Plasma Neutralization Research Articles

Expanded immune imprinting and neutralization spectrum by hybrid immunization following breakthrough infections with SARS-CoV-2 variants after three-dose vaccination

BackgroundDespite vaccination, SARS-CoV-2 evolution leads to breakthrough infections and reinfections worldwide. Knowledge of hybrid immunization is crucial for future broad-spectrum SARS-CoV-2 vaccines. MethodsIn this study, we investigated neutralizing antibodies (nAbs) against the SARS-CoV-2 ancestral virus (wild-type [WT]), pre-Omicron VOCs, Omicron subvariants, and SARS-CoV-1 using plasma collected from four distinct cohorts: individuals who received three doses of BBIBP-CorV/CoronaVac vaccines, those who experienced BA.5 breakthrough infections, those with XBB breakthrough infections, and those with BA.5-XBB consecutive infections following three-dose vaccination. FindingsFollowing Omicron breakthrough infections, the levels of nAbs against WT and pre-Omicron VOCs were higher due to immune imprinting established by WT-based vaccination, in comparison to nAbs against Omicron variants. Interestingly, the XBB breakthrough infections elicited a broader neutralization spectrum against SARS-CoV-2 variants compared to the BA.5 breakthrough infections. This observation suggests that the XBB variant demonstrates superior immunogenicity relative to BA.5. Notably, hybrid immunization of BA.5 breakthrough infections after WT vaccination led to additional immune imprinting, resulting in a broadened neutralization profile against both WT and BA.5 variants in BA.5-XBB consecutive infections. However, the duration of nAbs was shorter in these reinfections compared to the breakthrough infections. Additionally, the expanded immune imprinting from previous WT vaccination and BA.5 breakthrough infections account for the enhanced plasma neutralization immunodominance observed in the antigenic cartography for BA.5-XBB consecutive infections. InterpretationOverall, we demonstrated a persistent and expanded effect of immune imprinting from prior SARS-CoV-2 exposures. Thus, future vaccines should specifically address the latest variants, and booster shots should be given at a longer interval after the previous infection or vaccination. FundingAll the funding has been stated in the acknowledge section.

Effect of XBB.1.5-adapted booster vaccination on the imprinting of SARS-CoV-2 immunity

In the present study, Pušnik et al. investigated whether the XBB.1.5-adapted booster can overcome the persistent imprinting of SARS-CoV-2 immunity by wild-type based vaccines. The findings demonstrate increased plasma neutralization against the homologous variant following the booster vaccination. Formation of de novo humoral response against the mutated epitopes of XBB.1.5 variant’s surface proteins was observed in 3/20 individuals. The booster vaccination had no significant effect on T-cell response.

A novel HIV triple broadly neutralizing antibody (bNAb) combination-based passive immunization of infant rhesus macaques achieves durable protective plasma neutralization levels and mediates anti-viral effector functions.

To eliminate vertical HIV transmission and achieve therapy-free viral suppression among children living with HIV, novel strategies beyond antiretroviral therapy (ART) are necessary. Our group previously identified a triple broadly neutralizing antibody (bNAb) combination comprising of 3BNC117, PGDM1400 and PGT151 that mediates robust in vitro neutralization and non-neutralizing effector functions against a cross-clade panel of simian human immunodeficiency viruses (SHIVs). In this study, we evaluated the safety, pharmacokinetics, and antiviral potency of this bNAb combination in infant rhesus macaques (RMs). We demonstrate that subcutaneous infusion of the triple bNAb regimen was well tolerated in pediatric monkeys and resulted in durable systemic and mucosal distribution. Plasma obtained from passively-immunized RMs demonstrated potent HIV-neutralizing and Fc-mediated antiviral effector functions. Finally, using the predicted serum neutralization 80% inhibitory dilution titer (PT80) biomarker threshold of >200, which was recently identified as a surrogate endpoint for evaluation of the preventative efficacy of bNAbs against mucosal viral acquisition in human clinical trials, we demonstrated that our regimen has PT80>200 against a large panel of plasma and breast milk-derived HIV strains and cross-clade SHIV variants. This data will guide the development of combination bNAbs for eliminating vertical HIV transmission and for achieving ART-free viral suppression among children living with HIV.

