Multistate design of influenza antibodies improves affinity and breadth against seasonal viruses

Influenza is a yearly threat to global public health. Rapid changes in influenza surface proteins resulting from antigenic drift and shift events make it difficult to readily identify antibodies with broadly neutralizing activity against different influenza subtypes with high frequency, specifically antibodies targeting the receptor binding domain (RBD) on influenza HA protein. We developed an optimized computational design method that is able to optimize an antibody for recognition of large panels of antigens. To demonstrate the utility of this multistate design method, we used it to redesign an antiinfluenza antibody against a large panel of more than 500 seasonal HA antigens of the H1 subtype. As a proof of concept, we tested this method on a variety of known antiinfluenza antibodies and identified those that could be improved computationally. We generated redesigned variants of antibody C05 to the HA RBD and experimentally characterized variants that exhibited improved breadth and affinity against our panel. C05 mutants exhibited improved affinity for three of the subtypes used in design by stabilizing the CDRH3 loop and creating favorable electrostatic interactions with the antigen. These mutants possess increased breadth and affinity of binding while maintaining high-affinity binding to existing targets, surpassing a major limitation up to this point.

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Molecular Characterization of Seasonal Influenza A and B from Hospitalized Patients in Thailand in 2018–2019

Viruses ◽

10.3390/v13060977 ◽

2021 ◽

Vol 13 (6) ◽

pp. 977

Author(s):

Kobporn Boonnak ◽

Chayasin Mansanguan ◽

Dennis Schuerch ◽

Usa Boonyuen ◽

Hatairat Lerdsamran ◽

...

Keyword(s):

Amino Acid ◽

Influenza A ◽

Seasonal Influenza ◽

Influenza Viruses ◽

Surface Proteins ◽

Antigenic Drift ◽

Influenza B ◽

Receptor Binding Site ◽

Antigenic Sites ◽

Ha Protein

Influenza viruses continue to be a major public health threat due to the possible emergence of more virulent influenza virus strains resulting from dynamic changes in virus adaptability, consequent of functional mutations and antigenic drift in surface proteins, especially hemagglutinin (HA) and neuraminidase (NA). In this study, we describe the genetic and evolutionary characteristics of H1N1, H3N2, and influenza B strains detected in severe cases of seasonal influenza in Thailand from 2018 to 2019. We genetically characterized seven A/H1N1 isolates, seven A/H3N2 isolates, and six influenza B isolates. Five of the seven A/H1N1 viruses were found to belong to clade 6B.1 and were antigenically similar to A/Switzerland/3330/2017 (H1N1), whereas two isolates belonged to clade 6B.1A1 and clustered with A/Brisbane/02/2018 (H1N1). Interestingly, we observed additional mutations at antigenic sites (S91R, S181T, T202I) as well as a unique mutation at a receptor binding site (S200P). Three-dimensional (3D) protein structure analysis of hemagglutinin protein reveals that this unique mutation may lead to the altered binding of the HA protein to a sialic acid receptor. A/H3N2 isolates were found to belong to clade 3C.2a2 and 3C.2a1b, clustering with A/Switzerland/8060/2017 (H3N2) and A/South Australia/34/2019 (H3N2), respectively. Amino acid sequence analysis revealed 10 mutations at antigenic sites including T144A/I, T151K, Q213R, S214P, T176K, D69N, Q277R, N137K, N187K, and E78K/G. All influenza B isolates in this study belong to the Victoria lineage. Five out of six isolates belong to clade 1A3-DEL, which relate closely to B/Washington/02/2009, with one isolate lacking the three amino acid deletion on the HA segment at position K162, N163, and D164. In comparison to the B/Colorado/06/2017, which is the representative of influenza B Victoria lineage vaccine strain, these substitutions include G129D, G133R, K136E, and V180R for HA protein. Importantly, the susceptibility to oseltamivir of influenza B isolates, but not A/H1N1 and A/H3N2 isolates, were reduced as assessed by the phenotypic assay. This study demonstrates the importance of monitoring genetic variation in influenza viruses regarding how acquired mutations could be associated with an improved adaptability for efficient transmission.

