³Ô¹ÏÍøÕ¾

WHO, with support of the Strategic Advisory Group of Experts (SAGE) on Immunization and its COVID-19 Vaccines Working Group, is reviewing the emerging evidence on the need for and timing of vaccinating children and adolescents with the currently available COVID-19 vaccines which have received Emergency Use Listing (EUL). SAGE is continuously reviewing the literature and has reached out to vaccine manufacturers, the research community and Member States to obtain the most complete and recent data on the issue. This interim statement was developed with additional support from the Strategic and Technical Advisory Group of Experts (STAGE) on maternal, newborn, child, and adolescent health, and nutrition.

Background

Although the majority of COVID-19 vaccines are only approved for use in adults aged 18 years and above, an increasing number of vaccines are now also being authorized for use in children. Some countries have given emergency use authorization for mRNA vaccines for use in the adolescent age group (aged 12-17 years): BNT162b2 developed by Pfizer, and mRNA 1273 developed by Moderna. In November 2021, one stringent regulatory authority approved the mRNA vaccine BNT162b2 for the use in children aged 5-11. Trials in children as young as age 3 years were completed for two inactivated vaccines (Sinovac-CoronaVac and BBIBP-CorV) and these products were approved by Chinese authorities for the age indication of 3-17 years; although these vaccine products have received EUL for adults, they have not yet received WHO EUL for children. Covaxin, an adjuvanted inactivated vaccine developed by Bharat, was approved in India for the age indication of 12-17 years; but not yet received WHO EUL for this age indication. The Indian regulatory authorities have given approval to ZycovD, a novel DNA vaccine, for ages 12-17 years; however, this vaccine has not yet received WHO EUL. Several COVID-19 vaccines are undergoing trials in younger age groups (including as young as 6 months of age), but results have not yet been published.

The greatest burden of disease in terms of severe disease and deaths remains among older persons and those with comorbidities, the evidence of which led to the WHO Prioritization Roadmap which identifies high priority-use groups according to vaccine supplies available to countries(1). WHO recognizes that various countries are in different pandemic phases with different vaccination coverage rates. The WHO global vaccination strategy targets remain: 40% of each country’s population by end of 2021, and 70% by mid-2022(2). These coverage targets were set to ensure an equitable pace of global vaccine rollout & prioritization of those at highest risk. To date, these targets have not yet been achieved.

This interim statement examines the role of COVID-19 vaccines in adolescents and children in the global context of inequitable vaccine distribution across countries and globally limited vaccine supply.

Burden of disease in children and adolescents

Overall, there are proportionally fewer symptomatic infections, and cases with severe disease and deaths from COVID-19 in children and adolescents, compared with older age groups. Age-disaggregated cases reported to WHO from 30 December 2019 to 25 October 2021(3) show that children under five years of age represent 2% (1 890 756) of reported global cases and 0.1% (1 797) of reported global deaths. Older children and younger adolescents (5 to 14 years) account for 7% (7 058 748) of reported global cases and 0.1% (1 328) of reported global deaths while older adolescents and young adults (15 to 24 years) represent 15% (14 819 320) of reported global cases and 0.4% (7 023) of reported global deaths. Deaths for all ages less than 25 years represented less than 0.5% of reported global deaths.

Children and adolescents usually demonstrate fewer and milder symptoms of SARS-CoV-2 infection compared to adults and are less likely than adults to experience severe COVID-19(4). Milder symptoms and asymptomatic presentations may mean less frequent care seeking in these groups, thus children and adolescents tend to be tested less and cases may go unreported. An age-dependent risk of severe disease with those under one year of age experiencing more severe disease has been suggested(5), although several reviews show that neonates (infants in the first 28 days of life) have mild disease when compared with other paediatric patients(6, 7). It is important to note that children under the age of five years have a higher risk of other diseases with clinical presentations that overlap with COVID-19, such as pneumonia and other viral upper respiratory tract infections, which may lead to misclassification. Additionally, age disaggregation has not been systematically provided in the literature, and the results of these studies are context-specific depending on factors such as timing within the pandemic and an emphasis on hospitalized patients(8).

Children and adolescents can experience prolonged clinical symptoms (known as “long COVID-19”, post COVID-19 condition(9), or post-acute sequelae of SARS-CoV-2 infection), however, the frequency and characteristics of these conditions are still under investigation. Additionally, a hyperinflammatory syndrome, referred to as paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) in Europe and multisystem inflammatory syndrome in children (MIS-C) in the United States, although rare, has been reported to occur world-wide and complicate recovery from COVID-19(10).

Several risk factors for severe COVID-19 in children have been reported recently, including older age, obesity, and preexisting conditions. The preexisting conditions associated with higher risk of severe COVID-19 include type 2 diabetes, asthma, heart and pulmonary diseases, and neurologic and neuromuscular conditions(11).