Evolving antibody response to SARS-CoV-2 antigenic shift from XBB to JN.1.

The continuous evolution of SARS-CoV-2, particularly the emergence of BA.2.86/JN.1 lineage replacing XBB, necessitates re-evaluation of vaccine compositions 1-3. Here, we provide a comprehensive analysis of the humoral immune response to XBB and JN.1 human exposure. We demonstrate the antigenic distinctiveness of XBB and JN.1 lineages in SARS-CoV-2-naive individuals, and JN.1 infection elicits superior plasma neutralization against its subvariants. We highlight KP.3's strong immune evasion and receptor binding capability, supporting its foreseeable prevalence. Extensive analysis of the BCR repertoire, isolating ~2000 RBD-specific antibodies with their targeting epitopes characterized by deep mutational scanning (DMS), underscores the superiority of JN.1-elicited memory B cells 4,5. Class 1 IGHV3-53/3-66-derived neutralizing antibodies (NAbs) contribute majorly within wildtype-reactive NAbs against JN.1. However, KP.2 and KP.3 evade a substantial subset, even those induced by JN.1, advocating for booster updates to KP.2/KP.3. JN.1-induced Omicron-specific antibodies also demonstrate high potency across Omicron. Escape hotspots of these NAbs have already been mutated, resulting in higher immune barrier to escape, considering probable recovery of escaped NAbs. Additionally, the prevalence of IGHV3-53/3-66-derived antibodies, and their capability of competing with all Omicron-specific NAbs suggests their inhibitory role on the activation of Omicron-specific naive B cells, potentially explaining the heavy immune imprinting in mRNA-vaccinated individuals 6-8. These findings delineate the evolving antibody response to Omicron antigenic shift from XBB to JN.1, and highlight the importance of developing JN.1-lineage, especially KP.2/KP.3-based vaccine boosters.

Analysis of Memory Antibody Responses in Individuals with Zika-Associated Guillain-Barré Syndrome.

The Zika virus (ZIKV) was responsible for a major outbreak in 2015 in the Americas. Infections were associated with increased cases of microcephaly in infants and Guillain-Barré Syndrome (GBS) in adults. Our group previously demonstrated that Zika-associated GBS correlated with the increased neutralization of ZIKV and DENV2, but the antibody specificity was not analyzed. Here, we generated reporter virus particles (RVPs) of ZIKV with specific-point mutations that allowed us to investigate the specificity of circulating plasma antibodies at two different timepoints from individuals with Zika-associated GBS. We found that neutralizing antibody titers to ZIKV waned between one and two years post-ZIKV infection in GBS-negative but not GBS-positive individuals. Interestingly, plasma neutralization by GBS-negative individuals was more sensitive to a mutation at position N154A than plasma from GBS-positive individuals. To determine if waning was associated with different levels of B-cell activation at the time of infection, pro-inflammatory cytokines were measured, but no differences were observed in people with or without GBS. These data suggest subtle differences between GBS-positive and-negative individuals' circulating antibodies, where antibodies from GBS-positive individuals may target different epitopes and remain in circulation longer as compared to GBS-negative individuals.

Potent and broad HIV-1 neutralization in fusion peptide-primed SHIV-infected macaques.

An antibody-based HIV-1 vaccine will require the induction of potent cross-reactive HIV-1-neutralizing responses. To demonstrate feasibility toward this goal, we combined vaccination targeting the fusion-peptide site of vulnerability with infection by simian-human immunodeficiency virus (SHIV). In four macaques with vaccine-induced neutralizing responses, SHIV infection boosted plasma neutralization to 45%-77% breadth (geometric mean 50% inhibitory dilution [ID50] ∼100) on a 208-strain panel. Molecular dissection of these responses by antibody isolation and cryo-electron microscopy (cryo-EM) structure determination revealed 15 of 16 antibody lineages with cross-clade neutralization to be directed toward the fusion-peptide site of vulnerability. In each macaque, isolated antibodies from memory B cells recapitulated the plasma-neutralizing response, with fusion-peptide-binding antibodies reaching breadths of 40%-60% (50% inhibitory concentration [IC50]<50μg/mL) and total lineage-concentrations estimates of 50-200μg/mL. Longitudinal mapping indicated that these responses arose prior to SHIV infection. Collectively, these results provide invivo molecular examples for one to a few B cell lineages affording potent, broadly neutralizing plasma responses.

