A mathematical model of SARS-CoV-2 immunity predicts paxlovid rebound

Abstract

Nirmatrelvir/ritonavir (Paxlovid), an oral antiviral medication targeting SARS-CoV-2, remains an important treatment for COVID-19. Initial studies of nirmatrelvir/ritonavir were performed in SARS-CoV-2 unvaccinated patients without prior confirmed SARS-CoV-2 infection; however, most individuals have now either been vaccinated and/or have experienced SARS-CoV-2 infection. After nirmatrelvir/ritonavir became widely available, reports surfaced of "Paxlovid rebound," a phenomenon in which symptoms (and SARS-CoV-2 test positivity) would initially resolve, but after finishing treatment, symptoms and test positivity would return. We used a previously described parsimonious mathematical model of immunity to SARS-CoV-2 infection to model the effect of nirmatrelvir/ritonavir treatment in unvaccinated and vaccinated patients. Model simulations show that viral rebound after treatment occurs only in vaccinated patients, while unvaccinated (SARS-COV-2 naïve) patients treated with nirmatrelvir/ritonavir do not experience any rebound in viral load. This work suggests that an approach combining parsimonious models of the immune system could be used to gain important insights in the context of emerging pathogens.

Keywords: SARS coronavirus: virus classification; antiviral agents; computer modeling: biostatistics & bioinformatics; immune responses.

Figure 1:. Viral load over time with and without vaccination and with or without nirmatrelvir/ritonavir treatment.

The dash-dot red line represents when treatment with nirmatrelvir/ritonavir began. Time here is in arbitrary units because the model can be scaled to preserve the qualitative dynamics at any time scale.

Figure 2:. Simulated immune response to SARS-COV-2 infection and nirmatrelvir/ritonavir administration in vaccinated and unvaccinated patients.

The top timeline represents unvaccinated patients such as those in the initial clinical trial. The bottom timeline represents vaccinated patients (or those with acquired immunity from prior infection). Cv = viral infected cells, D = damaged/dysfunctional tissue, AI = adaptive immune response, T = time. Created with BioRender.com.