Young age, female sex, absence of comorbidities, and prior infection or vaccination are known epidemiological barriers for contracting the new infection and/or increased disease severity. Demographic trends from the recent coronavirus disease 2019 waves, which are believed to be driven by newer severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, indicate that the aforementioned epidemiological barriers are being breached and a larger number of younger and healthy individuals are developing severe disease. The new SARS-CoV-2 variants have key mutations that can induce significant changes in the virus-host interactions. Recent studies report that, some of these mutations, singly or in a group, enhance key mechanisms, such as binding of the receptor-binding domain (RBD) of the viral spike protein with the angiotensin-converting enzyme 2 (ACE2) receptor in the hostcells, increase the glycosylation of spike protein at the antigenic sites, and enhance the proteolytic cleavage of the spike protein, thus leading to improved host-cell entry and the replication of the virus. The putative changes in the virus-host interactions imparted by the mutations in the RBD sequence can potentially be the reason behind the breach of the observed epidemiological barriers. Susceptibility for contracting SARS-CoV-2 infection and the disease outcomes are known to be influenced by host-cell expressions of ACE2 and other proteases. The new variants can act more efficiently, and even with the lesser availability of the viral entryreceptor and the associated proteases, can have more efficient host-cell entry and greater replication resulting in high viral loads and prolonged viral shedding, widespread tissue-injury, and severe inflammation leading to increased transmissibility and lethality. Furthermore, the accumulating evidence shows that multiple new variants have reduced neutralization by both, natural and vaccine-acquired antibodies, indicating that repeated and vaccine breakthrough infections may arise as serious health concerns in the ongoing pandemic.

India has witnessed a devastating second wave of COVID-19, which peaked during the last week of April and the second week of May, 2021. We aimed to understand whether the arrival of second wave was predictable and whether it was driven by the existing SARS-CoV-2 strains or any of the emerging variants. We analyzed the monthly distribution of the genomic sequence data for SARS-CoV-2 from India and correlated that with the epidemiological data for new cases and deaths, for the corresponding period of the second wave. Our analysis shows that the first indications of arrival of the second wave were observable by January, 2021, and by March, 2021 it was clearly predictable. B.1.617 lineage variants drove the wave, particularly B.1.617.2 (a.k.a. delta variant). We propose that genomic surveillance of the SARS-CoV-2 variants augmented with epidemiological data can be a promising tool for predicting future COVID-19 waves.

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Importance: Higher risks of contracting infection, developing severe illness and mortality are known facts in aged and male sex if exposed to the wild type SARS-CoV-2 strains (Wuhan and B.1 strains). Now, accumulating evidence suggests greater involvement of lower age and narrowing the age and sex based differences for the severity of symptoms in infections with emerging SARS-CoV-2 variants. Delta variant (B.1.617.2) is now a globally dominant SARS-CoV-2 strain, however, current evidence on demographic characteristics for this variant are limited. Recently, delta variant caused a devastating second wave of COVID-19 in India. We performed a demographic characterization of COVID-19 cases in Indian population diagnosed with SARS-CoV-2 genomic sequencing for delta variant. Objective: To determine demographic characteristics of delta variant in terms of age and sex, severity of the illness and mortality rate, and post-vaccination infections. Design: A cross sectional study Setting: Demographic characteristics, including vaccination status (for two complete doses) and severity of the illness and mortality rate, of COVID-19 cases caused by wild type strain (B.1) and delta variant (B.1.617.2) of SARS-CoV-2 in Indian population were studied. Participants: COVID-19 cases for which SARS-CoV-2 genomic sequencing was performed and complete demographic details (age, sex, and location) were available, were included. Exposures: SARS-CoV-2 infection with Delta (B.1.617.2) variant and wild type (B.1) strain. Main Outcomes and Measures: The patient metadata containing details for demographic and vaccination status (two complete doses) of the COVID-19 patients with confirmed delta variant and WT (B.1) infections were analyzed [total number of cases (N) =9500, NDelta =6238, NWT=3262]. Further, severity of the illness and mortality were assessed in subsets of patients. Final data were tabulated and statistically analyzed to determine age and sex based differences in chances of getting infection and the severity of illness, and post-vaccination infections were compared between wild type and delta variant strains. Graphs were plotted to visualize the trends. Results: With delta variant, in comparison to wild type (B.1) strain, higher proportion of young age individuals (<20 year) (0-9 year: 4.47% vs. 2.3%, 10-19 year: 9% vs. 7%) were affected. The proportion of women contracting infection were increased (41% vs. 36%). The higher proportion of total young (0-19 year, 10% vs. 4%) (p=.017) population and young (14% vs. 3%) as well as adult (20-59 year, 75% vs. 55%) women developed symptoms/hospitalized with delta variant in comparison to B.1 infection (p< .00001). The mean age of contracting infection [Delta, men=37.9 (17.2) year, women=36.6 (17.6) year; B.1, men=39.6 (16.9) year and women= 40.1 (17.4) year (p<.001)] as well as developing symptoms/hospitalization [Delta, men=39.6(17.4) year, women=35.6(16.9) year; B.1, men=47(18) year and women= 49.5(20.9) year (p<.001)] was considerably lower. The total mortality was about 1.8 times higher (13% vs. 7%). Risk of death increased irrespective of the sex (Odds ratio: 3.034, 95% Confidence Interval: 1.7-5.2, p<0.001), however, increased proportion of women (32% vs. 25%) were demised. Further, multiple incidences of delta infections were noted following complete vaccination. Conclusions and Relevance: The increased involvement of young (0-19 year) and women, lower mean age for contracting infection and symptomatic illness/hospitalization, higher mortality, and frequent incidences of post-vaccination infections with delta variant compared to wild type strain raises significant epidemiological concerns.