Browse
Submit Data
Databases
API
Help

Dataset Information

27 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Complexity of Viral Epitope Surfaces as Evasive Targets for Vaccines and Therapeutic Antibodies.

ABSTRACT: The dynamic interplay between virus and host plays out across many interacting surfaces as virus and host evolve continually in response to one another. In particular, epitope-paratope interactions (EPIs) between viral antigen and host antibodies drive much of this evolutionary race. In this review, we describe a series of recent studies examining aspects of epitope complexity that go beyond two interacting protein surfaces as EPIs are typically understood. To structure our discussion, we present a framework for understanding epitope complexity as a spectrum along a series of axes, focusing primarily on 1) epitope biochemical complexity (e.g., epitopes involving N-glycans) and 2) antigen conformational/dynamic complexity (e.g., epitopes with differential properties depending on antigen state or fold-axis). We highlight additional epitope complexity factors including epitope tertiary/quaternary structure, which contribute to epistatic relationships between epitope residues within- or adjacent-to a given epitope, as well as epitope overlap resulting from polyclonal antibody responses, which is relevant when assessing antigenic pressure against a given epitope. Finally, we discuss how these different forms of epitope complexity can limit EPI analyses and therapeutic antibody development, as well as recent efforts to overcome these limitations.

SUBMITTER: Miller NL

PROVIDER: S-EPMC9247215 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Viral vector-based therapeutic cancer vaccines.

Project description:Most viruses are naturally immunogenic and can be engineered to express tumor antigen transgenes. Moreover, many types of recombinant viruses have been shown to infect professional antigen-presenting cells, specifically dendritic cells, and express their transgenes. This enhanced presentation of tumor antigens to the immune system has led to an increase in the frequency and avidity of cytotoxic T lymphocytes that target tumor cells expressing the tumor antigen(s) encoded in the vaccine vector. Logistically, recombinant viruses can be produced, administered, and quality controlled more easily compared with other immunotherapy strategies. The intrinsic properties of each virus have distinct advantages and disadvantages, which can determine their applicability in a particular therapeutic setting. The disadvantage of some vectors is the development of host-induced neutralizing antibodies to the vector itself, thus limiting its continued use. The "off-the-shelf" nature of viral vaccine platforms renders them exceptionally suitable for multicenter randomized trials. This review described and discussed the strategies used and results using viral-based vaccines, with emphasis on phases II and III clinical trials. Future directions will involve the evaluation of viral-based vaccines in the adjuvant and neoadjuvant settings, in patients with low burden metastatic disease, and in combination with other forms of therapy including immunotherapy.

| S-EPMC3207353 | biostudies-other

Engineering potent live attenuated coronavirus vaccines by targeted inactivation of the immune evasive viral deubiquitinase.

Project description:Coronaviruses express a papain-like protease (PLpro) that is required for replicase polyprotein maturation and also serves as a deubiquitinating enzyme (DUB). In this study, using a Middle East respiratory syndrome virus (MERS-CoV) PLpro modified virus in which the DUB is selectively inactivated, we show that the PLpro DUB is an important MERS-CoV interferon antagonist and virulence factor. Although the DUB-negative rMERS-CoVMA replicates robustly in the lungs of human dipeptidyl peptidase 4 knock-in (hDPP4 KI) mice, it does not cause clinical symptoms. Interestingly, a single intranasal vaccination with DUB-negative rMERS-CoVMA induces strong and sustained neutralizing antibody responses and sterilizing immunity after a lethal wt virus challenge. The survival of naïve animals also significantly increases when sera from animals vaccinated with the DUB-negative rMERS-CoVMA are passively transferred, prior to receiving a lethal virus dose. These data demonstrate that DUB-negative coronaviruses could be the basis of effective modified live attenuated vaccines.

| S-EPMC9973250 | biostudies-literature

Viral targets for vaccines against COVID-19.

