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1.
Nat Commun ; 13(1): 3451, 2022 06 15.
Article in English | MEDLINE | ID: covidwho-1890185

ABSTRACT

Many adults in India have received at least one dose of COVID-19 vaccine with or without a prior history SARS-CoV-2 infection. However, there is limited information on the effect of prior immunity on antibody response upon vaccination in India. As immunization of individuals continues, we aimed to assess whether pre-existing antibodies are further boosted by a single dose of BBV152, an inactivated SARS-CoV-2 vaccine, and, if these antibodies can neutralize SARS-CoV-2 Delta and Omicron variants. Here we show that natural infection during the second wave in 2021 led to generation of neutralizing antibodies against other lineages of SARS-CoV-2 including the Omicron variant, albeit at a significantly lower level for the latter. A single dose of BBV152 boosted antibody titers against the Delta and the Omicron variants but the antibody levels remained low against the Omicron variant. Boosting of antibodies showed negative correlation with baseline neutralizing antibody titers.


Subject(s)
COVID-19 , Viral Vaccines , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/prevention & control , COVID-19 Vaccines , Humans , SARS-CoV-2 , Vaccination
2.
EBioMedicine ; 78: 103938, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1739674

ABSTRACT

BACKGROUND: Rapid spread of the omicron SARS-CoV-2 variant despite extensive vaccination suggests immune escape. The neutralising ability of different vaccines alone or with natural SARS-CoV-2 infection against omicron is not well-known. METHODS: In this cross-sectional study, we tested the ability of vaccine and natural infection induced antibodies to neutralise omicron variant in a live virus neutralisation assay in four groups of individuals: (i) ChAdOx1 nCoV-19 vaccination, (ii) ChAdOx1 nCoV-19 vaccination plus prior SARS-CoV-2 infection, (iii) vaccination with inactivated virus vaccine (BBV152), and (iv) BBV152 vaccination plus prior SARS-CoV-2 infection. Primary outcome was fold-change in virus neutralisation titre against omicron compared with ancestral virus. FINDINGS: We included 80 subjects. The geometric mean titre (GMT) of the 50% focus reduction neutralisation test (FRNT50) was 380·4 (95% CI: 221·1, 654·7) against the ancestral virus with BBV152 vaccination and 379·3 (95% CI: 185·6, 775·2) with ChAdOx1 nCov-19 vaccination alone. GMT for vaccination plus infection groups were 806·1 (95% CI: 478·5, 1357·8) and 1526·2 (95% CI: 853·2, 2730·0), respectively. Against omicron variant, only 5 out of 20 in both BBV152 and ChAdOx1 nCoV-19 vaccine only groups, 6 out of 20 in BBV152 plus prior SARS-CoV-2 infection group, and 9 out of 20 in ChAdOx1 nCoV-19 plus prior SARS-CoV-2 infection group exhibited neutralisation titres above the lower limit of quantification (1:20) suggesting better neutralisation with prior infection. A reduction of 26·6 and 25·7 fold in FRNT50 titres against Omicron compared to ancestral SARS-CoV-2 strain was observed for individuals without prior SARS-CoV-2 infection vaccinated with BBV152 and ChAdOx1 nCoV-19, respectively. The corresponding reduction was 57·1 and 58·1 fold, respectively, for vaccinated individuals with prior infection. The 50% neutralisation titre against omicron demonstrated moderate correlation with serum anti-RBD IgG levels [Spearman r: 0·58 (0·41, 0·71)]. INTERPRETATION: Significant reduction in the neutralising ability of both vaccine-induced and vaccine plus infection-induced antibodies was observed for omicron variant which might explain immune escape. FUNDING: Department of Biotechnology, India; Bill & Melinda Gates Foundation, USA.


Subject(s)
COVID-19 Vaccines , COVID-19 , COVID-19/prevention & control , Cross-Sectional Studies , Humans , SARS-CoV-2 , Vaccines, Inactivated
3.
J Clin Virol Plus ; 2(1): 100061, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1616570

ABSTRACT

Background: SARS-CoV-2 infection in children frequently leads to only asymptomatic and mild infections. It has been suggested that frequent infections due to low-pathogenicity coronaviruses in children, impart immunity against SARS-CoV-2 in this age group. Methods: From a prospective birth cohort study prior to the pandemic, we identified children with proven low-pathogenicity coronavirus infections. Convalescent sera from these children were tested for antibodies against respective seasonal coronaviruses (OC43, NL63, and 229E) and SARS-CoV-2 by immunofluorescence and virus microneutralization assay respectively. Results: Forty-two children with proven seasonal coronavirus infection were included. Convalescent sera from these samples demonstrated antibodies against the respective seasonal coronaviruses. Of these, 40 serum samples showed no significant neutralization of SARS-CoV-2, while 2 samples showed inconclusive results. Conclusion: These findings suggest that the antibodies generated in low-pathogenicity coronavirus infections offer no protection from SARS-CoV-2 infection in young children.