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A Framework for Component Layout and Geometry Design of Mechanical Systems: Configuration Network and its Viewing Control

Volume 1: 21st Design Automation Conference ◽

10.1115/detc1995-0068 ◽

1995 ◽

Author(s):

Kikuo Fujita ◽

Shinsuke Akagi

Keyword(s):

Design Method ◽

Mechanical Systems ◽

Optimization Procedure ◽

Computational Design ◽

Object Oriented Programming ◽

Design System ◽

Air Conditioner ◽

Programming Technique ◽

Geometry Design ◽

Component Layout

Abstract A Framework of computational design method and model is proposed for layout and geometry design of complicated mechanical systems, which is named “configuration network and its viewing control”. In the method, a design object is represented with a set of declarative relationships among various elements of a system, that is, configurations, which is gradually extended from schematic structure to exact layout and geometry through design process. Since a whole of such configurations forms a too complicated network to compute all together, how to view subparts is controlled based on levels of granularity and width of scope range. Such a configuration network is made to grow and refined through embodying geometry and layout corresponding to a focused subpart with a numerical optimization procedure. The framework has also an ability to flexibly integrate with engineering analysis. Moreover, a design system is implemented with an object-oriented programming technique, and it is applied to a design problem of air conditioner units in order to show the validity and effectiveness of the framework.

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Computational Design for Digitally Fabricated 3D Inductive Power Transfer Coils

Journal of Computing and Information Science in Engineering ◽

10.1115/1.4053500 ◽

2022 ◽

pp. 1-28

Author(s):

Jun Xu ◽

Eugeni L. Doubrovski ◽

Jo Geraedts ◽

Yu Song

Keyword(s):

Design Method ◽

Computational Design ◽

Future Research ◽

Receiver Coil ◽

Power Transfer ◽

Coil Design ◽

Optimal Position ◽

Inductive Power Transfer ◽

Transmitter Coil ◽

Inductive Power

Abstract The geometric shapes and the relative position of coils influence the performance of a three-dimensional (3D) inductive power transfer system. In this paper, we propose a coil design method for specifying the positions and the shapes of a pair of coils to transmit the desired power in 3D. Given region of interests (ROIs) for designing the transmitter and the receiver coils on two surfaces, the transmitter coil is generated around the center of its ROI first. The center of the receiver coil is estimated as a random seed position in the corresponding 3D surface. At this position, we use the heatmap method with electromagnetic constraints to iteratively extend the coil until the desired power can be transferred via the set of coils. In each step, the shape of the extension, i.e. a new turn of the receiver coil, is found as a spiral curve based on the convex hulls of adjacent turns in the 2D projection plane along their normal direction. Then, the optimal position of the receiver coil is found by maximizing the efficiency of the system. In the next step, the position and the shape of the transmitter coil are optimized based on the fixed receiver coil using the same method. This zig-zag optimization process iterates until an optimum is reached. Simulations and experiments with digitally fabricated prototypes were conducted and the effectiveness of the proposed 3D coil design method was verified. Possible future research directions are highlighted well.

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Natural and directed antigenic drift of the H1 influenza virus hemagglutinin stalk domain

Scientific Reports ◽

10.1038/s41598-017-14931-7 ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 36

Author(s):

Christopher S. Anderson ◽

Sandra Ortega ◽

Francisco A. Chaves ◽

Amelia M. Clark ◽

Hongmei Yang ◽

...

Keyword(s):

Influenza Virus ◽

Viral Fitness ◽

Antigenic Drift ◽

Virus Infections ◽

Head Region ◽

Immune Pressure ◽

Stalk Domain ◽

Ha Protein

Abstract The induction of antibodies specific for the influenza HA protein stalk domain is being pursued as a universal strategy against influenza virus infections. However, little work has been done looking at natural or induced antigenic variability in this domain and the effects on viral fitness. We analyzed human H1 HA head and stalk domain sequences and found substantial variability in both, although variability was highest in the head region. Furthermore, using human immune sera from pandemic A/California/04/2009 immune subjects and mAbs specific for the stalk domain, viruses were selected in vitro containing mutations in both domains that partially contributed to immune evasion. Recombinant viruses encoding amino acid changes in the HA stalk domain replicated well in vitro, and viruses incorporating two of the stalk mutations retained pathogenicity in vivo. These findings demonstrate that the HA protein stalk domain can undergo limited drift under immune pressure and the viruses can retain fitness and virulence in vivo, findings which are important to consider in the context of vaccination targeting this domain.

