Background:
The role of children in SARS-CoV-2 transmission and their immune response after infection have been profoundly discussed. Hereby, we analyze both aspects in a Spanish pediatric population.
Methods:
Prospective, multicentre, longitudinal study performed from July 2020 to September 2021 in children up to 14 years old. Venous blood samples were collected every 6 months and serum was analyzed for antibodies against SARS-CoV-2 using a spike (S) and a nucleocapsid (N) protein assays. Household contacts of seropositive children were tested. Household transmission, antibody dynamics, and durability were analyzed.
Results:
Two hundred children were recruited and 28 had SARS-CoV-2 antibodies at the end of the study, resulting in an overall seroprevalence of 16.6% (95% CI: 9.5%–19.6%). Most of children (18/28) were secondary cases. The secondary attack rate (SAR) was lower in households with pediatric index cases than in those with adult index cases (P = 0.023). The median antibody titers in the first positive serology, for the seropositive patients, were 137 BAU/mL (IQR 83.3–427.4) for the S-assay and 132.5 COI (IQR 14.5–170.5) for the N-assay without significant differences between symptomatic and asymptomatic children. The median time between the RT-PCR and the last serology was 7.5 months (IQR 5.2–8.8), and the duration of SARS-CoV-2 antibodies after infection was proven to be at least 18 months. There were no cases of seroreversion.
Conclusions:
(1) Children are not the main drivers of SARS-CoV-2 household transmission. (2) They maintain SARS-CoV-2 antibodies for up to 18 months after infection and the titers are similar between symptomatic and asymptomatic children.
Keywords: SARS-CoV-2, transmission, family, antibodies, child
The World Health Organization declared COVID-19 a Public Health Emergency of International Concern on January 30, 2020, and a global pandemic on March 11 caused by the rapid increase of cases and spread throughout the world.1,2 As of June 23, 2022, more than 530,000,000 cases and 6,000,000 deaths have been reported worldwide.3 Among those, 237,795 cases and 2875 deaths have been declared in Asturias, a region in northern Spain.4
The role of children in the spread of SARS-CoV-2 has been debated since the beginning of the pandemic. Decisions regarding school openings or closures during the pandemic varied greatly between countries. While some countries kept schools mostly open or reopened early, others decided on prolonged closures. In Asturias, schools and kindergartens were closed from March 13 to September 22, 2020, opening after the summer holiday.5 Although data from some studies have reported that children do not amplify transmission in schools or households, and furthermore, they are unlikely to be the main drivers of the pandemic,6–9 this has been a matter of discussion in our region.
There is evidence that COVID-19 patients with severe disease develop a greater antibody response than those with mild or asymptomatic disease.10,11 Antibody titers and, hence, the level of protection have been a matter of concern since children typically have mild disease. However, most of the available data on long-term immunity against SARS-CoV-2 are from adults only, and few studies have compared antibody titers between symptomatic and asymptomatic children.12–15
The aims of this study were as follows: (1) to examine the antibody dynamics and durability in a pediatric population during the first year of the pandemic, as well as the association between antibody titers and disease severity and (2) to analyze the dynamics and contribution of children in household transmission.
MATERIALS AND METHODS
Study Design and Participants
This is a prospective multicenter longitudinal study in children in Asturias, a region in northern Spain with a population of 1,002,097 people and 95,698 children protected by the National Health System in 2021. Asturias is divided into 8 health areas with a network of primary healthcare centers as well as a reference hospital with pediatric assistance for each of the areas.16 A group of 20 pediatricians from the 8 health areas in Asturias was created.
This study was conducted within the frame of a seroprevalence study in children in Asturias.17 Patients were recruited between July 1 and September 30, 2020, from public hospitals and primary healthcare centers. Children, between 2 days and 14 years old who required a blood sample at the time of recruitment or voluntarily agreed to participate in the study, were eligible to participate. Two hundred participants were required (assuming a change in the seroprevalence between 1% in round 1 and 7% in the round 3, α of 0.05, β of 0.2, and a 15% dropout rate).
Venous blood samples were collected from participants during 3 testing rounds, every 6 months, and analyzed for SARS-CoV-2 antibodies: round 1 (July to September 2020), round 2 (January to March 2021), and round 3 (July to September 2021). A telephone questionnaire and chart review were conducted after each round to collect clinical and microbiological information.
