Pentamers Not Found in the Universal Proteome Can Enhance Antigen Specific Immune Responses and Adjuvant Vaccines

Abstract

Certain short peptides do not occur in humans and are rare or non-existent in the universal proteome. Antigens that contain rare amino acid sequences are in general highly immunogenic and may activate different arms of the immune system. We first generated a list of rare, semi-common, and common 5-mer peptides using bioinformatics tools to analyze the UniProtKB database. Experimental observations indicated that rare and semi-common 5-mers generated stronger cellular responses in comparison with common-occurring sequences. We hypothesized that the biological process responsible for this enhanced immunogenicity could be used to positively modulate immune responses with potential application for vaccine development. Initially, twelve rare 5-mers, 9-mers, and 13-mers were incorporated in frame at the end of an H5N1 hemagglutinin (HA) antigen and expressed from a DNA vaccine. The presence of some 5-mer peptides induced improved immune responses. Adding one 5-mer peptide exogenously also offered improved clinical outcome and/or survival against a lethal H5N1 or H1N1 influenza virus challenge in BALB/c mice and ferrets, respectively. Interestingly, enhanced anti-HBsAg antibody production by up to 25-fold in combination with a commercial Hepatitis B vaccine (Engerix-B, GSK) was also observed in BALB/c mice. Mechanistically, NK cell activation and dependency was observed with enhancing peptides ex vivo and in NK-depleted mice. Overall, the data suggest that rare or non-existent oligopeptides can be developed as immunomodulators and supports the further evaluation of some 5-mer peptides as potential vaccine adjuvants.

Epitopes for a 2019-nCoV vaccine

“…We followed the rationale that non-self sequences are highly immunogenic and uniquely viral epitopes should improve safety and efficacy by minimizing the risk for cross-reactions and increasing anti-viral specificity. [4][5][6] The analysis was conducted on the entire viral proteome but primarily focused on the surface spike glycoprotein (id = "QHD43416.1) because immune response against it is highly likely to exert a neutralizing effect. 2 The entire amino acid (aa) sequence of the 2019-nCoV was retrieved from https://www.ncbi.nlm.nih.gov/nuccore/MN908947 and dissected into pentapeptides overlapped by four residues for a total of n = 9661.…”

“…First, short peptides that are foreign to the host immune system have been experimentally validated not only as positive immunomodulants (i.e., adjuvants) in conjunction to vaccines, but are also evidenced as providing direct protection against lethal viral infections, at least in animal models. 6 Second, searching for the 107 human-foreign spike protein pentapeptides in the Immune Epitope Database (IEDB; www.iedb. org) 8 yielded a list of n = 66 epitopes (Table 1, Panel b).…”

Activity of the HMGB1-derived immunostimulatory peptide Hp91 resides in the helical C-terminal portion and is enhanced by dimerization

“…It still remains to be determined how dimerization affects UC1018 peptide as adjuvant, and covalently coupled antigen-UC1018 peptide would be another vaccine approach. Anotehr possibility to improve upon its potency would be the addition of non-HMGB1-derived antigenic amino acids (37) in an attempt to further increase adjuvanticity potential.…”

Absent from DNA and protein: genomic characterization of nullomers and nullpeptides across functional categories and evolution

“…Previous work carried out in 2009 identified 417 five amino acid primes that are not present in the universal proteome (over 6 million proteins analyzed at that time) 6 . Functional characterization of a 5-mer peptide (KWCEC) that is extremely rare within the universal proteome and absent from the human proteome, showed that it could potentially enhance immunogenicity when administered alongside an antigen 7 .…”