The preponderance of evidence on the risk for severe COVID-19 and death in children and adolescents comes from studies in high resource settings, so the applicability of the following observations to lower resource settings remains to be determined. One systematic review suggests that there may be larger impact of paediatric COVID-19 related fatality in low to middle income countries versus high income countries(12).

The role of children and adolescents in transmission of SARS-CoV-2

Multiple population-based SARS-CoV-2 seroprevalence and viral shedding studies have investigated whether children and adolescents are infected at the same rate as adults, but the results have been mixed, possibly because of the studies being conducted at different time points in the pandemic when populations were subjected to different public health and social measures (PHSM)(13). A serosurvey done in India during June-July 2021 after the second wave (Delta variant) showed that seropositivity in children 6-18 years was similar to that in older age groups – except in those older than 60 years in whom the immunization rate was high. Overall, it appeared that whether schools were open or closed, infection rates in children and adults were similar. Thus, it appears that children of all ages can become infected and can spread the virus to others.

Outbreaks of COVID-19 have been identified in secondary schools, summer camps and day care centres, particularly when neither physical distancing nor masks were used to reduce infection transmission risk. There is some preliminary evidence that younger children may be less infectious, as measured by secondary attack rates, than adolescents and adults(14). Data on the global incidence of COVID-19 suggest adolescents test positive for SARS-CoV-2 at a higher proportion than younger children, however seroprevalence surveys are required to provide more conclusive information on infection rates.

Children who become infected with SARS-CoV-2 shed the virus in their respiratory tract and also in their faeces(15). Amongst individuals positive for SARS-CoV-2 who were tested at the same time point after symptom onset, levels of SARS-CoV-2 viral RNA shedding in the respiratory tract appeared similar in children, adolescents, and adults(16).

The relationship between age, viral load, and transmission across the full symptom spectrum of SARS-CoV-2 infection has not been comprehensively investigated because people with no, or mild symptoms are seldom tested systematically. The relative transmissibility of SARS-CoV-2 at different ages remains uncertain, largely due to the challenges involved in disentangling the influences of biological, host, virus, variants of concern, and environmental factors(17).

Socio-economic impact of the COVID-19 pandemic and pandemic response on children and adolescents

Despite their lower risk of severe COVID-19 disease, children and adolescents have been disproportionately affected by COVID-19 control measures. The most important indirect effects are related to school closures which have disrupted the provision of educational services and increased emotional distress and mental health problems. When unable to attend school and in social isolation, children are more prone to maltreatment and sexual violence, adolescent pregnancy, and child marriage, all of which increase the probability of missing further education and of poor pregnancy outcomes. A range of follow-on effects of school closures occur. These include disruption in physical activity and routines and loss of access to a wide range of school-provided services such as school meals, health, nutrition, water, sanitation and hygiene (WASH) and services targeted to children with special needs such as learning support, speech therapy and social skills training. Children not attending school face enhanced risks of cyberbullying from other children, and the potential for predatory behavior from adults related to spending more time online. Longer-term, prolonged school closures lead to education loss and exacerbation of pre-existing inequalities and marginalization of learning. It is estimated that 24 million children are at risk of not returning to school owing to the pandemic(18); those affected have been estimated to incur a US$10 trillion loss in lifetime earnings(19). At societal level, economic devastation wrought by COVID-19 may take years to overcome, exacerbating economic inequalities, poverty, unemployment, household financial insecurity, food insecurity, and malnutrition, all of which negatively impact children, often disproportionately. Routine immunization services have also been negatively affected as a result of the pandemic response, thereby exacerbating the potential resurgence of vaccine-preventable diseases such as measles, tetanus, yellow fever, HPV, and others(20).

Efficacy and safety of COVID-19 vaccines in adolescents and children:

In Phase 2/3 trials for both mRNA vaccines, efficacy and immunogenicity were similar or higher compared to adults; safety and reactogenicity profiles in adolescents were similar to young adults. A very rare signal of myocarditis/pericarditis has been reported with mRNA COVID-19 vaccines as some countries have started to use these vaccines in their COVID-19 programmes. These cases occurred more often in younger men (16-24 years of age) and after the second dose of the vaccine, typically within a few days after vaccination. As the mRNA vaccines are just being rolled out in adolescents in some countries, the risk of myocarditis in that age group has not yet been fully determined. Available data suggest that the cases of myocarditis and pericarditis following vaccination are generally mild and respond to conservative treatment, and are less severe with better outcomes than classical myocarditis(21) or COVID-19. The risk of myocarditis/pericarditis associated with SARS-CoV-2 infection is higher than the risk after vaccination(21). In October 2021, the Global Advisory Committee on Vaccine Safety (GACVS) concluded that in all age groups the benefits of mRNA COVID-19 vaccines in reducing hospitalizations and deaths due to COVID-19 outweigh the risks. The risk of Thrombosis with Thrombocytopenia Syndrome (TTS) following adenoviral-vector vaccines, although overall low, was higher in younger adults compared to older adults, but no data are available on the risk below the age of 18 years.

