in covid

Effectiveness of BNT162b2 vaccine against SARS-CoV-2 infection and severe COVID-19 in children aged 5–11 years in Italy: a retrospective analysis of January–April, 2022

by colinnew July 6, 2022, 7:53 am 1.1k Views

Summary

Background

By April 13, 2022, more than 4 months after the approval of BNT162b2 (Pfizer–BioNTech) for children, less than 40% of 5–11-year-olds in Italy had been vaccinated against COVID-19. Estimating how effective vaccination is in 5–11-year-olds in the current epidemiological context dominated by the omicron variant (B.1.1.529) is important to inform public health bodies in defining vaccination policies and strategies.

Methods

In this retrospective population analysis, we assessed vaccine effectiveness against SARS-CoV-2 infection and severe COVID-19, defined as an infection leading to hospitalisation or death, by linking the national COVID-19 surveillance system and the national vaccination registry. All Italian children aged 5–11 years without a previous diagnosis of infection were eligible for inclusion and were followed up from Jan 17 to April 13, 2022. All children with inconsistent vaccination data, diagnosed with SARS-CoV-2 infection before the start date of the study or without information on the municipality of residence were excluded from the analysis. With unvaccinated children as the reference group, we estimated vaccine effectiveness in those who were partly vaccinated (one dose) and those who were fully vaccinated (two doses).

Findings

By April 13, 2022, 1 063 035 (35·8%) of the 2 965 918 children aged 5–11 years included in the study had received two doses of the vaccine, 134 386 (4·5%) children had received one dose only, and 1 768 497 (59·6%) were unvaccinated. During the study period, 766 756 cases of SARS-CoV-2 infection and 644 cases of severe COVID-19 (627 hospitalisations, 15 admissions to intensive care units, and two deaths) were notified. Overall, vaccine effectiveness in the fully vaccinated group was 29·4% (95% CI 28·5–30·2) against SARS-CoV-2 infection and 41·1% (22·2–55·4) against severe COVID-19, whereas vaccine effectiveness in the partly vaccinated group was 27·4% (26·4–28·4) against SARS-CoV-2 infection and 38·1% (20·9–51·5) against severe COVID-19. Vaccine effectiveness against infection peaked at 38·7% (37·7–39·7) at 0–14 days after full vaccination and decreased to 21·2% (19·7–22·7) at 43–84 days after full vaccination.

Interpretation

Vaccination against COVID-19 in children aged 5–11 years in Italy showed a lower effectiveness in preventing SARS-CoV-2 infection and severe COVID-19 than in individuals aged 12 years and older. Effectiveness against infection appears to decrease after completion of the current primary vaccination cycle.

Funding

None.

Translation

For the Italian translation of the summary see Supplementary Materials section.

Introduction

The global COVID-19 pandemic that started in 2019 continues to be an important public health threat worldwide in 2022. Although SARS-CoV-2 infection usually has a milder course in children than in adults it still has the potential to cause severe disease,especially in those with underlying health conditions. Children are also at risk of developing paediatric inflammatory multisystem syndrome. In Italy, COVID-19 has caused more than 10 000 hospitalisations and almost 200 admissions to intensive care units (ICUs) in children aged 11 years or younger since the start of the pandemic.

COVID-19 vaccination in young children could have three benefits: (1) a direct benefit by preventing severe and persistent COVID-19; (2) an indirect benefit by preventing SARS-CoV-2 infection, which could lead to social, psychological, and physical benefits by reducing school absenteeism and allowing a higher degree of social interaction between children; and (3) a benefit to the general population by reducing SARS-CoV-2 onward transmission to other age groups.

After the recommendation from the European Medicines Agency,

on Dec 7, 2021, the Italian Ministry of Health extended the use of the BNT162b2 (Pfizer–BioNtech) vaccine to children aged 5–11 years with a two dose regimen, (two 10 μg doses) to be given 21 days apart.