Multi-omics landscapes reveal heterogeneity in long COVID patients characterized with enhanced neutrophil activity

BackgroundOmicron variant impacts populations with its rapid contagiousness, and part of patients suffered from persistent symptoms termed as long COVID. The molecular and immune mechanisms of this currently dominant global variant leading to long COVID remain unclear, due to long COVID heterogeneity across populations.MethodsWe recruited 66 participants in total, 22 out of 66 were healthy control without COVID-19 infection history, and 22 complaining about long COVID symptoms 6 months after first infection of Omicron, referred as long COVID (LC) Group. The left ones were defined as non-long COVID (NLC) Group. We profiled them via plasma neutralizing antibody titer, SARS-CoV-2 viral load, transcriptomic and proteomics screening, and machine learning.ResultsNo serum residual SARS-CoV-2 was observed in the participants 6 months post COVID-19 infection. No significant difference in neutralizing antibody titers was found between the long COVID (LC) Group and the non-long COVID (NLC) Group. Transcriptomic and proteomic profiling allow the stratification of long COVID into neutrophil function upregulated (NU-LC) and downregulated types (ND-LC). The NU-LC, identifiable through a refined set of 5 blood gene markers (ABCA13, CEACAM6, CRISP3, CTSG and BPI), displays evidence of relatively higher neutrophil counts and function of degranulation than the ND-LC at 6 months after infection, while recovered at 12 months post COVID-19.ConclusionThe transcriptomic and proteomic profiling revealed heterogeneity among long COVID patients. We discovered a subgroup of long COVID population characterized by neutrophil activation, which might associate with the development of psychiatric symptoms and indicate a higher inflammatory state. Meanwhile, a cluster of 5 genes was manually curated as the most potent discriminators of NU-LC from long COVID population. This study can serve as a foundational exploration of the heterogeneity in the pathogenesis of long COVID and assist in therapeutic targeting and detailed epidemiological investigation of long COVID.

Plasma properties in the vicinity of the last closed flux surface in hydrogen and helium fusion plasma discharges

The origin of the bi-Maxwellian electron energy distribution function (EEDF) observed in the scrape-off layer (SOL) of tokamak plasmas by means of Langmuir probes is still under discussion. It has been assumed that the ionization of hydrogen and deuterium neutrals by thermal electrons penetrating the SOL from the bulk plasma is the main reason for the appearance of a second Maxwellian. To validate this assumption, radial measurements of the electron temperatures and densities, or the plasma properties in helium plasmas in the GOLEM tokamak and the TJ-II stellarator were performed. The radial profiles of the low-temperature electron group densities follow the trend of the calculated radial profiles of the electron sources arising from the ionization of neutrals in both deuterium and helium plasmas in TJ-II. The difference in the radial location where the bi-Maxwellian EEDF appears can be explained by the difference in the rate coefficients for ionization of deuterium and helium. The results of probe measurements in GOLEM and the WEST tokamak divertor, at one radial location in the SOL, are compatible with the hypothesis concerning the ionization of neutral atoms and the type of the EEDF.

Plasma proteomics analysis of Chinese HIV-1 infected individuals focusing on the immune and inflammatory factors afford insight into the viral control mechanism.

Long-term non-progressors (LTNPs) with HIV infection can naturally control viral replication for up to a decade without antiretroviral therapy (ART), but the underlying mechanisms of this phenomenon remain elusive. To investigate the relevant immune and inflammatory factors associated with this natural control mechanism, we collected plasma samples from 16 LTNPs, 14 untreated viral progressors (VPs), 17 successfully ART-treated patients (TPs), and 16 healthy controls (HCs). The OLINK immune response panel and inflammation panel were employed to detect critical proteins, and the plasma neutralizing activity against a global panel of pseudoviruses was assessed using TZM-bl cells. The combination of IL17C, IL18, DDX58, and NF2 contributed to discriminating LTNPs and VPs. IL18 and CCL25 were positively associated with CD4+ T cell counts but negatively correlated with viral load. Furthermore, CXCL9 and CXCL10 emerged as potential supplementary diagnostic markers for assessing the efficacy of antiretroviral therapy (ART). Finally, TNFRSF9 displayed positive correlations with neutralization breadth and Geometry Median Titer (GMT) despite the lack of significant differences between LTNPs and VPs. In summary, this study identified a set of biomarkers in HIV-infected individuals at different disease stages. These markers constitute a potential network for immune balance regulation in HIV infection, which is related to the long-term control of HIV by LTNPs. It provides important clues for further exploring the immune regulatory mechanism of HIV.

