Author Correction: Convalescent plasma for hospitalized patients with COVID-19: an open-label, randomized controlled trial (Nature Medicine, (2021), 27, 11, (2012-2024), 10.1038/s41591-021-01488-2)

In the version of this Article initially published, there was an omission in the member list for the CONCOR-1 Study Group. Valérie Arsenault (Héma-Québec, Montreal, Quebec, Canada) has now been included in the CONCOR-1 Study Group in the online version of the article

Integrated immunovirological profiling validates plasma SARS-CoV-2 RNA as an early predictor of COVID-19 mortality.

peer reviewedDespite advances in COVID-19 management, identifying patients evolving toward death remains challenging. To identify early predictors of mortality within 60 days of symptom onset (DSO), we performed immunovirological assessments on plasma from 279 individuals. On samples collected at DSO11 in a discovery cohort, high severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral RNA (vRNA), low receptor binding domain–specific immunoglobulin G and antibody-dependent cellular cytotoxicity, and elevated cytokines and tissue injury markers were strongly associated with mortality, including in patients on mechanical ventilation. A three-variable model of vRNA, with predefined adjustment by age and sex, robustly identified patients with fatal outcome (adjusted hazard ratio for log-transformed vRNA = 3.5). This model remained robust in independent validation and confirmation cohorts. Since plasma vRNA’s predictive accuracy was maintained at earlier time points, its quantitation can help us understand disease heterogeneity and identify patients who may benefit from new therapies

SARS-CoV-2 Accessory Protein ORF8 Decreases Antibody-Dependent Cellular Cytotoxicity

Viruses use many different strategies to evade host immune responses. In the case of SARS-CoV-2, its Spike mutates rapidly to escape from neutralizing antibodies. In addition to this strategy, ORF8, a small accessory protein encoded by SARS-CoV-2, helps immune evasion by reducing the susceptibility of SARS-CoV-2-infected cells to the cytotoxic CD8+ T cell response. Interestingly, among all accessory proteins, ORF8 is rapidly evolving and a deletion in this protein has been linked to milder disease. Here, we studied the effect of ORF8 on peripheral blood mononuclear cells (PBMC). Specifically, we found that ORF8 can bind monocytes as well as NK cells. Strikingly, ORF8 binds CD16a (FcγRIIIA) with nanomolar affinity and decreases the overall level of CD16 at the surface of monocytes and, to a lesser extent, NK cells. This decrease significantly reduces the capacity of PBMCs and particularly monocytes to mediate antibody-dependent cellular cytotoxicity (ADCC). Overall, our data identifies a new immune-evasion activity used by SARS-CoV-2 to escape humoral responses

A Recent SARS-CoV-2 Infection Enhances Antibody-Dependent Cellular Cytotoxicity against Several Omicron Subvariants following a Fourth mRNA Vaccine Dose

Since the beginning of the SARS-CoV-2 pandemic, several variants of concern (VOCs), such as the Alpha, Beta, Gamma, Delta and Omicron variants, have arisen and spread worldwide. Today, the predominant circulating subvariants are sublineages of the Omicron variant, which have more than 30 mutations in their Spike glycoprotein compared to the ancestral strain. The Omicron subvariants were significantly less recognized and neutralized by antibodies from vaccinated individuals. This resulted in a surge in the number of infections, and booster shots were recommended to improve responses against these variants. While most studies mainly measured the neutralizing activity against variants, we and others previously reported that Fc-effector functions, including antibody-dependent cellular cytotoxicity (ADCC), play an important role in humoral responses against SARS-CoV-2. In this study, we analyzed Spike recognition and ADCC activity against several Omicron subvariants by generating cell lines expressing different Omicron subvariant Spikes. We tested these responses in a cohort of donors, who were recently infected or not, before and after a fourth dose of mRNA vaccine. We showed that ADCC activity is less affected than neutralization by the antigenic shift of the tested Omicron subvariant Spikes. Moreover, we found that individuals with a history of recent infection have higher antibody binding and ADCC activity against all Omicron subvariants than people who were not recently infected. With an increase in the number of reinfections, this study helps better understand Fc-effector responses in the context of hybrid immunity