Global equity and public health goals

In the context of ongoing global COVID-19 vaccine supply constraints, the focus of immunization programs must remain on protecting sub-populations at highest risk of hospitalizations and deaths, according to the WHO Prioritization Roadmap. There is now overwhelming evidence that immunisation of all adults with COVID-19 vaccines provides important health returns on investment. Adult immunisation is feasible in all countries with the right investments and is being actively pursued in almost all countries. However, the benefits of vaccinating children to reduce the risk of severe disease and death are much less than those associated with vaccinating older adults. Countries with few or no vaccine supply constraints should consider the issues of global equity when making policy decisions about vaccinating children and adolescents. Any guidance on vaccine use prioritization, including booster dose policy, cannot ignore the current, on-going profound inequities in global vaccine access. While higher-income countries expand their vaccination programmes to adolescents, children, and, in some countries, booster doses to a large proportion of their populations, many lower-income countries still lack sufficient vaccine supply to offer a primary vaccination series to their highest priority-use groups, including older adults and health care workers who comprise only a small proportion of their populations.

Rationale for vaccinating adolescents and children

Vaccines which have received authorization by stringent regulatory authorities for the age indication of children and adolescents are safe and effective in reducing disease burden in these age groups.

Although benefit-risk assessments clearly underpin the benefit of vaccinating all age groups, including children and adolescents, the direct health benefit of vaccinating children and adolescents is lower compared with vaccinating older adults due to the lower incidence of severe COVID-19 and deaths in younger persons. Safety signals identified after widespread roll-out, such as myocarditis, albeit rare, are reported more frequently in young persons aged 16-24 years, particularly males; the risk of myocarditis in adolescents and/or children has not yet been determined.

Reducing intergenerational transmission is an important additional public health objective when vaccinating children and adolescents. Prior to the emergence of the delta variant, it was reported that the risk of symptomatic cases in household contacts of vaccinated cases was about 50% lower than that among household contacts of unvaccinated cases(22). However, the impact of vaccination on reducing transmission in the context of the more transmissible delta variant appears to be lower(23). Teachers, family members, and other adult contacts of children and adolescents should all be vaccinated.

Vaccinating children and adolescents may also help advance other highly valued societal goals. Maintaining education for all school-aged children should be an important priority during this pandemic. School attendance is critical to the well-being and life prospects of children and to parental participation in the economy. Vaccinating school-aged children may help minimize school disruptions by reducing the number of infections at school and the number of children required to miss school because of quarantine requirements.

The benefit of vaccinating children and adolescents may be lower in settings with high seropositivity rates in that age group, however, more evidence is needed on seroprevalence of school-aged children.

Conclusions

Countries should consider the individual and population benefits of immunising children and adolescents in their specific epidemiological and social context when developing their COVID-19 immunisation policies and programs. As children and adolescents tend to have milder disease compared to adults, unless they are in a group at higher risk of severe COVID-19, it is less urgent to vaccinate them than older people, those with chronic health conditions and health workers.

There are benefits of vaccinating children and adolescents that go beyond the direct health benefits. Vaccination that decreases COVID transmission in this age group may reduce transmission from children and adolescents to older adults, and may help reduce the need for mitigation measures in schools. Minimizing disruptions to education for children and maintenance of their overall well-being, health and safety are important considerations. Countries’ strategies related to COVID-19 control should facilitate children’s participation in education and other aspects of social life, and minimize school closures, even without vaccinating children and adolescents(24). UNICEF and WHO have developed guidance on how to minimize transmission in schools and keep schools open, regardless of vaccination of school-aged children(25).

Aligned and coordinated action is needed to achieve the global COVID-19 vaccination targets. Given current global inequity in vaccine access, the decision to vaccinate adolescents and children must account for prioritization to fully protect the highest risk subgroups through primary vaccination series, and as vaccine effectiveness declines with time since vaccination, through booster doses. As such, before considering implementing primary vaccination series in adolescents and children, attaining high coverage of primary series – and booster doses as needed based on evidence of waning and optimizing vaccination impact – in highest risk subgroups, such as older adults, must be considered(26).

As a matter of global equity, as long as many parts of the world are facing extreme vaccine shortages, countries that have achieved high vaccine coverage in their high-risk populations should prioritize global sharing of COVID-19 vaccines through the COVAX facility before proceeding to vaccination of children and adolescents who are at low risk for severe disease.

It is of utmost importance for children to continue to receive the recommended childhood vaccines for other infectious diseases.