4.
Mol Ther ; 30(5): 2058-2077, 2022 05 04.
Article in English | MEDLINE | ID: covidwho-1612108

ABSTRACT

The ongoing COVID-19 pandemic highlights the need to tackle viral variants, expand the number of antigens, and assess diverse delivery systems for vaccines against emerging viruses. In the present study, a DNA vaccine candidate was generated by combining in tandem envelope protein domain III (EDIII) of dengue virus serotypes 1-4 and a dengue virus (DENV)-2 non-structural protein 1 (NS1) protein-coding region. Each domain was designed as a serotype-specific consensus coding sequence derived from different genotypes based on the whole genome sequencing of clinical isolates in India and complemented with data from Africa. This sequence was further optimized for protein expression. In silico structural analysis of the EDIII consensus sequence revealed that epitopes are structurally conserved and immunogenic. The vaccination of mice with this construct induced pan-serotype neutralizing antibodies and antigen-specific T cell responses. Assaying intracellular interferon (IFN)-γ staining, immunoglobulin IgG2(a/c)/IgG1 ratios, and immune gene profiling suggests a strong Th1-dominant immune response. Finally, the passive transfer of immune sera protected AG129 mice challenged with a virulent, non-mouse-adapted DENV-2 strain. Our findings collectively suggest an alternative strategy for dengue vaccine design by offering a novel vaccine candidate with a possible broad-spectrum protection and a successful clinical translation either as a stand alone or in a mix and match strategy.


Subject(s)
COVID-19 , Dengue Vaccines , Dengue Virus , Dengue , Vaccines, DNA , Antibodies, Neutralizing , Antibodies, Viral , Dengue/prevention & control , Dengue Vaccines/genetics , Dengue Virus/genetics , Humans , Pandemics , Viral Envelope Proteins/genetics
5.
J Clin Virol ; 146: 105060, 2022 01.
Article in English | MEDLINE | ID: covidwho-1587311

ABSTRACT

Over 90% of the COVID-19 patients manifest mild/moderate symptoms or are asymptomatic. Although comorbidities and dysregulation of immune response have been implicated in severe COVID-19, the host factors that associate with asymptomatic or mild infections have not been characterized. We have collected serial samples from 23 hospitalized COVID-19 patients with mild symptoms and measured the kinetics of SARS-CoV-2 viral load in respiratory samples and markers of inflammation in serum samples. We monitored seroconversion during the acute phase of illness and quantitated the amount of total IgG against the receptor-binding domain of SARS-CoV-2 and estimated the virus neutralization potential of these antibodies. Viral load decreased by day 8 in all the patients but the detection of viral RNA in saliva samples did not correlate well with viral RNA detection in nasopharyngeal/oropharyngeal swab samples. 25% of the virus-positive patients had no detectable neutralizing antibodies in the serum and in other cases, the efficiency of antibodies to neutralize SARS-CoV-2 B1.1.7 strain was lower as compared to the circulating virus isolate. Decrease in viral load coincided with increase in neutralizing antibodies and interferon levels in serum. Most patients showed no increase in inflammatory cytokines such as IL-1ß or IL-6, however, elevated levels of IL-7 and other inflammatory mediators such as TNF-α and IL-8 was observed. These data suggest that most mild infections are associated with absence of inflammation coupled with an active innate immune response, T-cell activation and neutralizing antibodies.


