Mechanism Of Neutralization Research Articles

A single residue switch mediates the broad neutralization of Rotaviruses

Broadly neutralizing antibodies (bNAbs) could offer escape-tolerant and lasting protection against viral infections and therefore guide development of broad-spectrum vaccines. The increasing challenge posed by viral evolution and immune evasion intensifies the importance of the discovery of bNAbs and their underlying neutralization mechanism. Here, focusing on the pivotal viral protein VP4 of rotavirus (RV), we identify a potent bNAb, 7H13, exhibiting broad-spectrum neutralization across diverse RV genotypes and demonstrating strong prevention of virus infection in female mice. A combination of time-resolved cryo-electron microscopy (cryo-EM) and in situ cryo-electron tomography (cryo-ET) analysis reveals a counterintuitive dynamic process of virus inactivation, in which 7H13 asymmetrically binds to a conserved epitope in the capsid-proximal aspect of VP4, triggers a conformational switch in a critical residue—F418—thereby disrupts the meta-stable conformation of VP4 essential for normal viral infection. Structure-guided mutagenesis corroborates the essential role of the 7H13 heavy chain I54 in activating F418 switch and destabilizing VP4. These findings define an atypical NAbs’ neutralization mechanism and reveal a potential type of virus vulnerable site for universal vaccine and therapeutics design.

Neutralizing antibody landscape of the non-polio Enteroviruses and future strategy

The non-polio Enteroviruses (NPEVs), consist of enteroviruses, coxsackieviruses, echoviruses, and rhinoviruses, are causative agents for a wide variety of diseases, ranging from common cold to encephalitis and acute flaccid paralysis (AFP). In recent years, several NPEVs have become serious public health threats, include EV-A71, which has caused epidemics of hand-foot-and-mouth disease (HMFD) in Southeast Asia, and EV-D68, which caused outbreaks of severe respiratory disease in children worldwide. Infections with these viruses are associated with neurological diseases like aseptic meningitis and AFP. Currently, apart from inactivated EV-A71 vaccines that were developed in China, no effective measures are available to prevent or treat NPEV infections. Antibody-mediated immunity is crucial for preventing and limiting viral infections, and potent neutralizing antibodies could serve as potential therapeutic agents. In this review, we describe recent progress in the NPEVs neutralization antibodies, summarizing the characteristics, breadth, and potency against NPEVs, such as EV-A71, CVA16, EV-D68, and echovirus. We focus on not only through the study of viral epitopes but also through the understanding of virus-antibody interactions. Also, we decipher the role of antibodies in the attachment of the virus to receptors, internalization, and uncoating process, providing insight into virus neutralization mechanisms. Moreover, bi-specific antibodies or multivalent antibodies with better potency are also discussed. Therefore, an in-depth understanding of structures of enterovirus and mechanisms of antibody neutralization should be useful for future strategies in guiding the design of a rational antiviral agent against NPEVs infections.

A broadly neutralizing antibody against the SARS-CoV-2 Omicron sub-variants BA.1, BA.2, BA.2.12.1, BA.4, and BA.5

The global spread of Severe Acute Respiratory Syndrome Coronavirus 2. (SARS-CoV-2) and its variant strains, including Alpha, Beta, Gamma, Delta, and now Omicron, pose a significant challenge. With the constant evolution of the virus, Omicron and its subtypes BA.1, BA.2, BA.3, BA.4, and BA.5 have developed the capacity to evade neutralization induced by previous vaccination or infection. This evasion highlights the urgency in discovering new monoclonal antibodies (mAbs) with neutralizing activity, especially broadly neutralizing antibodies (bnAbs), to combat the virus.In the current study, we introduced a fully human neutralizing mAb, CR9, that targets Omicron variants. We demonstrated the mAb’s effectiveness in inhibiting Omicron replication both in vitro and in vivo. Structural analysis using cryo-electron microscopy (cryo-EM) revealed that CR9 binds to an epitope formed by RBD residues, providing a molecular understanding of its neutralization mechanism. Given its potency and specificity, CR9 holds promise as a potential adjunct therapy for treating Omicron infections. Our findings highlight the importance of continuous mAb discovery and characterization in addressing the evolving threat of COVID-19.

