ABSTRACT
The Omicron variant of SARS-CoV-2 is capable of infecting unvaccinated, vaccinated and previously-infected individuals due to its ability to evade neutralization by antibodies. With three sub-lineages of Omicron emerging in the last four months, there is inadequate information on the quantitative antibody response generated upon natural infection with Omicron variant and whether these antibodies offer cross-protection against other sub-lineages of Omicron variant. In this study, we characterized the growth kinetics of Kappa, Delta and Omicron variants of SARS-CoV-2 in Calu-3 cells. Relatively higher amounts infectious virus titers, cytopathic effect and disruption of epithelial barrier functions was observed with Delta variant whereas infection with Omicron variant led to a more robust induction of interferon pathway, lower level of virus replication and mild effect on epithelial barrier. The replication kinetics of BA.1 and BA.2 sub-lineages of the Omicron variant were comparable in cell culture and natural Omicron infection in a subset of individuals led to a significant increase in binding and neutralizing antibodies to both BA.1 and BA.2 sub-lineages but these levels were lower than that produced against the Delta variant. Finally, we show that Cu2+, Zn2+ and Fe2+ salts inhibited in vitro RdRp activity but only Cu2+ and Fe2+ inhibited both the Delta and Omicron variants in cell culture. Thus, our results suggest that high levels of interferons induced upon infection with Omicron variant may counter virus replication and spread. Waning neutralizing antibody titers rendered subjects susceptible to infection by Omicron variant and natural Omicron infection elicits neutralizing antibodies that can cross-react with other sub-lineages of Omicron and other variants of concern.
ABSTRACT
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.
ABSTRACT
Although efficacious vaccines have significantly reduced the morbidity and mortality due to COVID-19, there remains an unmet medical need for treatment options, which monoclonal antibodies (mAbs) can potentially fill. This unmet need is exacerbated by the emergence and spread of SARS-CoV-2 variants of concern (VOCs) that have shown some resistance to vaccine responses. Here we report the isolation of two highly potently neutralizing mAbs (THSC20.HVTR04 and THSC20.HVTR26) from an Indian convalescent donor, that neutralize SARS-CoV-2 VOCs at picomolar concentrations including the delta variant (B.1.617.2). These two mAbs target non-overlapping epitopes on the receptor-binding domain (RBD) of the spike protein thereby preventing the virus attachment to its host receptor, human angiotensin converting enzyme-2 (hACE2). Furthermore, the mAb cocktail demonstrated protection against the Delta variant at low antibody doses when passively administered in the K18 hACE2 transgenic mice model, highlighting their potential as cocktail for prophylactic and therapeutic applications. Developing the capacity to rapidly discover and develop mAbs effective against highly transmissible pathogens like coronaviruses at a local level, especially in a low- and middle-income country (LMIC) such as India, will enable prompt responses to future pandemics as an important component of global pandemic preparedness. HighlightsO_LIIdentification of an Indian convalescent donor prior to emergence of SARS-CoV-2 Delta variant whose plasma demonstrated neutralization breadth across SARS-CoV-2 variants of concern (VOCs). C_LIO_LITwo (THSC20.HVTR04 and THSC20.HVTR26) monoclonal antibodies isolated from peripheral memory B cells potently neutralize SARS-CoV-2 VOCs: Alpha, Beta, Gamma, Delta and VOIs: Kappa and Delta Plus. C_LIO_LITHSC20.HVTR04 and THSC20.HVTR26 target non-competing epitopes on the receptor binding domain (RBD) and represent distinct germline lineages. C_LIO_LIPassive transfer of THSC20.HVTR04 and THSC20.HVTR26 mAbs demonstrated protection against Delta virus challenge in K18-hACE2 mice at low antibody doses. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/474152v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@1f1b55corg.highwire.dtl.DTLVardef@1b9b438org.highwire.dtl.DTLVardef@e6d2a6org.highwire.dtl.DTLVardef@f92cd_HPS_FORMAT_FIGEXP M_FIG C_FIG
