Immunopeptidomics for next-generation bacterial vaccine development

Abstract

Antimicrobial resistance is an increasing global threat and alternative treatments substituting failing antibiotics are urgently needed. Vaccines are recognized as highly effective tools to mitigate antimicrobial resistance; however, the selection of bacterial antigens as vaccine candidates remains challenging. In recent years, advances in mass spectrometry-based proteomics have led to the development of so-called immunopeptidomics approaches that allow the untargeted discovery of bacterial epitopes that are presented on the surface of infected cells. Especially for intracellular bacterial pathogens, immunopeptidomics holds great promise to uncover antigens that can be encoded in viral vector-or nucleic acid-based vaccines. This review provides an overview of immunopeptidomics studies on intracellular bacterial pathogens and considers future directions and challenges in advancing towards next-generation vaccines. A need for next-generation antibacterial vaccinesWith the advent of antibiotics in the first half of the 20th century, many bacterial diseases lost their devastating dominance over humankind. Commonplace outbreaks of the plague, cholera, and many other bacterial diseases claimed a death toll in the hundreds of millions. A combination of improved sanitary standards, elevated living conditions, and the availability of antibiotics massively reduced these outbreaks; however, (over)use of antibiotics has accelerated the emergence of antimicrobial resistance (AMR). Annual AMR-related deaths are predicted to skyrocket from 700 000 in 2019 to 10 million globally in 2050 [1]. Hence, the World Health Organization (WHO) and the US Centers for Disease Control and Prevention (CDC) have identified pathogenic bacteria for which the AMR situation is particularly dire, including several intracellular pathogens such as Salmonella, Shigella spp. and Mycobacterium tuberculosis (Mtb) [2,3]. In addition to stringent antibiotic stewardship and fast development of novel antibacterial drugs by initiatives like the AMR Action Fund [4], vaccines are regarded as highly effective tools to mitigate resistance (recently reviewed in [5]). The prophylactic use of bacterial vaccines prevents infections, thereby reducing the need for antibiotic prescription and minimizing selective drug pressure [5]. In contrast to antibiotics, antibacterial vaccines remain effective against their target pathogen over time. Furthermore, high vaccination rates create a herd immunity that protects susceptible individuals who cannot be effectively vaccinated, like the elderly, immunosuppressed, or chronically sick people [5].Several antibacterial vaccines have been utilized successfully in the past and are routinely used nowadays, typically providing a high degree of immunity and safety. These include vaccines against tetanus, diphtheria, and pertussis, against Haemophilus influenzae type B (Hib), pneumococcus, as well as meningococcus [6,7]. There are also vaccines against typhoid fever, anthrax, and cholera that are administered in, and for those traveling...

Accurate MHC Motif Deconvolution of Immunopeptidomics Data Reveals a Significant Contribution of DRB3, 4 and 5 to the Total DR Immunopeptidome

“…Mass spectrometry (MS) based immunopeptidomics is becoming increasingly relevant for several biomedical applications including cancer neoantigen discovery, vaccine development and protein drug deimmunization pipelines (1)(2)(3)(4). The broad interest in MHC-derived MS relies on its ability to discover MHC presented peptides in real scenarios, such as biomarker discovery in cancer, autoimmune and infectious disease, and therefore identifying peptides that might induce T cell responses.…”

MS2Rescore: Data-Driven Rescoring Dramatically Boosts Immunopeptide Identification Rates

“…These epitopes are presented on the cell surface and enable T-cells to discern healthy cells from infected or malignant cells. While much effort has recently been invested in accurate prediction of these epitopes in silico (3), these are mostly limited to viruses as these contain fewer potential protein antigens (4). Moreover, these tools are not yet sufficiently precise to confidently identify epitopes (5,6) , Therefore, experimental immunopeptidomics workflows, such as epitope detection through liquid chromatography-mass spectrometry (LC-MS), are still the best way to accurately identify these immunopeptides (7).…”

De novo mass spectrometry peptide sequencing with a transformer model

“…However, relying on a database prevents the detection of unexpected peptide sequences, such as those that arise from genetic variation. A sequence database also cannot be used for the analysis of some types of immunopeptidomics data, for example, when a phenomenon known as V(D)J recombination results in peptides whose sequences are not encoded in the genome [1], in antibody sequencing [2], or in vaccine development when searching for bacterial peptides present on the surface of infected cells [3]. Finally, constructing an accurate database for metaproteomic analyses, such as the human microbiome or environmental samples, is nearly impossible [4].…”