A Dual-Approach Strategy to Optimize the Safety and Efficacy of Anti-Zika Virus Monoclonal Antibody Therapeutics.

Antibody-dependent enhancement of infection (ADE) is clinically relevant to Dengue virus (DENV) infection and poses a major risk to the application of monoclonal antibody (mAb)-based therapeutics against related flaviviruses such as the Zika virus (ZIKV). Here, we tested a two-tier approach for selecting non-cross-reactive mAbs combined with modulating Fc glycosylation as a strategy to doubly secure the elimination of ADE while preserving Fc effector functions. To this end, we selected a ZIKV-specific mAb (ZV54) and generated three ZV54 variants using Chinese hamster ovary cells and wild-type (WT) and glycoengineered ΔXF Nicotiana benthamiana plants as production hosts (ZV54CHO, ZV54WT, and ZV54ΔXF). The three ZV54 variants shared an identical polypeptide backbone, but each exhibited a distinct Fc N-glycosylation profile. All three ZV54 variants showed similar neutralization potency against ZIKV but no ADE activity for DENV infection, validating the importance of selecting the virus/serotype-specific mAbs for avoiding ADE by related flaviviruses. For ZIKV infection, however, ZV54CHO and ZV54ΔXF showed significant ADE activity while ZV54WT completely forwent ADE, suggesting that Fc glycan modulation may yield mAb glycoforms that abrogate ADE even for homologous viruses. In contrast to the current strategies for Fc mutations that abrogate all effector functions along with ADE, our approach allowed the preservation of effector functions as all ZV54 glycovariants retained antibody-dependent cellular cytotoxicity (ADCC) against the ZIKV-infected cells. Furthermore, the ADE-free ZV54WT demonstrated in vivo efficacy in a ZIKV-infection mouse model. Collectively, our study provides further support for the hypothesis that antibody-viral surface antigen and Fc-mediated host cell interactions are both prerequisites for ADE, and that a dual-approach strategy, as shown herein, contributes to the development of highly safe and efficacious anti-ZIKV mAb therapeutics. Our findings may be impactful to other ADE-prone viruses, including SARS-CoV-2.

Multifaceted roles of Fcγ receptors in COVID-19 and vaccine responses.

Recent data have revealed various effector functions of FcγRs in immune responses against challenges with SARS-CoV-2 virus. FcγRs act as a bridge between antibody specificity and effector cells. In many cases, IgG/FcγR interactions generate cell-mediated immune protection from infection via ADCP or ADCC. These responses are beneficial, as they may participate in virus elimination and persist longer than neutralizing anti-Spike antibodies. In contrast, these interactions may sometimes prove beneficial to the virus by enhancing viral uptake into phagocytic cells via ADE and causing excessive inflammation. Here, we summarize key features of FcγRs, discuss effector functions, clinical relevance, and factors influencing FcγR-mediated immune responses in COVID-19 and vaccine responses, and consider IVIg and kinase inhibitors for targeting FcγRs signaling in COVID-19.

GM Allotypes and COVID-19. A Pilot Study Performed on Sicilian Patients

Several studies suggest that genetic variants that influence the onset, maintenance and resolution of the immune response might be fundamental in predicting the evolution of COVID-19. In the present paper, we analysed the dis-tribution of GM allotypes (the genetic markers of immunoglobulin g chains) in symptomatic and asymptomatic COVID-19 patients and in healthy controls, all born and residing in Sicily. Indeed, the role played by GM allotypes in immune responses and infection control is well known. Our findings show that the GM23 allotype is significantly reduced in healthy controls. Interestingly, in a previous study, Sicilians carrying the GM23 allotype were associated with the risk of developing a symptomatic Human Cytomegalovirus infection. However, a note of caution should be considered, due to the small sample size of patients and controls.

SARS-CoV-2 Spike Expression at the Surface of Infected Primary Human Airway Epithelial Cells.