Study of Household Contacts
When the children were seropositive, their household contacts (adults and children) were contacted and offered to be tested for SARS-CoV-2 antibodies. A telephone questionnaire was also administered to the household contacts for clinical and microbiologic information (COVID-19-compatible symptoms, previous RT-PCR performed and dates).
Laboratory Analysis
The serum was tested for antibodies against SARS-CoV-2 in the Microbiology Laboratory of Hospital Universitario Central de Asturias using the following assays: Spike protein assay (DiaSorin LIAISON SARS-CoV-2 TrimericS IgG assay) and Nucleocapsid assay (Roche Elecsys anti-SARS-CoV-2) and the titers were determined. These tests have reported specificities of 100% and a sensitivity of 85% for the S-assay and 84% for the N-assay.18,19
Study Definitions
SARS-CoV-2 seropositivity was defined as a positive antibody test using the manufacturer’s advised positivity cutoff in at least one of the assays: ≥33.8 Binding antibody units (BAU)/mL for the Spike and cutoff index (COI) ≥ 1.0 for the Nucleocapsid immunoassays.
Contact tracing was performed for all the seropositive children in this study. Household contacts were defined as those living in the same household as the seropositive children. The chronology of symptoms or the SARS-CoV-2 Real-time polymerase chain reaction (RT-PCR) test data were considered to reflect the transmission dynamics. A pediatric index case was established when a child was the first infected household member. A pediatric secondary case was defined when an adult household member was infected before a child.
A confirmed COVID-19 case among household contacts was defined as any individual testing SARS-CoV-2 positive by real-time RT-PCR or having SARS-CoV-2 antibodies in the antibody test (a positive N or S-assay for unvaccinated and a positive N-assay for vaccinated contacts).
Statistical Analysis
SARS-CoV-2 crude seroprevalence in children and adjusted for test sensitivity and specificity (Rogan-Gladen formula)20 were calculated as a proportion with 95% confidence interval (95% CI). SARS-CoV-2 antibody titers were determined in the different rounds, and the durability and evolution after infection described.
Transmission within the household was analyzed, and the secondary attack rate (SAR) was defined as the number of nonindex household members with a PCR-positive result within 15 days after the index case, divided by the total number of nonindex household members.
Descriptive analysis was performed using frequencies and proportions for categorical variables and medians and interquartile ranges (IQR) for continuous variables. A Cochran’s Q test was used to analyze the statistical significance of seroprevalence considering the dependence between repeated observations of the same population over time. Different comparisons were performed: titers among symptomatic and asymptomatic children in the first positive serology, SAR between children and adults, and pediatric index and secondary cases. Fisher’s exact test, as appropriate (for categorical variables) and Mann-Whitney U test (for continuous quantitative variables) were carried out for the comparative analysis. A P value cutoff of 0.05 was considered statistically significant.
The analysis was performed using R software Version 4.2 (R Foundation, Vienna, Austria).
Ethical Aspects
This study was conducted in accordance with the 1964 Declaration of Helsinki and its subsequent amendments. It was approved by the Asturian Research Ethics Committee (2020-315). Written informed consent was obtained from the parents of the participating children. Children 12 years old and older were able to confirm their consent. Participants were free to decline their consent at any time.
RESULTS
Seropositivity in Children
In total, 204 children were recruited between June and September 2020, of whom 4 were excluded because they did not sign the informed consent (50.5% girls, median age 9.7 years [IQR: 6.1–11.9]). Of the 200 children, 195 participated in round 1, 176 in round 2 and 169 in the last round (dropout rate of 13.3%). The crude seroprevalence of SARS-CoV-2 in children significantly increased during the study: 1.5% (95% CI: 0.3–4.3) in round 1, 9.1% (95% CI: 4.6–12.7) in round 2, and 16.6% (95% CI: 9.5–19.6) in round 3 (P < 0.001). The adjustments for sensitivity and specificity of the antibody test moved the final estimates upwards, for a final adjusted seroprevalence of 1.8% (95% CI: 0.4–5.1) in round 1, 10.7% (95% CI: 5.4–14.9) in round 2, and 19.5% (95% CI: 11.2–23.1) in round 3. None of the children who were previously positive became seronegative during the time of the study.