Structural insights into hybridoma-derived neutralizing monoclonal antibodies against Omicron BA.5 and XBB.1.16 variants of SARS-CoV-2.

The ongoing evolution of SARS-CoV-2 has led to the emergence of variants capable of evading immune responses elicited by natural infection and vaccination, especially the highly transmissible and immune-evasive Omicron variants. This study generated and characterized a panel of monoclonal antibodies (mAbs) specifically targeting the RBD of the Omicron BA.5 variant, of which the ORB10 showed efficacy against Omicron BA.5 and XBB.1.16 variants both in vitro and in vivo. Cryo-EM structural analysis further elucidated the binding epitope interactions and neutralization mechanism between ORB10 and the BA.5 RBD protein. This study enhances our understanding of antibody-mediated neutralization of SARS-CoV-2 and provides valuable insights into the development of effective therapeutic strategies to combat ongoing SARS-CoV-2 variant infections.

Discovery and characterization of potent broadly neutralizing antibodies from human survivors of severe fever with thrombocytopenia syndrome

Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne phlebovirus that causes viral hemorrhagic fever. Pandemic concerns have arisen due to the increased human-to-human transmission and high mortality rate, highlighting the urgent need for specific therapeutics. Our observational study characterized the memory B cell response to natural SFTSV infection in four survivors. Monoclonal antibodies (mAbs) targeting the SFTSV glycoprotein N (Gn) were isolated and tested for invitro neutralizing activities and effects on virus binding. Structural analysis was performed to identify neutralizing epitopes recognized by the mAbs. Prophylactical and therapeutical protections were evaluated using a lethal SFTSV infection model. The selected mAbs exhibiting neutralizing activity primarily originate from the IGHV5-51 and IGHV3-30 germlines and target four distinct antigenic sites on SFTSV Gn. These elite mAbs effectively blocked the interaction between Gn and the cell receptor, preventing infections from five phylogenetically distinct SFTSV clades. Structural analysis revealed a novel neutralizing epitope located within SFTSV Gn domain I recognized by the elite mAbs. In mice of lethal infections with different SFTSV strains, administering a low dose of elite mAbs significantly improved survival rates in both prophylactic and therapeutic settings. This study identifies potent broadly neutralizing antibodies that holds promise for use in humans against SFTSV infection and highlights inhibition of receptor binding as a crucial mechanism for effective antibody-mediated neutralization against phleboviruses. The National Key Research and Development Plan of China (2018YFE0200401, 2022YFC2303300), National Natural Science Foundation of China (81825019), China Postdoctoral Science Foundation (2023M741824).

Evaluating the Synergistic Effects of Multi-Epitope Nanobodies on BA.2.86 Variant Immune Escape.

Addressing the frequent emergence of SARS-CoV-2 mutant strains requires therapeutic approaches with innovative neutralization mechanisms. The targeting of multivalent nanobodies can enhance potency and reduce the risk of viral escape, positioning them as promising drug candidates. Here, the synergistic mechanisms of the two types of nanobodies are investigated deeply. Our research revealed that the Fu2-1-Fu2-2 system exhibited significant synergy, whereas the Sb#15-Sb#68 system demonstrated antagonism, in which entropy was the dominant contributor to antagonism. Conformational analysis further demonstrated that the presence of a monomeric nanobody influenced the flexibility of residues near other epitopes, thereby affecting the overall synergy of the systems. Moreover, we identified that changes in the hydrogen bond network and the charge of residues played a critical role in the binding between nanobodies and spike. We hope this study will provide novel insights into the development of multivalent nanobody combinations.

Structural basis of different neutralization capabilities of monoclonal antibodies against H7N9 virus.

