Risk of SARS-CoV-2 reinfections in kids: a potential nationwide surveillance examine between January, 2020, and July, 2021, in England

When exposed to SARS-CoV-2, children are more likely than are adults to develop a mild, transient illness and less likely to develop severe disease, require admission to hospital or intensive care, or die of COVID-19.

Following infection, children develop robust humoral and cellular responses to SARS-CoV-2, targeted primarily against the spike protein of the virus, irrespective of whether they develop symptomatic illness or remain asymptomatic after infection.

Additionally, immunity is sustained for at least 12 months, potentially longer than in adults, with evidence of cross-protection against new SARS-CoV-2 variants.

Reinfection following primary SARS-CoV-2 infection is uncommon but has been described mainly in adults, even in the presence of SARS-CoV-2 antibodies.

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Additionally, breakthrough infections have been reported in vaccinated adults, with increasing risk with time since vaccination.

An increased risk of reinfection has also been reported following the emergence of the delta (B.1.617.2) variant, which is more transmissible than previous SARS-CoV-2 variants and able to at least partially evade both natural and vaccine-induced immunity.

However, little is known about the rate, risk factors, characteristics, severity, or outcomes of SARS-CoV-2 reinfections in children with the exception of a few case reports in immunocompromised children.

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In England, the first cases of SARS-CoV-2 emerged in late January, 2020, and infections increased rapidly, leading to a national lockdown including school closures in March, 2020.

Cases peaked in mid-April and then declined gradually, leading to easing of lockdown measures, including partial reopening of some school class years during June and July, 2020, and full reopening of all school years albeit with strict infection controls in September, 2020.

Early in the pandemic, testing for SARS-CoV-2 was limited to symptomatic cases in health-care settings, but community testing became available from June, 2020, initially for individuals with typical symptoms of COVID-19 (fever, new-onset cough, or loss of taste or smell) but soon became available for anyone wishing to be tested, with a 7-day rolling average of in excess of 100 000 tests per day by June 28, 2020.

During the surveillance period from Jan 27, 2020, to July 31, 2021, primary infection cases were low during the summer of 2020, then increased from the end of August just before the start of the Autumn school term and peaked at the end of December, 2020, following the emergence and rapid spread of the alpha variant across England from the middle of November, 2020 (figure 1). A national lockdown implemented in January, 2021, including school closures, was associated with a rapid decline in cases, with a small peak in March, 2021, when children returned to school while adults remained in national lockdown, followed by a larger peak starting from the end of May, 2021, with the easing of national lockdown alongside the emergence and rapid spread of the delta variant nationally.

Reinfection rates were very low in children during the alpha wave, at a time when the number of primary infection cases eligible for reinfections was also low. There was a small increase in reinfection cases during March, 2021 (given the relatively small number of infections in the community at that time) compared with the low number of reinfections in the December wave, when community rates were high. This difference was due to the cumulative count of primary cases eligible for reinfection increasing rapidly by almost 6-fold in March, 2021, compared with the number of cumulative cases during the winter peak in December, 2020 (figure 1). Reinfection cases then stabilised for 2 months before increasing rapidly from the end of May, 2021, and following the same trajectory as community infection rates during the delta wave, reaching a peak at the same time as primary infection rates in the middle of July, 2020. Weekly primary infection and reinfection cases subsequently declined after schools closed for the summer holidays.

Children aged 16 years or younger had not exceeded a weekly reinfection rate of 1 per 100 000 population individuals by the week beginning June 14, 2021 (figure 2). During the alpha wave, reinfections occurred mainly in older adults (age 80 years and older). As the adult population increasingly became vaccinated from December, 2020 (appendix p 3), the age distribution of reinfection cases changed; at the emergence of the delta variant, the reinfection risk was highest in younger adults (age 17–39 years), who remained largely unvaccinated or partially vaccinated with a single vaccine dose. During the peak delta wave, reinfection rates in 12–16 year-olds peaked in the week beginning July 12, 2021, and mirrored reinfection rates in those aged 50–59 years, 93% of whom had been vaccinated with a first dose, and 82% of whom had been vaccinated with a second dose, by June 1, 2021 (appendix pp 1–2).

