Lessons from a large-scale COVID-19 vaccine trial.

Global vaccination coverage remains indispensable in combatting the ongoing SARS-CoV-2 pandemic. Safety, efficacy, and durability of immune protection are the key parameters of randomized controlled trials (RCTs) and are essential for vaccine approvals, global distribution, and comprehensive population-vaccination programs. Immune protection from either vaccination or natural infection decreases over time, further challenged by rapid viral evolution. In this issue of the JCI, Sobieszczyk and colleagues report an update on the safety, efficacy, and durability of immune protection of AZD12222 in a large-scale, multinational, Phase III RCT. They report that protection lasted through 6 months, with immunity waning after 180 days. The study also highlights challenges facing vaccine trials, including the need for early unblinding for vulnerable participants, which may affect outcome measurements. Another challenge is to ensure fair representation of marginalized and minority ethnic groups in vaccine safety and efficacy studies worldwide.

Searching for escape-resistant anti-SARS-CoV-2 neutralizing antibodies.

A major goal of SARS-CoV-2 vaccination is the induction of neutralizing antibodies (nAbs) capable of blocking infection by preventing interaction of the SARS-CoV-2 Spike protein with ACE2 on target cells. Cocktails of monoclonal nAbs can reduce the risk of severe disease if administered early in infection. However, multiple variants of concern (VOCs) have arisen during the pandemic that may escape from nAbs. In this issue of the JCI, Jia Zou, Li Li, and colleagues used yeast display libraries to identify mAbs that bind to Spike proteins with a vast array of single amino acid substitutions. The authors identified mutation-resistant monoclonal nAbs for potential use as therapeutics. Multimerization further improved the potency of selected nAbs. These findings suggest a way forward in development of better nAb cocktails. However, the emergence of the highly mutated omicron (B.1.1.529) variant heightens the importance of finding effective anti-SARS-CoV-2 nAb therapeutics despite rapid viral evolution.

NIX-mediated mitophagy regulate metabolic reprogramming in phagocytic cells during mycobacterial infection.

RNASeq analysis of PBMCs from treatment naïve TB patients and healthy controls revealed that M. tuberculosis (Mtb) infection dysregulates several metabolic pathways and upregulates BNIP3L/NIX receptor mediated mitophagy. Analysis of publicly available transcriptomic data from the NCBI-GEO database indicated that M. bovis (BCG) infection also induces similar rewiring of metabolic and mitophagy pathways. Mtb chronic infection and BCG in-vitro infection both downregulated oxidative phosphorylation and upregulated glycolysis and mitophagy; therefore, we used non-pathogenic mycobacterial species BCG as a model for Mtb infection to gain molecular insights and outcomes of this phenomenon. BCG infection in PBMCs and THP-1 macrophages induce mitophagy and glycolysis, leading to differentiation of naïve macrophage to M1 phenotype. Glucose consumption and lactate production were quantified by NMR, while the mitochondrial mass assessment was performed by mitotracker red uptake assay. Infected macrophages predominantly exhibit M1-phenotype, which is indicated by an increase in M1 specific cytokines (IL-6, TNF-α, and IL-1ß) and increased NOS2/ARG1, CD86/CD206 ratio. NIX knockdown abrogates this upregulation of glycolysis, mitophagy, and secretion of pro-inflammatory cytokines in BCG infected cells, indicating that mycobacterial infection-induced immunometabolic changes are executed via NIX mediated mitophagy and are essential for macrophage differentiation and resolution of infection.