Search

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. [ABSTRACT FROM AUTHOR]

Background: Acquired immunity to Plasmodium falciparum malaria is mainly mediated by immunoglobulin G (IgG) targeting erythrocyte membrane protein 1 (PfEMP1). These adhesins mediate infected erythrocyte (IE) sequestration, protecting IEs from splenic destruction. PfEMP1-specific IgG is therefore thought to protect mainly by inhibiting IE sequestration. VAR2CSA-type PfEMP1 mediates placental IE sequestration, putting pregnant women exposed to P falciparum parasites at risk of placental malaria (PM)., Methods: Levels and Fc-afucosylation of VAR2CSA-specific plasma IgG were measured by a modified enzyme-linked immunosorbent assay (FEASI). We also measured the ability of the IgG to inhibit IE adhesion and to induce natural killer (NK) cell degranulation. The results were related to parity and clinical pregnancy outcomes., Results: Parity was positively correlated with levels and Fc-afucosylation of VAR2CSA-specific IgG, and with birth weight and plasma IgG inhibition of IE adhesion in vitro. Fc-afucosylation of VAR2CSA-specific IgG increased NK-cell degranulation. Women with Fc-afucosylated VAR2CSA-specific IgG had a reduced risk of delivering a low birth weight (LBW) baby, but not of PM or anemia., Conclusions: Fc-afucosylated VAR2CSA-specific IgG effectively induced NK-cell degranulation and was associated with protection against LBW, independent of IgG levels. Our study has implications for the development of VAR2CSA-based subunit vaccines, which exclusively induce Fc-fucosylated IgG., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

We compared the ability of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike-specific antibodies to induce natural killer cell-mediated antibody-dependent cellular cytotoxicity (ADCC) in patients with natural infection and vaccinated persons. Analyzing plasma samples from 39 coronavirus disease 2019 (COVID-19) patients and 11 vaccinated individuals, significant induction of ADCC could be observed over a period of more than 3 months in both vaccinated and recovered individuals. Although plasma antibody concentrations were lower in recovered patients, we found antibodies elicited by natural infection induced a significantly stronger ADCC response compared to those induced by vaccination, which may affect protection conferred by vaccination. [ABSTRACT FROM AUTHOR]

Background: There are limited data regarding immunological correlates of protection for the modified vaccinia Ankara (MVA) smallpox vaccine.Methods: A total of 523 vaccinia-naive subjects were randomized to receive 2 vaccine doses, as lyophilized MVA given subcutaneously, liquid MVA given subcutaneously (liquid-SC group), or liquid MVA given intradermally (liquid-ID group) 28 days apart. For a subset of subjects, antibody-dependent cellular cytotoxicity (ADCC), interferon-γ release enzyme-linked immunospot (ELISPOT), and protein microarray antibody-binding assays were conducted. Protein microarray responses were assessed for correlations with plaque reduction neutralization titer (PRNT), enzyme-linked immunosorbent assay, ADCC, and ELISPOT results.Results: MVA elicited significant microarray antibody responses to 15 of 224 antigens, mostly virion membrane proteins, at day 28 or 42, particularly WR113/D8L and WR101H3L. In the liquid-SC group, responses to 9 antigens, including WR113/D8L and WR101/H3L, correlated with PRNT results. Three were correlated in the liquid-ID group. No significant correlations were observed with ELISPOT responses. In the liquid-ID group, WR052/F13L, a membrane glycoprotein, correlated with ADCC responses.Conclusions: MVA elicited antibodies to 15 vaccinia strain antigens representing virion membrane. Antibody responses to 2 proteins strongly increased and significantly correlated with increases in PRNT. Responses to these proteins are potential correlates of protection and may serve as immunogens for future vaccine development.Clinical Trials Registration: NCT00914732. [ABSTRACT FROM AUTHOR]