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Immunological Responses to the Relapsing Fever SpirocheteBorrelia turicataein Infected Rhesus Macaques: Implications for Pathogenesis and Diagnosis

Infection and Immunity ◽

10.1128/iai.00900-18 ◽

2019 ◽

Vol 87 (4) ◽

Cited By ~ 1

Author(s):

Monica E. Embers ◽

Aparna Krishnavajhala ◽

Brittany A. Armstrong ◽

Michael W. Curtis ◽

Bapi Pahar ◽

...

Keyword(s):

Immune Responses ◽

B Cell ◽

Rhesus Macaques ◽

Surface Proteins ◽

Vaccine Antigen ◽

Global Public Health ◽

Relapsing Fever ◽

Primate Model ◽

Necrosis Factor Alpha ◽

Content Type

ABSTRACTThe global public health impact of relapsing fever (RF) spirochetosis is significant, since the pathogens exist on five of seven continents. The hallmark sign of infection is episodic fever and the greatest threat is to the unborn. With the goal of better understanding the specificity of B-cell responses and the role of immune responses in pathogenicity, we infected rhesus macaques withBorrelia turicatae(a new world RF spirochete species) by tick bite and monitored the immune responses generated in response to the pathogen. Specifically, we evaluated inflammatory mediator induction by the pathogen, host antibody responses to specific antigens, and peripheral lymphocyte population dynamics. Our results indicate thatB. turicataeelicits from peripheral blood cells key inflammatory response mediators (interleukin-1β and tumor necrosis factor alpha), which are associated with preterm abortion. Moreover, a global decline in peripheral B-cell populations was observed in all animals at 14 days postinfection. Serological responses were also evaluated to assess the antigenicity of three surface proteins: BipA, BrpA, and Bta112. Interestingly, a distinction was observed between antibodies generated in nonhuman primates and mice. Our results provide support for the nonhuman primate model not only in studies of prenatal pathogenesis but also for diagnostic and vaccine antigen identification and testing.

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Designing Optimal Origami Structures by Computational Evolutionary Embryogeny

Volume 5B: 38th Mechanisms and Robotics Conference ◽

10.1115/detc2014-34377 ◽

2014 ◽

Author(s):

Wei Li ◽

Daniel A. McAdams

Keyword(s):

Design Method ◽

Center Of Mass ◽

Computational Design ◽

Design Methods ◽

Performance Criteria ◽

Pattern Design ◽

Modern Computer ◽

Evolutionary Operators ◽

Origami Engineering ◽

Profile Position

As the advantages of foldable or deployable structures are being discovered, research into origami engineering has attracted more focus from both artists and engineers. With the aid of modern computer techniques, some computational origami design methods have been developed. Most of these methods focus on the problem of origami crease pattern design — the problem of determining a crease pattern to realize a specified origami final shape, but don’t provide computational solutions to actually developing a shape that meets some design performance criteria. This paper presents a design method that includes the computational design of the finished shape as well as the crease pattern. The origami shape will be designed to satisfy geometric, functional, and foldability requirements. This design method is named computational evolutionary embryogeny for optimal origami design (CEEFOOD), which is an extension of the genetic algorithm (GA) and an original computational evolutionary embryogeny (CEE). Unlike existing origami crease pattern design methods that adopt deductive logic, CEEFOOD implements an abductive approach to progressively evolve an optimal design. This paper presents how CEEFOOD — as a member of the GA family — determines the genetic representation (genotype) of candidate solutions, the formulation of the objective function, and the design of evolutionary operators. This paper gives an origami design problem, which has requirements on the folded-state profile, position of center of mass, and number of creases. Several solutions derived by CEEFOOD are listed and compared to highlight the effectiveness of this abductive design method.