According to the Italian COVID-19 vaccines report, by April 13, 2022, more than 1·2 million (38%) of about 3·6 million eligible 5–11-year-olds had received at least one dose of the vaccine and more than 1·1 million (34%) had completed the primary cycle of two doses. The randomised trial that led to the approval of the vaccine in 5–11-year-olds found that BNT162b2 was efficacious
and post-approval studies have confirmed its safety in this age group.
However, very few studies estimating real-world effectiveness are available, and the published studies have all been done in the USA.
Furthermore, the effectiveness of the vaccine against the current dominant variant in Europe, omicron (B.1.1.529), might have changed compared with the context in which the previous randomised trials were done. Estimating the degree of protection in young children against infection and severe disease could inform authorities in the implementation and planning of public health interventions targeting both children and the community at large.

Research in context

Evidence before this study

We aimed to identify all the available evidence around vaccine effectiveness of COVID-19 vaccines in children aged 5–11 years. With no restrictions on date or language, we searched PubMed for papers published from the inception of the database to April 4, 2022, with the search terms (“Comirnaty” OR “BNT162b2” OR “Pfizer”) AND (“vaccine*”) AND (“children” OR “adolescent*” OR “young”) AND (“effective*” OR “risk” OR “efficac*”) AND (“SARS-CoV-2” OR “COVID-19” OR “severe acute respiratory syndrome coronavirus 2” OR “coronavirus disease 2019”) AND (“severity” OR “hospitalisation” OR “hospitalization” OR “hospital” OR “emergency care” OR “mortality” OR “lethality” OR “death”). We also searched medRxiv and SSRN and websites of national institutes of public health in Europe (Germany, Spain, the UK, and France) and the USA for unpublished estimates of vaccine effectiveness using the same search terms. We identified three published studies and one preprint estimating vaccine effectiveness in children aged 5–11 years, all of them in omicron (B.1.1.529) prevalent contexts. All four studies were done in the USA, and they all estimated vaccine effectiveness with two doses using unvaccinated children as the control group. Only one published cohort study and the preprint cohort study estimated vaccine effectiveness against symptomatic or asymptomatic infection. The published cohort study estimated vaccine effectiveness to be 31% 14–82 days after the second dose; the preprint study reported an effectiveness of 65% at 0–13 days after the second dose, declining to 12% 28–34 days after the second dose. A test negative case-control trial estimated a vaccine effectiveness of 46% against urgent care and emergency department encounters; a second test negative case-control study estimated a vaccine effectiveness of 68% against hospitalisation with a median time of follow-up of 34 days. In both cases, the precision of the estimates was low due to the small number of severe events observed.

Added value of this study

Our study is the largest to date to estimate vaccine effectiveness in children aged 5–11 years and the only one done outside the USA. We estimated vaccine effectiveness against infection and severe COVID-19 with a higher precision than previous studies. By using individual-level data, we were able to adjust for several individual and contextual factors. To assess the presence of possible bias due to uncontrolled confounders, we did several sensitivity analyses based on different assumptions and control groups. Given the longitudinal nature of our data sources, we were also able to assess how vaccine effectiveness against infection evolved through time since vaccination during a longer period of follow-up than any previous study.

Implications of all the available evidence

Many countries in Europe and elsewhere have relatively low levels of vaccine coverage in children aged 5–11-years. Our results suggest that BNT162b2 vaccine is moderately effective in preventing infection and severe disease in this age group. However, effectiveness is lower than in other age groups and, at least against infection, it seems to wane. These results should be interpreted by public health authorities alongside data around vaccine safety and the probability of mortality and morbidity from COVID-19 in this age group.

The aim of this study was to estimate the effectiveness of the paediatric BNT162b2 vaccine in preventing SARS-CoV-2 infections and severe COVID-19 (hospitalisation or death) in children using routinely collected data in Italy.