Neutralizing antibodies (nAbs) are important for the treatment of emerging viral diseases and for effective vaccine development. In this study, we generated and evaluated three nAbs (1H9, 2D7, and C4H4) against H7N9 influenza viruses and found that they differ in their ability to inhibit viral attachment, membrane fusion, and egress. We resolved the cryo-electron microscopy (cryo-EM) structures of H7N9 hemagglutinin (HA) alone and in complex with the nAb antigen-binding fragments (Fabs) and identified the HA head-located epitope for each nAb, thereby revealing the molecular basis and key residues that determine the differences in these nAbs in neutralizing H7N9 viruses. Moreover, we found that the humanized nAb CC4H4 provided complete protection in mice against death caused by a lethal H7N9 virus infection, even when nAb was given 3 days after the mice were infected. These findings provide new insights into the neutralizing mechanism and structural basis for the rational design of H7N9 virus vaccines and therapeutics.IMPORTANCEH7N9 viruses have caused severe infections in both birds and humans since their emergence in early 2013 in China. Their persistent presence and variation in avian populations pose a significant threat to both poultry and humans. There are no treatments for human infections. In this study, we thoroughly investigated the neutralization mechanisms, structural basis, and therapeutic effects of three nAbs (1H9, 2D7, and C4H4) against H7N9 viruses. We revealed the molecular determinants underlying the varied performances of the three nAbs in neutralizing H7N9 viruses and protecting H7N9-infected mice. These insights provide a solid foundation for the rational design of vaccines and therapeutics against H7N9 viruses.

Continent‐wide analysis of moss diversity in Antarctica

Mosses play a key role in Antarctic ecosystems. Understanding of moss diversity and its likely drivers across Antarctica is, however, limited, as is the extent to which Antarctic Specially Protected Areas (ASPAs) represent this diversity. Both are important given changing climates and direct human impacts in the region. Here we investigate variation in moss diversity, the frequency distribution of their range sizes, and their continent‐wide conservation. Richness is positively related to temperature, but negatively related to latitude, distance from bird colonies and geothermal sites; terrain roughness showed weak, yet positive, effects. Beta‐diversity is similar to that found for assemblages separated by long distances, dominated by species turnover. Multi‐site turnover (zeta diversity) suggests that niche‐related mechanisms are likely more responsible for diversity patterns than neutral mechanisms, despite the significant role wind‐driven dispersal is thought to play in structuring Antarctic biodiversity patterns. The frequency distribution of range sizes of mosses was right skewed, indicating that several moss species have very small range sizes, while a few species have larger ranges. Where ASPAs include mosses, richness varies between 1 and 41 species, with 65.1% (71 species) of the 109 species known from the continent included in the ASPA network. Twenty‐four species lie within 25 km2 radius of an ASPA, and 14 species beyond this distance could be considered relatively more difficult to protect. These findings lend support to the proposal that changing temperatures and expanding ice‐free areas will substantially increase Antarctica's diversity. Nonetheless, the mosses are reasonably well represented by the ASPA network, contrasting with other Antarctic taxa.

SARS-CoV-2 Omicron variations reveal mechanisms controlling cell entry dynamics and antibody neutralization.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is adapting to continuous presence in humans. Transitions to endemic infection patterns are associated with changes in the spike (S) proteins that direct virus-cell entry. These changes generate antigenic drift and thereby allow virus maintenance in the face of prevalent human antiviral antibodies. These changes also fine tune virus-cell entry dynamics in ways that optimize transmission and infection into human cells. Focusing on the latter aspect, we evaluated the effects of several S protein substitutions on virus-cell membrane fusion, an essential final step in enveloped virus-cell entry. Membrane fusion is executed by integral-membrane "S2" domains, yet we found that substitutions in peripheral "S1" domains altered late-stage fusion dynamics, consistent with S1-S2 heterodimers cooperating throughout cell entry. A specific H655Y change in S1 stabilized a fusion-intermediate S protein conformation and thereby delayed membrane fusion. The H655Y change also sensitized viruses to neutralization by S2-targeting fusion-inhibitory peptides and stem-helix antibodies. The antibodies did not interfere with early fusion-activating steps; rather they targeted the latest stages of S2-directed membrane fusion in a novel neutralization mechanism. These findings demonstrate that single amino acid substitutions in the S proteins both reset viral entry-fusion kinetics and increase sensitivity to antibody neutralization. The results exemplify how selective forces driving SARS-CoV-2 fitness and antibody evasion operate together to shape SARS-CoV-2 evolution.