Different serological assays were rapidly generated to study humoral responses against the SARS-CoV-2 Spike glycoprotein. Due to the intrinsic difficulty of working with SARS-CoV-2 authentic virus, most serological assays use recombinant forms of the Spike glycoprotein or its receptor binding domain (RBD). Cell-based assays expressing different forms of the Spike, as well as pseudoviral assays, are also widely used. To evaluate whether these assays recapitulate findings generated when the Spike is expressed in its physiological context (at the surface of the infected primary cells), we developed an intracellular staining against the SARS-CoV-2 nucleocapsid (N) to distinguish infected from uninfected cells. Human airway epithelial cells (pAECs) were infected with authentic SARS-CoV-2 D614G or Alpha variants. We observed robust cell-surface expression of the SARS-CoV-2 Spike at the surface of the infected pAECs using the conformational-independent anti-S2 CV3-25 antibody. The infected cells were also readily recognized by plasma from convalescent and vaccinated individuals and correlated with several serological assays. This suggests that the antigenicity of the Spike present at the surface of the infected primary cells is maintained in serological assays involving expression of the native full-length Spike.

Asymmetric effects and volatility transmission from metals markets to solar energy stocks: Evidence from DCC, ADCC, and quantile regression approach

Detrimental environmental repercussions have recently given rise to an interest in green investments. Although solar energy stocks are appealing assets for ethical investors, little is known about their dynamic correlations and linkages with metal (silicon, lithium, and rare earth) markets, particularly during economic events which is essential for hedging effectiveness and asset allocation. This study investigates the nexus between metal markets, oil price volatility (OVX), market sentiments (VIX), and solar energy markets using DCC, ADCC models, and the quantile regression approach. The results show both symmetric and asymmetric shock spillover between metals markets, VIX, OVX, and solar energy markets which are more prominent during COVID-19 pandemic, US-China trade frictions, and Russian invasion of Ukraine. For portfolio management, the hedging effectiveness of lithium stocks is highest, followed by silicon and rare earth metals. However, the hedge ratios are time-varying, and the variability is highest during US-China trade frictions. The quantile regression estimates reveal that lithium market is the most persistent determinant of solar energy stocks followed by silicon market even after segregating the periods into Paris Agreement and COVID-19 pandemic. Thus, lithium and silicon are driving markets of solar energy markets and can be a cause of omitted variable bias if stay unobserved. Nonetheless, there is little influence of VIX, rare earth metals, and OVX on solar energy stocks. Lastly, the estimations of threshold regression suggest that market sentiments change the association between metal markets and solar energy markets after the VIX reaches a certain threshold level. © 2023

Longitudinal Neutralizing and Functional Antibody Responses to Severe Acute Respiratory Syndrome Coronavirus 2 Variants Following Messenger RNA Coronavirus Disease 2019 Vaccination.

In this longitudinal prospective cohort of healthy adults in the United States, we found that coronavirus disease 2019 messenger RNA primary series and booster vaccinations elicited high titers of broadly cross-reactive neutralizing and antibody-dependent cell-mediated cytotoxicity antibodies, which gradually waned over 6 months, particularly against severe acute respiratory syndrome coronavirus 2 variants. These data support the indication for a subsequent booster vaccination.

Corrigendum: Fc engineered ACE2-Fc is a potent multifunctional agent targeting SARS-CoV2.

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Augmenting Vaccine Efficacy against Delta Variant with 'Mycobacterium-w'-Mediated Modulation of NK-ADCC and TLR-MYD88 Pathways.