Background: Human cytomegalovirus (HCMV) may cause severe infections in lung transplant recipients (LTRs). The impact of the host antibody (AB)-dependent cytotoxicity (ADCC) on HCMV is still unclear. Therefore, we analyzed the AB-response against HCMV glycoprotein B (gB) and the pentameric complex (PC) and the ADCC response in HCMV-seropositive (R+) LTRs and in seronegative recipients of positive organs (D+/R-).Methods: Plasma samples were collected from 35 R+ and 28 D+/R- LTRs for 1 (R+) or 2 (D+/R-) years posttransplantation and from 114 healthy control persons. The PC- and gB-specific ABs were assessed by enzyme-linked immunosorbent assay. The ADCC was analyzed by focal expansion assay and CD107 cytotoxicity assay.Results: In R+ LTRs, significantly higher gB-specific AB levels developed within 1 year posttransplantation than in controls (immunoglobulin [Ig]G1, P < .001; IgG3, P < .001). In addition, higher levels of ADCC were observed by FEA and CD107 assay in R+ patients compared with controls (P < .001). In 23 D+R- patients, HCMV-specific ABs developed. Antibody-dependent cytotoxicity became detectable 3 months posttransplantation in these, with higher ADCC observed in viremic patients. Depletion of gB- and PC-specific ABs revealed that, in particular, gB-specific Abs were associated with the ADCC response.Conclusions: We show that a strong ADCC is elicited after transplantation and is especially based on gB-specific ABs. [ABSTRACT FROM AUTHOR]

Human infections caused by avian influenza A(H7N9) viruses have raised concerns of a pandemic. The capability of the current stockpiled A(H7N9) vaccines to induce cross-protective, nonneutralizing functional antibodies against antigenically drifted A(H7N9) viruses has not been evaluated before. Here we show that vaccination with either MF59- or AS03-adjuvanted inactivated A(H7N9) vaccines elicited robust, cross-reactive antibody-dependent cell-mediated cytotoxicity-mediating and neuraminidase-inhibiting functional antibodies against the antigenically drifted A(H7N9) viruses that emerged recently during the fifth-wave outbreak in China, including a highly pathogenic A(H7N9) human isolate. Such cross-reactive humoral immunity may provide vital first-line defense against fatal outcomes in case of an A(H7N9) pandemic. [ABSTRACT FROM AUTHOR]

Disease progression of human immunodeficiency virus type 1 (HIV-1) is delayed by HIV type 2 (HIV-2) in individuals with dual HIV-1/HIV-2 infection. The protective mechanisms, however, are still to be revealed. In the current study we examined type-specific and cross-reactive antibody-dependent cellular cytotoxicity (ADCC) in HIV-1 and HIV-2 monoinfection or dual infection. Of note, intertype cross-reactive antibodies that mediated HIV-1 envelope glycoprotein (Env)-targeted ADCC were frequently identified in HIV-2-infected individuals. Furthermore, the magnitude of HIV-1 cross-reactive ADCC activity during HIV-2 infections depended on the HIV-1 Env origin and was associated with the duration of infection. These results suggest that preexisting antibodies against HIV-2, which mediate intertype ADCC, might contribute to control of HIV-1 during dual infection. [ABSTRACT FROM AUTHOR]

Background: In the RV144 trial, human immunodeficiency virus (HIV)-1 gp120 V1V2 antibodies correlated inversely with risk of HIV-1 infection; however, the titers waned quickly. We hypothesized that a more potent adjuvant might enhance the magnitude and durability of V1V2 antibodies.Methods: We examined archived sera from a phase I randomized, double-blind placebo-controlled trial, conducted in HIV-1-uninfected individuals, vaccinated with HIV-1SF-2 rgp120 either adsorbed to aluminum hydroxide (aluminum hydroxide arm) or encapsulated in liposomes containing monophosphoryl lipid A (MPL®) and then adsorbed to aluminum hydroxide (liposomal arm).Results: The median immunoglobulin G antibody titers across weeks 10-112 were higher in the liposomal arm against subtypes B (2- to 16-fold), AE (4- to 8-fold), and C (4- to 16-fold) V1V2 proteins. High titers were maintained even at 10 months after last boost in the liposomal compared with the aluminum hydroxide arm. The antibodies exhibited antibody-dependent cellular cytotoxicity (ADCC) and α4β7-integrin receptor inhibition-binding functions.Conclusions: Inclusion of 2 adjuvants in the vaccine formulation, aluminum hydroxide, and liposomal MPL®, induced robust, durable, and functional antibodies. Based on the magnitude of antibody responses and the percentage of coiled and β-sheet in the predicted V2/V3-peptide structure, we speculate that liposomal gp120 was presented in a conformation that favored the induction of robust antibody responses. [ABSTRACT FROM AUTHOR]

