ABSTRACT
Data science has been an invaluable part of the COVID-19 pandemic response with multiple applications, ranging from tracking viral evolution to understanding the effectiveness of interventions. Asymptomatic breakthrough infections have been a major problem during the ongoing surge of Delta variant globally. Serological discrimination of vaccine response from infection has so far been limited to Spike protein vaccines used in the higher-income regions. Here, we show for the first time how statistical and machine learning (ML) approaches can discriminate SARS-CoV-2 infection from immune response to an inactivated whole virion vaccine (BBV152, Covaxin, India), thereby permitting real-world vaccine effectiveness assessments from cohort-based serosurveys in Asia and Africa where such vaccines are commonly used. Briefly, we accessed serial data on Anti-S and Anti-NC antibody concentration values, along with age, sex, number of doses, and number of days since the last vaccine dose for 1823 Covaxin recipients. An ensemble ML model, incorporating a consensus clustering approach alongside the support vector machine (SVM) model, was built on 1063 samples where reliable qualifying data existed, and then applied to the entire dataset. Of 1448 self-reported negative subjects, 724 were classified as infected. Since the vaccine contains wild-type virus and the antibodies induced will neutralize wild type much better than Delta variant, we determined the relative ability of a random subset of such samples to neutralize Delta versus wild type strain. In 100 of 156 samples, where ML prediction differed from self-reported uninfected status, Delta variant, was neutralized more effectively than the wild type, which cannot happen without infection. The fraction rose to 71.8% (28 of 39) in subjects predicted to be infected during the surge, which is concordant with the percentage of sequences classified as Delta (75.6%-80.2%) over the same period.
ABSTRACT
Disease caused by SARS-CoV-2 coronavirus (COVID-19) has resulted in significant morbidity and mortality world-wide. A systemic hyper-inflammation characterizes the severe COVID-19 disease often associated with acute respiratory distress syndrome (ARDS). Blood biomarkers capable of risk stratification are of great importance in effective triage and critical care of severe COVID-19 patients. In the present study we report higher plasma abundance of soluble urokinase-type plasminogen activator receptor (sUPAR), expressed by an abnormally expanded circulating myeloid cell population, in severe COVID-19 patients with ARDS. Plasma sUPAR level was found to be linked to a characteristic proteomic signature of plasma, linked to coagulation disorders and complement activation. Receiver operator characteristics curve analysis identified a cut-off value of sUPAR at 1996.809 pg/ml that could predict survival in our cohort (Odds ratio: 2.9286, 95% confidence interval 1.0427-8.2257). Lower sUPAR level than this threshold concentration was associated with a differential expression of the immune transcriptome as well as favourable clinical outcomes, both in terms of survival benefit (Hazard ratio: 0.3615, 95% confidence interval 0.1433-0.912) and faster disease remission in our patient cohort. Thus we identified sUPAR as a key pathogenic circulating molecule linking systemic hyperinflammation to the hypercoagulable state and stratifying clinical outcomes in severe COVID-19 patients with ARDS.
ABSTRACT
Delhi, the national capital of India, has experienced multiple SARS-CoV-2 outbreaks in 2020 and reached a population seropositivity of over 50% by 2021. During April 2021, the city became overwhelmed by COVID-19 cases and fatalities, as a new variant B.1.617.2 (Delta) replaced B.1.1.7 (Alpha). A Bayesian model explains the growth advantage of Delta through a combination of increased transmissibility and partial reduction of immunity elicited by prior infection (median estimates; x1.5-fold, 20% reduction). Seropositivity of an employee and family cohort increased from 42% to 86% between March and July 2021, with 27% reinfections, as judged by increased antibody concentration after previous decline. The likely high transmissibility and partial evasion of immunity by the Delta variant contributed to an overwhelming surge in Delhi. One-Sentence SummaryDelhi experienced an overwhelming surge of COVID-19 cases and fatalities peaking in May 2021 as the highly transmissible and immune evasive Delta variant replaced the Alpha variant.
ABSTRACT
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). 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 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), in particular to the clinically approved bamlavinimab and imdevimab monoclonal antibodies. B.1.617.2 demonstrated higher replication efficiency in both airway organoid and human airway epithelial systems as compared to B.1.1.7, associated with B.1.617.2 spike being in a predominantly cleaved state compared to B.1.1.7. 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 substantially reduced ChAdOx-1 vaccine efficacy against B.1.617.2 relative to non-B.1.617.2. 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.
ABSTRACT
Immunization is expected to confer protection against infection and severe disease for vaccinees, while reducing risks to unimmunized populations by inhibiting transmission. Here, based on serial serological studies, we show that during a severe SARS-CoV2 Delta-variant outbreak in Delhi, 25.3% (95% CI 16.9 - 35.2) of previously uninfected, ChAdOx1-nCoV19 double vaccinated, healthcare-workers (HCW) were infected within a period of less than two months, based on serology. Induction of anti-spike response was similar between groups with breakthrough infection (541 U/ml, IQR 374) or not (342 U/ml, IQR 497), as was induction of neutralization activity to wildtype. Most infections were unrecognized. The Delta-variant thus causes frequent unrecognized breakthrough infections in adequately immunized subjects, reducing any herd-effect of immunity, and requiring reinstatement of preventive measures such as masking.