Evolution of elite plasma neutralizing activity in HIV-1 infected infant following superinfection

Evolution of elite plasma neutralizing activity in HIV-1 infected infant following superinfection

Immune features revealed by single-cell RNA and single-cell TCR/BCR sequencing in patients with rheumatoid arthritis receiving COVID-19 booster vaccination.

Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, have profoundly affected human health. Booster COVID-19 vaccines have demonstrated significant efficacy in reducing infection and severe cases. However, the effects of booster COVID-19 vaccines on key immune cell subsets and their responses in rheumatoid arthritis (RA) are not well understood. By using single-cell RNA sequencing (scRNA-seq) combined with scTCR/BCR-seq analysis, a total of 8 major and 27 minor cell clusters were identified from paired peripheral blood mononuclear cells (PBMCs) which were collected 1 week before and 4 weeks after booster vaccination in stable RA patients. Booster vaccination only had limited impact on the composition and proportions of PBMCs cell clusters. CD8+ cytotoxic T cells (CD8+T_CTL) showed a trend toward an increase after vaccination, while naive B cells and conventional dendritic cells (cDCs) showed a trend toward a decrease. Transcriptomic changes were observed after booster vaccination, primarily involving T/B cell receptor signaling pathways, phagosome, antigen processing and presenting, and viral myocarditis pathways. Interferon (IFN) and pro-inflammatory response gene sets were slightly upregulated across most major cell subpopulations in COVID-19 booster-vaccinated RA individuals. Plasma neutralizing antibody titers significantly increased after booster COVID-19 vaccination (p = 0.037). Single-cell TCR/BCR analysis revealed increased B cell clone expansion and repertoire diversity postvaccination, with no consistent alterations in T cells. Several clonotypes of BCRs and TCRs were identified to be significantly over-represented after vaccination, such as IGHV3-15 and TRBV28. Our study provided a comprehensive single-cell atlas of the peripheral immune response and TCR/BCR immune repertoire profiles to inactivated SARS-CoV-2 booster vaccination in RA patients, which helps us to understand vaccine-induced immune responses better.

One-dimensional, multi-fluid model of the plasma wall transition. I. Hot electrons

The plasma-wall transition in a plasma containing singly charged positive ions and two groups of electrons is studied with a one-dimensional steady-state multifluid model, which is presented in some detail. When the temperature and the initial density ratio between the two groups of electrons are varied, a transition between the two types of solutions to the model equations is observed. When the density and temperature of the hot electrons are above certain critical values, a high solution is observed. If the ion mass is decreased, these critical values increase. However, this effect only occurs with artificially small ion masses, which are significantly lower than the proton mass. In the high solution, the potential drop is determined by the hot electrons and is greater in absolute terms than in the low solution, where it is determined by the base electron population. The transition between the low and high solutions is very sharp if a neutrality condition is imposed. However, if the neutrality condition is replaced by the Poisson equation, the transition becomes blurred and the solutions exhibit oscillations. The temperature profiles of the ions are analyzed, and it is confirmed that the ion sound and the ion fluid velocity become equal at the breaking point of the plasma neutrality. It is shown how the ion source term, the initial ion velocity, and the initial electric field are found to be self-consistent. The density profiles of the negatively biased particles resulting from the fluid equations deviate very little those of from the Boltzmann-distributed particles, even if the corresponding source terms are quite large.

A VRC13-like bNAb response is associated with complex escape pathways in HIV-1 envelope.

