SARS-CoV-2 infection in children and implications for vaccination.

The COVID-19 pandemic caused by novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for more than 500 million cases worldwide as of April 2022. Initial estimates in 2020 found that children were less likely to become infected with SARS-CoV-2 and more likely to be asymptomatic or display mild COVID-19 symptoms. Our early understanding of COVID-19 transmission and disease in children led to a range of public health measures including school closures that have indirectly impacted child health and wellbeing. The emergence of variants of concern (particularly Delta and Omicron) has raised new issues about transmissibility in children, as preliminary data suggest that children may be at increased risk of infection, especially if unvaccinated. Global national prevalence data show that SARS-CoV-2 infection in children and adolescents is rising due to COVID-19 vaccination among adults and increased circulation of Delta and Omicron variants. To mitigate this, childhood immunisation programmes are being implemented globally to prevent direct and indirect consequences of COVID-19 including severe complications (e.g., MIS-C), debilitating long-COVID symptoms, and the indirect impacts of prolonged community and school closures on childhood education, social and behavioural development and mental health. This review explores the current state of knowledge on COVID-19 in children including COVID-19 vaccination strategies. IMPACT: Provides an up-to-date account of SARS-CoV-2 infections in children. Discusses the direct and indirect effects of COVID-19 in children. Provides the latest information on the current state of global COVID-19 vaccination in children.

Comparison of antibody responses to SARS-CoV-2 variants in Australian children.

There is limited understanding of antibody responses in children across different SARS-CoV-2 variants. As part of an ongoing household cohort study, we assessed the antibody response among unvaccinated children infected with Wuhan, Delta, or Omicron variants, as well as vaccinated children with breakthrough Omicron infection, using a SARS-CoV-2 S1-specific IgG assay and surrogate virus neutralization test (% inhibition). Most children infected with Delta (100%, 35/35) or Omicron (81.3%, 13/16) variants seroconverted by one month following infection. In contrast, 37.5% (21/56) children infected with Wuhan seroconverted, as previously reported. However, Omicron-infected children (geometric mean concentration 46.4 binding antibody units/ml; % inhibition = 16.3%) mounted a significantly lower antibody response than Delta (435.5 binding antibody untis/mL, % inhibition = 76.9%) or Wuhan (359.0 binding antibody units/mL, % inhibition = 74.0%). Vaccinated children with breakthrough Omicron infection mounted the highest antibody response (2856 binding antibody units/mL, % inhibition = 96.5%). Our findings suggest that despite a high seropositivity rate, Omicron infection in children results in lower antibody levels and function compared with Wuhan or Delta infection or with vaccinated children with breakthrough Omicron infection. Our data have important implications for public health measures and vaccination strategies to protect children.

Virology and immune dynamics reveal high household transmission of ancestral SARS-CoV-2 strain.

BACKGROUND: Household studies are crucial for understanding the transmission of SARS-CoV-2 infection, which may be underestimated from PCR testing of respiratory samples alone. We aim to combine the assessment of household mitigation measures; nasopharyngeal, saliva, and stool PCR testing; along with mucosal and systemic SARS-CoV-2-specific antibodies, to comprehensively characterize SARS-CoV-2 infection and transmission in households. METHODS: Between March and September 2020, we obtained samples from 92 participants in 26 households in Melbourne, Australia, in a 4-week period following the onset of infection with ancestral SARS-CoV-2 variants. RESULTS: The secondary attack rate was 36% (24/66) when using nasopharyngeal swab (NPS) PCR positivity alone. However, when respiratory and nonrespiratory samples were combined with antibody responses in blood and saliva, the secondary attack rate was 76% (50/66). SARS-CoV-2 viral load of the index case and household isolation measures were key factors that determine secondary transmission. In 27% (7/26) of households, all family members tested positive by NPS for SARS-CoV-2 and were characterized by lower respiratory Ct values than low transmission families (Median 22.62 vs. 32.91; IQR 17.06-28.67 vs. 30.37-34.24). High transmission families were associated with enhanced plasma antibody responses to multiple SARS-CoV-2 antigens and the presence of neutralizing antibodies. Three distinguishing saliva SARS-CoV-2 antibody features were identified according to age (IgA1 to Spike 1, IgA1 to nucleocapsid protein (NP)), suggesting that adults and children generate distinct mucosal antibody responses during the acute phase of infection. CONCLUSION: Utilizing respiratory and nonrespiratory PCR testing, along with the measurement of SARS-CoV-2-specific local and systemic antibodies, provides a more accurate assessment of infection within households and highlights some of the immunological differences in response between children and adults.

Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in children younger than 5 years in 2019: a systematic analysis.

BACKGROUND: Respiratory syncytial virus (RSV) is the most common cause of acute lower respiratory infection in young children. We previously estimated that in 2015, 33·1 million episodes of RSV-associated acute lower respiratory infection occurred in children aged 0-60 months, resulting in a total of 118 200 deaths worldwide. Since then, several community surveillance studies have been done to obtain a more precise estimation of RSV associated community deaths. We aimed to update RSV-associated acute lower respiratory infection morbidity and mortality at global, regional, and national levels in children aged 0-60 months for 2019, with focus on overall mortality and narrower infant age groups that are targeted by RSV prophylactics in development. METHODS: In this systematic analysis, we expanded our global RSV disease burden dataset by obtaining new data from an updated search for papers published between Jan 1, 2017, and Dec 31, 2020, from MEDLINE, Embase, Global Health, CINAHL, Web of Science, LILACS, OpenGrey, CNKI, Wanfang, and ChongqingVIP. We also included unpublished data from RSV GEN collaborators. Eligible studies reported data for children aged 0-60 months with RSV as primary infection with acute lower respiratory infection in community settings, or acute lower respiratory infection necessitating hospital admission; reported data for at least 12 consecutive months, except for in-hospital case fatality ratio (CFR) or for where RSV seasonality is well-defined; and reported incidence rate, hospital admission rate, RSV positive proportion in acute lower respiratory infection hospital admission, or in-hospital CFR. Studies were excluded if case definition was not clearly defined or not consistently applied, RSV infection was not laboratory confirmed or based on serology alone, or if the report included fewer than 50 cases of acute lower respiratory infection. We applied a generalised linear mixed-effects model (GLMM) to estimate RSV-associated acute lower respiratory infection incidence, hospital admission, and in-hospital mortality both globally and regionally (by country development status and by World Bank Income Classification) in 2019. We estimated country-level RSV-associated acute lower respiratory infection incidence through a risk-factor based model. We developed new models (through GLMM) that incorporated the latest RSV community mortality data for estimating overall RSV mortality. This review was registered in PROSPERO (CRD42021252400). FINDINGS: In addition to 317 studies included in our previous review, we identified and included 113 new eligible studies and unpublished data from 51 studies, for a total of 481 studies. We estimated that globally in 2019, there were 33·0 million RSV-associated acute lower respiratory infection episodes (uncertainty range [UR] 25·4-44·6 million), 3·6 million RSV-associated acute lower respiratory infection hospital admissions (2·9-4·6 million), 26 300 RSV-associated acute lower respiratory infection in-hospital deaths (15 100-49 100), and 101 400 RSV-attributable overall deaths (84 500-125 200) in children aged 0-60 months. In infants aged 0-6 months, we estimated that there were 6·6 million RSV-associated acute lower respiratory infection episodes (4·6-9·7 million), 1·4 million RSV-associated acute lower respiratory infection hospital admissions (1·0-2·0 million), 13 300 RSV-associated acute lower respiratory infection in-hospital deaths (6800-28 100), and 45 700 RSV-attributable overall deaths (38 400-55 900). 2·0% of deaths in children aged 0-60 months (UR 1·6-2·4) and 3·6% of deaths in children aged 28 days to 6 months (3·0-4·4) were attributable to RSV. More than 95% of RSV-associated acute lower respiratory infection episodes and more than 97% of RSV-attributable deaths across all age bands were in low-income and middle-income countries (LMICs). INTERPRETATION: RSV contributes substantially to morbidity and mortality burden globally in children aged 0-60 months, especially during the first 6 months of life and in LMICs. We highlight the striking overall mortality burden of RSV disease worldwide, with one in every 50 deaths in children aged 0-60 months and one in every 28 deaths in children aged 28 days to 6 months attributable to RSV. For every RSV-associated acute lower respiratory infection in-hospital death, we estimate approximately three more deaths attributable to RSV in the community. RSV passive immunisation programmes targeting protection during the first 6 months of life could have a substantial effect on reducing RSV disease burden, although more data are needed to understand the implications of the potential age-shifts in peak RSV burden to older age when these are implemented. FUNDING: EU Innovative Medicines Initiative Respiratory Syncytial Virus Consortium in Europe (RESCEU).