Twenty-eight children had SARS-CoV-2 antibodies at the end of the study (53.6% girls, median age 8.8 years [IQR: 4.2–11.8]). Of these, 10 (35.7%) were asymptomatic. Only 12/28 (42.9%) had a positive virological test. None of them required hospitalization, there were no deaths or immediate sequelae.
Titer Distribution
The median antibody titers in the first positive serology, for the 28 seropositive patients, were: 137 BAU/mL (IQ:R 83.3–427.4) for the Spike (S) assay and 132.5 COI (IQR: 14.5–170.5) for the Nucleocapsid (N) assay. The titer distribution was compared between symptomatic (n = 18) and asymptomatic participants (n = 10), and no significant differences were found (P = 0.832 for the S-assay; P = 0.475 for the N-assay) (Fig. 1).
FIGURE 1.
Comparison of SARS-CoV-2 antibody titers between symptomatic and asymptomatic children. (A) median antibody titers for the Spike assay. (B) median antibody titers for the Nucleocapsid assay.
The median time between the positive RT-PCR and the first serology test was 1.7 months (IQR: 1–4.2) and between the RT-PCR and the last serology 7.5 months (IQR: 5.2–8.8). The duration of SARS-CoV-2 antibodies after infection was proven to be at least 18 months. The dynamics of the anti-S and anti-N antibodies after infection is represented in Figure 2. As shown, the titers of SARS-CoV-2 antibodies decreased during the time of the study: 9.6% per month (IQR: 13.3–3.1) for the S-assay and 6.9% per month (IQR: 9.1–1.4) for the N-assay with no significant differences between them (P = 0.072). None of the seropositive children became seronegative during study period.
FIGURE 2.
Evolution of SARS-CoV-2 antibody titers after infection. (A) Evolution of SARS-CoV-2 antibodies for the Spike assay (blue). (B) Evolution of SARS-CoV-2 antibodies for the Nucleocapsid assay (red). The points reflect the moments where the serologic tests were performed. Time zero refers to SARS-CoV-2 infection.
Six of the 28 seropositive children were tested for SARS-CoV-2 (RT-PCR) after the first infection, all of which were negative.
Household Contacts
A total of 108 household contacts were linked to the 28 seropositive children. Of these, 46 (42.6%) agreed to participate in the study and were tested for SARS-CoV-2 antibodies at least 1 time (58.7% women, median age 42.2 years [IQR: 33.1–45.8]). The baseline characteristics are shown in Table 1. More than half of the contacts (25/46; 54.3%) were asymptomatic and the most common symptoms were fever (18/46; 39.1%) and cough (11/46; 22.9%). Of the 46 participating household contacts, 28 (60.9%) were seropositive (23 adults and 5 children under 14 years). None of them required hospitalization, there were no deaths or immediate sequelae.
TABLE 1.
Characteristics of Household Contacts of SARS-CoV-2 Seropositive Children
| Round 1 (n = 8) | Round 2 (n = 23) | Round 3 (n = 15) | |
|---|---|---|---|
| Sex | |||
| Female | 5 (62.5%) | 14 (60.8%) | 8 (53.3%) |
| Age (median years/IQR) | 44.1 (41.4–47.5) | 41.3 (30.8–45.3) | 42.16 (38.1–45.9) |
| Family relationship | |||
| Father | 3 (37.5%) | 8 (34.7%) | 5 (33.3%) |
| Mother | 3 (37.5%) | 9 (39.1%) | 7 (46.7%) |
| Sibling | 1 (12.5%) | 5 (21.7%) | 3 (20%) |
| Grandparents | 1 (12.5%) | 0 | 0 |
| Others | 0 | 1 (4.3%) | 0 |
| Symptoms (yes) | 6 (75%) | 10 (43.4%) | 5 (33.3%) |
| Fever | 5 (62.5%) | 8 (34.7%) | 5 (33.3%) |
| Cough | 5 (62.5%) | 3 (13%) | 5 (33.3%) |
| Shortness of breath | 1 (12.5%) | 0 | 0 |
| Fatigue | 1 (12.5%) | 6 (26.1%) | 1 (6.7%) |
| Headache | 1 (12.5%) | 1 (4.3%) | 0 |
| Diarrhea | 0 | 0 | 0 |
| Sore throat | 0 | 0 | 0 |
| Anosmia/ageusia | 1 (12.5%) | 2 (8.6%) | 0 |
| Previous virologic tests performed (yes) | 7 (87.5%) | 20 (71.4%) | 9 (60%) |
| Previously diagnosed with COVID-19 by virological test (yes) | 2 (28.5%) | 9 (45%) | 5 (55.5%) |
Data above correspond to n (%) for categorical parameters and median (IQR) for continuous variables.
