Viral dynamics during SARS-CoV-2 omicron infection highlight presymptomatic and asymptomatic infectiousness

To the editor,

Peaking of SARS-CoV-2 viral shedding usually correlates with high infectiousness.¹ Despite of early awareness of prevalent presymptomatic viral shedding that may evade control measures and drive stealth transmission,² SARS-CoV-2 viral kinetics during presymptomatic stage or asymptomatic infections was still poorly understood due to requiring repeated tests in asymptomatic population. SARS-CoV-2 omicron infections were more likely to be asymptomatic or milder comparing to delta infections,3, 4, 5 which were associated with shifting virological characteristics of omicron in animal models,6, 7, 8 and might offer key evolutionary advantage over prior variants.⁹

Here, we provided evidence of peak viral shedding at presymptomatic stage and during asymptomatic omicron infections by analyzing viral RNA kinetics during the entire infection course. 1,085 SARS-CoV-2 PCR-positive cases in Guang'an city of western China, who were admitted to West China Guang'an Hospital between 2022/5/9 and 2022/6/3 were enrolled in this study. Characteristics of the cohort were summarized in Table 1 . Methods of population screening for omicron infections and in-hospital procedures including PCR testing and symptom monitoring were detailed in the Supplementary Materials. The human study protocols have been approved by West China Guang'an Hospital and all patient identifications were replaced by anonymous codes during abstraction as stipulated by the Declaration of Helsinki.

Table 1.

Demographic and clinical characteristics of the cohort.

	All cases (n = 1085)	Asymptomatic (n = 766)	Symptomatic (n = 319)	P*
Age in years, median (IQR)	43 (17–56)	42 (16–55)	47 (18–57)	.039
<18, n (%)	291 (26.8)	215 (28.1)	76 (23.8)	.079
18–59, n (%)	606 (55.9)	430 (56.1)	176 (55.2)
≥60, n (%)	188 (17.3)	121 (15.8)	67 (21.0)
Female sex at birth, n (%)	652 (60.1)	443 (57.8)	209 (65.5)	.021
Days of RNA-positive, median (IQR)	13 (11–17)	13 (10–17)	14 (11–17)	.049
Days from first RNA-positive to symptom onset, median (IQR) [n]	0 (0–4) [319]	/	0 (0–4) [319]	/
Days from first RNA-positive to peak RNA load, median (IQR) [n]	3 (2–5) [298]	3 (2–5) [222]	3 (2–5) [76]	.583
Vaccination status, n (%)
Unvaccinated	29 (2.7)	18 (2.4)	11 (3.5)	.063
Partial vaccination	9 (0.8)	3 (0.4)	6 (1.9)
Full vaccination without booster	346 (31.9)	248 (32.4)	98 (30.8)
Full vaccination with booster	699 (64.4)	496 (64.8)	203 (63.8)
Unknown	2 (0.2)	1 (0.1)	1 (0.3)
Days from last vaccination to first RNA-positive, median (IQR) [n]	152 (133–265) [782]	152 (137–258) [524]	151 (128–267) [258]	.916
COVID-19 severity, n (%)
Asymptomatic	766 (70.6)	766 (100)	0 (0)	/
Mild	319 (29.4)	0 (0)	319 (100)
COVID-19 symptoms, n (%)
Respiratory	285 (26.3)	0 (0)	285 (90.5)	/
Neuromuscular	75 (6.9)	0 (0)	75 (23.8)	/
Gastrointestinal	17 (1.6)	0 (0)	17 (5.4)	/
Other	4 (0.4)	0 (0)	4 (1.3)	/
Comorbidities, n (%)
Respiratory disorders	13 (1.2)	8 (1.0)	5 (1.6)	.541
Cardiovascular disorders	96 (8.8)	67 (8.8)	29 (9.1)	.907
Metabolic disorders	31 (2.9)	22 (2.9)	9 (2.8)	1.00
Immune disorders	7 (0.6)	3 (0.4)	4 (1.3)	.204
Other infectious diseases	11 (1.0)	8 (1.0)	3 (0.9)	1.00
Cancer	12 (1.1)	6 (0.8)	6 (1.9)	.122
Other	3 (0.3)	3 (0.4)	0 (0)	.560

^⁎Categorical variables were assessed by Fisher's exact test or Chi-square test and continuous variables were assessed by Mann-Whitney U test. Tests were performed between asymptomatic and symptomatic groups. Abbreviations: IQR, interquartile range.