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Evolutionary, genetic, structural characterization and its functional implications for the influenza A (H1N1) infection outbreak in India from 2009 to 2017

Scientific Reports ◽

10.1038/s41598-019-51097-w ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 3

Author(s):

Sara Jones ◽

Shijulal Nelson-Sathi ◽

Yejun Wang ◽

Raji Prasad ◽

Sabrina Rayen ◽

...

Keyword(s):

Influenza A ◽

Influenza Viruses ◽

Surface Proteins ◽

Antigenic Drift ◽

Global Perspective ◽

Global Circulation ◽

Influenza A H1n1 ◽

Indian Isolates ◽

H1n1 Strain ◽

The Tropics

Abstract Influenza A (H1N1) continues to be a major public health threat due to possible emergence of a more virulent H1N1 strain resulting from dynamic changes in virus adaptability consequent to functional mutations and antigenic drift in the hemagglutinin (HA) and neuraminidase (NA) surface proteins. In this study, we describe the genetic and evolutionary characteristics of H1N1 strains that circulated in India over a period of nine years from 2009 to 2017 in relation to global strains. The finding is important from a global perspective since previous phylogenetic studies have suggested that the tropics contributed substantially to the global circulation of influenza viruses. Bayesian phylogenic analysis of HA sequences along with global strains indicated that there is a temporal pattern of H1N1 evolution and clustering of Indian isolates with globally circulating strains. Interestingly, we observed four new amino acid substitutions (S179N, I233T, S181T and I312V) in the HA sequence of H1N1 strains isolated during 2017 and two (S181T and I312V) were found to be unique in Indian isolates. Structurally these two unique mutations could lead to altered glycan specificity of the HA gene. Similarly, sequence and structural analysis of NA domain revealed that the presence of K432E mutation in H1N1 strains isolated after 2015 from India and in global strains found to induce a major loop shift in the vicinity of the catalytic site. The findings presented here offer an insight as to how these acquired mutations could be associated to an improved adaptability of the virus for efficient human transmissibility.

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Toward the computational design of protein crystals with improved resolution

Acta Crystallographica Section D Structural Biology ◽

10.1107/s2059798319013226 ◽

2019 ◽

Vol 75 (11) ◽

pp. 1015-1027 ◽

Cited By ~ 2

Author(s):

Jeliazko R. Jeliazkov ◽

Aaron C. Robinson ◽

Bertrand García-Moreno E. ◽

James M. Berger ◽

Jeffrey J. Gray

Keyword(s):

Weak Interactions ◽

Design Method ◽

Point Mutations ◽

Computational Design ◽

Data Bank ◽

Protein Crystals ◽

Single Individual ◽

Space Group ◽

Protein Backbones ◽

Crystal Space

Substantial advances have been made in the computational design of protein interfaces over the last 20 years. However, the interfaces targeted by design have typically been stable and high-affinity. Here, we report the development of a generic computational design method to stabilize the weak interactions at crystallographic interfaces. Initially, we analyzed structures reported in the Protein Data Bank to determine whether crystals with more stable interfaces result in higher resolution structures. We found that for 22 variants of a single protein crystallized by a single individual, the Rosetta-calculated `crystal score' correlates with the reported diffraction resolution. We next developed and tested a computational design protocol, seeking to identify point mutations that would improve resolution in a highly stable variant of staphylococcal nuclease (SNase). Using a protocol based on fixed protein backbones, only one of the 11 initial designs crystallized, indicating modeling inaccuracies and forcing us to re-evaluate our strategy. To compensate for slight changes in the local backbone and side-chain environment, we subsequently designed on an ensemble of minimally perturbed protein backbones. Using this strategy, four of the seven designed proteins crystallized. By collecting diffraction data from multiple crystals per design and solving crystal structures, we found that the designed crystals improved the resolution modestly and in unpredictable ways, including altering the crystal space group. Post hoc, in silico analysis of the three observed space groups for SNase showed that the native space group was the lowest scoring for four of six variants (including the wild type), but that resolution did not correlate with crystal score, as it did in the preliminary results. Collectively, our results show that calculated crystal scores can correlate with reported resolution, but that the correlation is absent when the problem is inverted. This outcome suggests that more comprehensive modeling of the crystallographic state is necessary to design high-resolution protein crystals from poorly diffracting crystals.