Project description:Vaccines are urgently needed to control the coronavirus disease 2019 (COVID-19) pandemic and to help the return to pre-pandemic normalcy. A great many vaccine candidates are being developed, several of which have completed late-stage clinical trials and are reporting positive results. In this Progress article, we discuss which viral elements are used in COVID-19 vaccine candidates, why they might act as good targets for the immune system and the implications for protective immunity.

| S-EPMC7747004 | biostudies-literature

Universal influenza virus vaccines and therapeutic antibodies.

Project description:BackgroundCurrent influenza virus vaccines are effective when well matched to the circulating strains. Unfortunately, antigenic drift and the high diversity of potential emerging zoonotic and pandemic viruses make it difficult to select the right strains for vaccine production. This problem causes vaccine mismatches, which lead to sharp drops in vaccine effectiveness and long response times to manufacture matched vaccines in case of novel pandemic viruses.AimsTo provide an overview of universal influenza virus vaccines and therapeutic antibodies in preclinical and clinical development.SourcesPubMed and clinicaltrials.gov were used as sources for this review.ContentUniversal influenza virus vaccines that target conserved regions of the influenza virus including the haemagglutinin stalk domain, the ectodomain of the M2 ion channel or the internal matrix and nucleoproteins are in late preclinical and clinical development. These vaccines could confer broad protection against all influenza A and B viruses including drift variants and thereby abolish the need for annual re-formulation and re-administration of influenza virus vaccines. In addition, these novel vaccines would enhance preparedness against emerging influenza virus pandemics. Finally, novel therapeutic antibodies against the same conserved targets are in clinical development and could become valuable tools in the fight against influenza virus infection.ImplicationsBoth universal influenza virus vaccines and therapeutic antibodies are potential future options for the control of human influenza infections.

| S-EPMC5389886 | biostudies-literature

Epitope Mapping of Therapeutic Antibodies Targeting Human LAG3.

Project description:Lymphocyte activation gene 3 protein (LAG3; CD223) is an inhibitory receptor that is highly upregulated on exhausted T cells in tumors and chronic viral infection. Consequently, LAG3 is now a major immunotherapeutic target for the treatment of cancer, and many mAbs against human (h) LAG3 (hLAG3) have been generated to block its inhibitory activity. However, little or no information is available on the epitopes they recognize. We selected a panel of seven therapeutic mAbs from the patent literature for detailed characterization. These mAbs were expressed as Fab or single-chain variable fragments and shown to bind hLAG3 with nanomolar affinities, as measured by biolayer interferometry. Using competitive binding assays, we found that the seven mAbs recognize four distinct epitopes on hLAG3. To localize the epitopes, we carried out epitope mapping using chimeras between hLAG3 and mouse LAG3. All seven mAbs are directed against the first Ig-like domain (D1) of hLAG3, despite their different origins. Three mAbs almost exclusively target a unique 30-residue loop of D1 that forms at least part of the putative binding site for MHC class II, whereas four mainly recognize D1 determinants outside this loop. However, because all the mAbs block binding of hLAG3 to MHC class II, each of the epitopes they recognize must at least partially overlap the MHC class II binding site.

| S-EPMC9696730 | biostudies-literature

Viral proteases as therapeutic targets.

Project description:Some medically important viruses-including retroviruses, flaviviruses, coronaviruses, and herpesviruses-code for a protease, which is indispensable for viral maturation and pathogenesis. Viral protease inhibitors have become an important class of antiviral drugs. Development of the first-in-class viral protease inhibitor saquinavir, which targets HIV protease, started a new era in the treatment of chronic viral diseases. Combining several drugs that target different steps of the viral life cycle enables use of lower doses of individual drugs (and thereby reduction of potential side effects, which frequently occur during long term therapy) and reduces drug-resistance development. Currently, several HIV and HCV protease inhibitors are routinely used in clinical practice. In addition, a drug including an inhibitor of SARS-CoV-2 main protease, nirmatrelvir (co-administered with a pharmacokinetic booster ritonavir as Paxlovid®), was recently authorized for emergency use. This review summarizes the basic features of the proteases of human immunodeficiency virus (HIV), hepatitis C virus (HCV), and SARS-CoV-2 and discusses the properties of their inhibitors in clinical use, as well as development of compounds in the pipeline.

| S-EPMC9706241 | biostudies-literature

Novel Antigenic Targets of HPV Therapeutic Vaccines.

