Background: The course of the COVID-19 pandemic has been driven by several dynamic behavioral, immunological, and viral factors. We used mathematical modeling to explore how the concurrent reopening of schools, increasing levels of hybrid immunity, and the emergence of the Omicron variant affected the trajectory of the pandemic in India, using Andhra Pradesh (pop: 53 million) as an exemplar Indian state.

Methods: We constructed an age- and contact-structured compartmental model that allows for individuals to proceed through various states depending on whether they have received zero, one, or two doses of the COVID-19 vaccine. We calibrated our model using results from another model (ie, INDSCI-SIM) as well as available context-specific serosurvey data. The introduction of the Omicron variant is modelled alongside protection gained from hybrid immunity. We predict disease dynamics in the background of hybrid immunity coming from infections and an ongoing vaccination program, given prior levels of seropositivity from earlier waves of infection. We describe the consequences of school reopening on cases across different age-bands, as well as the impact of the Omicron (BA.2) variant.

Findings: We show the existence of an epidemic peak in India that is strongly related to the value of background seroprevalence. As expected, because children were not vaccinated in India, re-opening schools increases the number of cases in children more than in adults, although in all scenarios, the peak number of active hospitalizations was never greater than 0.45 times the corresponding peak in the Delta wave before schools were reopened. We varied the level of infection induced seropositivity in our model and found the height of the peak associated with schools reopening reduced as background infection-induced seropositivity increased from 20% to 40%. At reported values of seropositivity of 64% from representative surveys done in India, no discernable peak was observed. We also explored counterfactual scenarios regarding the effect of vaccination on hybrid immunity. We found that in the absence of vaccination, even at high levels of seroprevalence (>60%), the emergence of the Omicron variant would have resulted in a large rise in cases across all age bands by as much as 1.8 times. We conclude that the presence of high levels of hybrid immunity resulted in fewer cases in the Omicron wave than in the Delta wave.

Interpretation: In India, decreasing prevalence of immunologically naïve individuals of all ages was associated with fewer cases reported once schools were reopened. In addition, hybrid immunity, together with the lower intrinsic severity of disease associated with the Omicron variant, contributed to low reported COVID-19 hospitalizations and deaths.

Funding: World Health Organization, Mphasis.