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Understanding the quality of immune repertoire triggered during natural infection can provide vital clues that form the basis for development of humoral immune response in some individuals capable of broadly neutralizing pan SARS-CoV-2 variants. We assessed the diversity of neutralizing antibody responses developed in an unvaccinated individual infected with ancestral SARS-CoV-2 by examining the ability of the distinct B cell germline-derived monoclonal antibodies (mAbs) in neutralizing known and currently circulating Omicron variants by pseudovirus and authentic virus neutralization assays. The ability of the antibodies developed post vaccination in neutralizing Omicron variants was compared to that obtained at baseline of the same individual and to those obtained from Omicron breakthrough infected individuals by pseudovirus neutralization assay. Broadly SARS-CoV-2 neutralizing mAbs representing unique B cell lineages with non-overlapping epitope specificities isolated from a single donor varied in their ability to neutralize Omicron variants. Plasma antibodies developed post vaccination from this individual demonstrated neutralization of Omicron BA.1, BA.2 and BA.4 with increased magnitude and found to be comparable with those obtained from other vaccinated individuals who were infected with ancestral SARS-CoV-2. Development of B cell repertoire capable of producing antibodies with distinct affinity and specificities for the antigen immediately after infection capable of eliciting broadly neutralizing antibodies offers highest probability in protecting against evolving SARS-CoV-2 variants. ImportanceDevelopment of robust neutralizing antibodies in SARS-CoV-2 convalescent individuals is known, however varies at population level. We isolated monoclonal antibodies from an individual infected with ancestral SARS-CoV-2 in early 2020 that not only varied in their B cell lineage origin but also varied in their capability and potency to neutralize all the known VOC and currently circulating Omicron variants. This indicated establishment of unique lineages that contributed in forming B cell repertoire in this particular individual immediately following infection giving rise to diverse antibody responses that could compensate each other in providing broadly neutralizing polyclonal antibody response. Individuals who were able to produce such potent polyclonal antibody responses after infection have a higher chance of being protected from evolving SARS-CoV-2 variants.
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Social contact mixing patterns are critical to the transmission of communicable diseases and have been employed to model disease outbreaks including COVID-19. Nonetheless, there is a paucity of studies on contact mixing in low and middle-income countries such as India. Furthermore, mathematical models of disease outbreaks do not account for the temporal nature of social contacts. We conducted a longitudinal study of social contacts in rural north India across three seasons and analysed the temporal differences in contact patterns. A contact diary survey was performed across three seasons from October 2015-16, in which participants were queried on the number, duration, and characteristics of contacts that occurred on the previous day. A total of 8,421 responses from 3,052 respondents (49% females) recorded characteristics of 180,073 contacts. Respondents reported a significantly higher number and duration of contacts in the winter, followed by the summer and the monsoon season (Nemenyi post-hoc, p<0.001). Participants aged 0-9 years and 10-19 years of age reported the highest median number of contacts (16 (IQR 12-21), 17 (IQR 13-24) respectively) and were found to have the highest node centrality in the social network of the region (pageranks = 0.20, 0.17). Employed males across all age groups were found to have a higher number of contacts than unemployed males (Negative Binomial Regression: rate ratio 1.18, 95% CI: 1.05-1.31). A large proportion (>80%) of contacts that were reported in schools or on public transport involved physical contact. To the best of our knowledge, our study is the first from India to show that contact mixing patterns vary by the time of the year and provides useful implications for pandemic control. Our results can be used to parameterize more accurate mathematical models for prediction of epidemiological trends of infections in rural India.
