Long-term Durable Humoral Immune Response to Heterologous Antigenic Exposure Post six months by Natural SARS-CoV-2 Infection and Vaccination

Importance Both 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. Objective To 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. Design Cross-sectional observational study conducted between November 2021 and January 2022. Setting Participants were drawn from a DBT COVID-19 Research Consortium cohort in Delhi National Capital Region, India. Participants We 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. Exposure Age, 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. Results The 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 [χ2 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 Relevance Considering the wide seropositivity rates due to natural SARS-CoV-2 infection, recommendation for boosters should take into account past infections in the population. Question What 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? Findings Cross-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. Meaning Humoral immunity may last longer due to heterologous antigenic exposure following vaccination and natural infection emphasizing the need for contextualizing the booster policy. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This research was supported by Ind-CEPI grant (102/IFD/SAN/5477/2018-2019) to Translational Health Science and Technology Institute, Faridabad; COVID-19 Bioresource grant (BT/PR40401/BIOBANK/03/2020); SARS-CoV-2 diagnostics development grant (Grant No. BT/PR40333/COD/139/11/2020) to Translational Health Science and Technology Institute, Faridabad by the Department of Biotechnology and; GIISER South Asia grant from Bill and Melinda Gates Foundation, Seattle, USA. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee of Translational Health Science and Technology Institute, Faridabad; All India Institute of Medical Science, New Delhi; Maulana Azad Medical College and Lok Nayak Hospital, New Delhi and; ESIC Medical College and Hospital, Faridabad have given ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The deidentified dataset and related codes for analysis may be available to researchers upon request addressed to the corresponding author after publication after the approval of the Department of Biotechnology, Government of India.