The SARS-CoV-2 B.1.617.2 (Delta) variant was first identified in the state of Maharashtra in late 2020 and spread throughout India, outcompeting pre-existing lineages including B.1.617.1 (Kappa) and B.1.1.7 (Alpha) 1 . In vitro, B.1.617.2 is 6-fold less sensitive to serum neutralising antibodies from recovered individuals, and 8-fold less sensitive to vaccine-elicited antibodies as compared to wild type (WT) Wuhan-1 bearing D614G. Serum neutralising titres against B.1.617.2 were lower in ChAdOx-1 versus BNT162b2 vaccinees. B.1.617.2 spike pseudotyped viruses exhibited compromised sensitivity to monoclonal antibodies against the receptor binding domain (RBD) and N-terminal domain (NTD). B.1.617.2 demonstrated higher replication efficiency in both airway organoid and human airway epithelial systems compared to B.1.1.7, associated with B.1.617.2 spike in a predominantly cleaved state compared to B.1.1.7. The B.1.617.2 spike protein was able to mediate highly efficient syncytium formation that was less sensitive to inhibition by neutralising antibody as compared to WT spike. Additionally we observed that B.1.617.2 had higher replication and spike mediated entry as compared to B.1.617.1, potentially explaining B.1.617.2 dominance. In an analysis of over 130 SARS-CoV-2 infected healthcare workers across three centres in India during a period of mixed lineage circulation, we observed reduced ChAdOx-1 vaccine effectiveness against B.1.617.2 relative to non-B.1.617.2, with the caveat of possible residual confounding. Compromised vaccine efficacy against the highly fit and immune evasive B.1.617.2 Delta variant warrants continued infection control measures in the post-vaccination era. India's first wave of SARS-CoV-2 infections in mid-2020 was relatively mild and was controlled by a nationwide lockdown. Since easing of restrictions, India has seen expansion in cases of COVID-19 since March

Summary SARS-CoV-2 Spike protein is critical for virus infection via engagement of ACE2 1 , and is a major antibody target. Here we report chronic SARS-CoV-2 with reduced sensitivity to neutralising antibodies in an immune suppressed individual treated with convalescent plasma, generating whole genome ultradeep sequences over 23 time points spanning 101 days. Little change was observed in the overall viral population structure following two courses of remdesivir over the first 57 days. However, following convalescent plasma therapy we observed large, dynamic virus population shifts, with the emergence of a dominant viral strain bearing D796H in S2 and ΔH69/ΔV70 in the S1 N-terminal domain NTD of the Spike protein. As passively transferred serum antibodies diminished, viruses with the escape genotype diminished in frequency, before returning during a final, unsuccessful course of convalescent plasma. In vitro , the Spike escape double mutant bearing ΔH69/ΔV70 and D796H conferred modestly decreased sensitivity to convalescent plasma, whilst maintaining infectivity similar to wild type. D796H appeared to be the main contributor to decreased susceptibility but incurred an infectivity defect. The ΔH69/ΔV70 single mutant had two-fold higher infectivity compared to wild type, possibly compensating for the reduced infectivity of D796H. These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy associated with emergence of viral variants with evidence of reduced susceptibility to neutralising antibodies.

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Although two-dose mRNA vaccination provides excellent protection against SARS-CoV-2, there is little information about vaccine efficacy against variants of concern (VOC) in individuals above eighty years of age1. Here we analysed immune responses following vaccination with the BNT162b2 mRNA vaccine2 in elderly participants and younger healthcare workers. Serum neutralization and levels of binding IgG or IgA after the first vaccine dose were lower in older individuals, with a marked drop in participants over eighty years old. Sera from participants above eighty showed lower neutralization potency against the B.1.1.7 (Alpha), B.1.351 (Beta) and P.1. (Gamma) VOC than against the wild-type virus and were more likely to lack any neutralization against VOC following the first dose. However, following the second dose, neutralization against VOC was detectable regardless of age. The frequency of SARS-CoV-2 spike-specific memory B cells was higher in elderly responders (whose serum showed neutralization activity) than in non-responders after the first dose. Elderly participants showed a clear reduction in somatic hypermutation of class-switched cells. The production of interferon-γ and interleukin-2 by SARS-CoV-2 spike-specific T cells was lower in older participants, and both cytokines were secreted primarily by CD4 T cells. We conclude that the elderly are a high-risk population and that specific measures to boost vaccine responses in this population are warranted, particularly where variants of concern are circulating.

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A new pattern of response, so-called hyperprogressive disease (HPD), is emerging during treatment with immune checkpoint inhibitors (ICIs). Our aim was to investigate the prevalence of such a phenomenon and to assess its association with clinical variables and metabolic parameters by 18 F-FDG PET/CT. Methods: Data from 50 patients (34 men and 16 women; median age, 73 y) with non-small cell lung carcinoma treated with ICIs were prospectively collected. All patients underwent contrast-enhanced CT, 18 F-FDG PET/CT, and complete peripheral blood sampling at baseline before ICI treatment. HPD was defined according to clinical and radiologic criteria. Because of rapid disease progression or worsening of clinical condition, radiologic response assessment was available for only 46 of the 50 patients. Overall survival (OS) was analyzed using the Kaplan-Meier method and the log-rank test. A Cox proportional hazards regression analysis was used to evaluate factors independently associated with OS. Median follow-up was 12.4 mo (range, 9.7-15.2 mo). Results: We identified the following response categories: 10 cases as complete or partial response, 17 cases as stable disease, 5 cases as progressive disease, and 14 cases as HPD. Among metabolic parameters, we observed a statistically significant association between HPD status and tumor burden, expressed by both TLG (756.1 cm 3 for HPD vs. 475.6 cm 3 for non-HPD, P 5 0.042) and MTV (287.3 for HPD vs. 62.1 for non-HPD, P 5 0.011). Among clinical variables, 12 of 14 patients (85.7%) within the HPD group, compared with 8 of 32 patients (25%) in the non-HPD group, had more than 2 metastatic sites (P , 0.001). In addition, the derived neutrophil-to-lymphocyte ratio and platelet count were significantly associated with HPD status (P 5 0.038 and P 5 0.025, respectively). Survival analysis showed a median OS of 4 mo for the HPD group, compared with 15 mo for the non-HPD group (P 5 0.003). Likewise, median OS was significantly different when we considered all the response categories: complete or partial response, stable disease, progressive disease, and HPD (P 5 0.001). Finally, multivariate analysis identified metabolic tumor volume and derived neutrophil-to-lymphocyte ratio as independent predictors for OS. Conclusion: Our results suggest that the use of ICIs might represent a concern in patients with high metabolic tumor burden and inflammatory indices at baseline. However, additional studies are needed.