The emergence and evolution of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants that could compromise vaccine efficacy (VE) with re-infections in immunized individuals have necessitated continuous surveillance of VE. Here, the occurrence and dynamics of SARS-CoV-2 infections in the context of vaccination during the second wave of infection in Mumbai were evaluated. RT-PCR cycle threshold (Ct) values of the open reading frame (ORF)/envelope (E)/nucleocapsid (N) genes obtained from a total of 42415 samples, comprising unvaccinated (96.88%) and vaccinated cases (3.12%) were analyzed between December 28, 2020, and August 30, 2021. A lower incidence of SARS-CoV-2 infection in fully vaccinated cases (5.07%) compared to partially vaccinated cases (6.5%) and unvaccinated cases (13.453%) was recorded. VE was significant after the first dose of vaccination (ORF gene p-value = 0.003429, and E/N gene p-value = 0.000866). Furthermore, VE was observed to be significant when the post-immunization (first dose) period was stratified to within 30 days (ORF gene p-value = 0.0094 and E/N gene p-value = 0.0023) and to 60 days following the second dose of vaccination (ORF gene p-value = 0.0238). Also, significantly higher efficacy was observed within individuals receiving two doses compared to a single dose (ORF gene p-value = 0.0132 and E/N gene p-value = 0.0387). The emergence of breakthrough infections was also evident (odds ratio= 0.34; 95% confidence interval= 0.27-0.43). Interestingly, viral loads trended towards being higher in some groups of partially vaccinated individuals compared to completely vaccinated and unvaccinated populations. Finally, our results delineated a significantly higher incidence of SARS-CoV-2 acquisition in males, asymptomatic individuals, individuals with comorbidities, and those who were unvaccinated.