We formulate and theoretically analyze a mathematical model of COVID-19 transmission mechanism incorporating vital dynamics of the disease and two key therapeutic measures—vaccination of susceptible individuals and recovery/treatment of infected individuals. Both the disease-free and endemic equilibrium are globally asymptotically stable when the effective reproduction number
R
0
v
is, respectively, less or greater than unity. The derived critical vaccination threshold is dependent on the vaccine efficacy for disease eradication whenever
R
0
v
>
1
, even if vaccine coverage is high. Pontryagin’s maximum principle is applied to establish the existence of the optimal control problem and to derive the necessary conditions to optimally mitigate the spread of the disease. The model is fitted with cumulative daily Senegal data, with a basic reproduction number
R
0
=
1.31
at the onset of the epidemic. Simulation results suggest that despite the effectiveness of COVID-19 vaccination and treatment to mitigate the spread of COVID-19, when
R
0
v
>
1
, additional efforts such as nonpharmaceutical public health interventions should continue to be implemented. Using partial rank correlation coefficients and Latin hypercube sampling, sensitivity analysis is carried out to determine the relative importance of model parameters to disease transmission. Results shown graphically could help to inform the process of prioritizing public health intervention measures to be implemented and which model parameter to focus on in order to mitigate the spread of the disease. The effective contact rate
b
, the vaccine efficacy
ε
, the vaccination rate
v
, the fraction of exposed individuals who develop symptoms, and, respectively, the exit rates from the exposed and the asymptomatic classes
σ
and
ϕ
are the most impactful parameters.
Novel Ordered Stepped-Wedge Cluster Trial Designs for Detecting Ebola Vaccine Efficacy Using a Spatially Structured Mathematical Model