Defining the features and structure of neutralizing antibody targeting the silent face of the SARS-CoV-2 spike N-terminal domain.

Research on virus/receptor interactions has uncovered various mechanisms of antibody-mediated neutralization against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, understanding of neutralization by antibodies targeting the silent face, which recognize epitopes on glycan shields, remains limited, and their potential protective efficacy in vivo is not well understood. This study describes a silent face neutralizing antibody, 3711, which targets a non-supersite on the N-terminal domain (NTD) of the spike protein. Cryo-EM structure determination of the 3711 Fab in the spike complex reveals a novel neutralizing epitope shielded by glycans on the spike's silent face. Antibody 3711 inhibits the interaction between the receptor-binding domain (RBD) and human angiotensin-converting enzyme 2 (hACE2) through steric hindrance and exhibits superior in vivo protective effects compared to other reported NTD-targeted monoclonal antibodies (mAbs). Competition assays and antibody repertoire analysis indicate the rarity of antibodies targeting the 3711-related epitope in SARS-CoV-2 convalescents, suggesting the infrequency of NTD silent face-targeted neutralizing antibodies during SARS-CoV-2 infection. As the first NTD silent face-targeted neutralizing antibody against SARS-CoV-2, the identification of mAb 3711, with its novel neutralizing mechanism, enhances our understanding of neutralizing epitopes on glycan shields and elucidates epitope-guided viral mutations that evade specific antibodies.

Performance of surfactant supplementation on alleviating membrane fouling in treatment of waste activated sludge: Experimental and modeling analyses

In this research, surfactant supplementation was investigated as a novel strategy for alleviation of membrane fouling in waste activated sludge (WAS) membrane filtration process. The effect of WAS pre-treatment with different surfactants on membrane performance were investigated in terms of flux variation, membrane rejection and fouling mechanisms. A generalization form of blocking law was developed to determine membrane fouling mechanism. According to the results, cationic surfactant below critical micelle concentration (CMC) values improved membrane performance, while anionic and non-ionic surfactant showed a negative impact at all dosages. It was observed that WAS pretreatment with 300 mg/L Cetyltrimethylammonium bromide (CTAB) could increase the water flux from 195 to 611 L/m2/h (LMH) and decrease the rejection rate from 93% to 85%, respectively. Although CTAB addition increased the total extracellular polymeric substances (EPSs) amount from 56.16 to 119.6 mg/L which was due to the surfactant solubilization property, the total resistance decreased from 0.33 × 1010 to 0.11 × 1010 m−1. This was attributed to the flock formation induced by CTAB through charge neutralization and bridging mechanism. Modeling simulation of the results indicated that CTAB addition transformed fouling mechanism from cake to intermediate-blocking model. The environmental risk assessment revealed that only 0.3 mg/L surfactant penetrated in permeate which was low ecological risk (risk quotients (RQ) < 0.5) to the aquatic environment. Our finding suggested CTAB treatment at low dosage (0.1 g/L) as a promising and efficient approach for fouling mitigation and improving membrane process for wastewater treatment.

Competing mechanisms of charge-induced electric field distortion and charge-involved neutralization on surface discharge

Charge-induced surface discharge poses a critical risk to the operational reliability of high-voltage direct current gas-insulated equipment and pulsed power system. In this study, we investigate the effects of charge-induced electric field distortion and charge involvement during surface discharge by separately depositing charge spots on two dielectric layers. The results show that deposited positive charges inhibit positive streamer development, whereas negative charges facilitate it, primarily due to electric field distortion induced by deposited charges. Nevertheless, the involvement of deposited charges in streamer development predominantly exhibits a neutralizing effect, exerting an opposite influence on the streamers. This highlights a competitive relationship between deposited charge involvement and electric field distortion. Additionally, the neutralization of deposited charges with electron avalanches reduces the impact of charge-induced electric field distortion, thereby mitigating its effects on discharge.