Project description:Human papillomavirus (HPV) infection is the cause of the majority of cervical cancers and head and neck cancers worldwide. Although prophylactic vaccines and cervical cancer screening programs have shown efficacy in preventing HPV-associated cervical cancer, cervical cancer is still a major cause of morbidity and mortality, especially in third world countries. Furthermore, head and neck cancer cases caused by HPV infection and associated mortality are increasing. The need for better therapy is clear, and therapeutic vaccination generating cytotoxic T cells against HPV proteins is a promising strategy. This review covers the current scene of HPV therapeutic vaccines in clinical development and discusses relevant considerations for the design of future HPV therapeutic vaccines and clinical trials, such as HPV protein expression patterns, immunogenicity, and exhaustion in relation to the different stages and types of HPV-associated lesions and cancers. Ultimately, while the majority of the HPV therapeutic vaccines currently in clinical testing target the two HPV oncoproteins E6 and E7, we suggest that there is a need to include more HPV antigens in future HPV therapeutic vaccines to increase efficacy and find that especially E1 and E2 could be promising novel targets.

| S-EPMC8621534 | biostudies-literature

Mouse Models for Studying HCV Vaccines and Therapeutic Antibodies.

Project description:In spite of the immense progress in hepatitis C virus (HCV) research, efforts to prevent infection, such as generating a vaccine, have not yet been successful. The high price tag associated with current treatment options for chronic infection and the spike in new infections concurrent with growing opioid abuse are strong motivators for developing effective immunization and understanding neutralizing antibodies' role in preventing infection. Humanized mice-both human liver chimeras as well as genetically humanized models-are important platforms for testing both possible vaccine candidates as well as antibody-based therapies. This chapter details the variety of ways humanized mouse technology can be employed in pursuit of learning how HCV infection can be prevented.

| S-EPMC6699619 | biostudies-literature

Effective induction of high-titer antibodies by viral vector vaccines.

Project description:Protein-in-adjuvant vaccines have shown limited success against difficult diseases such as blood-stage malaria. Here we show that a recombinant adenovirus-poxvirus prime-boost immunization regime (known to induce strong T cell immunogenicity) can also induce very strong antigen-specific antibody responses, and we identify a simple complement-based adjuvant to further enhance immunogenicity. Antibodies induced against a blood-stage malaria antigen by this viral vector platform are highly effective against Plasmodium yoelii parasites in mice and against Plasmodium falciparum in vitro.

| S-EPMC4822545 | biostudies-literature

Identifying the Epitope Regions of Therapeutic Antibodies Based on Structure Descriptors.

Project description:Therapeutic antibodies are widely used for disease detection and specific treatments. However, as an exogenous protein, these antibodies can be detected by the human immune system and elicit a response that can lead to serious illnesses. Therapeutic antibodies can be engineered through antibody humanization, which aims to maintain the specificity and biological function of the original antibodies, and reduce immunogenicity. However, the antibody drug effect is synchronously reduced as more exogenous parts are replaced by human antibodies. Hence, a major challenge in this area is to precisely detect the epitope regions in immunogenic antibodies and guide point mutations of exogenous antibodies to balance both humanization level and drug effect. In this article, the latest dataset of immunoglobulin complexes was collected from protein data bank (PDB) to discover the spatial features of immunogenic antibody. Furthermore, a series of structure descriptors were generated to characterize and distinguish epitope residues from non-immunogenic regions. Finally, a computational model was established based on structure descriptors, and results indicated that this model has the potential to precisely predict the epitope regions of therapeutic antibodies. With rapid accumulation of immunoglobulin complexes, this methodology could be used to improve and guide future antibody humanization and potential clinical applications.

| S-EPMC5751102 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data