Mycobacterium-w (Mw) was shown to boost adaptive natural killer (ANK) cells and protect against COVID-19 during the first wave of the pandemic. As a follow-up of the trial, 50 healthcare workers (HCW) who had received Mw in September 2020 and subsequently received at least one dose of ChAdOx1 nCoV-19 vaccine (Mw + ChAdOx1 group) were monitored for symptomatic COVID-19 during a major outbreak with the delta variant of SARS-CoV-2 (April-June 2021), along with 201 HCW receiving both doses of the vaccine without Mw (ChAdOx1 group). Despite 48% having received just a single dose of the vaccine in the Mw + ChAdOx1 group, only two had mild COVID-19, compared to 36 infections in the ChAdOx1 group (HR-0.46, p = 0.009). Transcriptomic studies revealed an enhanced adaptive NK cell-dependent ADCC in the Mw + ChAdOx1 group, along with downregulation of the TLR2-MYD88 pathway and concomitant attenuation of downstream inflammatory pathways. This might have resulted in robust protection during the pandemic with the delta variant.

Longitudinal analysis of serum neutralization of SARS-CoV-2 Omicron BA.2, BA.4, and BA.5 in patients receiving monoclonal antibodies.

The emergence of Omicron sublineages impacts the therapeutic efficacy of anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) monoclonal antibodies (mAbs). Here, we evaluate neutralization and antibody-dependent cellular cytotoxicity (ADCC) activities of 6 therapeutic mAbs against Delta, BA.2, BA.4, and BA.5. The Omicron subvariants escape most antibodies but remain sensitive to bebtelovimab and cilgavimab. Consistent with their shared spike sequence, BA.4 and BA.5 display identical neutralization profiles. Sotrovimab is the most efficient at eliciting ADCC. We also analyze 121 sera from 40 immunocompromised individuals up to 6 months after infusion of Ronapreve (imdevimab + casirivimab) or Evusheld (cilgavimab + tixagevimab). Sera from Ronapreve-treated individuals do not neutralize Omicron subvariants. Evusheld-treated individuals neutralize BA.2 and BA.5, but titers are reduced. A longitudinal evaluation of sera from Evusheld-treated patients reveals a slow decay of mAb levels and neutralization, which is faster against BA.5. Our data shed light on antiviral activities of therapeutic mAbs and the duration of effectiveness of Evusheld pre-exposure prophylaxis.

The Fc-effector function of COVID-19 convalescent plasma contributes to SARS-CoV-2 treatment efficacy in mice.

COVID-19 convalescent plasmas (CCPs) are chosen for plasma therapy based on neutralizing titers and anti-Spike immunoglobulin levels. However, CCP characteristics that promote SARS-CoV-2 control are complex and incompletely defined. Using an in vivo imaging approach, we demonstrate that CCPs with low neutralizing (ID50 ≤ 1:250), but moderate to high Fc-effector activity, in contrast to those with poor Fc function, delay mortality and/or improve survival of SARS-CoV-2-challenged K18-hACE2 mice. The impact of innate immune cells on CCP efficacy depended on their residual neutralizing activity. Fractionation of a selected CCP revealed that IgG and Ig(M + A) were required during therapy, but the IgG fraction alone sufficed during prophylaxis. Finally, despite reduced neutralization, ancestral SARS-CoV-2-elicited CCPs significantly delayed Delta and Beta-induced mortality suggesting that Fc-effector functions contribute to immunity against VOCs. Thus, Fc activity of CCPs provide a second line of defense when neutralization is compromised and can serve as an important criterion for CCP selection.

Dynamic risk management in European energy portfolios: Evolution of the role of clean and carbon markets

This paper examines the potential of clean energy stocks and emission permits to reduce downside risk when combining them in a portfolio with dirty energy assets. We propose a strategy for building portfolios that are well diversified between equity energy and carbon markets that takes into account their dynamic price relationship. The asset allocation proposed is framed in a volatility-timing context, which reacts to changing market conditions, holding different weights at different times. To achieve this objective, we use multivariate GARCH models, specifically the Asymmetric Dynamic Conditional Correlations family, which allow us to obtain good estimations of the conditional covariance matrices of the daily asset returns. To determine the weights of the optimum minimum-risk portfolio, we use a method based on Engle and Colacito (2006) to compare the portfolio volatilities obtained with different models. The analysed period runs from January 19, 2010, to April 4, 2022, which, on the one hand, includes more than twelve years of the EU Emissions Trading System (EU ETS) beyond the Phase I pilot;and, on the other, considers the latest crisis episodes (Sovereign debt crisis, Brexit COVID-19, and the recent Russo–Ukrainian war). Our findings show that investing in clean energy companies is now valuable not only because of its contribution to a sustainable energy transition to renewable sources, but also due to its attractiveness from a financial point of view. This fact provides a ray of hope in terms of the climate emergency and avoiding the current geopolitical conflicts principally caused by certain countries’ energy dependence because their energy mix is still heavily overpowered by fossil fuels. The results of this research should encourage investors to decarbonise their equity portfolios, thus promoting the needed alignment of the financial system with the requirements of the energy transition. © 2022 The Authors

