After escaping relatively unscathed during the first wave of the COVID-19 pandemic, India witnessed a ferocious second COVID-19 wave, starting in March 2021 and accounting for about half of global cases by the first week of May. SARS-CoV-2 had spread widely throughout India in the first wave, with the third national serosurvey in January 2021 finding that 21.4% of adults and 25.3% of 10-to 17-year-old adolescents were seropositive (1). Delhi, the national capital, was not included in the national serosurvey but had undergone multiple periods of high transmission in 2020 (Fig. 1A). In a district-wise stratified serosurvey conducted by the Delhi Government in January 2021, overall seropositivity was reported to be 56.1% (95% CI, 55.5-56.8%), ranging from 49.1% to 62.2% across 11 districts (2). This was expected to confer some protection from future outbreaks.Despite high seropositivity, Delhi was amongst the most affected cities during the second wave. The rise in new cases was exceptionally rapid in April, going from approximately 2000 to 20,000 between 31 March and 16 April. This was accompanied by a rapid rise in hospitalizations and ICU admissions (Fig. 1B). In this emergency situation with saturated bed occupancy by 12 April, major private hospitals were declared by the state as full COVID care-only and senior medical students, including from alternative medicine branches, were pressed into service (3). Deaths rose proportionately (Fig. 1C) and the case-fatality ratio (CFR), estimated as the scaling factor between time-advanced cases and deaths (Fig. 1D), was stable (mean, SD; 1.9, 0.3%). Population spread of SARS-CoV-2 is underestimated by test positive cases alone (1, 2). To better understand the degree of spread and the factors leading to the unexpectedly severe outbreak, we used all available data including testing, sequencing, serosurveys, and serially followed cohorts.In the absence of finely resolved or serial data from national and state surveys, we focused on data for Delhi participants of a national serosurvey of Council of Scientific and

In April 2021, after successfully enduring three waves of the SARS-CoV2 pandemic in 2020, and having reached population seropositivity of about 50%, Delhi, the national capital of India was overwhelmed by the fourth wave. Here, we trace viral, host, and social factors contributing to the scale and exponent of the fourth wave, when compared to preceding waves, in an epidemiological context. Genomic surveillance data from Delhi and surrounding states shows an early phase of the upsurge driven by the entry of the more transmissible B.1.1.7 variant of concern (VOC) into the region in January, with at least one B.1.1.7 super spreader event in February 2021, relatable to known mass gatherings over this period. This was followed by seeding of the B.1.617 VOC, which too is highly transmissible, with rapid expansion of B.1.617.2 sub-lineage outpacing all other lineages. This unprecedented growth of cases occurred in the background of high seropositivity, but with low median neutralizing antibody levels, in a serially sampled cohort. Vaccination breakthrough cases over this period were noted, disproportionately related to VOC in sequenced cases, but usually mild. We find that this surge of SARS-CoV2 infections in Delhi is best explained by the introduction of a new highly transmissible VOC, B.1.617.2, with likely immune-evasion properties; insufficient neutralizing immunity, despite high seropositivity; and social behavior that promoted transmission.

To understand the spread of SARS-CoV2, in August and September 2020, the Council of Scientific and Industrial Research (India), conducted a sero-survey across its constituent laboratories and centers across India. Of 10,427 volunteers, 1058 (10.14%) tested positive for SARS CoV2 anti-nucleocapsid (anti-NC) antibodies; 95% of which had surrogate neutralization activity. Three-fourth of these recalled no symptoms. Repeat serology tests at 3 (n=607) and 6 (n=175) months showed stable anti-NC antibodies but declining neutralization activity. Local sero-positivity was higher in densely populated cities and was inversely correlated with a 30 day change in regional test positivity rates (TPR). Regional seropositivity above 10% was associated with declining TPR. Personal factors associated with higher odds of sero-positivity were high-exposure work (Odds Ratio, 95% CI, p value; 2∙23, 1∙92–2∙59, <0.0001), use of public transport (1∙79, 1∙43–2∙24, <0.0001), not smoking (1∙52, 1∙16–1∙99, 0∙0257), non-vegetarian diet (1∙67, 1∙41–1∙99, <0.0001), and B blood group (1∙36,1∙15-1∙61, 0∙001).

