General discussion 9 283 viral replication (unpublished data). A systematic review of available literature, in which our study was included, noted a possible modest therapeutic effect of vaccination on long COVID[89]. This effect is insufficient for vaccination to be recommended for therapeutic use, although conclusions that can be drawn from observational data remain limited due to residual confounding and bias. Given that randomised clinical trials in which vaccination would be withheld in one group would be unethical, however, it is unlikely that vaccination will be a treatment option for long COVID. Care must be taken to ensure that individuals with long COVID are not discouraged from being vaccinated given that vaccination offers protection from severe disease. 9.2.2 Summary of key gaps in our knowledge of long COVID At the time of writing, there are numerous key knowledge gaps in our understanding of long COVID that are particularly relevant for the future. Although vaccination appears to lower the risk of developing long COVID following a breakthrough infection[90, 91], less is known about relative long COVID risk as a result of a reinfection compared to a primary infection. Available initial evidence, performed in a cohort of mainly ethnically-white, older adult males[92], suggests that reinfection may be associated with a cumulatively higher risk of developing at least one persistent sequela of COVID-19. This naturally raises concern about the growing burden of long COVID as many countries have lifted all public health restrictions in 2023. On the one hand, it may be argued that the adverse effects of public health restrictions on the economy, mental and physical health mean that it is no longer proportional to use NPIs to limit further cases of long COVID. On the other hand, in the absence of effective therapeutic tools for long COVID, prevention of infection remains our best strategy of limiting additional disease. We are in urgent need of effective prevention measures that can be targeted at those most at risk, instead of subjecting entire populations to invasive measures to prevent SARS-CoV-2 transmission. This ultimately demands a thorough understanding of the pathophysiology of long COVID. A second key knowledge gap is the relative risk of long COVID arising from infection with different SARS-CoV-2 variants. As selective pressure from natural and vaccine-derived immunity continues to drive SARS-CoV-2 to evolve, both the acute and long-term clinical features of infection may change over time. The Omicron variant (Pango lineage BA.1XBB), for instance, appears to trigger a more mild acute illness and also exhibit onequarter to one-half the risk of long COVID compared to the Delta variant (Pango lineage
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