This study elucidated the clinical, humoral immune response and genomic analysis of vaccine breakthrough (VBT) infections after ChAdOx1 nCoV-19/Covishield vaccine in healthcare workers (HCWs). Amongst 1858 HCWs, 1639 had received either two doses (1346) or a single dose (293) of ChAdOx1 nCoV-19 vaccine. SARS-CoV-2 IgG antibodies and neutralizing antibodies were measured in the vaccinated group and the development of SARS-CoV-2 infection was monitored.Forty-six RT-PCR positive samples from the 203 positive samples were subjected to whole genome sequencing (WGS). Of the 203 (10.92%) infected HCWs, 21.46% (47/219) were non-vaccinated, which was significantly more than 9.52% (156/1639) who were vaccinated and infection was higher in doctors and nurses. Unvaccinated HCWs had 1.57 times higher risk compared to partially vaccinated HCWs and 2.49 times higher risk than those who were fully vaccinated.The partially vaccinated were at higher risk than the fully vaccinated (RR 1.58). Antibody non-response was seen in 3.44% (4/116), low antibody levels in 15.51% (18/116) and medium levels were found in 81.03% (94/116). Fully vaccinated HCWs had a higher antibody response at day 42 than those who were partially vaccinated (8.96 + 4.00 vs. 7.17 + 3.82). Whole genome sequencing of 46 samples revealed that the Delta variant (B.1.617.2) was predominant (69.5%). HCWs who had received two doses of vaccine showed better protection from mild, moderate, or severe infection, with a higher humoral immune response than those who had received a single dose. The genomic analysis revealed the predominance of the Delta variant (B.1.617.2) in the VBT infections.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) manifests a broad spectrum of clinical presentations, varying in severity from asymptomatic to mortality. As the viral infection spread, it evolved and developed into many variants of concern. Understanding the impact of mutations in the SARS-CoV-2 genome on the clinical phenotype and associated co-morbidities is important for treatment and preventionas the pandemic progresses. Based on the mild, moderate, and severe clinical phenotypes, we analyzed the possible association between both, the clinical sub-phenotypes and genomic mutations with respect to the severity and outcome of the patients. We found a significant association between the requirement of respiratory support and co-morbidities. We also identified six SARS-CoV-2 genome mutations that were significantly correlated with severity and mortality in our cohort. We examined structural alterations at the RNA and protein levels as a result of three of these mutations: A26194T, T28854T, and C25611A, present in the Orf3a and N protein. The RNA secondary structure change due to the above mutations can be one of the modulators of the disease outcome. Our findings highlight the importance of integrative analysis in which clinical and genetic components of the disease are co-analyzed. In combination with genomic surveillance, the clinical outcome-associated mutations could help identify individuals for priority medical support.