Vaccination against COVID-19 from 6 months of age on. Completing the circle of prevention in paediatrics

Vaccination against SARS-CoV-2 in the paediatric age group has reached its third phase from the perspective of vaccine licensing by drug regulatory agencies for the different age groups of childhood.

However, decisions on vaccination must take into account the epidemiological situation of COVID-19, that severe forms in healthy children are very rare (multisystemic inflammatory syndrome), that persistent COVID-19 is less frequent than in adults and that, in addition, a high percentage of children have natural immunity due to previous infection, which has been widely present in families and schools in the seventh wave of the pandemic. Furthermore, the severity of COVID-19 has decreased with the circulation of the omicron variant over the past year.

The publication of this third editoiral completes the cycle of prevention in the paediatric age group that we began in a first editorial, in May 2021, dedicated to the vaccination of teenagers,¹ coinciding with the first authorisation by the Canadian Medicines Regulatory Agency on 4 May and by the US Food and Drug Administration on 10 May of the extension of the emergency use of the BioNTech-Pfizer vaccine (Comirnaty®) to the paediatric age group, and by the US Food and Drug Administration on 10 May, of the extension of the emergency use of BioNTech-Pfizer's vaccine (Comirnaty®) to the 12 to 15 year age group, since its first approval, 5 months earlier, was for people aged 16 years and older. A few days later, on 28 May, the European Medicines Agency (EMA) approved this extension, and on 22 June, in the eighth update of the COVID-19 Vaccination Strategy in Spain, a group was added to the vaccination prioritisations that included teenagers aged 12 to 19 years.²

In a second editorial,³ in December 2021, we referred to paediatric vaccination before adolescence, specifically from 5 to 11 years of age, when the EMA had just authorised Comirnaty® on 25 November for this age group and the epidemiological situation in Spain was worrying due to the epidemic wave of the highly transmissible and contagious omicron variant, which even led some schools to bring forward the start of the Christmas holidays. The Public Health Commission then agreed on 7 December 2021 to vaccinate all children aged 5–11 years, which was launched on 15 December.⁴ In November 2022, the EMA approved the bivalent Comirnaty Original/ Omicron BA.4-5 adapted bivalent vaccine, 10 μg per dose, for use as a booster dose in children aged 5–11 years,⁵ and the Food and DrugAdministration has also licensed the bivalent adapted vaccine Moderna for children aged 6–11 years.

And we come to this third editorial after the EMA, on 19 October 2022 (and in Spain on 17 November),jointly approved the 2 mRNA vaccines, Comirnaty® and Spikevax®, from 6 months of age.^6–8 On 6 December, the EMA emergency working group considered that bivalent matched mRNA vaccines could be used for primary vaccination in previously unvaccinated children and adults.⁹ Finally, infants younger than 6 months, who have higher hospitalisation rates than other paediatric age groups and who are not eligible for vaccination with current vaccines, should be protected through maternal vaccination.¹⁰

The 2 vaccines were authorised by the EMA with 2 different dosages diferentes^7,8:

- Comirnaty® 3 μg/dose concentrate for injectable dispersion of mRNA (tozinameran) is indicated in infants and children aged 6 months to 4 years. Primovaccination consists of 3 doses of 3 μg each (one tenth of the adult dose); the first 2 doses are given 3 weeks apart, followed by a third dose at least 8 weeks after the second dose. The 3-week interval between the first 2 doses can be extended to 8 weeks, which improves the immune response. The need for a booster dose has not been determined. If a child reaches the age of 5 years between doses of the vaccination schedule, he/she should complete the schedule with the same 3 μg dose.

- Spikevax® 0.1 mg/ml for mRNA dispersion for injection (elasomeran) is indicated for children aged 6 months to 5 years. The primary vaccination consists of 2 doses of 25 μg (one quarter of the adult dose) each, 4 weeks apart, which can be extended to 8 weeks. The need for a booster dose has not been determined.

With regard to the safety data for Comirnaty®, the technical data sheet of the Spanish Agency for Medicines and Health Products⁷states that in the Phase II/III clinical trial, mild cases of reactogenicity were observed. The most frequent adverse reactions in infants aged 6–23 months were irritability (> 60%), somnolence (> 40%), decreased appetite (> 30%), pain on palpation at the injection site (> 20%), redness at the injection site and fever (> 10%); and in children aged 2–4 years injection site pain and fatigue (> 40%), and redness at the injection site and fever (> 10%). No data are available on the risk of myocarditis and pericarditis after vaccination, but it is known to be much lower in children aged 5–11 years than in those aged 12–17 years. Given the small number of children included in clinical trials, post-marketing surveillance is essential.

In the Comirnaty® study, an immunogenicity analysis was performed in two subgroups, one aged 6–23 months and one aged 2–4 years. Neutralising antibody titres were compared one month after the primary regimen of 3 doses of 3 μg and those of a group aged 16–25 years one month after the primary regimen of 2 doses of 30 μg. The results showed that the pre-specified criteria for bridging immunogenicity or non-inferiority were met.