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Computational Simulations of the Anterior Vertebral Surface for Optimal Surgical Instrumentation Design

Journal of Medical Devices ◽

10.1115/1.3439667 ◽

2010 ◽

Vol 4 (2) ◽

Cited By ~ 2

Author(s):

Francisco Casesnoves

Keyword(s):

Vertebral Body ◽

Design Method ◽

Computational Design ◽

Human Bone ◽

Mechanical Forces ◽

Grid Data ◽

Statistical Parameters ◽

Surgical Instrumentation ◽

The Individual ◽

Fitting Model

The engineering design of surgical instrumentation to apply mechanical forces and linear moments on the human bones during the operations constitutes a rather difficult task. This is due both to the natural and pathological irregularities of the human bone morphology and surfaces and also to the individual variations from one patient to another. Usually, the forces are applied by the surgeon only on a determined part of the bone surfaces. This paper describes an innovative computational design method to digitalize, simulate, and fit mathematically the anterior vertebral body facet. We used real experimental data from 17 human cadaveric specimens to get and store a large amount of numerical surface digital values. The complete anterior vertebral body side was visualized and analyzed with grid data Subroutine, which was also used first to select the so-called natural regions of interest (ROIs). These ROIs correspond to those parts of the surface in contact with the surgical instrumentation, where the mechanical forces are applied. Subsequently, a numerical mathematical fitting-model was implemented for these ROIs. This was carried out with the development of a 3D geometrical least-squares optimization algorithm and appropriate software designed according to the proper numerical method selected. In doing so, the 3D superficies equations of the anterior vertebral body (L3, L4, L5, and S1) were determined after these fittings were mathematically checked as appropriate. Statistical parameters and determination coefficients that define the error boundaries and the goodness of this optimal fitting-model were calculated and NURBS error data in similar studies were commented. It was proven that the principal source of error was the micro- and macro-irregularities of human bone facets. The final surface equations, and their geodesics, were used to obtain accurate data for the spinal surgery instrumentation manufacturing. The industrial bioengineering result was the application of these equations for the design of a new spinal vertebral surgical distractor. This innovative distractor separates two adjacent vertebrae while keeping them parallel. That is, at their natural inclination, avoiding hammering the vertebrae to make the intervertebral space wider. The device mechanics also minimizes the necessary force to be carried out by the surgeon during the operation.

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Targeting Hemagglutinin: Approaches for Broad Protection against the Influenza A Virus

Viruses ◽

10.3390/v11050405 ◽

2019 ◽

Vol 11 (5) ◽

pp. 405 ◽

Cited By ~ 13

Author(s):

Zhang ◽

Xu ◽

Zhang ◽

Liu ◽

Xue ◽

...

Keyword(s):

Influenza A Virus ◽

Influenza A ◽

Protective Efficacy ◽

Structure And Function ◽

Antigenic Drift ◽

Influenza A Viruses ◽

Universal Vaccine ◽

Vaccine Candidates ◽

And Function ◽

Ha Protein

Influenza A viruses are dynamically epidemic and genetically diverse. Due to the antigenic drift and shift of the virus, seasonal vaccines are required to be reformulated annually to match with current circulating strains. However, the mismatch between vaccinal strains and circulating strains occurs frequently, resulting in the low efficacy of seasonal vaccines. Therefore, several “universal” vaccine candidates based on the structure and function of the hemagglutinin (HA) protein have been developed to meet the requirement of a broad protection against homo-/heterosubtypic challenges. Here, we review recent novel constructs and discuss several important findings regarding the broad protective efficacy of HA-based universal vaccines.

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