Introduction: The recurrent multi-wave nature of COVID-19 necessitates updating its symptomatology. Before the omicron era, Hong Kong was relatively unscathed and had a low vaccine uptake rate among the old-old, giving us an opportunity to study the intrinsic severity of SARS-CoV-2 variants. A comparison of symptom patterns across variants and vaccination status in Hong Kong has yet to be undertaken. The intrinsic severity of variants and symptoms predictive of severe outcomes are also understudied as COVID-19 evolves. We therefore aim to characterize the effect of variants on symptom presentation, identify the symptoms predictive and protective of death, and quantify the effect of vaccination on symptom development. Methods: With the COVID-19 case series in Hong Kong from inception to 25 August 2022, an iterative multi-tier text-matching algorithm was developed to identify symptoms from free text. Cases were fully vaccinated if they completed two doses. Multivariate regression was used to measure associations between variants, symptom development, death and vaccination status. A least absolute shrinkage and selection operator technique was used to identify a parsimonious set of symptoms jointly associated with death. Results: Overall, 70.9% (54450/76762) of cases were symptomatic. We identified a wide spectrum of symptoms (n=102), with cough, fever, runny nose and sore throat being the most common (8.16-47.0%). Intrinsically, the wild-type and delta variant caused similar symptoms, with runny nose, sore throat, itchy throat and headache more frequent in the delta cohort; whereas symptoms were heterogeneous between the wild-type and omicron variant, with seven symptoms (fatigue, fever, chest pain, runny nose, sputum production, nausea/vomiting and sore throat) more frequent in the omicron cohort. With full vaccination, omicron was still more likely than delta to cause fever. Fever, blocked nose and shortness of breath were robustly jointly predictive of death as the virus evolved. Number of vaccine doses required for reduction in occurrence varied by symptoms. Discussion: This is the first large-scale study to evaluate the changing symptomatology by COVID-19 variants and vaccination status using free-text reporting by patients. We substantiate existing findings that omicron has a different clinical presentation compared to previous variants. Syndromic surveillance can be bettered with reduced reliance on symptom-based case identification, increased weighing on symptoms robustly predictive of mortality in outcome prediction, strengthened infection control in care homes through universal individual-based risk assessment to enable early risk stratification, adjusting the stockpile of medicine to tally with the changing symptom profiles across vaccine doses, and incorporating free-text symptom reporting by patients.

The authors have declared no competing interest.

We would like to acknowledge support from Health and Medical Research Fund (reference numbers: INF-CUHK-1, 17160302, 18170312, CID-CUHK-A, COVID1903008), General Research Fund (reference numbers: 14112818, 24104920), Wellcome Trust Fund (reference number: 200861/Z/16/Z) and Group Research Scheme of The Chinese University of Hong Kong.

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ETHICAL STATEMENT This study was approved by the Survey and Behavioral Research Ethics Committee of The Chinese University of Hong Kong (reference: SBRE-19-595). DATA STATEMENT The availability of the data set is subject to approval from Hong Kong Centre for Health and Protection, Department of Health and relevant government departments.

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The availability of the data set is subject to approval from Hong Kong Centre for Health and Protection, Department of Health and relevant government departments.