ABSTRACT
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% with surrogate neutralization activity. Three-fourth recalled no symptoms. Repeat serology tests at 3 (n=346) and 6 (n=35) months confirmed stability of antibody response and neutralization potential. 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{middle dot}23, 1{middle dot}92-2{middle dot}59, 6{middle dot}5E-26), use of public transport (1{middle dot}79, 1{middle dot}43-2{middle dot}24, 2{middle dot}8E-06), not smoking (1{middle dot}52, 1{middle dot}16-1{middle dot}99, 0{middle dot}02), non-vegetarian diet (1{middle dot}67, 1{middle dot}41-1{middle dot}99, 3{middle dot}0E-08), and B blood group (1{middle dot}36,1{middle dot}15-1{middle dot}61, 0{middle dot}001). Impact StatementWidespread asymptomatic and undetected SARS-CoV2 infection affected more than a 100 million Indians by September 2020. Declining new cases thereafter may be due to persisting humoral immunity amongst sub-communities with high exposure. FundingCouncil of Scientific and Industrial Research, India (CSIR)
ABSTRACT
IntroductionA single center open label phase II randomised control trial was done to assess the pathogen and host-intrinsic factors influencing clinical and immunological benefits of passive immunization using convalescent plasma therapy (CPT), in addition to standard of care (SOC) therapy in severe COVID-19 patients, as compared to patients only on SOC therapy. MethodsConvalescent plasma was collected from patients recovered from COVID-19 following a screening protocol which also included measuring plasma anti SARS-CoV2 spike IgG content. Retrospectively, neutralizing antibody content was measured and proteome was characterized by LC-MS/MS for all convalescent plasma units that were transfused to patients. Severe COVID-19 patients with evidence for acute respiratory distress syndrome (ARDS) with PaO2/FiO2 ratio 100-300 (moderate ARDS) were recruited and randomised into two parallel arms of SOC and CPT, N=40 in each arm. Peripheral blood samples were collected on the day of enrolment (T1) followed by day3/4 (T2) and day 7 (T3). RT-PCR and sequencing was done for SARS-CoV2 RNA isolated from nasopharyngeal swabs collected at T1. A panel of cytokines and neutralizing antibody content were measured in plasma at all three timepoints. Patients were followed up for 30 days post-admission to assess the primary outcomes of all cause mortality and immunological correlates for clinical benefits. ResultsWhile across all age-groups no statistically significant clinical benefit was registered for patients in the CPT arm, significant immediate mitigation of hypoxia, reduction in hospital stay as well as survival benefit was recorded in severe COVID-19 patients with ARDS aged less than 67 years receiving convalescent plasma therapy. In addition to its neutralizing antibody content a prominent effect of convalescent plasma on attenuation of systemic cytokine levels possibly contributed to its benefits. ConclusionPrecise targeting of severe COVID-19 patients is necessary for reaping the clinical benefits of convalescent plasma therapy. Clinical trial registrationClinical Trial Registry of India No. CTRI/2020/05/025209
ABSTRACT
BackgroundSARS-CoV-2 infection has caused 64,469 deaths in India, with 7, 81, 975 active cases till 30th August 2020, lifting it to 3rd rank globally. To estimate the burden of the disease with time it is important to undertake a longitudinal seroprevalence study which will also help to understand the stability of anti SARS-CoV-2 antibodies. Various studies have been conducted worldwide to assess the antibody stability. However, there is very limited data available from India. Healthcare workers (HCW) are the frontline workforce and more exposed to the COVID-19 infection (SARS-CoV-2) compared to the community. This study was conceptualized with an aim to estimate the seroprevalence in hospital and general population and determine the stability of anti SARS-CoV-2 antibodies in HCW. MethodsStaff of a tertiary care hospital in Delhi and individuals visiting that hospital were recruited between April to August 2020. Venous blood sample, demographic, clinical, COVID-19 symptoms, and RT-PCR data was collected from all participants. Serological testing was performed using the electro-chemiluminescence based assay developed by Roche Diagnostics, in Cobas Elecsys 411. Seropositive participants were followed- upto 83 days to check for the presence of antibodies. ResultsA total of 780 participants were included in this study, which comprised 448 HCW and 332 individuals from the general population. Among the HCW, seroprevalence rates increased from 2.3% in April to 50.6% in July. The cumulative prevalence was 16.5% in HCW and 23.5% (78/332) in the general population with a large number of asymptomatic individuals. Out of 74 seropositive HCWs, 51 were followed-up for the duration of this study. We observed that in all seropositive cases the antibodies were sustained even up to 83 days. ConclusionThe cumulative prevalence of seropositivity was lower in HCWs than the general population. There were a large number of asymptomatic cases and the antibodies developed persisted through the duration of the study. More such longitudinal serology studies are needed to better understand the antibody response kinetics.
ABSTRACT
In the last few months, there has been a global catastrophic outbreak of severe acute respiratory syndrome disease caused by the novel corona virus SARS-CoV-2 affecting millions of people worldwide. Early diagnosis and isolation is key to contain the rapid spread of the virus. Towards this goal, we report a simple, sensitive and rapid method to detect the virus using a targeted mass spectrometric approach, which can directly detect the presence of virus from naso-oropharyngeal swabs. Using a multiple reaction monitoring we can detect the presence of two peptides specific to SARS-CoV-2 in a 2.3 minute gradient run with 100% specificity and 90.4 % sensitivity when compared to RT-PCR. Importantly, we further show that these peptides could be detected even in the patients who have recovered from the symptoms and have tested negative for the virus by RT-PCR highlighting the sensitivity of the technique. This method has the translational potential of in terms of the rapid diagnostics of symptomatic and asymptomatic COVID-19 and can augment current methods available for diagnosis of SARS-CoV-2.
