ T cell responses. One patient exhibiting significant expansion of a reactive T cell clone survived for 21 months, considerably in excess of the expected 6-month average for patients with this stage of disease.

Vaccines against infectious disease have to date proved much more successful than vaccines against cancer, essentially because pathogens are non-self and present a much larger immunological target which stimulate strong innate, humoral and cellular immunity. Nonetheless, significant progress has been made in the identification of antigens other than foreign pathogens, e.g., neoantigens and tumour associated antigens (TAA) that can be exploited by vaccine technology, particularly using peptide vaccines. These advances, together with recent developments in the clinical application of IO agents, offer the prospect of personalised combination therapies that could be transformative in the treatment of many cancers.

Note that the research articles collected in this Research Topic are heavily focused on the design of peptide vaccines. For a border perspective on peptide vaccines especially cancer peptide vaccines, see the review article by Stephens et al.

SJ, MG and XNX drafted this article. All authors contributed to the article and approved the submitted version.

SJ is funded by Innovate UK, grant number 104992 & 133783, and by grants from the CBI and Oxford Vacmedix UK Ltd. MG is supported by Chinese National Natural Science Funding program (81771221, 81870967 and 82071384). The funders were not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.

SJ and XNX are founder or consultant of Oxford Vacmedix UK Ltd which develops peptide-based vaccines.

The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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