Uncertainty in COVID-19 transmission could undermine our ability to predict long COVID.

As SARS-CoV-2 has transitioned from a novel pandemic-causing pathogen into an established seasonal respiratory virus, focus has shifted to post-acute sequelae of COVID-19 (PASC, colloquially 'long COVID'). We use compartmental mathematical models simulating emergence of new variants to help identify key sources of uncertainty in PASC trajectories. Some parameters (such as the duration and equilibrium prevalence of infection, as well as the fraction of infections that develop PASC) matter more than others (such as the duration of immunity and secondary vaccine efficacy against PASC). Even if newer variants carry the same risk of PASC as older types, the dynamics of selection can give rise to greater PASC prevalence. However, identifying plausible PASC prevalence trajectories requires accurate knowledge of the transmission potential of COVID-19 variants in the endemic phase. Precise estimates for secondary vaccine efficacy and duration of immunity will not greatly improve forecasts for PASC prevalence. Researchers involved with Living Evidence Synthesis, or other similar initiatives focused on PASC, are well advised to ascertain primary efficacy against infection, duration of infection and prevalence of active infection in order to facilitate predictions.