References:

1. WHO SAGE roadmap for prioritizing uses of COVID-19 vaccines in the context of limited supply. Geneva: World Health Organization; 2020 [updated 16 JUL 2021. Available from: 16 JUL 2021.
2. Strategy to Achieve Global Covid-19 Vaccination by mid-2022 2021 [Available from:
3. WHO Coronavirus (COVID-19) Dashboard | WHO Coronavirus (COVID-19) Dashboard With Vaccination Data.
4. J Clin Virol. 2020;128:104395.
5. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection in Children and Adolescents: A Systematic Review. JAMA Pediatr. 2020;174(9):882-9.
6. Vardhelli V, Pandita A, Pillai A, Badatya SK. Perinatal COVID-19: review of current evidence and practical approach towards prevention and management. Eur J Pediatr. 2021;180(4):1009-31.
7. Sheth S, Shah N, Bhandari V. Outcomes in COVID-19 Positive Neonates and Possibility of Viral Vertical Transmission: A Narrative Review. Am J Perinatol. 2020;37(12):1208-16.
8. COVID-19 disease in children and adolescents: Scientific brief, 29 September 2021 [Available from:
9. Post COVID-19 condition [Available from:
10. Jiang L, Tang K, Levin M, Irfan O, Morris SK, Wilson K, et al. COVID-19 and multisystem inflammatory syndrome in children and adolescents. Lancet Infect Dis. 2020;20(11):e276-e88.
11. Risk factors for poor prognosis in children and adolescents with COVID-19: A systematic review and meta-analysis. EClinicalMedicine. 2021;41:101155.
12. Kitano T, Kitano M, Krueger C, Jamal H, Al Rawahi H, Lee-Krueger R, et al. The differential impact of pediatric COVID-19 between high-income countries and low- and middle-income countries: A systematic review of fatality and ICU admission in children worldwide. PLoS One. 2021;16(1):e0246326.
13. Gaythorpe KAM, Bhatia S, Mangal T, Unwin HJT, Imai N, Cuomo-Dannenburg G, et al. Children’s role in the COVID-19 pandemic: a systematic review of early surveillance data on susceptibility, severity, and transmissibility. Sci Rep. 2021;11(1):13903.
14. Xu W, Li X, Dozier M, He Y, Kirolos A, Lang Z, et al. What is the evidence for transmission of COVID-19 by children in schools? A living systematic review. J Glob Health. 2020;10(2):021104.
15. Xu Y, Li X, Zhu B, Liang H, Fang C, Gong Y, et al. Characteristics of pediatric SARS-CoV-2 infection and potential evidence for persistent fecal viral shedding. Nat Med. 2020;26(4):502-5.
16. Madera S, Crawford E, Langelier C, Tran NK, Thornborrow E, Miller S, et al. Nasopharyngeal SARS-CoV-2 viral loads in young children do not differ significantly from those in older children and adults. Sci Rep. 2021;11(1):3044.
17. Rajmil L. Role of children in the transmission of the COVID-19 pandemic: a rapid scoping review. BMJ Paediatr Open. 2020;4(1):e000722.
18. UNICEF. UNICEF Executive Director Henrietta Fore’s remarks at a press conference on new updated guidance on school-related public health measures in the context of COVID-19. New York; 2020.
19. The World Bank (2020). Simulating the Potential Impacts of the COVID-19 school closures on schooling and learning outcomes: a set of global estimates. Washington DC2020 [Available from:
20. Gaythorpe KA, Abbas K, Huber J, Karachaliou A, Thakkar N, Woodruff K, et al. Impact of COVID-19-related disruptions to measles, meningococcal A, and yellow fever vaccination in 10 countries. Elife. 2021;10.
21. [Available from:
22. Harris RJ, Hall JA, Zaidi A, Andrews NJ, Dunbar JK, Dabrera G. Effect of Vaccination on Household Transmission of SARS-CoV-2 in England. N Engl J Med. 2021;385(8):759-60.
23. Singanayagam A, Hakki S, Dunning J, Madon KJ, Crone MA, Koycheva A, et al. Community transmission and viral load kinetics of the SARS-CoV-2 delta (B.1.617.2) variant in vaccinated and unvaccinated individuals in the UK: a prospective, longitudinal, cohort study. Lancet Infect Dis. 2021.
24. WHO, UNICEF, UNESCO. Considerations for school-related public health measures in the context of COVID-19: annex to considerations in adjusting public health and social measures in the context of COVID-19, 14 September 2020. Geneva: World Health Organization; 2020 2020. Contract No.: WHO/2019-nCoV/Adjusting_PH_measures/Schools/2020.2.
25. Framework for Reopening Schools [Available from: .
26. Interim recommendations for use of the Pfizer–BioNTech COVID-19 vaccine, BNT162b2, under Emergency Use Listing [Available from: