Identification of New Features from Known Bacterial Protective Vaccine Antigens Enhances Rational Vaccine Design

Abstract

With many protective vaccine antigens reported in the literature and verified experimentally, how to use the knowledge mined from these antigens to support rational vaccine design and study underlying design mechanism remains unclear. In order to address the problem, a systematic bioinformatics analysis was performed on 291 Gram-positive and Gram-negative bacterial protective antigens with experimental evidence manually curated in the Protegen database. The bioinformatics analyses evaluated included subcellular localization, adhesin probability, peptide signaling, transmembrane α-helix and β-barrel, conserved domain, Clusters of Orthologous Groups, and Gene Ontology functional annotations. Here we showed the critical role of adhesins, along with subcellular localization, peptide signaling, in predicting secreted extracellular or surface-exposed protective antigens, with mechanistic explanations supported by functional analysis. We also found a significant negative correlation of transmembrane α-helix to antigen protectiveness in Gram-positive and Gram-negative pathogens, while a positive correlation of transmembrane β-barrel was observed in Gram-negative pathogens. The commonly less-focused cytoplasmic and cytoplasmic membrane proteins could be potentially predicted with the help of other selection criteria such as adhesin probability and functional analysis. The significant findings in this study can support rational vaccine design and enhance our understanding of vaccine design mechanisms.

COVID-19 Coronavirus Vaccine Design Using Reverse Vaccinology and Machine Learning

“…The Vaxign RV analysis predicted six SARS-CoV-2 proteins (S protein, nsp3, 3CL-PRO, and nsp8-10) as adhesive proteins ( Table 3 ). Adhesin plays a critical role in the virus adhering to the host cell and facilitating the virus entry to the host cell ( 38 ), which has a significant association with the vaccine-induced protection ( 39 ). In SARS-CoV-2, S protein was predicted to be adhesin, matching its primary role in virus entry.…”

Cwp22, a novel peptidoglycan cross‐linking enzyme, plays pleiotropic roles in Clostridioides difficile

“…Although the exact role of each CWP in pathogenesis remains to be further elucidated, antibodies to many CWPs have been found in serum samples from CDI patients, and investigational vaccines targeting Cwp84 Sandolo et al, 2011) have been developed, indicating that certain CWPs are surface exposed in vivo and could be developed into vaccines (Pechine et al, 2005;Wright et al, 2008;Biazzo et al, 2013). CWPs and adhesins are favourable protective antigens for vaccine development against infection with Gram-positive bacterial pathogens (He et al, 2014;Ong et al, 2017). A recent study of manually annotated protective vaccine antigens from over 10 Gram-positive bacteria found 56.8% of these protective antigens are adhesins or adhesin-like proteins.…”

“…A recent study of manually annotated protective vaccine antigens from over 10 Gram-positive bacteria found 56.8% of these protective antigens are adhesins or adhesin-like proteins. In addition, 19.8% of the protective antigens in Gram-positive bacteria were found to be located in the cell wall, and 87.5% of these protective cell wall antigens are also adhesins (Ong et al, 2017). Cwp22, like the other CWPs Cwp2, Cwp6, CwpV, Cwp22, Cwp19 and Cwp84, is also an abundant and conserved protein in C. difficile through gel free analysis of the extracts (Ferreira et al, 2017), suggesting that it is required for some cellular processes.…”

Emerging Concepts and Technologies in Vaccine Development

“…A computationally designed antigen found to be protective in animal models was first reported for the respiratory syncytial virus (RSV) F antigen in 2013 ( 79 ). Many challenging vaccine targets have since been developed rationally for HIV ( 80 – 82 ), hepatitis C ( 83 , 84 ), herpes ( 85 ), Zika ( 86 , 87 ), RSV ( 82 ), HPV ( 88 ), as well as for bacteria ( 82 , 89 ), fungi ( 90 ), and cancers ( 91 ). Rational vaccine design has also been utilized to improve VLP and NP vaccines by selecting a repetitive and predictive protein backbone structure for enhanced antigen presentation ( 92 ).…”