Background: New treatments for severe influenza are needed. Passive transfer of influenza-specific hyperimmune pooled immunoglobulin (Flu-IVIG) boosts neutralizing antibody responses to past strains in influenza-infected subjects. The effect of Flu-IVIG on antibodies with Fc-mediated functions, which may target diverse influenza strains, is unclear.Methods: We studied the capacity of Flu-IVIG, relative to standard IVIG, to bind to Fcγ receptors and mediate antibody-dependent cellular cytotoxicity in vitro. The effect of Flu-IVIG infusion, compared to placebo infusion, was examined in serial plasma samples from 24 subjects with confirmed influenza infection in the INSIGHT FLU005 pilot study.Results: Flu-IVIG contains higher concentrations of Fc-functional antibodies than IVIG against a diverse range of influenza hemagglutinins. Following infusion of Flu-IVIG into influenza-infected subjects, a transient increase in Fc-functional antibodies was present for 1-3 days against infecting and noninfecting strains of influenza.Conclusions: Flu-IVIG contains antibodies with Fc-mediated functions against influenza virus, and passive transfer of Flu-IVIG increases anti-influenza Fc-functional antibodies in the plasma of influenza-infected subjects. Enhancement of Fc-functional antibodies to a diverse range of influenza strains suggests that Flu-IVIG infusion could prove useful in the context of novel influenza virus infections, when there may be minimal or no neutralizing antibodies in the Flu-IVIG preparation. [ABSTRACT FROM AUTHOR]

The article presents comments of the author on an effective cytomegalovirus (CMV) vaccine. It is stated that CMV gB vaccine was extensively studied in clinical trials and was developed in the late 1980s by Chiron Corp. after acquisition by Sanofi-Pasteur in the 1990s. It is noted that clinical trials performed with the gB vaccine have targeted 2 groups of individuals in particular need of vaccination.

Herpes simplex virus (HSV) infections manifest as recurrent oral or genital mucosal lesions, meningoencephalitis, corneal blindness, and perinatal disease. Subunit vaccines have advanced into the clinic without success. None were tested preclinically in male mice. We compared a single-cycle candidate vaccine deleted in HSV-2 glycoprotein D (ΔgD-2) and subunit gD-2 or gD-1 protein vaccines in a male murine skin model. The ΔgD-2 provided complete protection against 10 times the lethal dose of HSV-1 or HSV-2 clinical isolates, and no latent virus was detected, whereas gD-1- and gD-2-adjuvanted proteins provided little or no protection. Protection correlated with Fc receptor activating but not neutralizing antibody titers. [ABSTRACT FROM AUTHOR]

Background: Older adults are at high risk of influenza disease, but generally respond poorly to vaccination. Antibody-dependent cellular cytotoxicity (ADCC) may be an important component of protection against influenza infection. An improved understanding of the ADCC response to influenza vaccination in older adults is required.Methods: We studied sera samples from 3 groups of subjects aged ≥65 years (n = 16-17/group) receiving the 2008/2009 seasonal trivalent influenza vaccine (TIV). Subjects had minimal pre-existing hemagglutination inhibiting (HAI) antibodies and TIV induced either no, low, or high HAI responses. Serum ADCC activity was analyzed using Fc receptor cross-linking, NK cell activation, and influenza-infected cell killing.Results: Most subjects from TIV nonresponder, low responder, and high responder groups had detectable ADCC antibodies prevaccination, but baseline ADCC was not predictive of HAI vaccine responsiveness. Interestingly, ADCC and HAI responses tracked closely across all groups, against all 3 TIV hemagglutinins, and in all ADCC assays tested.Conclusions: Older adults commonly have pre-existing ADCC antibodies in the absence of high HAI titers to circulating influenza strains. In older vaccinees, ADCC response mirrored HAI antibodies and was readily detectable despite high postvaccination HAI titers. Alternate measures of vaccine responsiveness and improved vaccinations in this at-risk group are needed. [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus (HIV) type 1 uses the CD4 molecule as its principal receptor to infect T cells. HIV-1 integrates its viral genome into the host cell, leading to persistent infection wherein HIV-1 can remain transcriptionally silent in latently infected CD4+ T cells. On reactivation of replication-competent provirus, HIV-1 envelope glycoproteins (Env) are expressed and accumulate on the cell surface, allowing infected cells to be detected and targeted by endogenous immune responses or immune interventions. HIV-1 Env-specific antibodies have the potential to bind HIV-1 cell surface Env and promote elimination of infected CD4+ T cells by recruiting cytotoxic effector cells, such as natural killer cells, monocytes, and polymorphonuclear cells. Harnessing humoral and innate cellular responses has become one focus of research to develop innovative strategies to recruit and redirect cytotoxic effector cells to eliminate the HIV-1 latently infected CD4+ T-cell reservoir. [ABSTRACT FROM AUTHOR]

