New review highlights variant-specific differences in long COVID, underscoring vaccine role and future directions for research and care

Long COVID, or post-acute sequelae of COVID-19 (PASC), has become a significant public health concern as persistent symptoms affect millions worldwide, long after the acute phase of infection subsides. A review published in MedComm – Future Medicine, led by a team at the Faculty of Medicine at Macau University of Science and Technology, examines how long COVID symptoms differ between SARS-CoV-2 variants, drawing on data from a range of populations and study designs. Dr. Olivia Monteiro, co-corresponding author of this review explained, “As COVID-19 variants emerged, they demonstrated distinct behaviors in terms of immune evasion, transmissibility, and pathogenicity. Our review aims to synthesize these observations and explore the interplay between variants, vaccination, and long COVID.”

The review highlights key differences in the clinical manifestations of long COVID depending on the variant. For instance, Alpha and Delta variants have been linked to a higher prevalence of cardiopulmonary symptoms, such as breathlessness and chest pain, while Omicron infections show fewer severe cardiopulmonary effects but relatively higher incidences of fatigue and brain fog. The review also explores the potential differences in the pathogenesis of long COVID caused by different SARS-CoV-2 variants. Immune dysregulation, viral persistence in tissues, reactivation of latent viruses, and potential autoimmune responses triggered by the virus can all play a role. The immune dysregulation hypothesis is particularly relevant in Omicron cases, as studies show Omicron infections stimulate a slower interferon response, possibly contributing to reduced symptom severity in long COVID.

The review also highlights the apparent decreasing incidence and severity of long COVID from the ancestral to Omicron variants, particularly among vaccinated individuals. Indeed, data from multiple studies indicate that vaccinated individuals are less likely to develop long COVID symptoms. People infected with Omicron post-vaccination report notably fewer and less severe symptoms compared to unvaccinated individuals infected with Alpha or Delta. “Vaccinations contribute significantly to reducing both acute and long-term symptoms by bolstering the immune response, which likely prevents prolonged viral persistence and reduces the risk of immune-related complications,” said Dr. Laurence Lok, co-lead author. “Studies included in the review reveal that as vaccination rates increase, the incidence of long COVID has shown a corresponding decrease across different SARS-CoV-2 variant periods.”

The review authors emphasize the need for clear, standardized diagnostic criteria for long COVID to better identify and manage the condition. The review also emphasizes that one of the difficulties in conducting long COVID research is the lack of a clearly defined population in which to study this condition. The review highlights ongoing work by the authors in the Macau Special Administrative Region (SAR), China which provides a unique context for studying long COVID in an environment with controlled variant exposure. Strict lockdowns kept the population largely unexposed to early variants until the arrival of the Omicron wave, when a single variant infected the majority of the population in a short period. Researchers have launched the LOng COvid in MACau (LOCOMAC) project to study long COVID in individuals with only Omicron infections without previous variant exposures. Dr. Daniel Baptista-Hon, co-corresponding author of the review and LOCOMAC lead explained, “This isolated exposure scenario presents a rare opportunity to understand long COVID in a unique epidemiological setting, potentially offering insights that can inform global research and healthcare strategies.”

The nature of long COVID is dynamic and vaccination is critical in reducing its impact. Understanding how different variants affect long COVID incidence and symptom profiles will be vital for future healthcare planning. The insights from this study contribute to a growing body of knowledge that aims to improve outcomes for those affected by long COVID and to guide public health responses as new variants arise.