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ImportanceBoth vaccination and natural infection lead to immunity and may augment mutual immune response against SARS-CoV-2. There is a need for an evidence-driven booster vaccination policy depending on durability of immune response. ObjectiveTo determine the durability of humoral immune response with varying age, vaccine type, duration, and previous natural infection at least six months after complete vaccination with ChAdOx1 nCov-19 or BBV152. DesignCross-sectional observational study conducted between November 2021 and January 2022. SettingParticipants were drawn from a DBT COVID-19 Research Consortium cohort in Delhi National Capital Region, India. ParticipantsWe included 2003 individuals who had completed six months after complete vaccination: (i) vaccination with ChAdOx1 nCoV-19 and aged 18-59 years, (ii) vaccination with ChAdOx1 nCoV-19 and aged [≥]60 years (iii) vaccination with BBV152 and aged 18-59 years (iv) vaccination with BBV152 and aged [≥]60 years (v) vaccination with either vaccine plus SARS-CoV-2 infection referred as those having hybrid immunity. A group of 94 unvaccinated individuals was also included for comparison. ExposureAge, vaccination type, prior SARS-CoV-2 infection and duration from vaccination/infection. Main Outcome(s) and Measure(s)Humoral immune response determined by anti-RBD IgG concentrations and the presence of anti-nucleocapsid IgG. ResultsThe serum anti-RBD IgG antibodies were detected (cut-off 24 BAU/ml) in 85% participants with a median titer of 163 (IQR 73, 403) BAU/ml. In the hybrid immunity group, 97.6% [295 (IQR 128, 687) BAU/mL] tested positive for anti-RBD IgG compared to 81.3% [139 (IQR 62, 326) BAU/ml] of only vaccinated participants [{chi}2 test: p <0.001]. The median anti-RBD IgG titers were higher in the ChAdOx1 nCoV-19 versus BBV152 groups. The median anti-RBD IgG titer in the anti-nucleocapsid positive participants [326 (IQR 132, 739) BAU/ml] was significantly higher than in those without anti-nucleocapsid antibodies [131 (IQR 58, 288) BAU/ml; p <0.001]. The IgG anti-RBD antibodies was present in 85% of participants beyond a median of 8 months after complete vaccination. Conclusions and RelevanceConsidering the wide seropositivity rates due to natural SARS-CoV-2 infection, recommendation for boosters should take into account past infections in the population. Key pointsO_ST_ABSQuestionC_ST_ABSWhat is the extent of waning of humoral immune response in various groups of vaccinated individuals at least six months after complete vaccination with ChAdOx1 nCov-19 or BBV152 with or without prior natural infection? FindingsCross-sectional observational study demonstrates persistence of anti-RBD IgG in 85% of participants even beyond a median of 8 months after complete vaccination. The antibody concentrations were significantly higher in those with hybrid immunity. MeaningHumoral immunity may last longer due to heterologous antigenic exposure following vaccination and natural infection emphasizing the need for contextualizing the booster policy.
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BackgroundRapid expansion of the omicron SARS-CoV-2 variant of concern despite extensive vaccine coverage might be related to decreased neutralising ability of vaccine induced antibodies. The neutralising ability of different vaccines with or without natural SARS-CoV-2 infection against omicron is however not well known. MethodsWe tested the ability of vaccine and natural infection induced antibodies to neutralise omicron variant in a live virus neutralisation assay. Four groups of individuals were included: (i) complete vaccination with ChAdOx1 nCoV-19 (n=20), (ii) complete vaccination with ChAdOx1 nCoV-19 plus prior SARS-CoV-2 infection during the delta variant driven surge (n=20), (iii) complete vaccination with inactivated whole virus vaccine (BBV152) (n=20), (iv) complete vaccination with BBV152 plus prior SARS-CoV-2 infection (n=20). Primary outcome was fold-change in the virus neutralisation ability of plasma against the omicron variant compared with ancestral and delta variant. FindingsThe neutralisation geometric mean titre (GMT) was 384 (95% CI: 662, 223) against the ancestral virus with BBV152 vaccination alone and 383 (95% CI: 709, 207) with ChAdOx1 nCov-19 vaccination alone. The corresponding values for hybrid immunity groups were 795 (95% CI: 1302, 486) and 1424 (95% CI: 2581,786) respectively. Against the omicron variant, only 5 out of 20 in both BBV152 and ChAdOx1 nCoV-19 vaccine only groups, 5 out of 19 in BBV152 plus SARS-CoV-2 infection group, and 9 out of 20 in ChAdOx1 nCoV-19 plus SARS-CoV-2 infection group exhibited neutralisation titres above the lower limit of quantification (1:20) suggesting better neutralization in those with prior infection. The 50% neutralisation