scholarly journals A 3D structural affinity model for multi-epitope in silico germinal center simulations

2019 ◽  
Author(s):  
Philippe A. Robert ◽  
Michael Meyer-Hermann
Keyword(s):  
Germinal Center ◽  
In Silico ◽  
Vaccine Development ◽  
Cross Reactivity ◽  
Affinity Maturation ◽  
Structural Basis ◽  
Computational Time ◽  
Structural Representation ◽  
Structural Lattice ◽  
Complex Phenomena

AbstractVaccine development for mutating pathogens is challenged by their fast evolution, the complexity of immunodominance, and the heterogeneous immune history of individuals. Mathematical models are critical for predicting successful vaccine conditions or designing potent antibodies. Existing models are limited by their abstract and poorly structural representations of antigen epitopes. Here, we propose a structural lattice-based model for antibody–antigen affinity. An efficient algorithm is given that predicts the best binding structure of an antibody’s amino acid sequence around an antigen with shortened computational time. This structural representation contains key physiological properties, such as affinity jumps and cross-reactivity, and successfully reflects the topology of antigen epitopes, such as pockets and shielded residues. It is suitable for large simulations of affinity maturation. We perform in silico immunizations via germinal center simulations and show that our model can explain complex phenomena like recognition of the same epitope by unrelated clones. We show that the use of cocktails of similar epitopes promotes the development of cross-reactive antibodies. This model opens a new avenue for optimizing multivalent vaccines with combined antigen cocktails or sequential immunizations, and to reveal reasons for vaccine success or failure on a structural basis.

scholarly journals Structural basis for Zika envelope domain III recognition by a germline version of a recurrent neutralizing antibody

2020 ◽  
Vol 117 (18) ◽  
pp. 9865-9875
Author(s):  
Shannon R. Esswein ◽  
Harry B. Gristick ◽  
Andrea Jurado ◽  
Avery Peace ◽  
Jennifer R. Keeffe ◽  
...  
Keyword(s):  
West Nile Virus ◽  
Envelope Protein ◽  
Yellow Fever Virus ◽  
Cross Reactivity ◽  
Affinity Maturation ◽  
Protein Domain ◽  
Structural Basis ◽  
Maturation Process ◽  
West Nile ◽  
Domain Iii

Recent epidemics demonstrate the global threat of Zika virus (ZIKV), a flavivirus transmitted by mosquitoes. Although infection is usually asymptomatic or mild, newborns of infected mothers can display severe symptoms, including neurodevelopmental abnormalities and microcephaly. Given the large-scale spread, symptom severity, and lack of treatment or prophylaxis, a safe and effective ZIKV vaccine is urgently needed. However, vaccine design is complicated by concern that elicited antibodies (Abs) may cross-react with other flaviviruses that share a similar envelope protein, such as dengue virus, West Nile virus, and yellow fever virus. This cross-reactivity may worsen symptoms of a subsequent infection through Ab-dependent enhancement. To better understand the neutralizing Ab response and risk of Ab-dependent enhancement, further information on germline Ab binding to ZIKV and the maturation process that gives rise to potently neutralizing Abs is needed. Here we use binding and structural studies to compare mature and inferred-germline Ab binding to envelope protein domain III of ZIKV and other flaviviruses. We show that affinity maturation of the light-chain variable domain is important for strong binding of the recurrent VH3-23/VK1-5 neutralizing Abs to ZIKV envelope protein domain III, and identify interacting residues that contribute to weak, cross-reactive binding to West Nile virus. These findings provide insight into the affinity maturation process and potential cross-reactivity of VH3-23/VK1-5 neutralizing Abs, informing precautions for protein-based vaccines designed to elicit germline versions of neutralizing Abs.

scholarly journals Towards Quantitative and Standardized Serological and Neutralization Assays for COVID-19

2021 ◽  
Vol 22 (5) ◽  
pp. 2723
Author(s):  
Linhua Tian ◽  
Elzafir B. Elsheikh ◽  
Paul N. Patrone ◽  
Anthony J. Kearsley ◽  
Adolfas K. Gaigalas ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Vaccine Development ◽  
Neutralizing Antibody ◽  
Epidemiologic Studies ◽  
Cross Reactivity ◽  
Receptor Binding Domain ◽  
Proof Of Concept ◽  
Reference Standard ◽  
Improve Measurement ◽  
Antibody Titers