Subject(s)
COVID-19 , Antibodies, Viral , Humans , Immunity , SARS-CoV-2 , Viral Load
6.
J Gen Virol ; 102(4)2021 04.
Article in English | MEDLINE | ID: covidwho-1393559

ABSTRACT

Reactive oxygen species (ROS) are chemically active species which are involved in maintaining cellular and signalling processes at physiological concentrations. Therefore, cellular components that regulate redox balance are likely to play a crucial role in viral life-cycle either as promoters of viral replication or with antiviral functions. Zinc is an essential micronutrient associated with anti-oxidative systems and helps in maintaining a balanced cellular redox state. Here, we show that zinc chelation leads to induction of reactive oxygen species (ROS) in epithelial cells and addition of zinc restores ROS levels to basal state. Addition of ROS (H2O2) inhibited dengue virus (DENV) infection in a dose-dependent manner indicating that oxidative stress has adverse effects on DENV infection. ROS affects early stages of DENV replication as observed by quantitation of positive and negative strand viral RNA. We observed that addition of ROS specifically affected viral titres of positive strand RNA viruses. We further demonstrate that ROS specifically altered SEC31A expression at the ER suggesting a role for SEC31A-mediated pathways in the life-cycle of positive strand RNA viruses and provides an opportunity to identify drug targets regulating oxidative stress responses for antiviral development.


Subject(s)
Dengue Virus/drug effects , Hydrogen Peroxide/pharmacology , Reactive Oxygen Species/pharmacology , Virus Replication , Zinc/pharmacology , Adolescent , Aedes , Animals , Caco-2 Cells , Child , Child, Preschool , Chlorocebus aethiops , Cricetinae , Dengue/virology , Dengue Virus/physiology , Humans , Oxidative Stress , RNA, Viral
7.
Mol Ther Nucleic Acids ; 26: 321-332, 2021 Dec 03.
Article in English | MEDLINE | ID: covidwho-1284428

ABSTRACT

The recent SARS-CoV-2 outbreak has been declared a global health emergency. It will take years to vaccinate the whole population to protect them from this deadly virus, hence the management of SARS-CoV-2 largely depends on the widespread availability of an accurate diagnostic test. Toward addressing the unmet need of a reliable diagnostic test in the current work by utilizing the power of Systematic Evolution of Ligands by EXponential enrichment, a 44-mer G-quadruplex-forming DNA aptamer against spike trimer antigen of SARS-CoV-2 was identified. The lead aptamer candidate (S14) was characterized thoroughly for its binding, selectivity, affinity, structure, and batch-to-batch variability by utilizing various biochemical, biophysical, and in silico techniques. S14 has demonstrated a low nanomolar KD, confirming its tight binding to a spike antigen of SARS-CoV-2. S14 can detect as low as 2 nM of antigen. The clinical evaluation of S14 aptamer on nasopharyngeal swab specimens (n = 232) has displayed a highly discriminatory response between SARS-CoV-2 infected individuals from the non-infected one with a sensitivity and specificity of ∼91% and 98%, respectively. Importantly, S14 aptamer-based test has evinced a comparable performance with that of RT-PCR-based assay. Altogether, this study established the utility of aptamer technology for the detection of SARS-CoV-2.

8.
Pediatr Infect Dis J ; 39(12): e452-e454, 2020 12.
Article in English | MEDLINE | ID: covidwho-762166

ABSTRACT

In this birth cohort, coronavirus acute respiratory infection was detected in 6.5% of the episodes; the commonest strain was OC43, followed by NL63, HKU1, and 229E. Children with coronavirus acute respiratory infection during infancy had significantly decreased forced expiratory volume in 0.5 seconds, forced expiratory flow between 25% and 75% of forced vital capacity, and peak expiratory flow at 3 years of age.


Subject(s)
Coronavirus Infections/epidemiology , Coronavirus Infections/physiopathology , Coronavirus , Health Impact Assessment , Lung/physiopathology , Respiratory Tract Infections/epidemiology , Respiratory Tract Infections/physiopathology , Child, Preschool , Cohort Studies , Coronavirus Infections/diagnosis , Coronavirus Infections/virology , Female , Follow-Up Studies , Humans , India/epidemiology , Infant , Infant, Newborn , Lung/virology , Male , Public Health Surveillance , Recurrence , Respiratory Tract Infections/diagnosis , Respiratory Tract Infections/virology , Symptom Assessment
9.
Front Mol Biosci ; 7: 586254, 2020.
Article in English | MEDLINE | ID: covidwho-1021900