against ancestral strain and omicron demonstrated strong correlation with anti-RBD IgG levels [Pearson r: 0.94 (0.91, 0.96) p: <0.001 and 0.92 (0.88, 0.95) p:<0.001 respectively]. InterpretationOmicron variant shows significant reduction in neutralising ability of both vaccine induced and hybrid immunity induced antibodies which might explain immune escape and high transmission even in the presence of widespread vaccine coverage. FundingDBT, India; GIISER-BMGF, USA Research in contextO_ST_ABSEvidence before this studyC_ST_ABSThe Omicron variant of SARS-CoV-2 is fast becoming the dominant circulating strain world-wide. We did a literature search on PubMed between 01 November 2020 to 04 January 2022 using the terms "Omicron" and "neutralisation" and found 11 results for virus neutralisation against omicron by vaccine/natural infection induced antibodies. We identified two published and one preprint articles relevant to omicron virus neutralisation using live virus neutralization. Preliminary reports suggest that omicron variant is significantly less susceptible to in-vitro neutralisation by antibodies among recipients of mRNA vaccines (BNT162b2 and mRNA-1273), adenovirus vectored vaccine (ChAdOx1 nCoV-19 vaccines) and no virus neutralization was observed in subjects who received Coronavac (inactivated virus vaccine). Data regarding immune escape among those with natural SARS-CoV2 infection and vaccination are not available. Added value of this studyWe report here that the proportion of neutralisers (those who demonstrated a FRNT50 titre >1:20) was significantly reduced against the omicron variant as compared to the ancestral and delta variant. The geometric mean titre of neutralisation among the vaccinated individuals without a history of previous natural infection was significantly reduced against the omicron variant as compared with ancestral and delta variants. The titres among the those with a history of previous infection also followed the same pattern, but the neutralising ability was better in them than those who did not have previous infection. Implications of all the available evidenceOmicron variant of SARS-CoV-2 is capable of escaping immunity provided by currently available vaccines and even natural infection due to significant mutations in its spike protein. The drop in neutralisation might be alarming, but the real-world impact of these reduced neutralisation titres on major public health indices like hospitalisation rates and mortality rates have to be interpreted along with the other factors such as inherent pathogenicity of the variant, immunization uptakes and seroprevalence from natural infection in different geographical regions and the expected role of cellular immune responses to the variant. Our data may guide policy on booster vaccination to deal with an impending public health emergency as a result of surge in omicron cases.
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Clinical and epidemiological characteristics of SARS-CoV-2 infection are now widely available, but there are few data on longitudinal serology in large cohorts, particularly from low-and middle-income countries. We established an ongoing prospective cohort of 3840 SARS-CoV-2 RT-PCR positive individuals in the Delhi-National Capital Region of India, to document clinical and immunological characteristics during illness and convalescence. The IgG responses to the receptor binding domain (RBD) and nucleocapsid were assessed at 0-7, 10-28 days and 6-10 weeks after infection. The clinical predictors of seroconversion were identified by multivariable regression analysis. The seroconversion rates in the post-infection windows of 0-7 days, 10-28 days and 6-10 weeks were 46%, 84.7% and 85.3% respectively (n=782). The proportion with a serological response increased with severity of COVID-19 disease. All participants with severe disease, 89.6% with mild to moderate infection and 77.3% of asymptomatic participants had IgG antibodies to the RBD antigen. The threshold values in the nasopharyngeal viral RNA RT-PCR in a subset of asymptomatic and symptomatic seroconverters were comparable (p value: 0.48), with similar results among non-seroconverters (p value: 0.16) (n=169). This is the first report of longitudinal humoral immune responses to SARS-CoV-2 infection over a period of ten weeks from South Asia. The low seropositivity in asymptomatic participants and differences between assays highlight the importance of contextualizing the understanding of population serosurveys. SummaryWe measured anti-SARS-CoV-2 RBD and NC protein IgG in a multi-hospital-based prospective cohort from northern India up to ten weeks post-infection. The lower seroconversion rate among asymptomatic RT-PCR positive participants has public health significance particularly for interpreting community seroprevalence estimates.