Influenza A(H7N9) Pandemic Preparedness: Assessment of the Breadth of Heterologous Antibody Responses to Emerging Viruses from Multiple Pre-Pandemic Vaccines and Population Immunity.

Influenza A(H7N9) viruses remain as a high pandemic threat. The continued evolution of the A(H7N9) viruses poses major challenges in pandemic preparedness strategies through vaccination. We assessed the breadth of the heterologous neutralizing antibody responses against the 3rd and 5th wave A(H7N9) viruses using the 1st wave vaccine sera from 4 vaccine groups: 1. inactivated vaccine with 2.8 µg hemagglutinin (HA)/dose + AS03A; 2. inactivated vaccine with 5.75 µg HA/dose + AS03A; 3. inactivated vaccine with 11.5 µg HA/dose + MF59; and 4. recombinant virus like particle (VLP) vaccine with 15 µg HA/dose + ISCOMATRIX™. Vaccine group 1 had the highest antibody responses to the vaccine virus and the 3rd/5th wave drifted viruses. Notably, the relative levels of cross-reactivity to the drifted viruses as measured by the antibody GMT ratios to the 5th wave viruses were similar across all 4 vaccine groups. The 1st wave vaccines induced robust responses to the 3rd and Pearl River Delta lineage 5th wave viruses but lower cross-reactivity to the highly pathogenic 5th wave A(H7N9) virus. The population in the United States was largely immunologically naive to the A(H7N9) HA. Seasonal vaccination induced cross-reactive neuraminidase inhibition and binding antibodies to N9, but minimal cross-reactive antibody-dependent cell-mediated cytotoxicity (ADCC) antibodies to A(H7N9).

Dynamic Linkage between Bitcoin and Traditional Financial Assets: A Comparative Analysis of Different Time Frequencies.

This study employs the ADCC-GARCH approach to investigate the dynamic correlation between bitcoin and 14 major financial assets in different time-frequency dimensions over the period 2013-2021, for which the risk diversification, hedging and safe-haven properties of bitcoin for those traditional assets are further examined. The results show that, first, bitcoin is positively linked to risk assets, including stock, bond and commodity, and negatively linked to the U.S. dollar, which is a safe-haven asset, so bitcoin is closer in nature to a risk asset than a safe-haven asset. Second, the high short-term volatility and speculative nature of the bitcoin market makes its long-term correlation with other assets stronger than the short-term. Third, the positive linkage between the prices of bitcoin and risk assets increases sharply under extreme shocks (e.g., the outbreak of COVID-19 in early 2020). Fourth, bitcoin can hedge against the U.S. dollar, and in the long term, bitcoin can hedge against the Chinese stock market and act as a safe haven for the U.S. stock market and crude oil. However, for most other traditional assets, bitcoin is only an effective diversifier.

The impact of COVID-19 induced panic on stock market returns: A two-year experience.

