Two doses of CoronaVac are safe and provoke a strong antibody response among children and adolescents aged 3-17 years, according to a randomised controlled trial of 550 young people published in The Lancet Infectious Diseases journal.
Qiang Gao, of Sinovac Life Sciences Co, Ltd, China, said: “Children and adolescents with COVID-19 usually have mild or asymptomatic infections compared with adults; however, a small number may still be at risk of severe illness. They can also transmit the virus to others, making it vital to test the safety and effectiveness of COVID-19 vaccines in younger age groups.
Our finding that CoronaVac was well tolerated and induced strong immune responses is very encouraging, and suggests that further studies in other regions, involving larger, multi-ethnic populations, could provide valuable data to inform immunisation strategies involving children and adolescents.”
The authors conducted a randomised, double-blind, controlled phase 1/2 clinical trial of CoronaVac in healthy children and adolescents aged 3-17 years in Zanhuang County, China. Between October 31 and December 2, 2020, 72 participants were enrolled in phase 1, with 480 participants enrolled in phase 2 between December 12 and December 30, 2020.
The vaccine (either 1.5μg or 3μg per dose) or a control was given by intramuscular injection in two doses, at day 0 and day 28. In studies involving adults aged 18-59 years and people aged 60 years and older, participants received two doses of 1.5μg, 3μg, or 6μg, with 3μg doses suggested for use in further research.
Among the 550 participants who received at least one dose of vaccine or the control, adverse reactions within 28 days occurred in 56 (26%) of 219 participants in the 1.5μg group, 63 (29%) of 217 in the 3μg group, and 27 (24%) of 114 in the control group.
Most adverse reactions were mild or moderate, with pain at the injection site (13%, 73/550 participants) the most commonly reported symptom. Only one serious adverse reaction – a case of pneumonia – was reported in the control group; however, this was unrelated to the COVID-19 vaccination.
In phase 1, 100% of participants in both the 1.5μg and 3μg groups (27/27 and 26/26 participants, respectively) generated antibodies against SARS-CoV-2. Stronger immune responses – determined by the amount of antibodies produced that can neutralise the virus, expressed as geometric mean titre (GMT) – were detected among the 3μg group compared with the 1.5μg group (GMTs of 117 and 55, respectively).
In phase 2, 97% (180/186) of participants in the 1.5μg group produced antibodies against SARS-CoV-2, compared with 100% (180/180 participants) in the 3μg group. Participants in the 3μg group again produced a stronger immune response that those in the 1.5μg group (GMTs of 142 and 86, respectively).
Similar to findings for other vaccines that increasing age is linked with reduced immune responses, the authors note that immune responses among children and adolescents were higher than those in adults aged 18-59 years and elderly aged 60 years and older (GMTs of 44 and 42, respectively).
No significant differences in immune response were detected in an analysis by age group, with more than 93% of those in the 1.5μg and 3μg groups aged 3-5 years, 6-11 years, and 12-17 years producing antibodies against SARS-CoV-2 (with GMTs ranging from 78 to 146) at day 28 after the second dose.
In each age group, there were significant differences in GMTs between the 1·5 μg and3·0 μg groups after the second dose, except in the group aged 12-17 years old in phase 1.
Based on their results, the authors recommend two 3μg doses of the vaccine for children and adolescents aged 3-17 years.
The authors acknowledge some limitations to their study. T cell responses – which play an important role in SARS-CoV-2 infections—were not assessed in the study, though these have been investigated in related studies. The study involved a small number of participants and all were of Han ethnicity, highlighting a need for larger studies in other regions and involving multi-ethnic populations.
Long-term safety and immune response data were not available, though participants will be followed for at least 1 year. Owing to the small number of participants in the study, the results should be interpreted with caution as it was not possible to draw strong statistical conclusions.
Writing in a linked Comment, Professor Bin Cao, of the China-Japan Friendship Hospital, China, highlights the need to include children in immunisation campaigns, explaining: “Herd immunity against COVID-19 is the prerequisite to end this pandemic, either through vaccinations or natural infection.