Quantitative and robust serology assays are critical measurements underpinning global COVID-19 response to diagnostic, surveillance, and vaccine development. Here, we report a proof-of-concept approach for the development of quantitative, multiplexed flow cytometry-based serological and neutralization assays. The serology assays test the IgG and IgM against both the full-length spike antigens and the receptor binding domain (RBD) of the spike antigen. Benchmarking against an RBD-specific SARS-CoV IgG reference standard, the anti-SARS-CoV-2 RBD antibody titer was quantified in the range of 37.6 µg/mL to 31.0 ng/mL. The quantitative assays are highly specific with no correlative cross-reactivity with the spike proteins of MERS, SARS1, OC43 and HKU1 viruses. We further demonstrated good correlation between anti-RBD antibody titers and neutralizing antibody titers. The suite of serology and neutralization assays help to improve measurement confidence and are complementary and foundational for clinical and epidemiologic studies.

scholarly journals SARS-CoV-2 RBD in vitro evolution parrots and predicts contagious mutation spread

2021 ◽  
Author(s):  
Gideon Schreiber ◽  
Jiri Zahradník ◽  
Shir Marciano ◽  
Maya Shemesh ◽  
Eyal Zoler ◽  
...  
Keyword(s):  
South African ◽  
Convergent Evolution ◽  
Vaccine Development ◽  
Spike Protein ◽  
Structural Basis ◽  
Receptor Binding Domain ◽  
In Vitro Evolution ◽  
High Affinity ◽  
Future Drug

Abstract SARS-CoV-2 is continually evolving, with more contagious mutations spreading rapidly. Using in vitro evolution to affinity maturate the receptor-binding domain (RBD) of the spike protein towards ACE2 resulted in the more contagious mutations, S477N, E484K, and N501Y, to be among the first selected, explaining the convergent evolution of the “European” (20E-EU1), “British” (501.V1),”South African” (501.V2), and Brazilian variants (501.V3). Plotting the binding affinity to ACE2 of all RBD mutations against their incidence in the population shows a strong correlation between the two. Further in vitro evolution enhancing binding by 600-fold provides guidelines towards potentially new evolving mutations with even higher infectivity. For example, Q498R epistatic to N501Y. Nevertheless, the high-affinity RBD is also an efficient drug, inhibiting SARS-CoV-2 infection. The 2.9Å Cryo-EM structure of the high-affinity complex, including all rapidly spreading mutations, provides a structural basis for future drug and vaccine development and for in silico evaluation of known antibodies.

scholarly journals In silico identification of vaccine targets for 2019-nCoV

F1000Research ◽  
2020 ◽  
Vol 9 ◽  
pp. 145 ◽  
Author(s):  
Chloe Hyun-Jung Lee ◽  
Hashem Koohy
Keyword(s):  
T Cell ◽  
In Silico ◽  
Vaccine Development ◽  
De Novo ◽  
Cell Receptor ◽  
Binding Potential ◽  
Hla Alleles ◽  
Immunogenic Peptides ◽  
Novel Coronavirus ◽  
Positional Weight

Background: The newly identified coronavirus known as 2019-nCoV has posed a serious global health threat. According to the latest report (18-February-2020), it has infected more than 72,000 people globally and led to deaths of more than 1,016 people in China. Methods: The 2019 novel coronavirus proteome was aligned to a curated database of viral immunogenic peptides. The immunogenicity of detected peptides and their binding potential to HLA alleles was predicted by immunogenicity predictive models and NetMHCpan 4.0. Results: We report in silico identification of a comprehensive list of immunogenic peptides that can be used as potential targets for 2019 novel coronavirus (2019-nCoV) vaccine development. First, we found 28 nCoV peptides identical to Severe acute respiratory syndrome-related coronavirus (SARS CoV) that have previously been characterized immunogenic by T cell assays. Second, we identified 48 nCoV peptides having a high degree of similarity with immunogenic peptides deposited in The Immune Epitope Database (IEDB). Lastly, we conducted a de novo search of 2019-nCoV 9-mer peptides that i) bind to common HLA alleles in Chinese and European population and ii) have T Cell Receptor (TCR) recognition potential by positional weight matrices and a recently developed immunogenicity algorithm, iPred, and identified in total 63 peptides with a high immunogenicity potential. Conclusions: Given the limited time and resources to develop vaccine and treatments for 2019-nCoV, our work provides a shortlist of candidates for experimental validation and thus can accelerate development pipeline.

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