Molecular basis of SARS-CoV-2 Omicron variant evasion from shared neutralizing antibody response.

Understanding the molecular features of neutralizing epitopes is important for developing vaccines/therapeutics against emerging SARS-CoV-2 variants. We describe three monoclonal antibodies (mAbs) generated from COVID-19 recovered individuals during the first wave of the pandemic in India. These mAbs had publicly shared near germline gene usage and potently neutralized Alpha and Delta, poorly neutralized Beta, and failed to neutralize Omicron BA.1 SARS-CoV-2 variants. Structural analysis of these mAbs in complex with trimeric spike protein showed that all three mAbs bivalently bind spike with two mAbs targeting class 1 and one targeting a class 4 receptor binding domain epitope. The immunogenetic makeup, structure, and function of these mAbs revealed specific molecular interactions associated with the potent multi-variant binding/neutralization efficacy. This knowledge shows how mutational combinations can affect the binding or neutralization of an antibody, which in turn relates to the efficacy of immune responses to emerging SARS-CoV-2 escape variants.

Correction: Current status of therapeutic monoclonal antibodies against SARS-CoV-2.

[This corrects the article DOI: 10.1371/journal.ppat.1009885.].

Structural Profiles of SARS-CoV-2 Variants in India.

India was severely affected by several waves of SARS-CoV-2 infection that occurred during April-June 2021 (second wave) and December 2021-January 2022 (third wave) and thereafter, resulting in >10 million new infections and a significant number of deaths. Global Initiative on Sharing Avian Influenza Data database was used to collect the sequence information of ~10,000 SARS-CoV-2 patients from India and our sequence analysis identified three variants B.1.1.7 (alpha, α), B1.617.2 (delta, Δ), B.1.1.529 (Omicron, Oo) and one Omicron sub-variant BA.2.75 as the primary drivers for SARS-CoV-2 waves in India. Structural visualization and analysis of important mutations of alpha, delta, Omicron and its sub-variants of SARS-CoV-2 Receptor-Binding Domain (RBD) was performed and our analysis clearly shows that mutations occur throughout the RBD, including the RBD surface responsible for human angiotensin-converting enzyme 2 (hACE-2) receptor-binding. A comparison between alpha, delta and omicron variants/sub-variants reveals many omicron mutations in the hACE-2 binding site and several other mutations within 5 Å of this binding region. Further, computational analysis highlights the importance of electrostatic interactions in stabilizing RBD-hACE-2-binding, especially in the omicron variant. Our analysis explores the likely role of key alpha, delta and omicron mutations on binding with hACE-2. Taken together, our study provides novel structural insights into the implications of RBD mutations in alpha, delta and omicron and its sub-variants that were responsible for India's SARS-CoV-2 surge.

Profiles of host immune impairment in Plasmodium and SARS-CoV-2 infections.

Over the past two decades, many countries that have reported a steady decline in reported cases of malaria and a few countries like China have been declared malaria-free by the World Health Organization. In 2020, global total malaria cases 108 malaria-endemic countries as in 2000, while the number of deaths from malaria has declined since 2000. COVID-19 pandemic has adversely affected overall public health efforts and thus it is feasible that there might be resurgence of malaria. COVID-19 and malaria share some similarities in the immune responses of the patient and these two diseases also share overlapping early symptoms such as fever, headache, nausea, and muscle pain/fatigue. In the absence of early diagnostics there can be a misdiagnosis of the infection(s) that can pose additional challenges due to delayed treatment. In both SARS-CoV-2 and Plasmodium infections there is a rapid release of cytokines/chemokines that play a key role in disease pathophysiology. In this review, we have discussed the cytokine/chemokine storm observed during COVID-19 and malaria. We observe that: (1) Severity in malaria and COVID-19 is likely a consequence primarily of an uncontrolled 'cytokine storm'; (2) five pro-inflammatory cytokines (IL-6, IL-10, TNF-α, type I IFN and IFN-γ) are significantly increased in severe/critically ill patients in both diseases; (3) Plasmodium and SARS-CoV-2 share some similar clinical manifestations and thus may result in fatal consequences if misdiagnosed during onset.

Structural insights for neutralization of Omicron variants BA.1, BA.2, BA.4, and BA.5 by a broadly neutralizing SARS-CoV-2 antibody.

In this study, by characterizing several human monoclonal antibodies (mAbs) isolated from single B cells of the COVID-19-recovered individuals in India who experienced ancestral Wuhan strain (WA.1) of SARS-CoV-2 during early stages of the pandemic, we found a receptor binding domain (RBD)-specific mAb 002-S21F2 that has rare gene usage and potently neutralized live viral isolates of SARS-CoV-2 variants including Alpha, Beta, Gamma, Delta, and Omicron sublineages (BA.1, BA.2, BA.2.12.1, BA.4, and BA.5) with IC50 ranging from 0.02 to 0.13 µg/ml. Structural studies of 002-S21F2 in complex with spike trimers of Omicron and WA.1 showed that it targets a conformationally conserved epitope on the outer face of RBD (class 3 surface) outside the ACE2-binding motif, thereby providing a mechanistic insights for its broad neutralization activity. The discovery of 002-S21F2 and the broadly neutralizing epitope it targets have timely implications for developing a broad range of therapeutic and vaccine interventions against SARS-CoV-2 variants including Omicron sublineages.

Characterization of neutralizing versus binding antibodies and memory B cells in COVID-19 recovered individuals from India.

India is one of the most affected countries by COVID-19 pandemic; but little is understood regarding immune responses to SARS-CoV-2 in this region. Herein we examined SARS-CoV-2 neutralizing antibodies, IgG, IgM, IgA and memory B cells in COVID-19 recovered individual from India. While a vast majority of COVID-19 recovered individuals showed SARS-CoV-2 RBD-specific IgG, IgA and IgM antibodies (38/42, 90.47%; 21/42, 50%; 33/42, 78.57% respectively), only half of them had appreciable neutralizing antibody titers. RBD-specific IgG, but not IgA or IgM titers, correlated with neutralizing antibody titers and RBD-specific memory B cell frequencies. These findings have timely significance for identifying potential donors for plasma therapy using RBD-specific IgG assays as surrogate measurement for neutralizing antibodies in India. Further, this study provides useful information needed for designing large-scale studies towards understanding of inter-individual variation in immune memory to SARS CoV-2 natural infection for future vaccine evaluation and implementation efforts.