Antibodies that mediate antibody-dependent cellular cytotoxicity (ADCC) against avian influenza virus subtypes, including H7N9 and H5N1, have been detected in human sera. Using NK cell activation and NK cytotoxicity assays, we compared ADCC-mediating antibodies (ADCC-Abs) in sera collected from healthy infants, children and adults against H7N9 virus-infected cells and recombinant hemagglutinin (HA), neuraminidase (NA), and nucleoprotein (NP) proteins. High titers of ADCC-Abs against H7N9 virus-infected cells were detected in sera from adults and children but not infants. ADCC-Abs titers directed against H7N9 HA or NA proteins. Further analysis showed that ADCC-Abs titers were significantly higher toward H7N9 NP, as compared with H7N9 HA or NA proteins, and correlated strongly with ADCC-Abs titers against H7N9 virus-infected cells. Indeed, ADCC-Abs to NPs of seasonal H1N1 and H3N2 viruses correlated strongly with ADCC-Abs to H7N9 NP, suggesting that seasonal influenza infections and vaccinations may induce these cross-reactive antibodies. Targeting ADCC-Abs to internal proteins may be a potential mechanism of universal vaccine design. [ABSTRACT FROM AUTHOR]

Cross-reactive influenza virus-specific antibody-dependent cellular cytotoxicity (ADCC)-activating antibodies are readily detected in healthy adults. However, little is known about the kinetics of these ADCC responses. We used retrospective serial blood samples from healthy donors to investigate this topic. All donors had ADCC responses against 2009 pandemic influenza A(H1N1) virus (A[H1N1]pdm09) and avian influenza A(H7N9) virus hemagglutinins (HAs) despite being seronegative for these viruses in standard hemagglutination inhibition and microneutralization serological assays. A(H1N1)pdm09 exposure did not boost ADCC responses specific for H7 HA antigens. H7 HA ADCC responses were variable longitudinally within donors, suggesting that these cross-reactive antibodies are unstable. We found no correlation between ADCC responses to the H7 HA and either influenza virus-specific immunoglobulin G1 concentration or age. [ABSTRACT FROM AUTHOR]

Background: Nonneutralizing antibodies (Abs) involved in antibody-dependent cellular cytotoxicity (ADCC) may provide some protection from influenza virus infection. The ability of influenza vaccines to induce ADCC-mediating Abs (ADCC-Abs) in adults and children is unclear.Methods: We quantified ADCC-Abs in serum samples from adults who received a dose of inactivated subunit vaccine (ISV) targeting monovalent 2009 pandemic influenza A(H1N1) virus or live-attenuated influenza vaccine (LAIV) or who had laboratory-confirmed influenza A(H1N1) virus infection. We also measured ADCC-Abs in children who either received a dose of trivalent seasonal ISV followed by trivalent seasonal LAIV or 2 doses of LAIV. Finally, we assessed the ability of low and high ADCC-Ab titers to protect adults from experimental challenge with influenza A/Wisconsin/67/131/2005(H3N2) virus.Results: Adults and children who received a dose of ISV had a robust increase in ADCC-Ab titers to both recombinant hemagglutinin (rHA) protein and homologous virus-infected cells. There was no detectable increase in titers of ADCC-Abs to rHA or virus-infected cells in adults and children who received LAIV. Higher titers (≥320) of preexisting ADCC-Abs were associated with lower virus replication and a significant reduction in total symptom scores in experimentally infected adults.Conclusions: ADCC-Ab titers increased following experimental influenza virus infection in adults and after ISV administration in both children and adults. [ABSTRACT FROM AUTHOR]

Background. Intravenous immunoglobulin (IVIG) is a purified pool of human antibodies from thousands of donors that is used to prevent or treat primary immune deficiency, several infectious diseases, and autoimmune diseases. The antibodies that mediate antibody-dependent cellular cytotoxicity (ADCC) against heterologous influenza strains may be present in IVIG preparations.Methods. We tested 8 IVIG preparations prior to the 2009 H1N1 swine-origin influenza pandemic and 10 IVIG preparations made after 2010 for their ability to mediate influenza-specific ADCC.Results. ADCC mediating antibodies to A(H1N1)pdm09 hemagglutinin (HA) and neuraminidase (NA) were detected in IVIG preparations prior to the 2009-H1N1 pandemic. The HA-specific ADCC targeted both the HA1 and HA2 regions of A(H1N1)pdm09 HA and was capable of recognizing a broad range of HA proteins including those from recent avian influenza strains A(H5N1) and A(H7N9). The low but detectable ADCC recognition of A(H7N9) was likely due to rare individuals in the population contributing cross-reactive antibodies to IVIG.Conclusions. IVIG preparations contain broadly cross-reactive ADCC mediating antibodies. IVIG may provide at least some level of protection for individuals at high risk of severe influenza disease, especially during influenza pandemics prior to the development of effective vaccines. [ABSTRACT FROM AUTHOR]