A case report describing the immune response of an infant with congenital heart disease and severe COVID-19.

Background: Children with SARS-CoV-2 infection generally present with milder symptoms or are asymptomatic in comparison with adults, however severe disease occurs in a subset of children. To date, the immune correlates of severe COVID-19 in young children have been poorly characterised. Methods: We report the kinetics of immune responses in relation to clinical and virological features in an infant with acute severe COVID-19 using high-dimensional flow cytometry and multiplex cytokine analysis. Results: Systemic cellular and cytokine profiling show an initial increase in neutrophils and monocytes with depletion of lymphoid cell populations (particularly CD8 + T and NK cells) and elevated inflammatory cytokines. Expansion of memory CD4 + T (but not CD8 + T) cells occurred over time, with a predominant Th2 bias. Marked activation of T cell populations observed during the acute infection gradually resolved as the child recovered. Substantial in vitro activation of T-cell populations and robust cytokine production, in response to inactivated SARS-CoV-2 stimulation, was observed 3 months after infection indicating durable, long-lived cellular immune memory. Conclusions: These findings provide important insights into the immune response of a young infant with severe COVID-19 and will help to inform future research into therapeutic targets for high-risk groups.

Virology and immune dynamics reveal high household transmission of ancestral SARS-CoV-2 strain (preprint)

Background: Household studies are crucial for understanding the transmission of SARS-CoV-2 infection, which may be underestimated from PCR testing of respiratory samples alone. We aim to combine assessment of household mitigation measures; nasopharyngeal, saliva and stool PCR testing; along with mucosal and systemic SARS-CoV-2 specific antibodies, to comprehensively characterise SARS-CoV-2 infection and transmission in households. Methods: Between March and September 2020, we obtained samples from 92 participants in 26 households in Melbourne, Australia, in a 4-week period following onset of infection with ancestral SARS-CoV-2 variants. Results: The secondary attack rate was 36% (24/66) when using nasopharyngeal swab (NPS) PCR positivity alone. However, when respiratory and non-respiratory samples were combined with antibody responses in blood and saliva, the secondary attack rate was 76% (50/66). SARS-CoV-2 viral load of the index case and household isolation measures were key factors that determine secondary transmission. In 27% (7/26) of households, all family members tested positive by NPS for SARS-CoV-2 and were characterised by lower respiratory Ct-values than low transmission families (Median 22.62 vs 32.91; IQR 17.06 to 28.67 vs 30.37 to 34.24). High transmission families were associated with enhanced plasma antibody responses to multiple SARS-CoV-2 antigens and the presence of neutralising antibodies. Three distinguishing saliva SARS-CoV-2 antibody features were identified according to age (IgA1 to Spike 1, IgA1 to nucleocapsid protein (NP), suggesting that adults and children generate distinct mucosal antibody responses during the acute phase of infection. Conclusion: Utilising respiratory and non-respiratory PCR testing, along with measurement of SARS-CoV-2 specific local and systemic antibodies, provides a more accurate assessment of infection within households and highlights some of the immunological differences in response between children and adults.

Comparison of Seroconversion in Children and Adults With Mild COVID-19.