In children, at the peak of reinfections in the week beginning July 12, 2021, there was an age-related gradient, with the lowest reinfection rate of 0·9 per 100 000 population in children younger than age 5 years compared with 1·9 per 100 000 population in those aged 5–11 years and 5·5 per 100 000 population in those aged 12–16-years. These rates were 23, 11, and four times lower than in adults aged 20–29 years, who were unvaccinated and had the highest reinfection rate at the time (figure 2; appendix p 2).

During the 19-month surveillance period (January, 2020, to July, 2021), primary childhood infection rates were higher in infants (those younger than age 1 year) than in those aged 1 and 2 years, before increasing with age up to 16 years (figure 3). However, reinfections were lowest in infants (23 cases) and remained low among those aged 1–6 years with an average of 43 cases per year group, before increasing with age, reaching 364 cases among those aged 16 years (figure 3).

In England, primary infections in children started increasing in February, 2020, with the first reinfection in a child identified in late July, 2020. By the end of July, 2021, there were 688 418 primary infections and 2343 reinfections in children under 16 years in England. There were no differences in sex or ethnicity between primary and secondary infections (table). The overall reinfection rate for this period was 66·88 per 100 000 population, being higher in adults (72·53 per 100 000 population) than in children (21·53 per 100 000 population). Reinfection rates after primary infection over the same period were 0·68 per 100 primary infections overall, 0·73 per 100 primary infections in adults, and 0·34 per 100  primary infections in children. Reinfection rates by age group are summarised in figure 4.

Several important factors need to be considered when assessing the risk of reinfection in this cohort. First, reinfection cases were based on sequential positive tests with an interval of at least 90 days and did not require a negative PCR result between infection episodes or a genetically distinct SARS-CoV-2 strain at each episode, as specified in other definitions.

As of Oct 31, 2021, there were only 441 confirmed reinfections with genetically distinct strains in England.

We used a pragmatic definition applied to surveillance data that allowed sufficient time for clinical recovery and for the initial PCR test to become negative before a second infection was diagnosed to rule out persistent infections, while acknowledging that reinfection might rarely occur within 90 days of primary infection. The population reinfection rates in England increased sharply following the emergence of the omicron variant from November, 2021, onwards. From this point reinfections accounted for increased proportion of all first infections and reinfections in all ages.

Secondly, only limited testing for SARS-CoV-2 was available during the early stages of the pandemic, with testing restricted primarily to symptomatic individuals attending health-care settings. Because children are significantly less likely than are adults to develop symptomatic infection, severe disease, or be admitted to hospital for COVID-19, earlier infections would probably not have been confirmed in a laboratory.

Our serosurveillance in educational settings estimated that 11·2% of primary school students (age 5–11 years) had been infected with SARS-CoV-2 by June, 2020,

and 12·8% of secondary school students (age 11–16 years) by September, 2020.

Thirdly, community testing became more widely available from June, 2020, including for children, but was primarily targeted to symptomatic individuals with typical COVID-19 symptoms (fever, new-onset cough, and loss of taste or smell). Because children are more likely than are adults to develop a mild, transient illness when exposed to SARS-CoV-2 (and therefore, not seek medical attention for testing or treatment) and to develop non-respiratory symptoms,

they would potentially be less likely than adults to undergo testing even after community testing was available. Fourthly, national testing data would not include asymptomatic primary infections or reinfections unless individuals were tested because they were concerned over exposure to a case, and children are more likely to be asymptomatic—and therefore, less likely to be tested— than are adults.

Fifthly, the introduction of twice-weekly rapid home testing with LFDs for secondary school pupils since March, 2021, will probably have enhanced case ascertainment, including asymptomatic infections, leading to reduced virus introduction and in-school transmission in 11–16 year-olds. Finally, the risk of reinfection is also likely to vary with time since primary infection and with different SARS-CoV-2 variants. However, comparison of relative risks between variants is not possible because they emerged at different times, such that both the number of people with primary infections who became susceptible to reinfection, and the interval between primary infection and reinfection, were far greater during the delta wave in July, 2021, than in the alpha wave in December, 2020.

Furthermore, comparison with adults is hampered by differential exposure risks over time, with prolonged periods of national lockdown, which at times included school closures. Schools remained open for in-person teaching for some age groups during national lockdown in June–July, 2020, November, 2020, and March–May, 2021, but closed during January–February, 2021, when England was experiencing the second pandemic wave due to the alpha variant.