Methods

Study design and population

This was a nationwide retrospective analysis of 5–11-year-olds in Italy. All 5–11-year-olds for whom records could be linked were screened for inclusion. All children with incongruent vaccination data (ie, more than two doses or at least one non-BNT162b2 dose), diagnosed with SARS-CoV-2 infection before the start date of the study (Jan 17, 2022), or without information on the municipality of residence were excluded from the analysis. Dissemination of COVID-19 surveillance data was authorised by Decree Law number 24 on March 24, 2022 (article 13).

Procedures

We used deterministic record linkage by individual tax code to combine data from the national vaccination registry, which was held by the Ministry of Health and collected individual information on COVID-19 vaccinations administered in Italy, with data on SARS-CoV-2 notified infections (confirmed by antigen or PCR positive tests, or both, from either public or private laboratories and pharmacies) from the Italian National COVID-19 Integrated Surveillance System, coordinated by the National Institute of Health.
Data were extracted on April 13, 2022, from both sources. The number of people in the non-vaccinated population, and without a SARS-CoV-2 notified infection, was obtained by subtracting the number of people who were vaccinated or with a previous SARS-CoV-2 diagnosis from the Italian resident population stratified by sex, age, and municipality of residence, as of Jan 1, 2021. The Italian resident population was derived from census data updated yearly by the National Institute of Statistics using the demographic balance from the population registry of each Italian municipality.

Outcomes

We measured two outcomes: the incidence of notified SARS-CoV-2 infection (asymptomatic or symptomatic) and the incidence of severe COVID-19, defined as a SARS-CoV-2 infection resulting in hospital admission or death within 28 days. Only deaths for which COVID-19 was the most likely cause are recorded in the national surveillance system, as per Italian guidelines based on indications from WHO.
Equally, the surveillance system foresees that cases are recorded as hospitalised only if the hospitalisation is directly attributable to SARS-CoV-2 infection and not due to other causes.

The timeline for each event are reported in figure 1. The study start date was Jan 17, 2022, 14 days after the first children received the second dose of BNT162b2 mRNA vaccine. Participants were followed up until the date of diagnosis or the end of the follow-up period, whichever occurred first. We used different dates of end-to-follow-up to account for time from diagnosis to disease progression. The end date for the outcome of severe COVID-19 was March 13, 2022, and the end date for the analysis of SARS-CoV-2 infection was April 10, 2022. The two end dates made it possible to consider all notified cases of confirmed infection with a follow-up period of at least 28 days after diagnosis to document possible worsening of clinical symptoms, and to account for 3 days of possible delay in notification. The study period was characterised by the predominance of the omicron variant.

Figure thumbnail gr1 — Figure 1Timeline of periods of selection and events in the study population

Statistical analysis

Individual time of exposure was divided according to vaccination status and into weekly time intervals. Vaccination status was defined in three categories: unvaccinated, partly vaccinated (one dose), and fully vaccinated (two doses). On the basis of previous studies,

¹⁵

¹⁶

we allowed 14 days from the time of vaccine inoculation to its immunological effect. Thus, children were classified as unvaccinated for the first 14 days after the first dose and as partly vaccinated for the first 14 days after the second dose. Incidence rate ratios (IRRs) of SARS-CoV-2 infections and severe COVID-19 for partly and fully vaccinated children compared with unvaccinated children were estimated using the negative binomial generalised linear mixed model, including geographical region of residence as the random effect and exposure measured in days as offset. We included two individual variables, sex and age (as categorical variables), as fixed effects. We used three contextual variables: (1) vaccination coverage at the municipal level in the population aged 30–50 years, split into two categories low (≤75%) and high (>75%); (2) level of urbanisation of the municipality of residence (urban, semi-urban, and rural) from the 2011 census, as reported by the National Institute of Statistics using the European Degree of Urbanisation classification;

¹⁷

and (3) the weekly regional incidence of COVID-19 in the general population. Vaccine effectiveness was calculated as (1 minus the IRR) multiplied by 100.