The rational design of HIV-1 immunogens to trigger the development of broadly neutralizing antibodies (bNAbs) requires understanding the viral evolutionary pathways influencing this process. An acute HIV-1-infected individual exhibiting >50% plasma neutralization breadth developed neutralizing antibody specificities against the CD4-binding site (CD4bs) and V1V2 regions of Env gp120. Comparison of pseudoviruses derived from early and late autologous env sequences demonstrated the development of >2 log resistance to VRC13 but not to other CD4bs-specific bNAbs. Mapping studies indicated that the V3 and CD4-binding loops of Env gp120 contributed significantly to developing resistance to the autologous neutralizing response and that the CD4-binding loop (CD4BL) specifically was responsible for the developing resistance to VRC13. Tracking viral evolution during the development of this cross-neutralizing CD4bs response identified amino acid substitutions arising at only 4 of 11 known VRC13 contact sites (K282, T283, K421, and V471). However, each of these mutations was external to the V3 and CD4BL regions conferring resistance to VRC13 and was transient in nature. Rather, complete resistance to VRC13 was achieved through the cooperative expression of a cluster of single amino acid changes within and immediately adjacent to the CD4BL, including a T359I substitution, exchange of a potential N-linked glycosylation (PNLG) site to residue S362 from N363, and a P369L substitution. Collectively, our data characterize complex HIV-1 env evolution in an individual developing resistance to a VRC13-like neutralizing antibody response and identify novel VRC13-associated escape mutations that may be important to inducing VRC13-like bNAbs for lineage-based immunogens.IMPORTANCEThe pursuit of eliciting broadly neutralizing antibodies (bNAbs) through vaccination and their use as therapeutics remains a significant focus in the effort to eradicate HIV-1. Key to our understanding of this approach is a more extensive understanding of bNAb contact sites and susceptible escape mutations in HIV-1 envelope (env). We identified a broad neutralizer exhibiting VRC13-like responses, a non-germline restricted class of CD4-binding site antibody distinct from the well-studied VRC01-class. Through longitudinal envelope sequencing and Env-pseudotyped neutralization assays, we characterized a complex escape pathway requiring the cooperative evolution of four amino acid changes to confer complete resistance to VRC13. This suggests that VRC13-class bNAbs may be refractory to rapid escape and attractive for therapeutic applications. Furthermore, the identification of longitudinal viral changes concomitant with the development of neutralization breadth may help identify the viral intermediates needed for the maturation of VRC13-like responses and the design of lineage-based immunogens.

Self‐organization of plasma edge turbulence in interaction with recycling neutrals

AbstractExperimental results from several tokamaks suggest a strong impact of divertor density regimes on turbulent transport in the edge plasma. Reciprocally, the change in transverse transport and SOL width affects the access to density regimes, making it a fundamental topic for heat exhaust issue. Such phenomenology is highly nonlinear and can only be approached quantitatively using numerical simulations treating turbulence and neutrals recycling physics self‐consistently. In this study, the SOLEDGE3X edge multi‐fluid code is used to investigate the mutual interaction between edge plasma turbulence and neutrals recycling. A fluid neutrals model based on the assumption of a charge‐exchange‐dominated plasma‐neutral interaction has been implemented. Two simulations in circular geometry are compared: one without neutrals, where the particle flux is driven by a constant in flux from the core region, and the other one with neutrals recycling included in which the particle input to the system is self‐consistently injected by a gas puff from the midplane. The presence of the neutrals triggers three types of perturbations on the plasma: a local and non‐axisymmetric one driven by the gas puff, a global perturbation affecting both profiles and turbulence properties in the whole domain, and a local one in the vicinity of the limiter where recycling occurs. The largest effect of the inclusion of self‐consistent neutrals recycling is a large‐scale reorganization of the plasma profiles and turbulence properties due to the dissociation of particle and energy fluxes. These effects are expected to be more important at higher densities regimes or in diverted configuration.

B cell repertoire sequencing of HIV-1 pediatric elite-neutralizers identifies multiple broadly neutralizing antibody clonotypes.