Household Transmission
According to the study definitions, 64.3% (18/28) of children were secondary cases: 16 from an adult case, and 2 from another child. Six children were household index cases: 6/28 (21.4%). It was not possible to determine the directionality of the transmission in 4 cases: 4/28 (14.3%). The median SAR was 45% (IQR: 25–66.7), and it was significantly lower in households with pediatric index cases than in those with adult index cases (19% vs. 50%; P = 0.023). Three of the pediatric index cases did not transmit the infection to any of the household contacts. In contrast, all adult index cases infected at least someone else in the household.
Pediatric index and secondary cases were compared. Pediatric index cases were significantly older than pediatric secondary cases (11.9 years [IQR: 11.2–12.3] versus 7.2 years [IQR: 3.2–8.8]; P = 0.004). All pediatric index cases were older than 10, while most of pediatric secondary cases were younger than 4 years of age (Table 2). No differences regarding sex, household size, comorbidities, or symptoms were found between the 2 groups.
TABLE 2.
Epidemiologic Characteristics of Pediatric Index and Secondary Cases
| Index Cases (n = 6)* | Secondary Cases (n = 18)* | P | |
|---|---|---|---|
| Sex | 0.357† | ||
| Male | 4 (66.7%) | 7 (38.9%) | |
| Female | 2 (33.3%) | 11 (61.1%) | |
| Age, years | 11.9 (11.2–12.3) | 7.2 (3.2–8.8) | 0.0043‡ |
| 0–4 | 0 | 8 (44.4%) | |
| 5–9 | 0 | 7 (38.9%) | |
| 10–14 | 6 (100%) | 3 (16.7%) | |
| Household size | 3.5 (3-4) | 4 (3.3-4.8) | 0.289§ |
| ≤3 | 3 (50%) | 5 (27.8%) | |
| 4-5 | 3 (50%) | 13 (72.2%) | |
| >5 | 0 | 0 | |
| Place of residence | 1.000† | ||
| Urban | 6 (100%) | 15 (83.3%) | |
| Peri-urban | 0 | 2 (11.1%) | |
| Rural | 0 | 1(5.6%) | |
| Comorbidities (yes) | 3 (50%) | 9 (50%) | 1.000† |
| Symptoms (yes) | 5 (83.3%) | 11 (61.1%) | 0.621† |
Comorbidities (pulmonary disease, cardiologic disease, diabetes mellitus, prematurity, neurologic disease, immunologic disease, others).
n (%); Median (IQR).
Fisher’s exact test.
Values in bold indicate statistically significant results.
Mann-Withney U test.
DISCUSSION
Most of the children develop asymptomatic or mild forms of COVID-19 disease. Natural protection after infection and the role of children in spreading SARS-CoV-2 has been discussed since the beginning of the pandemic, and data have been lacking on this topic. This is the first SARS-CoV-2 seroprevalence study conducted in children in our region. The longitudinal design and contact tracing study allow us not only to describe the evolution of seroprevalence and antibody titers in children, but also to understand the dynamics of SARS-CoV-2 transmission within households.
In our study, we found that by September 2021, 28 children participating in the study had developed SARS-CoV-2 antibodies, resulting in an overall seroprevalence of 16.6% (95% CI: 9.5%–19.6%).17 All of them had mild disease, 35.7% were asymptomatic and none required hospitalization. There is evidence that symptomatic patients develop a significantly greater antibody response than those with asymptomatic disease.15,21,22 However, some studies reported that the antibody titers were only significantly higher in those patients with severe disease.10,11 In our study, the median IgG titers were similar among symptomatic and asymptomatic patients for both (Spike protein and Nucleocapsid) assays. Accordingly, the presence of symptoms in children may not influence the antibody response, even though, these results should be interpreted carefully, as none of our symptomatic patients had a severe disease.