Incorporating the Cluster A and V1V2 Targets into a Minimal Structural Unit of the HIV-1 Envelope to Elicit a Cross-Clade Response with Potent Fc-Effector Functions

The generation of a potent vaccine for the prevention and/or control of HIV-1 has been unsuccessful to date, despite decades of research. Existing evidence from both infected individuals and clinical trials support a role for non-neutralizing or weakly neutralizing antibodies with potent Fc-effector functions in the prevention and control of HIV-1 infection. Vaccination strategies that induce such antibodies have proven partially successful in preventing HIV-1 infection. This is largely thought to be due to the polyclonal response that is induced in a vaccine setting, as opposed to the infusion of a single therapeutic antibody, which is capable of diverse Fc-effector functions and targets multiple but highly conserved epitopes. Here, we build on the success of our inner domain antigen, ID2, which incorporates conformational CD4-inducible (CD4i) epitopes of constant region 1 and 2 (C1C2 or Cluster A), in the absence of neutralizing antibody epitopes, into a minimal structural unit of gp120. ID2 has been shown to induce Cluster A-specific antibodies in a BALB/c mouse model with Fc-effector functions against CD4i targets. In order to generate an immunogen that incorporates both epitope targets implicated in the protective Fc-effector functions of antibodies from the only partially successful human vaccine trial, RV144, we incorporated the V1V2 domain into our ID2 antigen generating ID2-V1V2, which we used to immunize in combination with ID2. Immunized BALB/c mice generated both Cluster A- and V1V2-specific antibodies, which synergized to significantly improve the Fc-mediated effector functions compared to mice immunized with ID2 alone. The sera were able to mediate both antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). We therefore conclude that ID2-V1V2 + ID2 represents a promising vaccine immunogen candidate for the induction of antibodies with optimal Fc-mediated effector functions against HIV-1

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

Humoral Responses Elicited after a Fifth Dose of SARS-CoV-2 mRNA Bivalent Vaccine

While an important part of the world’s population is vaccinated against SARS-CoV-2, new variants continue to emerge. We observe that even after a fifth dose of the mRNA bivalent vaccine, most vaccinated individuals have antibodies that poorly neutralize several Omicron subvariants, including BQ.1.1, XBB, XBB.1.5, FD.1.1, and CH.1.1. However, Fc-effector functions remain strong and stable over time against new variants, which may partially explain why vaccines continue to be effective. We also observe that donors who have been recently infected have stronger antibody functional activities, including neutralization and Fc-effector functions, supporting the observations that hybrid immunity leads to better humoral responses

Cross-Sectional Evaluation of Humoral Responses against SARS-CoV-2 Spike

International audienceSARS-CoV-2 is responsible for the coronavirus disease 2019 (COVID-19) pandemic, infecting millions of people and causing hundreds of thousands of deaths. The Spike glycoproteins of SARS-CoV-2 mediate viral entry and are the main targets for neutralizing antibodies. Understanding the antibody response directed against SARS-CoV-2 is crucial for the development of vaccine, therapeutic, and public health interventions. Here, we perform a cross-sectional study on 106 SARS-CoV-2-infected individuals to evaluate humoral responses against SARS-CoV-2 Spike. Most infected individuals elicit anti-Spike antibodies within 2 weeks of the onset of symptoms. The levels of receptor binding domain (RBD)-specific immunoglobulin G (IgG) persist over time, and the levels of anti-RBD IgM decrease after symptom resolution. Although most individuals develop neutralizing antibodies within 2 weeks of infection, the level of neutralizing activity is significantly decreased over time. Our results highlight the importance of studying the persistence of neutralizing activity upon natural SARS-CoV-2 infection