This paper explores the relationship between the stock markets of emerging and developed economies and the fear triggered by the COVID-19 pandemic crisis in a period that spans from mid-January 2020 to mid-February 2022. The potential relations are analyzed in terms of Granger causality and dynamic correlation, both from the view of raw undecomposed returns and different time-frequency decompositions derived from a previous wavelet transform screening approach. Overall, our Granger and dynamic correlation results suggest that changes in panic indexes resulting from the COVID-19 pandemic do not have a significant relation with the raw stock market returns, but the reverse occurs in terms of time-frequency decompositions. Correlation analysis also indicates that all countries have a quite similar pattern of phase transitions, with certain stages preceded by a hump and others by a valley, i.e., they exhibit both positive and negative correlations. Despite a gradual reduction in media coverage, both causal relationships and correlations between financial markets and panic indexes held in 2021 and early 2022.

Fc engineered ACE2-Fc is a potent multifunctional agent targeting SARS-CoV2.

Joining a function-enhanced Fc-portion of human IgG to the SARS-CoV-2 entry receptor ACE2 produces an antiviral decoy with strain transcending virus neutralizing activity. SARS-CoV-2 neutralization and Fc-effector functions of ACE2-Fc decoy proteins, formatted with or without the ACE2 collectrin domain, were optimized by Fc-modification. The different Fc-modifications resulted in distinct effects on neutralization and effector functions. H429Y, a point mutation outside the binding sites for FcγRs or complement caused non-covalent oligomerization of the ACE2-Fc decoy proteins, abrogated FcγR interaction and enhanced SARS-CoV-2 neutralization. Another Fc mutation, H429F did not improve virus neutralization but resulted in increased C5b-C9 fixation and transformed ACE2-Fc to a potent mediator of complement-dependent cytotoxicity (CDC) against SARS-CoV-2 spike (S) expressing cells. Furthermore, modification of the Fc-glycan enhanced cell activation via FcγRIIIa. These different immune profiles demonstrate the capacity of Fc-based agents to be engineered to optimize different mechanisms of protection for SARS-CoV-2 and potentially other viral pathogens.

Functional Antibody Responses to Severe Acute Respiratory Syndrome Coronavirus 2 Variants in Children With Coronavirus Disease 2019, Multisystem Inflammatory Syndrome in Children, and After Two Doses of BNT162b2 Vaccination.

BACKGROUND: Although neutralizing antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) correlate with protection against coronavirus disease 2019 (COVID-19), little is known about the neutralizing and antibody-dependent cell-mediated cytotoxicity (ADCC) responses to COVID-19, multisystem inflammatory syndrome in children (MIS-C), and COVID-19 vaccination in children. METHODS: We enrolled children 0-21 years of age with a history of COVID-19 (n = 13), MIS-C (n = 13), or 2 doses of BNT162b2 vaccination (n = 14) into a phlebotomy protocol. We measured pseudovirus neutralizing and functional ADCC antibodies to SARS-CoV-2 variants, including Omicron (B.1.1.529). RESULTS: The primary BNT162b2 vaccination series elicited higher neutralizing and ADCC responses with greater breadth to SARS-CoV-2 variants than COVID-19 or MIS-C, although these were diminished against Omicron. CONCLUSIONS: Serologic responses were significantly reduced against variants, particularly Omicron.

Single domain antibodies derived from ancient animals as broadly neutralizing agents for SARS-CoV-2 and other coronaviruses.

With severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as an emergent human virus since December 2019, the world population is susceptible to coronavirus disease 2019 (COVID-19). SARS-CoV-2 has higher transmissibility than the previous coronaviruses, associated by the ribonucleic acid (RNA) virus nature with high mutation rate, caused SARS-CoV-2 variants to arise while circulating worldwide. Neutralizing antibodies are identified as immediate and direct-acting therapeutic against COVID-19. Single-domain antibodies (sdAbs), as small biomolecules with non-complex structure and intrinsic stability, can acquire antigen-binding capabilities comparable to conventional antibodies, which serve as an attractive neutralizing solution. SARS-CoV-2 spike protein attaches to human angiotensin-converting enzyme 2 (ACE2) receptor on lung epithelial cells to initiate viral infection, serves as potential therapeutic target. sdAbs have shown broad neutralization towards SARS-CoV-2 with various mutations, effectively stop and prevent infection while efficiently block mutational escape. In addition, sdAbs can be developed into multivalent antibodies or inhaled biotherapeutics against COVID-19.