Enterovirus Antibodies: Friends and Foes.

Enteroviruses (EV) initiate replication by binding to their cellular receptors, leading to the uncoating and release of the viral genome into the cytosol of the host cell. Neutralising antibodies (NAbs) binding to epitopes on enteroviral capsid proteins can inhibit this infectious process through several mechanisms of neutralisation in vitro. Fc-mediated antibody effector functions such as antibody-dependent cell-mediated cytotoxicity and antibody-dependent cellular phagocytosis have also been described for some EV. However, antibody binding to virions does not always result in viral neutralisation. Non-neutralising antibodies, or sub-neutralising concentrations of antibodies, can enhance infection of viruses, leading to more severe pathologies. This phenomenon, known as antibody-dependent enhancement (ADE) of infection, has been described in vitro and/or in vivo for EV including poliovirus, coxsackievirus B and EV-A71. It has been shown that ADE of EV infection is mediated by FcγRs expressed by monocytes, macrophages, B lymphocytes and granulocytes. Antibodies play a crucial role in the diagnosis and monitoring of infections. They are valuable markers that have been used to establish a link between enteroviral infection and chronic diseases such as type 1 diabetes. Monoclonal and polyclonal antibodies targeting enteroviral proteins have been developed and shown to be effective to prevent or combat EV infections in vitro and in vivo. In addition, vaccines are under development, and clinical trials of vaccines are underway or have been completed, providing hope for the prevention of diseases due to EV. However, the ADE of the infection should be considered in the development of anti-EV antibodies or safe vaccines.

Aptamer-Encapsulated Cellular Nanoparticles for Neurotoxin Neutralization.

Aptamers are single-stranded oligonucleotides that fold into defined architectures for specific target binding. In this study, aptamers are selected that specifically bind to small-molecule neurotoxins and encapsulate them into cell membrane-coated nanoparticles (referred to as 'cellular nanoparticles' or 'CNPs') for effective neutralization of neurotoxins. Specifically, six different aptamers are selected that bind to saxitoxin (STX) or tetrodotoxin (TTX) and encapsulate them into metal-organic framework cores, which are then coated with neuronal cell membrane. The resulting CNPs exhibit high colloidal stability, minimal aptamer leakage, and effective protection of aptamer payloads against enzyme degradation. This detoxification platform combines membrane-enabled broad-spectrum neutralization with aptamer-based specific toxin binding, offering dual-modal neutralization mechanisms for efficient neurotoxin neutralization. The in vitro neutralization efficacy is demonstrated using a neuron osmotic swelling assay, a Na+ flux fluorescence assay, and a cytotoxicity assay. The in vivo neutralization efficacy is further validated using mouse models of STX and TTX intoxication in both therapeutic and preventative regimens. Overall, integrating aptamers with CNPs combines the strengths of both technologies, resulting in a robust solution for broad-spectrum toxin-neutralization applications.

Generation of a Nonbilayer Lipid Nanoenvironment after Epitope Binding Potentiates Neutralizing HIV-1 MPER Antibody.