Most estimates placed the threshold at 65-70% of the population gaining immunity, mainly by vaccination. However, widely circulating virus variants and persistent hesitancy on vaccine make this threshold difficult to reach. (…) Thus, the calculation has to be revised upward and children must be covered in the immunisation campaign.”
In calling for longer follow-up assessments in children, Professor Cao also emphasises the vital importance of determining the safety of vaccines in younger age groups, saying: “While vaccinating children is essential to reach herd immunity and limit the severity of COVID-19, safety should be the paramount factor to be considered before COVID-19 vaccines can be rolled out in younger children.”
WHO today validated the Sinovac-CoronaVac COVID-19 vaccine for emergency use, giving countries, funders, procuring agencies and communities the assurance that it meets international standards for safety, efficacy and manufacturing. The vaccine is produced by the Beijing-based pharmaceutical company Sinovac.
“The world desperately needs multiple COVID-19 vaccines to address the huge access inequity across the globe,” said Dr Mariângela Simão, WHO Assistant-Director General for Access to Health Products. “We urge manufacturers to participate in the COVAX Facility, share their knowhow and data and contribute to bringing the pandemic under control.”
WHO’s Emergency Use Listing (EUL) is a prerequisite for COVAX Facility vaccine supply and international procurement. It also allows countries to expedite their own regulatory approval to import and administer COVID-19 vaccines.
The EUL assesses the quality, safety and efficacy of COVID-19 vaccines, as well as risk management plans and programmatic suitability, such as cold chain requirements. The assessment is performed by the product evaluation group, composed by regulatory experts from around the world and a Technical Advisory Group (TAG), in charge of performing the risk-benefit assessment for an independent recommendation on whether a vaccine can be listed for emergency use and, if so, under which conditions.
In the case of the Sinovac-CoronaVac vaccine, the WHO assessment included on-site inspections of the production facility.
The Sinovac-CoronaVac product is an inactivated vaccine. Its easy storage requirements make it very manageable and particularly suitable for low-resource settings.
WHO’s Strategic Advisory Group of Experts on Immunization (SAGE) has also completed its review of the vaccine. On the basis of available evidence, WHO recommends the vaccine for use in adults 18 years and older, in a two-dose schedule with a spacing of two to four weeks. Vaccine efficacy results showed that the vaccine prevented symptomatic disease in 51% of those vaccinated and prevented severe COVID-19 and hospitalization in 100% of the studied population.
Few older adults (over 60 years) were enrolled in clinical trials, so efficacy could not be estimated in this age group. Nevertheless, WHO is not recommending an upper age limit for the vaccine because data collected during subsequent use in multiple countries and supportive immunogenicity data suggest the vaccine is likely to have a protective effect in older persons. There is no reason to believe that the vaccine has a different safety profile in older and younger populations.
WHO recommends that countries using the vaccine in older age groups conduct safety and effectiveness monitoring to verify the expected impact and contribute to making the recommendation more robust for all countries.
WHO emergency use listing
The emergency use listing (EUL) procedure assesses the suitability of novel health products during public health emergencies. The objective is to make medicines, vaccines and diagnostics available as rapidly as possible to address the emergency, while adhering to stringent criteria of safety, efficacy and quality. The assessment weighs the threat posed by the emergency as well as the benefit that would accrue from the use of the product against any potential risks.
The EUL pathway involves a rigorous assessment of late phase II and phase III clinical trial data as well as substantial additional data on safety, efficacy, quality and a risk management plan with a focus on low- and middle-income country needs. These data are reviewed by independent experts and WHO teams who consider the current body of evidence on the vaccine under consideration, the plans for monitoring its use, and plans for further studies.
As part of the EUL process, the company producing the vaccine must commit to continue to generate data to enable full licensure and WHO prequalification of the vaccine. The WHO prequalification process will assess additional clinical data generated from vaccine trials and deployment on a rolling basis to ensure the vaccine meets the necessary standards of quality, safety and efficacy for broader availability.
More information: Bihua Han et al, Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine (CoronaVac) in healthy children and adolescents: a double-blind, randomised, controlled, phase 1/2 clinical trial, The Lancet Infectious Diseases (2021). DOI: 10.1016/S1473-3099(21)00319-4