The Oxford-Astra Zeneca COVID 19 vaccine (AZD1222 or ChAdOx1) is an important part of the global vaccine roll-out against SARS-CoV-2, and a locally manufactured version (Covishield by Serum Institute, Pune, India) is the most commonly used vaccine in India. The vaccination program started in January 2021 and here we report effectiveness of the first dose of Covishield in generating antibody response and its kinetics. We further report differences in the quantitative antibody response amongst individuals who had pre-existing antibodies to SARS CoV2 and those who did not. In a group of 135 healthcare workers administered Covishield, we measured antibodies to SARS-CoV-2 directed against the spike protein (S-antigen) using Elecsys Anti-SARS-CoV-2 S quantitative antibody detection kit (Roche Diagnostics) at days 0, 7, 14, and 28. In 44 subjects (32.5%) who had already developed antibodies to SARS-CoV-2 at day 0 (before immunization), it was observed that antibody response was significantly higher at each time point, with the maximum increase seen between days 0 and 7. In contrast the sero-negative group (n=91) started developing antibody response only after 14 days or later. Three sero-negative individuals did not develop any antibody response even at day 28 of vaccination. It is noted that median antibody response at 28 days in seronegative subjects was similar to that of seropositive subjects at baseline (day 0) and was on a rising trajectory. Our data suggests that ChAdOx1 is highly immunogenic, particularly so where previous SARS CoV2 antibody-response is established. Given the high background seropositivity in India, this may be useful in determining optimal timing of the second dose during mass immunization within the constraints of vaccine supply and administration.

Immunization is expected to confer protection against infection and severe disease for vaccines while reducing risks to unimmunized populations by inhibiting transmission. Here, based on serial serological studies of an observational cohort of healthcare workers, we show that during a Severe Acute Respiratory Syndrome -Coronavirus 2 Delta-variant outbreak in Delhi, 25.3% (95% Confidence Interval 16.9-35.2) of previously uninfected, ChAdOx1-nCoV19 double vaccinated, healthcare workers were infected within less than two months, based on serology. Induction of anti-spike response was similar between groups with breakthrough infection (541 U/ml, Inter Quartile Range 374) and without (342 U/ml, Inter Quartile Range 497), as was the induction of neutralization activity to wildtype. This was not vaccine failure since vaccine effectiveness estimate based on infection rates in an unvaccinated cohort were about 70% and most infections were asymptomatic. We find that while ChAdOx1-nCoV19 vaccination remains effective in preventing severe infections, it is unlikely to be completely able to block transmission and provide herd immunity.

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BackgroundIndia has been amongst the most affected nations during the SARS-CoV2 pandemic, with sparse data on country-wide spread of asymptomatic infections and antibody persistence. This longitudinal cohort study was aimed to evaluate SARS-CoV2 sero-positivity rate as a marker of infection and evaluate temporal persistence of antibodies with neutralization capability and to infer possible risk factors for infection.MethodsCouncil of Scientific and Industrial Research, India (CSIR) with its more than 40 laboratories and centers in urban and semi-urban settings spread across the country piloted the pan country surveillance. 10427 adult individuals working in CSIR laboratories and their family members based on voluntary participation were assessed for antibody presence and stability was analyzed over 6 months utilizing qualitative Elecsys SARS CoV2 specific antibody kit and GENScript cPass SARS-CoV2 Neutralization Antibody Detection Kit. Along with demographic information, possible risk factors were evaluated through self to be filled online forms with data acquired on blood group type, occupation type, addiction and habits including smoking and alcohol, diet preferences, medical history and transport type utilized. Symptom history and information on possible contact and compliance with COVID 19 universal precautions was also obtained.Findings1058 individuals (10·14%) had antibodies against SARS-CoV2. A follow-up on 346 sero-positive individuals after three months revealed stable to higher antibody levels against SARS-CoV2 but declining plasma activity for neutralizing SARS-CoV2 receptor binding domain and ACE2 interaction. A repeat sampling of 35 individuals, at six months, revealed declining antibody levels while the neutralizing activity remained stable compared to three months. Majority of sero-positive individuals (75%) did not recall even one of nine symptoms since March 2020. Fever was the most common symptom with one-fourth reporting loss of taste or smell. Significantly associated risks for sero-positivity (Odds Ratio, 95% CI, p value) were observed with usage of public transport (1·79, 1·43 – 2·24, 2·81561E-06), occupational responsibilities such as security, housekeeping personnel etc. (2·23, 1·92 – 2·59, 6·43969E-26), non-smokers (1·52, 1·16 – 1·99, 0·02) and non-vegetarianism (1·67, 1·41 – 1·99, 3·03821E-08). An iterative regression analysis was confirmatory and led to only modest changes to estimates. Predilections for sero-positivity was noted with specific ABO blood groups -O was associated with a lower risk.InterpretationIn a first-of-its-kind study from India, we report the sero-positivity in a country-wide cohort and identify variable susceptible associations for contacting infection. Serology and Neutralizing Antibody response provides much-sought-for general insights on the immune response to the virus among Indians and will be an important resource for designing vaccination strategies.FundingCouncil of Scientific and Industrial Research, India (CSIR)