A limited subset of HIV-1 infected adult individuals typically after at least 2-3 years of chronic infection, develop broadly neutralizing antibodies (bnAbs), suggesting that highly conserved neutralizing epitopes on the HIV-1 envelope glycoprotein are difficult for B cell receptors to effectively target, during natural infection. Recent studies have shown the evolution of bnAbs in HIV-1 infected infants. We used bulk BCR sequencing (BCR-seq) to profile the B cell receptors from longitudinal samples (3 time points) collected from a rare pair of antiretroviralnaïve, HIV-1 infected pediatric monozygotic twins (AIIMS_329 and AIIMS_330) who displayed elite plasma neutralizing activity against HIV-1. BCR-seq of both twins revealed convergent antibody characteristics including V-gene use, CDRH3 lengths and somatic hypermutation (SHM). Further, antibody clonotypes with genetic features similar to highly potent bnAbs isolated from adults showed ongoing development in donor AIIMS_330 but not in AIIMS_329, corroborating our earlier findings based on plasma bnAbs responses. An increase in SHM was observed in sequences of the IgA isotype from AIIMS_330. This study suggests that children living with chronic HIV-1 can develop clonotypes of HIV-1 bnAbs against multiple envelope epitopes similar to those isolated from adults, highlighting that such B cells could be steered to elicit bnAbs responses through vaccines aimed to induce bnAbs against HIV-1 in a broad range of people including children.

COVID-19 booster enhances IgG mediated viral neutralization by human milk in vitro.

Facilitated by the inability to vaccinate, and an immature immune system, COVID-19 remains a leading cause of death among children. Vaccinated lactating mothers produce specific SARS-CoV-2 antibodies in their milk, capable of neutralizing the virus in vitro. Our objective for this study is to assess the effect of COVID-19 booster dose on SARS-CoV-2 antibody concentration and viral neutralization in milk, plasma, and infant stool. Thirty-nine mothers and 25 infants were enrolled from December 2020 to May 2022. Milk, maternal plasma, and infants' stool were collected at various time-points up to 12 months following mRNA COVID-19 vaccination. A subgroup of 14 mothers received a booster dose. SARS-CoV-2 antibody levels and their neutralization capacities were assessed. Booster vaccination led to significantly higher IgG levels within human milk and breastfed infants' stool. In vitro neutralization of VSV-gfp-SARS-CoV-2-S-gp, a laboratory safe SARS-CoV-2 like pseudovirus, improved following the booster, with a 90% increase in plasma neutralization and a 60% increase in milk neutralization. We found that post-booster neutralization by human milk was highly correlated to SARS-CoV-2 IgG level. In support of our correlation result, Protein G column depletion of IgG in milk yielded a significant reduction in viral neutralization (p = 0.04). The substantial increase in neutralizing IgG levels in milk and breastfed infants' stool post-booster, coupled with the decrease in milk neutralization capabilities upon IgG depletion, underscores the efficacy of booster doses in augmenting the immune response against SARS-CoV-2 in human milk.

Humoral and cell-mediated immune responses in HIV-vertically infected young patients after three doses of the BNT162b2 mRNA SARS-CoV-2 vaccine.

Data on the efficacy of three SARS-CoV-2 mRNA BNT162b2 vaccine doses and the role of previous SARS-CoV-2-infection in enhancing vaccine immunogenicity in HIV-vertically-infected people living with HIV (PLWH) are limited, as is the duration of vaccine-induced responses. SARS-CoV-2 plasma neutralizing activity (NA) against the European (B.1), Delta (B.1.617.2) and Omicron (B.1.1.529) variants and cell-mediated immunity (CMI) were analyzed in 29 ART-treated young PLWH (mean age 27.9 years) and 30 healthy controls (HC) who received three BNT162b2 vaccine doses. Individuals were stratified based on the presence/absence of previous SARS-CoV-2 infection (infected and vaccinated -SIV-; uninfected and vaccinated -SV-). Analyses were performed before vaccination (T0), 25 days from the second dose (T1), the day the third dose was administered (T2), and 3 months after the third dose (T3). In PLWH: i) NA against all variants was higher in SIV compared to SV at T2 and was increased at T3; ii) switched-memory plasmablasts were augmented in SIV alone at T2 and T3; iii) a SARS-CoV-2 specific T cell memory was generated; iv) IFN-γ-secreting CD4+ and CD8+ T lymphocytes were boosted at T3 mainly in SV. CMI magnitude was reduced in PLWH compared to HC. Notably, after the third dose of vaccine viremia was unmodified, but CD4 T cell counts were reduced>20% in 3/29 PHLW. A third dose of BNT162b2 vaccine induces strong humoral and CMI responses in young ART-treated PLWH independently from a previous SARS-CoV-2 natural infection. The lower magnitude of CMI responses should be considered when planning mRNA vaccine booster doses in PLWH.