Establishment of interactions with the envelope lipids is a cardinal feature of broadly neutralizing antibodies (bnAbs) that recognize the Env membrane-proximal external region (MPER) of HIV. The lipid envelope constitutes a relevant component of the full "quinary" MPER epitope, and thus antibodies may be optimized through engineering their capacity to interact with lipids. However, the role of the chemically complex lipid nanoenvironment in the mechanism of MPER molecular recognition and viral neutralization remains poorly understood. To approach this issue, we computationally and experimentally investigated lipid interactions of broadly neutralizing antibody 10E8 and optimized versions engineered to enhance their epitope and membrane affinity by grafting bulky aromatic compounds. Our data revealed a correlation between neutralization potency and the establishment of favorable interactions with small headgroup lipids cholesterol and phosphatidylethanolamine, evolving after specific engagement with MPER. Molecular dynamics simulations of chemically modified Fabs in complex with an MPER-Transmembrane Domain helix supported the generation of a nanoenvironment causing localized deformation of the thick, rigid viral membrane and identified sphingomyelin preferentially occupying a phospholipid-binding site of 10E8. Together, these interactions appear to facilitate insertion of the Fabs through their engagement with the MPER epitope. These findings implicate individual lipid molecules in the neutralization function of MPER bnAbs, validate targeted chemical modification as a method to optimize MPER antibodies, and suggest pathways for MPER peptide-liposome vaccine development.

Plant-Based Flocculants as Sustainable Conditioners for Enhanced Sewage Sludge Dewatering

With the aim to establish clean and sustainable sludge treatment, green conditioning using natural flocculants has recently gained a growing interest. In this study, a variety of plant materials, namely Moringa (Moringa oleifera) seeds, Fenugreek (Trigonella foenum-graecum) seeds, Potato (Solanum tuberosum) peels, Aloe (Aloe vera) leaves, Cactus (Opuntia ficus indica) cladodes, and Phragmites (Phragmites australis) stems, were evaluated for their potential bioflocculant activity in conditioning sewage sludge. They were thoroughly characterized to determine their active flocculating compounds. Sludge dewaterability was evaluated by assessing various sludge parameters, including specific resistance to filtration (SRF), dryness of filtration cake (DC), and total suspended solid removal (TSS) from sludge filtrate. The collected results from various physicochemical characterizations of plant materials suggest that the main flocculating agents are carbohydrates in Cactus and Fenugreek and proteins in Moringa, Potato, and Phragmites. Additionally, all tested plant-based flocculants demonstrated effective dewatering performance. Interestingly, compared to the chemical flocculant polyaluminum chloride, Moringa and Cactus showed superior conditioning effects, yielding the lowest SRF values and the highest DC. As a result, the use of these natural flocculants improved sewage sludge filterability, leading to a significant removal of total suspended solids from the filtrate. The conditioning properties of Moringa and Cactus can be attributed to their high protein and sugar content, which facilitates the effective separation of bound water from solids through charge neutralization and bridging mechanisms. Thus, green conditioning using plant-based flocculants, particularly Moringa and Cactus materials, presents a promising and eco-friendly approach to enhance sewage sludge dewatering for safer disposal and valorization.

Effect of the duration of homogenization of rubber latex with a coagulating agent on the decrease in aggregative stability

The article examines the effect of the duration of homogenization of rubber latex with coagulating agents on the process of rubber separation. The production of synthetic rubber involves a number of complex chemical and physical processes that can have a significant impact on efficiency and energy consumption. One of the key factors to consider is the thermal effect associated with changes in the internal energy of the system. The paper examines two approaches to the production of rubber: the use of salt as a coagulant and the use of a cationic electrolyte. Studies have shown that when using sodium chloride, coagulation proceeds by a concentration mechanism, and when using N,N-dimethyl-N,N-diallylammonium chloride - by a neutralization mechanism. At the same time, the duration of combining rubber latex with a solution of sodium chloride affects the consumption of the coagulant necessary for the complete separation of rubber from latex. However, when using N,N-dimethyl-N,N-diallylammonium chloride as a coagulant, this effect was not detected. These differences highlight the different coagulation mechanisms depending on the reagent used. The consumption of the cationic electrolyte for the separation of one ton of rubber from latex remained constant. The data obtained are of both scientific and practical importance for optimizing technological schemes and reducing energy consumption.

Mechanisms of AAV2 neutralization by human alpha-defensins.