ABSTRACT

The gold standard for the diagnosis of SARS-CoV-2, the causative agent of COVID-19, is real-time polymerase chain reaction (PCR), which is labor-intensive, expensive, and not widely available in resource-poor settings. Therefore, it is imperative to develop novel, accurate, affordable, and easily accessible assays/sensors to diagnose and isolate COVID-19 cases. To address this unmet need, we utilized the catalytic potential of peroxidase-like DNAzyme and developed a simple visual detection assay for SARS-CoV-2 RNA using a conventional thermal cycler by the PCR-induced generation of DNAzyme sensor. The performance of RT-PCR DNAzyme-based sensor was comparable to that of real-time PCR. The pilot scale validation of RT-PCR DNAzyme-based sensor has shown ~100% sensitivity and specificity in clinical specimens (nasopharyngeal swab, n = 34), with a good correlation (Spearman r = 0.799) with the Ct-value of fluorescence probe-based real-time PCR. These findings clearly indicate the potential of this inexpensive, sensitive, and specific molecular diagnostic test to extend our testing capabilities for the detection of SARS-CoV-2 to curtail COVID-19 transmission.

10.
mSphere ; 5(3)2020 05 27.
Article in English | MEDLINE | ID: covidwho-774837

ABSTRACT

Zinc supplementation in cell culture has been shown to inhibit various viruses, like herpes simplex virus, rotavirus, severe acute respiratory syndrome (SARS) coronavirus, rhinovirus, and respiratory syncytial virus (RSV). However, whether zinc plays a direct antiviral role in viral infections and whether viruses have adopted strategies to modulate zinc homeostasis have not been investigated. Results from clinical trials of zinc supplementation in infections indicate that zinc supplementation may be beneficial in a pathogen- or disease-specific manner, further underscoring the importance of understanding the interaction between zinc homeostasis and virus infections at the molecular level. We investigated the effect of RSV infection on zinc homeostasis and show that RSV infection in lung epithelial cells leads to modulation of zinc homeostasis. The intracellular labile zinc pool increases upon RSV infection in a multiplicity of infection (MOI)-dependent fashion. Small interfering RNA (siRNA)-mediated knockdown of the ubiquitous zinc uptake transporter ZIP1 suggests that labile zinc levels are increased due to the increased uptake by RSV-infected cells as an antiviral response. Adding zinc to culture medium after RSV infection led to significant inhibition of RSV titers, whereas depletion of zinc by a zinc chelator, N,N,N',N'-tetrakis(2-pyridinylmethyl)-1,2-ethanediamine (TPEN) led to an increase in RSV titers. The inhibitory effect of zinc was specific, as other divalent cations had no effect on RSV titers. Both RSV infection and zinc chelation by TPEN led to reactive oxygen species (ROS) induction, whereas addition of zinc blocked ROS induction. These results suggest a molecular link between RSV infection, zinc homeostasis, and oxidative-stress pathways and provide new insights for developing strategies to counter RSV infection.IMPORTANCE Zinc deficiency rates in developing countries range from 20 to 30%, and zinc supplementation trials have been shown to correct clinical manifestations attributed to zinc deficiency, but the outcomes in the case of respiratory infections have been inconsistent. We aimed at understanding the role of zinc homeostasis in respiratory syncytial virus (RSV) infection. Infection of lung epithelial cell lines or primary small-airway epithelial cells led to an increase in labile zinc pools, which was due to increased uptake of zinc. Zinc supplementation inhibited RSV replication, whereas zinc chelation had an opposing effect, leading to increases in RSV titers. Increases in labile zinc in RSV-infected cells coincided with induction of reactive oxygen species (ROS). Both zinc depletion and addition of exogenous ROS led to enhanced RSV infection, whereas addition of the antioxidant inhibited RSV, suggesting that zinc is part of an interplay between RSV-induced oxidative stress and the host response to maintain redox balance.


Subject(s)
Respiratory Syncytial Virus Infections/pathology , Respiratory Syncytial Virus, Human/metabolism , Virus Replication/drug effects , Zinc/metabolism , Zinc/pharmacology , A549 Cells , Adolescent , Cation Transport Proteins/genetics , Cell Line , Child , Child, Preschool , Epithelial Cells/metabolism , Ethylenediamines/pharmacology , Female , Host-Pathogen Interactions , Humans , Lung/cytology , Lung/metabolism , Male , Oxidative Stress/physiology , RNA Interference , RNA, Small Interfering/genetics , Reactive Oxygen Species/metabolism , Respiratory Mucosa/metabolism , Respiratory Mucosa/virology
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