key: cord-0739258-t5nifh6e authors: Faustini, Sian; Shields, Adrian; Banham, Gemma; Wall, Nadezhda; Al-Taei, Saly; Tanner, Chloe; Ahmed, Zahra; Efstathiou, Elena; Townsend, Neal; Goodall, Margaret; Plant, Tim; Perez-Toledo, Marisol; Jasiulewicz, Aleksandra; Price, Ruth; McLaughlin, James; Farnan, John; Moore, Julie; Robertson, Louise; Nesbit, Andrew; Curry, Grace; Black, Amy; Cunningham, Adam; Harper, Lorraine; Moore, Tara; Drayson, Mark; Richter, Alex title: Cross reactivity of spike glycoprotein induced antibody against Delta and Omicron variants before and after third SARS-CoV-2 vaccine dose in healthy and immunocompromised individuals date: 2022-01-10 journal: J Infect DOI: 10.1016/j.jinf.2022.01.002 sha: 20caf2694b6067c2cd189d66f8278f12ea8e610e doc_id: 739258 cord_uid: t5nifh6e nan  IgG anti-SARS-CoV-2 Omicron spike glycoprotein antibodies were detected in 100% of health care workers, a real world population attending general practice for vaccination and haemodialysis patients 4 weeks after a third SARS-CoV-2 vaccine dose (Pfizer-BioNtech 162b2).  Against both Delta and Omicron variants, antibody levels were higher in the cohort who had previously received two doses of AstraZeneca ChAdOx1 nCoV-19 vaccine than two doses of Pfizer-BioNtech 162b2.  Prior to this third vaccine dose and 6 months post second vaccine dose, there was evidence of significant waning of antibody reactivity against Delta and Omicron variants of concern, particularly in individuals initially receiving two doses of AstraZeneca ChAdOx1 nCoV-19. COVID-19, SARS-CoV-2, Haemodialysis, Chronic kidney disease, vaccination, antibody response, Variants of Concern, Cross reactivity, Delta, Omicron Dear Editor, SARS-CoV-2 variants of concern threaten evasion of natural and vaccine-induced immunity. There is an urgent need to know how effective different vaccine strategies will be in reducing the transmission of and disease severity arising from the Omicron variant of concern (VOC). In the UK, two main vaccines have formed the basis of the national immunisation strategy: the AstraZeneca We have recruited three well-characterised cohorts: firstly, a health care worker cohort from University Hospitals Birmingham from the Determining the immune response to SARS-CoV-2 infection in convalescent health care workers (COCO) study, who had PFZ as their primary two-dose vaccine course followed by PFZ booster (PPP cohort). Secondly, individuals classed as clinically extremely vulnerable (CEV) attending general practice for vaccination in Ulster, who had the AZ vaccine as their primary two-dose vaccine course followed by a PFZ third dose (AAP). Lastly, individuals on haemodialysis under renal care at the University Hospitals Birmingham; 70.3% of which had AZ as their primary course (HD cohort) followed by a PFZ third dose. Serum samples were taken 6 months following their second vaccination of their primary course, prior to the third dose with PFZ, and also 28 days following vaccination. There was evidence of suboptimal seropositivity 6 months post primary dose of vaccination in all groups but particularly amongst HD and CEV patients. Samples taken 6 months post-primary vaccine course showed that for the HD cohort, 58.9% of individuals were seropositive against the Wuhan strain, 34.4% against Delta and 62.2% against Omicron strains. For the PPP cohort, seropositivity was maintained at 92.2 % against Wuhan, 90% against Delta and 91.1% against Omicron strains. For the AAP cohort, seropositivity was 62.5% against Wuhan, 45.8% against Delta and 91.7% against Omicron strains (Table 1, Figure 1a-c) . Post third vaccine dose, there was a significant increase in the percentage of individuals who were seropositive and a rise in the median serum antibody concentration (as measured by optical density or OD) of these seropositive individuals. For the HD cohort, seropositivity was 98.8% against the Wuhan, 97.6% against Delta and 100% against Omicron strains. For the PPP and AAP cohorts seropositivity was 100% against all 3 strains ( We also compared antibody concentrations following booster immunisation between the PPP and AAP groups: in the AAP group there was a higher median OD for the Wuhan (2.88 v 3.52, p<0.0001) and Delta strains (3.08 v 3.45, p=0.0022) but not for the Omicron strain (3.37 v 3.46, ns) compared to the PPP group suggesting heterologous vaccine strategies may demonstrate enhanced immunogenicity against these SARS-CoV-2 variants. Lastly, the WHO NIBSC 20/136 standard was run as a standard curve in the Wuhan, Delta and Omicron ELISAs and no significant loss of antibody binding was observed against any VOC Figure 1a) . Similarly, a dilution series from 6.5 mg/ml to 0.003 mg/ml of Sotrovimab (GSK) found no loss of antibody binding against Omicron (Supplementary Figure 1b) . Strong correlations exist between antibody binding and neutralisation (8) and between the presence of neutralising antibodies and protection against severe COVID-19 (9) . Understanding the pre-existing seroprevalence of antibodies directed against novel SARS-CoV-2 VOC and their induction following third-primary or booster immunisation is of critical importance in guiding public health policy during the ongoing SARS-CoV-2 pandemic. This knowledge is of particular relevance to immunologically vulnerable groups who either do not make a robust serological response to vaccination or fail to retain a serological response over time. In this study, we provide evidence supporting the need of a third dose of vaccination due to a waning antibody response at 6 months and the broadly cross-reactive humoral immunogenicity of the third vaccine dose against rapidly evolving SARS-CoV-2 VOC in healthy, CEV, and HD patients. However, it is important to note that antibody binding doesn't necessarily equate with functionality of antibodies, particularly in immunosuppressed individuals. Therefore, this is the best-case scenario and this study will need to be repeated with neutralisation assays going forward. The COCO study was ethically approved for this work by the London -Camden and Kings Cross Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. Lancet Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine SARS-CoV-2 variants of concern and variants under investigation in England Validation of a combined ELISA to detect IgG, IgA and IgM antibody responses to SARS-CoV-2 in mild or moderate non-hospitalised patients Development of a high-sensitivity ELISA detecting IgG, IgA and IgM antibodies to the SARS-CoV-2 spike glycoprotein in serum and saliva Site-specific glycan analysis of the SARS-CoV-2 spike WHO International Standard First WHO International Standard for anti-SARS-CoV-2 immunoglobulin (human) NIBSC code: 20/136 Instructions for use (Version 2.0, Dated 17/12/2020) Evidence for antibody as a protective correlate for COVID-19 vaccines. Vaccine Figure Legends: Figure 1: Percentage of cohort with antibodies against Wuhan, Delta and Omicron strain A-Detection of anti-Wuhan spike IgG in pre-2019 controls, a dialysis population, a cohort of health care workers who have had three PFZ vaccines and a Clinically Extremely Vulnerable population in general practice who have had two AZ and one PFZ vaccine. Results are given for pre and post 3 rd dose of vaccination B-Detection of anti-Delta spike IgG for the same populations C-Detection of anti-Omicron spike IgG for the same populations Pre-pre-3 rd dose of vaccine and 6 months post 2 nd dose. Post-28 days post 3 rd dose of vaccine Pfizer-BioNtech vaccines given in this cohort. AAP-two AstraZeneca ChAdOx1 nCoV-19 vaccines and the one Pfizer-BioNtech vaccine given in this cohort We thank the staff and patients that have kindly volunteered for this study. Thanks also to Abingdon