Background. During the 2009 pandemic of influenza A virus subtype H1N1 (A[H1N1]pdm09) infection, older individuals were partially protected from severe disease. It is not known whether preexisting antibodies with effector functions such as antibody-dependent cellular cytotoxicity (ADCC) contributed to the immunity observed.Methods. We tested serum specimens obtained from 182 individuals aged 1–72 years that were collected either immediately before or after the A(H1N1)pdm09 pandemic for ADCC antibodies to the A(H1N1)pdm09 hemagglutinin (HA) protein.Results. A(H1N1)pdm09 HA-specific ADCC antibodies were detected in almost all individuals aged >45 years (28/31 subjects) before the 2009 A(H1N1) pandemic. Conversely, only approximately half of the individuals aged 1–14 years (11/31) and 15–45 years (17/31) had cross-reactive ADCC antibodies before the 2009 A(H1N1) pandemic. The A(H1N1)pdm09-specific ADCC antibodies were able to efficiently mediate the killing of influenza virus–infected respiratory epithelial cells. Further, subjects >45 years of age had higher ADCC titers to a range of seasonal H1N1 HA proteins, including from the 1918 virus, compared with younger individuals.Conclusions. ADCC antibodies may have contributed to the protection exhibited in older individuals during the 2009 A(H1N1) pandemic. This work has significant implications for improved vaccination strategies for future influenza pandemics. [ABSTRACT FROM AUTHOR]

Background: Older adults are at high risk of influenza disease, but generally respond poorly to vaccination. Antibody-dependent cellular cytotoxicity (ADCC) may be an important component of protection against influenza infection. An improved understanding of the ADCC response to influenza vaccination in older adults is required., Methods: We studied sera samples from 3 groups of subjects aged ≥65 years (n = 16-17/group) receiving the 2008/2009 seasonal trivalent influenza vaccine (TIV). Subjects had minimal pre-existing hemagglutination inhibiting (HAI) antibodies and TIV induced either no, low, or high HAI responses. Serum ADCC activity was analyzed using Fc receptor cross-linking, NK cell activation, and influenza-infected cell killing., Results: Most subjects from TIV nonresponder, low responder, and high responder groups had detectable ADCC antibodies prevaccination, but baseline ADCC was not predictive of HAI vaccine responsiveness. Interestingly, ADCC and HAI responses tracked closely across all groups, against all 3 TIV hemagglutinins, and in all ADCC assays tested., Conclusions: Older adults commonly have pre-existing ADCC antibodies in the absence of high HAI titers to circulating influenza strains. In older vaccinees, ADCC response mirrored HAI antibodies and was readily detectable despite high postvaccination HAI titers. Alternate measures of vaccine responsiveness and improved vaccinations in this at-risk group are needed., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Combination antiretroviral therapy (cART) effectively controls human immunodeficiency virus (HIV) infection but does not eliminate HIV, and lifelong treatment is therefore required. HIV-specific cytotoxic T lymphocyte (CTL) responses decline following cART initiation. Alterations in other HIV-specific immune responses that may assist in eliminating latent HIV infection, specifically antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent phagocytosis (ADP), are unclear., Methods: A cohort of 49 cART-naive HIV-infected subjects from Thailand (mean baseline CD4 count, 188 cells/µL; mean viral load, 5.4 log10 copies/mL) was followed for 96 weeks after initiating cART. ADCC and ADP assays were performed using serum samples obtained at baseline and after 96 weeks of cART., Results: A 35% reduction in HIV type 1 envelope (Env)-specific ADCC-mediated killing of target cells (P<.001) was observed after 96 weeks of cART. This was corroborated by a significant reduction in the ability of Env-specific ADCC antibodies to activate natural killer cells (P<.001). Significantly reduced ADP was also observed after 96 weeks of cART (P=.018)., Conclusions: This longitudinal study showed that cART resulted in significant reductions of HIV-specific effector antibody responses, including ADCC and ADP. Therapeutic vaccines or other immunomodulatory approaches may be required to improve antibody-mediated control of HIV during cART., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)