Infection

This section is aimed at assisting public health professionals and is based on an ongoing rapid review of the latest evidence.

Incubation period

(Latest update: 17 March 2022)

The incubation period is the time between exposure to a virus and the development of symptoms (referred to as symptom onset). Based on a number of systematic reviews and meta-analyses in studies investigating infections with ancestral strains of SARS-CoV-2, the incubation period of COVID-19 is, on average, five to six days, with most studies reporting a range of two to 14 days [1-5].

Recent evidence suggests that the incubation period of emerging SARS-CoV-2 variants can differ from that of ancestral strains [6-8]. For example, several studies have determined the Delta variant to have a shorter incubation period of around four days [8-10]. This information is important for determining when to test after a known exposure. Evidence from early studies of the Omicron variant suggests an even shorter incubation period of approximately three days, however further studies are needed to verify these findings [11-13].

Infectivity and viral kinetics

(Latest update: 17 March 2022)

Infectivity

The exact duration of infectivity of COVID-19 patients (the period during which they can transmit the virus to others) is still unknown and is likely to vary between virus variants as well as individuals. It is dependent on numerous factors, such as pre-existing immunity through vaccination or prior infection and disease severity [14-16]. The live virus can be isolated from clinical samples as a surrogate for measuring infectivity, however this is rare and, when undertaken it is mainly to research the biological properties of the virus. In studies of non-severe cases, the virus was successfully isolated up to 10 days from onset of symptoms [15,17-19]. However, patients with severe COVID-19 and immunocompromised patients can be infectious for a longer period [15,20,21].

Viral load and viral RNA shedding

One of the most frequently used diagnostic tests to detect SARS-CoV-2 infection is the nucleic acid amplification test (NAAT) which detects viral genetic material (RNA) in a specimen. Real-time reverse transcription (RT)-PCR tests are the gold standard for the detection of COVID-19 and provide both a qualitative result (detected/not detected) and a quantitative result in the form of a cycle threshold (Ct) value (number of amplification cycles required for the detection signal to cross the background level - i.e. to generate a positive result). As Ct values are determined by the amount of viral RNA in the sample, they are often used as a proxy for the viral load (defined as the quantity of virus particles or viral genome copies in a given volume of the specimen) and can relate to the amount of virus present in the specimen.

It is important to note that the presence of SARS-CoV-2-RNA identified through RT-PCR (i.e. viral RNA shedding) in a patient is not the same as the presence of infectious SARS-CoV-2 (viable viral shedding). However, higher viral RNA loads have been correlated with positive viral culture [15,22,23].

Studies have reported that viral loads peak around the time of symptom onset and then gradually decrease [24-26]. Viral loads are highly individual. Patients with severe disease have higher viral loads than patients with mild disease [27,28]. Advanced age (>60 years) has also been associated with higher viral loads [26,29,30]. Children have viral loads similar to those of adults [31]. Prolonged viral shedding with high viral load has been associated with poor outcome in hospitalised patients [26]. It is generally accepted that a high viral load is associated with transmission, although as yet the relationship has not been precisely evaluated.

Detection of both viral RNA and infectious virus has been reported in pre-symptomatic patients (before the onset of symptoms) and even asymptomatic individuals. Asymptomatic individuals can have viral loads that are just as high as those of symptomatic cases, indicating that asymptomatic carriers can play a major role in transmitting SARS-CoV-2 [32-35]. In fact, several studies have shown that secondary transmissions from an index case (the first case identified in a cluster of cases) could occur as early as three days before the onset of symptoms in the index case, indicating that the pre-symptomatic phase of SARS-CoV-2 is highly infectious [36-39].

Viral RNA has been detected in upper and lower respiratory tract, as well as gastrointestinal specimens. The duration of viral RNA shedding varies for specimens and patients [17]. Some COVID-19 patients have positive RT-PCR results long after clinical diagnosis (e.g. 60 to >100 days) but this does not mean that they are still infectious [17,40-45].

Impact of variants of concern (VOC) on viral kinetics

Transmissibility, incubation period, duration of infectiousness and peak viral load may differ among virus variants. For example, increased viral loads have been reported with the Alpha and Delta variant of concern (VOC) compared to the ancestral strain [46-48]. Epidemiological evidence has shown that the Delta VOC was more transmissible than the ancestral and Alpha strains, with transmissibility nearly double that of the wild-type SARS-CoV-2 virus that circulated during autumn 2020 [8,49-52]. This increased transmissibility was a key factor in the rapid dominance of the Delta VOC in 2021. Data on variations in the virological characteristics of the Omicron VOC are limited. At present, it is unclear whether there are significant differences in viral load with Omicron infection, as has been observed for infections with other VOCs.

Assessing the virological characteristics of newly emerging variants of concern is challenging. Due to the increase in immunity against SARS-CoV-2 in the population, it is difficult to determine whether differences are attributable to immunity in a largely vaccinated or/and infected population, or due to the intrinsic characteristics of the different variants of concern.

Impact of vaccination on viral kinetics

Studies of viral load in SARS-CoV-2-infected individuals conducted from late 2020 to early 2021 indicate that viral load is reduced in those who have received a COVID-19 vaccine. More recent results indicate that vaccination may have less effect in reducing viral load in infections caused by the Delta VOC [53,54]. However, a shorter duration of infectious virus and viral RNA shedding in vaccinated individuals has been suggested by several studies conducted during the period when the Delta VOC was the dominant variant [55]. A multicentre, retrospective cohort study from Singapore, comparing vaccinated individuals to unvaccinated individuals, reported a faster decline in viral RNA loads [56]. A prospective cohort study from the UK showed that vaccinated individuals, once infected with the Delta VOC, can reach similar viral loads to unvaccinated individuals infected with Delta VOC. However, vaccinated individuals clear the virus more rapidly than unvaccinated individuals [16]. Another study from the US also showed faster viral clearance among the vaccinated than the unvaccinated [14]. A more rapid clearance may have implications on how long vaccinated and unvaccinated individuals remain infectious, which may indicate that vaccinated individuals, even if infected, transmit the virus for a shorter time than unvaccinated individuals.

As the proportion of the vaccinated and/or previously infected population increases, it becomes more difficult to investigate the impact of vaccination. The limited evidence available for the Omicron VOC shows similar kinetics for viral load and duration of infectious virus shedding in vaccinated individuals infected with the Omicron VOC as for those vaccinated individuals who were infected with the Delta VOC [18,57]. A recent large population-based household transmission study from Denmark during the circulation of Omicron VOC found ‘an increased transmission for unvaccinated individuals, and a reduced transmission for booster-vaccinated individuals, compared to fully vaccinated individuals’. This finding shows that vaccinated individuals, particularly those recently having received a booster dose, do not transmit the virus to the same extent as unvaccinated individuals [58].

References

Supporting document: List of references