The efficacy analysis of the phase III clinical trial was conducted in the combined population of participants aged 6 months to 4 years based on confirmed cases among 873 participants in the vaccinated group and 381 in the placebo group (randomisation ratio of 2:1) who received all 3 doses during the masked follow-up period when the SARS-CoV-2 omicron variant (BA.1) was predominantly circulating. Vaccine efficacy after the third dose in participants aged 6 months to 4 years was 73.2% (95% confidence interval [95% CI]: 43.8–87.6).⁷

The results of the randomised, double-blind, placebo-controlled, double-blind phase II/III^8,11,12 clinical trial of Spikevax® (6,388 participants) showed that this vaccine is safe. Most local adverse reactions (66.1%) were grade 1–2 and lasted 1–3 days. The most common systemic reactions (65.9%) were fatigue, irritability, tearfulness, drowsiness, loss of appetite and fever, and were more frequent after the second dose. Reactogenicity was lower than in children in the 6–11 years age group.

Immunogenicity in the 2 age subgroups (6–23 months and 2–5 years), compared (immunopuent) with that of the group of adults aged 18–25 years from a previous study who received 2 doses of 100 μg, was comparable and non-inferiority criteria were met.

Efficacy of the vaccine in this study was estimated during the period when variant B.1.1.529 (omicron) was predominant. Efficacy from 14 days after the second dose for prevention of laboratory-confirmed symptomatic COVID-19 was 37.8% (95% CI 20.9–51.1) for children aged 2–5 years and 50.6% (95% CI 21.4–68.6) for children aged 6–23 months.

Vaccine safety data have been published in the US from a post-marketing study conducted after administration of one million doses of mRNA vaccines in children 6 months to 5 years of age (Vaccine Adverse EventsReportingSystem data).¹³ The report is consistent with data from the licensing clinical trials. Mild to moderate local and systemic reactions (more frequent in the 6–23 month group than in the 2–5 year olds) were the most common and no serious adverse events related to vaccination were reported. Myocarditis was also not reported.

Reflections

The authorisation of these 2 preparations allows us to have vaccines against SARS-CoV-2 that are safe, immunogenic and effective for the vaccination of infants from 6 months of age and children up to 4–5 years of age, with Comirnaty® or Spikevax®, respectively. However, it remains to be established which vaccination strategy should be recommended for this age group (the health authorities have not yet made a written statement) taking into account the following circumstances: in Spain, with the current epidemiological situation and the good vaccination coverage of the population, the high percentage of people already infected (especially with the omicron variant since December 2021), with the current vaccines that have a limited duration of protection and when the third year of the pandemic is about to begin.

There are 3 scenarios to consider. A first priority vaccination phase, to be launched now, for infants and children in this age group with very high-risk diseases or situations, which will be incorporated into the rest of this type of patients of all ages, considered in the seventh update of the vaccination strategy in Spain in May 2021.¹⁴ In addition, all patients with chronic diseases, especially neurological, chronic respiratory and cardiovascular diseases, obesity and diabetes, will have to be included. On 15 December 2022 the Public Health Commission updated the recommendations for vaccination against COVID-19 for autumn-winter in Spain, and included the paediatric population aged 6–59 months with very high-risk conditions that induce a high degree of immunosuppression.

A second aspect to consider is routine vaccination of this population group. This is not currently a priority and can be postponed due to the epidemiological and vaccination situation in our environment. Moreover, vaccination provides little protection against infection, so the influence of immunisation of this group on the evolution of the pandemic will be limited. Some countries, such as the United States, recommend vaccination against COVID-19 for all children 6 months of age and older, and have included it in the vaccination schedule, as the Advisory Committee on Immunization Practices determined that the benefits of vaccination (in terms of hospitalisations and deaths) outweigh the risks for this population.^11,13

Third, it must be clear to the public that a safe and effective vaccine is available and should be available to parents who wish to vaccinate their children, after hearing information from the paediatrician (severe forms and persistent COVID exist, and vaccination is effective in preventing these situations) and after discussing the decision making with the paediatrician (the so-called "shared clinical decision"). In a Kaiser Family Foundation survey¹⁵ in May 2022, 18% of parents surveyed wanted to vaccinate their children under 5 years of age as soon as possible, 38% would wait to see how the vaccine works, and 11% would vaccinate them only if necessary.

The most important thing to consider, in terms of possible modifications to this dynamic vaccination strategy, is that it is essential to monitor the epidemiological surveillance of SARS-CoV-2 infection, especially in view of the possible appearance of other variants and subvariants, and the authorisation of new vaccines is necessary,¹⁶ especially those that can prevent infection and its transmission (intranasal mucosal vaccines) and those that have a broader and longer-lasting protection that allows for at least annual booster doses, as is the case with the influenza vaccine.

As a final reflection on the pandemic in general, I would like to recall what we wrote in the first months of its onset (April 2020): although the threat of a pandemic had been announced for years and countries were warned of the need to be prepared, we were not. Many mistakes have been made, from which we must all learn, but first and foremost governments, which must be advised by expert and independent scientists regarding the challenge posed by emerging and re-emerging microorganisms.¹⁷