The duration of SARS-CoV-2 antibodies after infection in our study was proven to be at least 18 months. Few data are available on long-term immunity against SARS-CoV-2. Most reports suggest that the titers of antibodies against SARS-CoV-2 decline over time after COVID-19 infection.10,23 Recent studies have shown that SARS-CoV-2 antibodies remained detectable 8, 10, or 12 months after infection.24–26 In our study, the titers of antibodies decreased during the follow-up but there were no cases of seroreversion, contrary to the National seroepidemiologic study (ENE-COVID), which found a seroreversion of 14.4% between April and June 2020.27
Within their households, most of pediatric COVID-19 cases were secondary to an adult case (57.1%) and, most significantly, only 6 children (21.4%) were household index cases. This is consistent with the results of other studies on household SARS-CoV-2 transmission.6,9,28,29 All our pediatric index cases were older than 10 years of age, showing that young children did not have a big role in household transmission. Other studies have also described how the proportion of pediatric index cases increases with age.30
The SAR found in this study (45%) is higher than most results from other publications,31–33 even though very different rates have been reported: 18.1% with significant heterogeneity in the meta-analysis by Wee Chian Koh et al.34 or 62.3% in the study conducted in Cataluña by Soriano-Arandes et al.9 Main circulating SARS-CoV-2 variants in Spain during the time of our study were Alpha and Delta. This work was carried out before Omicron appeared, which is important because this variant spread more easily than earlier strains of the virus.35 Although COVID-19 spread in a significant proportion within households, the SAR for SARS-CoV-2 infection was significantly lower in households where children instead of adults had transmitted SARS-CoV-2 (19% vs. 50%). Therefore, almost 3-fold fewer household members were infected when children were drivers of SARS-CoV-2 infection. This is also consistent with the results from other studies9,29; however, a recent article focused attention on the heterogeneity of household contact studies and suspected the difference between children and adults to be related to bias.36
This study has some limitations that should be acknowledged. First, there is a selection bias in terms of who is being tested for SARS-CoV-2 antibodies, since we used a convenience sampling, which is not completely representative of the population. Second, the absolute size of seropositive children, as well as the number of household contacts was relatively small, which could bias the analysis. Third, the information regarding COVID-19 compatible symptoms was gathered retrospectively, which could cause memory bias. Fourth, the index case in each household was defined as the person who first developed symptoms or first tested SARS-CoV-2 positive. Consequently, the contribution of asymptomatic individuals to the transmission may be then underestimated. We also cannot exclude the possibility that some household contacts might have acquired the virus from another source. Finally, this study was conducted before the Omicron wave occurred, which changed the SARS-CoV-2 landscape.
This study also has several strengths. First, this is a prospective multicenter study that included children from all the different health areas in Asturias. Second, the longitudinal design allowed us to observe the dynamics of SARS-CoV-2 seroprevalence and antibody titers. Third, the serological tests performed on children and their household contacts, as well as the telephone questionnaire, enabled us to describe the transmission within the household. Fourth, the investigation of seroprevalence provides a better insight into the susceptibility of children, revealing asymptomatic cases, and finally, the combination of 2 serological assays, targeting different SARS-CoV-2 proteins has been shown to improve sensitivity.37
In conclusion, the results presented in this article suggest that most pediatric COVID-19 cases are secondary to an adult case, and moreover, the SAR for SARS-CoV-2 infection is significantly lower in households with pediatric index cases than in those with adult index cases. Therefore, in our study, children are unlikely to spread SARS-CoV-2 to their cohabiting family members. They maintain SARS-CoV-2 antibodies for up to 18 months after infection and the titer distribution is similar between symptomatic and asymptomatic children.
Footnotes
E.G.-G. received partial financial support from Fundación Ernesto Sánchez Villares, Sociedad de Pediatría de Asturias, Cantabria y Castilla y León (SCCALP; grant number 2021/02). The remaining authors received no external funding.
The authors have no conflicts of interest to disclose.
Contributor Information
Laura Calle-Miguel, Email: laura.calle.miguel@hotmail.com.
David Pérez-Solís, Email: doctorin@gmail.com.
Ignacio Carvajal Urueña, Email: ignacio.carvajal@sespa.es.
Águeda García Merino, Email: agueda.garciam@sespa.es.
María Morán Poladura, Email: mariamoran81@gmail.com.
Mercedes Rodríguez-Pérez, Email: mercedes.rodriguezp@sespa.es.
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