Among school-aged children, testing rates were heavily influenced by school closure due to lockdowns or school term breaks.

The national rollout of COVID-19 vaccines from December, 2020, with gradual extension of eligibility down the age groups to those aged 12 and older, also affected comparison of risk and rates over time.

While keeping these considerations in mind, we have for the first time estimated the risk of reinfection in children under 16 years and compared them to the risk in adults over a 19-month period. Reinfections occur frequently after infection with seasonal coronaviruses, which cause the common cold (229E, OC43, NL63, and HKU1) because of short-lasting, poorly cross-protective immunity between infections.

Reinfections have also been reported with SARS-CoV-2, although the risk was previously estimated to be very low during the first few months after primary infection in adults and even lower in children, although data on reinfections are scarce in the paediatric population.

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Our study confirms a lower risk of reinfection in children compared with in adults, especially unvaccinated young adults and, within the childhood age groups, reinfection rates broadly tracked with primary infection rates by age in years except in infants (younger than age 1 year) who had a higher primary infection rate than reinfection rate. This result is likely to be a testing artefact because of screening in newborns for SARS-CoV-2 and as part of infection screens in young infants presenting to hospital with fever or an infectious illness.

While the vast majority of individuals develop robust protection after SARS-CoV-2 exposure, there is wide heterogeneity in the immune response after primary infection, in terms of neutralising antibodies and T and B cell repertoire, which might render a small proportion of individuals susceptible to reinfection, especially those who were asymptomatic or had mild illness with their primary infection.

Reinfections might also occur because of waning immunity with time since primary infection; while most children and adults retain high antibody concentrations with virus neutralising activity for at least 12 months after primary infection, they do wane to undetectable concentrations in a small proportion of individuals.

Waning of immunity has also been reported among vaccinated adults, resulting in increasing risk of breakthrough infections with time since vaccination,

although this risk appears to be lower in mRNA-vaccinated adults with previous SARS-CoV-2 infection than in mRNA-vaccinated adults without previous infection.

Importantly, the risk of reinfection appears to be associated with emergence of new variants—such as the beta, gamma, delta and, more recently, omicron variants—which can at least partially evade immunity from previous infection as well as vaccination.

In our cohort, reinfection rates were much higher during the delta wave than the alpha wave, which might be because the alpha variant is antigenically similar to previously circulating SARS-CoV-2 strains while the delta variant, like the beta variant, are antigenically distant.

This observation is consistent with the lower neutralising activity of antibodies after natural infection,

or vaccination,

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as well as lower vaccine effectiveness after mRNA vaccination

against the delta variant than the alpha and previous variants. Reassuringly, previous infection or COVID-19 vaccination (and more so, a combination of the two) have been shown to be highly protective against severe disease and death due to COVID-19, irrespective of the responsible variant, with studies reporting higher rates of asymptomatic infection and mild illness following reinfection than primary infection in the same individuals.

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This result was also observed in our cohort of children who were more likely to be asymptomatic with their reinfection than with their primary infection.

However, the picture of SARS-CoV-2 infection and reinfection is everchanging with the emergence of new variants. The omicron variant was first detected in England in late November, 2021, and outcompeted delta to become the dominant variant nationally a few weeks later.

omicron possesses multiple new mutations compared with previous SARS-CoV-2 variants, including some in the spike protein, which enhance its ability to further evade both natural and vaccine-induced immunity.

Omicron’s potential for rapid transmission with a shorter incubation period has led to record numbers of daily reported cases and elevated numbers of reinfection cases in England.

Early data from South Africa, where the variant was first identified, reassuringly indicate a decrease in disease severity with the omicron compared with the delta variant,

which is likely to be due to a combination of factors, including virus characteristics, previous SARS-CoV-2 infection with other variants, and COVID-19 vaccination. Our ongoing national surveillance will continue to monitor the risks, severity, and outcomes of reinfection with this new variant.

In our cohort of children with reinfection, the risk of hospital admission was similar to overall admission rates for confirmed childhood COVID-19,

while ICU admissions were rare and less than in primary infection cases, and mainly in those with severe underlying comorbidities. In the UK, COVID-19 mRNA vaccination is recommended for all those aged 12–15 years and at-risk 5–11-year-olds with underlying co-morbidities, which will help reduce their risk of severe disease after primary infection or reinfection.