Characterization of antibody-dependent cellular phagocytosis in patients infected with hepatitis C virus with different clinical outcomes.

Early neutralizing antibodies against hepatitis C virus (HCV) and CD8 + T cell effector responses can lead to viral clearance. However, these functions alone are not sufficient to protect patients against HCV infection, thus undefined additional antiviral immune mechanisms are required. In recent years, Fc-receptor-dependent antibody effector functions, particularly, antibody-dependent cellular phagocytosis (ADCP) were shown to offer immune protection against several RNA viruses. However, its development and clinical role in patients with HCV infection remain unknown. In this study, we found that patients with chronic GT1a or GT3a HCV infection had significantly higher concentrations of anti-envelope 2 (E2) antibodies, predominantly IgG1 subclass, than patients that cleared the viruses while the latter had antibodies with higher affinities. 97% of the patients with HCV had measurable ADCP of whom patients with chronic disease showed significantly higher ADCP than those who naturally cleared the virus. Epitope mapping studies showed that patients with antibodies that target antigenic domains on the HCV E2 protein that are known to associate with neutralization function are also strongly associated with ADCP, suggesting antibodies with overlapping/dual functions. Correlation studies showed that ADCP significantly correlated with plasma anti-E2 antibody levels and neutralization function regardless of clinical outcome and genotype of infecting virus, while a significant correlation between ADCP and affinity was only evident in patients that cleared the virus. These results suggest ADCP was mostly driven by antibody titer in patients with chronic disease while maintained in clearers due to the quality (affinity) of their anti-E2 antibodies despite having lower antibody titers.

Self-consistent multi-component simulation of plasma turbulence and neutrals in detached conditions

Simulations of high-density deuterium plasmas in a lower single-null magnetic configuration based on a TCV discharge are presented. We evolve the dynamics of three charged species (electrons, D+ and D2+ ), interacting with two neutrals species ( D and D2 ) through ionization, charge-exchange, recombination and molecular dissociation processes. The plasma is modelled by using the drift-reduced fluid Braginskii equations, while the neutral dynamics is described by a kinetic model. To control the divertor conditions, a D2 puffing is used and the effect of increasing the puffing strength is investigated. The increase in fuelling leads to an increase of density in the scrape-off layer and a decrease of the plasma temperature. At the same time, the particle and heat fluxes to the divertor target decrease and the detachment of the inner target is observed. The analysis of particle and transport balance in the divertor volume shows that the decrease of the particle flux is caused by a decrease of the local neutral ionization together with a decrease of the parallel velocity, caused by the lower plasma temperature and the increase in momentum losses. The relative importance of the different collision terms is assessed, showing the crucial role of molecular interactions, as they are responsible for increasing the atomic neutral density and temperature, since most of the D neutrals are produced by molecular activated recombination and D2 dissociation. The presence of strong electric fields in high-density plasmas is also shown, revealing the role of the E × B drift in setting the asymmetry between the divertor targets. Simulation results are in agreement with experimental observations of increased density decay length, attributed to a decrease of parallel transport, together with an increase of plasma blob size and radial velocity.

Dissecting the intricacies of human antibody responses to SARS-CoV-1 and SARS-CoV-2 infection

The 2003 severe acute respiratory syndrome coronavirus (SARS-CoV-1) causes more severe disease than SARS-CoV-2, which is responsible for COVID-19. However, our understanding of antibody response to SARS-CoV-1 infection remains incomplete. Herein, we studied the antibody responses in 25 SARS-CoV-1 convalescent patients. Plasma neutralization was higher and lasted longer in SARS-CoV-1 patients than in severe SARS-CoV-2 patients. Among 77 monoclonal antibodies (mAbs) isolated, 60 targeted the receptor-binding domain (RBD) and formed 7 groups (RBD-1 to RBD-7) based on their distinct binding and structural profiles. Notably, RBD-7 antibodies bound to a unique RBD region interfaced with the N-terminal domain of the neighboring protomer (NTD proximal) and were more prevalent in SARS-CoV-1 patients. Broadly neutralizing antibodies for SARS-CoV-1, SARS-CoV-2, and bat and pangolin coronaviruses were also identified. These results provide further insights into the antibody response to SARS-CoV-1 and inform the design of more effective strategies against diverse human and animal coronaviruses.