AAVs are commonly used as gene therapy vectors due to their broad tropism and lack of disease association; however, host innate immune factors, such as human alpha-defensin antimicrobial peptides, can hinder gene delivery. Although it is becoming increasingly evident that human alpha-defensins can block infection by a wide range of nonenveloped viruses, including AAVs, their mechanism of action remains poorly understood. In this study, we describe for the first time how two types of abundant human alpha-defensins neutralize a specific AAV serotype, AAV2. We found that one defensin prevents AAV2 from binding to cells, the first step in infection, while both defensins block a critical later step in AAV2 entry. Our findings support the emerging idea that defensins use a common strategy to block infection by DNA viruses that replicate in the nucleus. Through understanding how innate immune effectors interact with and impede AAV infection, vectors can be developed to bypass these interventions and allow more efficient gene delivery.

Molecular mechanism and structure-guided humanization of a broadly neutralizing antibody against SFTSV.

Severe fever with thrombocytopenia syndrome virus (SFTSV) is a novel tick-borne bunyavirus that causes severe fever with thrombocytopenia syndrome (SFTS), with a high mortality rate of up to 30%. The envelope glycoproteins of SFTSV, glycoprotein N (Gn) and glycoprotein C (Gc), facilitate the recognition of host receptors and the process of membrane fusion, allowing the virus to enter host cells. We previously reported a monoclonal antibody, mAb 40C10, capable of neutralizing different genotypes of SFTSV and SFTSV-related viruses. However, the specific neutralization mechanism is poorly understood. In this study, we elucidated the high-resolution structure of the SFTSV Gn head domain in complex with mAb 40C10, confirming that the binding epitope in the domain I region of SFTSV Gn, and it represented that a novel binding epitope of SFTSV Gn was identified. Through in-depth structural and sequence analyses, we found that the binding sites of mAb 40C10 are relatively conserved among different genotypes of SFTSV and SFTSV-related Heartland virus and Guertu virus, elucidating the molecular mechanism underlying the broad-spectrum neutralizing activity of mAb 40C10. Furthermore, we humanized of mAb 40C10, which is originally of murine origin, to reduce its immunogenicity. The resulting nine humanized antibodies maintained potent affinity and neutralizing activity. One of the humanized antibodies exhibited neutralizing activity at picomolar IC50 values and demonstrated effective therapeutic and protective effects in a mouse infection model. These findings provide a novel target for the future development of SFTSV vaccines or drugs and establish a foundation for the research and development of antibody therapeutics for clinical applications.

PROBLEMS OF MANAGING THE IMMUNE RESPONSE UNDER CONDITIONS OF COMPETITIVE ADSORPTION, DIFFUSION PERTURBATIONS AND TEMPERATURE RESPONSE OF THE ORGANISM

Analysis of the problems associated with the rapid spread of infectious diseases indicates the need for new approaches to the diagnosis and develop- ment of effective personalized treatment programs. One of the important aspects of solving this problem is the creation of a mathematical modeling toolkit for predicting the dynamics of infectious diseases, taking into account spatial effects, concentrated effects, various mechanisms of body protec- tion in the conditions of the application of various types of therapeutic methods of treatment. An important component of complex methods of treat- ment of a wide range of infectious diseases is the use of adsorption drugs, which, along with detoxification of the body, are able to provide an addi- tional mechanism of neutralization of viral elements. In the process of using such means, not only pathogenic elements and toxins will be adsorbed, but also various types of immune agents, which will affect the dynamics of the immune response. In the paper the infectious disease model is generalized to take into account the features of competitive adsorption of antigens and immune agents in the conditions of diffusion perturbations, concentrated influences and temperature reaction of the body. By synthesizing the ideas of step-by-step procedures, asymptotic and numerical methods, an effective computational technology of step-by-step approximation of the solution of the original model singularly perturbed problem was built. The results of the computer experiments presented in the paper illustrate the features of reducing the predicted concentration of viral elements during their competi- tive adsorption together with immune agents, in particular, the effect of reducing the efficiency of the use of non-specific adsorbents. It is emphasized that taking into account the features of the action of competitive adsorption is important for making decisions regarding the formation of rational treatment programs with the complex use of adsorbing substances and immunological drugs.