High-affinity FcγRIIIa genetic variants and potent NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) responses contributing to severe COVID-19.

PURPOSE: Host genetic variants in activating natural killer (NK) cell receptors may contribute to differences in severity of COVID-19. NK cell-mediated antibody-mediated cellular cytotoxicity (ADCC) responses play, however, a controversial role in SARS-CoV-2 infections. It is unclear whether proinflammatory and cytotoxic SARS-CoV-2-specific ADCC responses limit disease severity or rather contribute to the immunopathogenesis of severe COVID-19. METHODS: Using a genetic association approach and subsequent in vitro antibody-dependent NK cell activation experiments, we investigated whether genetic variants in the FcγRIIIa-encoding FCGR3A gene, resulting in expression of either a low-affinity or high-affinity variant, and individual SARS-CoV-2-specific ADCC response contribute to COVID-19 severity. RESULTS: In our study, we showed that the high-affinity variant of the FcγRIIIa receptor, 158-V/V, is significantly over-represented in hospitalized and deceased patients with COVID-19, whereas the low-affinity FcγRIIIa-158-F/F variant occurs more frequently in patients with mild COVID-19 (P < .0001). Furthermore, functional SARS-CoV-2 antibody-specific NK cell-mediated ADCC assays revealed that significantly higher proinflammatory ADCC responses occur in hospitalized patients with COVID-19, and are especially observed in NK cells expressing the FcγRIIIa-158-V/V variant (P < .0001). CONCLUSION: Our study provides evidence that pronounced SARS-CoV-2-specific NK cell-mediated ADCC responses are influenced by NK cell FcγRIIIa genetic variants and are a hallmark of severe COVID-19.

Taking on SARS-CoV-2.

A new study sheds light on how SARS-CoV-2 influences the way natural killer cells can recognize and kill infected cells.

The impact of the COVID-19 pandemic on the nexus between the investor’s sentiment and the financial market dynamics: evidence from the Chinese market

Purpose: This study aims to investigate the impact of the COVID-19 pandemic on both of stock prices and investor's sentiment in China during the onset of the COVID-19 crisis. Design/methodology/approach: In this study, the ADCC-GARCH model was used to analyze the asymmetric volatility and the time-varying conditional correlation among the Chinese stock market, the investors' sentiment and its variation. The authors relied on Diebold and Yilmaz (2012, 2014) methodology to construct network-associated measures. Then, the wavelet coherence model was applied to explore the co-movements between these variables. To check the robustness of the study results, the authors referred to the RavenPack COVID sentiments and the Chinese VIX, as other measures of the investor's sentiment using daily data from December 2019 to December 2021. Findings: Using the ADCC-GARCH model, a strong co-movement was found between the investor's sentiment and the Shanghai index returns during the COVID-19 pandemic. The study results provide a significant peak of connectivity between the investor's sentiment and the Chinese stock market return during the 2015–2016 and the end of 2019–2020 turmoil periods. These periods coincide, respectively, with the 2015 Chinese economy recession and the COVID-19 pandemic outbreak. Furthermore, the wavelet coherence analysis confirms the ADCC results, which revealed that the used proxies of the investor's sentiment can detect the Chinese investors' behavior especially during the health crisis. Practical implications: This study provides two main types of implications: on the one hand, for investors since it helps them to understand the economic outlook and accordingly design their portfolio strategy and allocate decisions to optimize their portfolios. On the other hand, for portfolios managers, who should pay attention to the volatility spillovers between investor sentiment and the Chinese stock market to predict the financial market dynamics during crises periods and hedge their portfolios. Originality/value: This study attempted to examine the time-varying interactions between the investor's sentiment proxies and the stock market dynamics. Findings showed that the investor's sentiment is considered a prominent channel of shock spillovers during the COVID-19 crisis, which typically confirms the behavioral contagion theory. © 2022, Emerald Publishing Limited.