Guang'an reported no prior SARS-CoV-2 outbreaks and >95% vaccine coverage. Patient zero with asymptomatic infection of omicron BA.2.2 sub-variant arrived in Guang'an on 2022/5/4 and was the index of and outbreak that lead to more than 1,000 cases despite early interventions (Fig. S1). Viral RNA kinetics of 962 cases showed prevalent asymptomatic and presymptomatic peaks (Fig. S2). 69% (668/962) of them, who were asymptomatic till the end of follow-up, showed comparable peak viral RNA levels (geometric mean 4.4 × 10⁵ vs 2.7 × 10⁵ copies/ml, p=.173) and peak timing (median 5 vs 5 days, p=.378) with symptomatic cases (Fig. 1A and B).

Interestingly, 21% (61/294) symptomatic cases showed pre-symptomatic peaking of viral RNA, which were rarely seen in pre-alpha and alpha variant infections,¹ with higher peak viral loads than other symptomatic (geometric mean 1.1 × 10⁶ vs 1.9 × 10⁵ copies/ml, p<.001) or asymptomatic cases (geometric mean 1.1 × 10⁶ vs 4.4 × 10⁵ copies/ml, p=.014) (Fig. 1 C). Simultaneous or post-symptomatic peaks were dominant in pre-alpha and alpha variant infections,¹ whereas they were less common in early-stage (≤5 days post-lockdown, 41/83) than late-stage omicron cases in our cohort (192/211, p<.0001).

Fig. 1.

Peak viral RNA loads and timing according to symptomatic status or stage of outbreak.

(A,B) Comparison of peak viral RNA levels (A) and time from viral RNA-positive to peak viral RNA (B) between asymptomatic (n = 668) and symptomatic cases (n = 294). Lines indicate geometric means ± 95% confidence intervals (A) or medians (B). Viral RNA concentration was calculated based on the Ct value of Orf1ab gene as described in the Supplementary Materials. Lower limit of viral RNA concentration was set at 19 copies/mL, which corresponded to cut-off Ct value of 38 for Orf1ab gene. (C) Comparison of peak viral RNA levels between asymptomatic (n = 668), pre-symptomatic peaking (n = 61) and post-symptomatic peaking cases (n = 233). The pre-symptomatic and post-symptomatic peaking cases together made the symptomatic group in (A). Lines indicate geometric means ± 95% confidence intervals. (D) Comparison of peak viral RNA levels between early- (≤5 days after lockdown, n = 436) and late-stage cases (n = 526). Lines indicate geometric means ± 95% confidence intervals. Statistical significance was assessed by Mann-Whitney U tests.

Intriguingly, late-stage infections had lower peak viral loads (geometric mean 1.3 × 10⁶ vs 1.5 × 10⁵ copies/ml, p<.0001) at the time of increased preventive measures (Fig. 1D), whereas among those infected, vaccination was not associated with peak viral load, duration of viral clearance, or symptomatic disease (Fig. S3). Of note, endocrine disorders such as diabetes were associated with higher peak viral loads, whereas chronic infections such as HBV infections were also associated with higher peak viral loads despite of not reaching statistical significance due to small number of positive cases (Fig. S3).

These findings together provided evidence of an early and asymptomatic window of infectiousness during some omicron infections. Such front-loaded infectiousness of omicron poses significant challenges to pandemic control policies, and measure undertaken earlier were less likely to be effective in this circumstance. Symptom-based testing and extended quarantine used to be an effective strategy to block SARS-CoV-2 transmission in pre-omicron era due to the long infectious window post-symptom onset.¹⁰ However, ongoing epidemic in countries with strict COVID-19 policies suggested that omicron carriers may already spread infections before being quarantined,¹⁰ which had exactly happened in Guang'an and could only be contained by early detection and interventions. Hopefully, upcoming omicron-adapted vaccines could control the pandemic; otherwise, more efficient and cost-effective screening techniques for asymptomatic population might be needed for future variants with high virulence.

Role of the funding source

This study was supported by the National Natural Science Foundation of China (grants 82072862 and 82272949 to YX).

Author contributions

LJ abstracted case information and did clinical investigations; LT did epidemiological investigations and statistical analysis; LZ, SY and WC collected PCR Ct values; YZhu analyzed viral kinetics and interpreted findings; YF did survey of Guang'an residents; XY, SY, YZheng and YX interpreted findings and did investigations; PH conceived the study, analyzed data, and wrote the manuscript. No authors were precluded from accessing data in the study, and they accept responsibility to submit for publication. All authors participate in the revision of the manuscript and approve the final manuscript.

Declaration of Competing Interest

The authors declare no competing interests.