Importance: The immune response in children with SARS-CoV-2 infection is not well understood. Objective: To compare seroconversion in nonhospitalized children and adults with mild SARS-CoV-2 infection and identify factors that are associated with seroconversion. Design, Setting, and Participants: This household cohort study of SARS-CoV-2 infection collected weekly nasopharyngeal and throat swabs and blood samples during the acute (median, 7 days for children and 12 days for adults [IQR, 4-13] days) and convalescent (median, 41 [IQR, 31-49] days) periods after polymerase chain reaction (PCR) diagnosis for analysis. Participants were recruited at The Royal Children's Hospital, Melbourne, Australia, from May 10 to October 28, 2020. Participants included patients who had a SARS-CoV-2-positive nasopharyngeal or oropharyngeal swab specimen using PCR analysis. Main Outcomes and Measures: SARS-CoV-2 immunoglobulin G (IgG) and cellular (T cell and B cell) responses in children and adults. Seroconversion was defined by seropositivity in all 3 (an in-house enzyme-linked immunosorbent assay [ELISA] and 2 commercial assays: a SARS-CoV-2 S1/S2 IgG assay and a SARS-CoV-2 antibody ELISA) serological assays. Results: Among 108 participants with SARS-CoV-2-positive PCR findings, 57 were children (35 boys [61.4%]; median age, 4 [IQR, 2-10] years) and 51 were adults (28 women [54.9%]; median age, 37 [IQR, 34-45] years). Using the 3 established serological assays, a lower proportion of children had seroconversion to IgG compared with adults (20 of 54 [37.0%] vs 32 of 42 [76.2%]; P < .001). This result was not associated with viral load, which was similar in children and adults (mean [SD] cycle threshold [Ct] value, 28.58 [6.83] vs 24.14 [8.47]; P = .09). In addition, age and sex were not associated with seroconversion within children (median age, 4 [IQR, 2-14] years for both seropositive and seronegative groups; seroconversion by sex, 10 of 21 girls [47.6%] vs 10 of 33 boys [30.3%]) or adults (median ages, 37 years for seropositive and 40 years for seronegative adults [IQR, 34-39 years]; seroconversion by sex, 18 of 24 women [75.0%] vs 14 of 18 men [77.8%]) (P > .05 for all comparisons between seronegative and seropositive groups). Symptomatic adults had 3-fold higher SARS-CoV-2 IgG levels than asymptomatic adults (median, 227.5 [IQR, 133.7-521.6] vs 75.3 [IQR, 36.9-113.6] IU/mL), whereas no differences were observed in children regardless of symptoms. Moreover, differences in cellular immune responses were observed in adults compared with children with seroconversion. Conclusions and Relevance: The findings of this cohort study suggest that among patients with mild COVID-19, children may be less likely to have seroconversion than adults despite similar viral loads. This finding has implications for future protection after SARS-CoV-2 infection in children and for interpretation of serosurveys that involve children. Further research to understand why seroconversion and development of symptoms are potentially less likely in children after SARS-CoV-2 infection and to compare vaccine responses may be of clinical and scientific importance.

Can early measles vaccination control both measles and respiratory syncytial virus infections?

Measles virus and respiratory syncytial virus (RSV) are two important global health pathogens causing substantial morbidity and mortality worldwide. The current measles vaccination schedule has the first dose given at 9-12 months of age and the second dose given at 15-18 months of age. Measles outbreaks have been associated with an increase in severe RSV infections in children younger than 6 months, probably as a result of measles-induced immunosuppression. A resurgence in measles cases was already occurring before the COVID-19 pandemic, which has affected global immunisation programmes, resulting in millions of children, mostly in low-income and middle-income countries (LMICs), missing out on their measles vaccine. This will leave many children living in the most vulnerable of circumstances highly susceptible to measles and RSV infections when current COVID-19 public health control measures are lifted. This Viewpoint discusses these issues and highlights the need for urgent action to address this looming crisis. The use of early measles vaccination at 4 months of age could be an effective strategy to prevent severe morbidity and death from both measles and RSV infections in many LMICs.

Children and Adults in a Household Cohort Study Have Robust Longitudinal Immune Responses Following SARS-CoV-2 Infection or Exposure.

Children have reduced severity of COVID-19 compared to adults and typically have mild or asymptomatic disease. The immunological mechanisms underlying these age-related differences in clinical outcomes remain unexplained. Here, we quantify 23 immune cell populations in 141 samples from children and adults with mild COVID-19 and their PCR-negative close household contacts at acute and convalescent time points. Children with COVID-19 displayed marked reductions in myeloid cells during infection, most prominent in children under the age of five. Recovery from infection in both children and adults was characterised by the generation of CD8 TCM and CD4 TCM up to 9 weeks post infection. SARS-CoV-2-exposed close contacts also had immunological changes over time despite no evidence of confirmed SARS-CoV-2 infection on PCR testing. This included an increase in low-density neutrophils during convalescence in both exposed children and adults, as well as increases in CD8 TCM and CD4 TCM in exposed adults. In comparison to children with other common respiratory viral infections, those with COVID-19 had a greater change in innate and T cell-mediated immune responses over time. These findings provide new mechanistic insights into the immune response during and after recovery from COVID-19 in both children and adults.

Persistence of SARS-CoV-2-Specific IgG in Children 6 Months After Infection, Australia.

The duration of the humoral immune response in children infected with severe acute respiratory syndrome coronavirus 2 is unknown. We detected specific IgG 6 months after infection in children who were asymptomatic or had mild symptoms of coronavirus disease. These findings will inform vaccination strategies and other prevention measures.

The use of dried blood spots for the serological evaluation of SARS-CoV-2 antibodies.

BACKGROUND: To determine if dried blood spot specimens (DBS) can reliably detect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies, we compared the SARS-CoV-2 IgG antibody response in paired serum and eluates from DBS specimens. METHODS: A total of 95 paired DBS and serum samples were collected from 74 participants (aged 1-63 years) as part of a household cohort study in Melbourne, Australia. SARS-CoV-2 IgG antibodies specific for the receptor-binding domain (RBD) and S1 proteins between serum and eluates from DBS specimens were compared using an FDA-approved ELISA method. RESULTS: Among the 74 participants, 42% (31/74) were children and the rest were adults. A total of 16 children and 13 adults were SARS-CoV-2 positive by polymerase chain reaction. The IgG seropositivity rate was similar between serum and DBS specimens (18.9% (18/95) versus 16.8% (16/95)), respectively. Similar RBD and S1-specific IgG levels were detected between serum and DBS specimens. Serum IgG levels strongly correlated with DBS IgG levels (r = 0.99, P < 0.0001) for both SARS-CoV-2 proteins. Furthermore, antibodies remained stable in DBS specimens for >3 months. CONCLUSIONS: DBS specimens can be reliably used as an alternative to serum samples for SARS-CoV-2 antibody measurement. The use of DBS specimens would facilitate serosurveillance efforts particularly in hard-to-reach populations and inform public health responses including COVID-19 vaccination strategies.

Immune responses to SARS-CoV-2 in three children of parents with symptomatic COVID-19.

Compared to adults, children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have predominantly mild or asymptomatic infections, but the underlying immunological differences remain unclear. Here, we describe clinical features, virology, longitudinal cellular, and cytokine immune profile, SARS-CoV-2-specific serology and salivary antibody responses in a family of two parents with PCR-confirmed symptomatic SARS-CoV-2 infection and their three children, who tested repeatedly SARS-CoV-2 PCR negative. Cellular immune profiles and cytokine responses of all children are similar to their parents at all timepoints. All family members have salivary anti-SARS-CoV-2 antibodies detected, predominantly IgA, that coincide with symptom resolution in 3 of 4 symptomatic members. Plasma from both parents and one child have IgG antibody against the S1 protein and virus-neutralizing activity detected. Using a systems serology approach, we demonstrate higher levels of SARS-CoV-2-specific antibody features of these family members compared to healthy controls. These data indicate that children can mount an immune response to SARS-CoV-2 without virological confirmation of infection, raising the possibility that immunity in children can prevent the establishment of SARS-CoV-2 infection. Relying on routine virological and serological testing may not identify exposed children, with implications for epidemiological and clinical studies across the life-span.

Can data from paediatric cohorts solve the COVID-19 puzzle?

COVID-19, caused by SARS-CoV-2, is significantly more severe in adults than in children. The biological reasons for this difference remain to be elucidated. We have compared the most recent virological and immunological data related to COVID-19 between adults and children and contrasted this with earlier data from severe acute respiratory syndrome (SARS) caused by the related SARS-CoV-1 in 2003. Based on these available data, a number of hypotheses are proposed to explain the difference in COVID-19 clinical outcomes between adults and children. NF-kB may be a key factor that could explain the severe clinical manifestations of COVID-19 in adults as well as rare complications associated with paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) in paediatric COVID-19 patients.