Using the same multivariable regression model, we assessed the possible loss of immunity provided by the paediatric vaccination against SARS-CoV-2 infection at 14-day intervals from full vaccination (0–14 days, 15–28 days, 29–42 days, and 43–84 days).

A sensitivity analysis was done to assess the robustness of our results with respect to the exclusion criteria used to define the study population. We estimated IRRs of SARS-CoV-2 infections and severe COVID-19; all 599 169 notified infections that preceded vaccination were included in the analysis (appendix 2 p 2). We then estimated vaccine effectiveness excluding people with SARS-CoV-2 infection diagnosed in the previous 90 days (appendix 2 p 2). The rationale was that in Italy, and other European countries, reinfections are only considered as such 90 days after the primary infection. Both models included previous diagnosis as a fixed effect covariate.

To avoid possible confounding factors arising from differences between the vaccinated and the unvaccinated populations, we did another sensitivity analysis estimating vaccine effectiveness on the vaccinated population alone. In this analysis, we used the exposure interval of 4–10 days from the first dose of vaccine as a reference (appendix 2 p 2). We did not consider the time intervals of 11–14 days and 0–3 days after first dose because some protection might be evident 10 days after the first dose of vaccine, and, from days 0 to 3, a deferral bias could affect the incidence in the first few days after the first dose (eg, people with symptoms probably postponed vaccination).

¹⁸

Adjusted vaccine effectiveness was estimated using the same model, including the frailty status (healthy, immunocompromised, or affected by a chronic pathology) as an additional covariate (information available only for people who were vaccinated through the national vaccination registry and obtained at the time of vaccination; appendix 2 p 3).

All the analyses were done using R (version 4.1.2).

¹⁹

The negative binomial generalised linear mixed model was estimated using the R package glmmTMB.

²⁰

We described the methods and presented findings according to the reporting guidelines for observational studies that are based on routinely collected health data (appendix 2 p 4).

Role of the funding source

There was no funding source for this study.

Results

In Italy, the vaccination campaign against COVID-19 in 5–11-year-olds started on Dec 16, 2021. The beginning of the study period (Jan 17, 2022) coincides with the date when the first children completed the primary cycle (ie, had received two doses of BNT162b2). 2 965 918 children were included in the study with a median follow-up of 71 days (figure 2); the population characteristics and demographics at the end of the study (April 13, 2022) are reported in table 1. On April 13, 2022, 1 063 035 (35·8%) children had completed the primary cycle of two doses, 134 386 (4·5%) had received one dose, and 1 768 497 (59·6%) were unvaccinated. Vaccination coverage increased with age and was lower in areas where uptake in 30–50-year-olds was low. We also observed that children in rural and semi-urban areas were more frequently unvaccinated than those living in urban municipalities. We did not observe differences in vaccination status according to sex (table 1).

Figure thumbnail gr2 — Figure 2Study profile

Figure thumbnail gr3 — Figure 2Study profile

	Not vaccinated group (n=1 768 497)	Partly vaccinated group (n=134 386)	Fully vaccinated group (n=1 063 035)
Sex
Male	911 202 (51·5%)	69 830 (52·0%)	543 720 (51·1%)
Female	857 295 (48·5%)	64 556 (48·0%)	519 315 (48·9%)
Age
5 years	301 157 (17·0%)	14 060 (10·5%)	95 788 (9·0%)
6 years	270 983 (15·3%)	16 081 (12·0%)	126 147 (11·9%)
7 years	262 018 (14·8%)	18 063 (13·4%)	139 516 (13·1%)
8 years	251 694 (14·2%)	19 023 (14·2%)	150 768 (14·2%)
9 years	248 813 (14·1%)	20 495 (15·3%)	164 652 (15·5%)
10 years	232 431 (13·1%)	22 769 (16·9%)	179 765 (16·9%)
11 years	201 401 (11·4%)	23 895 (17·8%)	206 399 (19·4%)
Municipality vaccine uptake in 30-50-year-olds
Low (≤75%)	25 657 (1·5%)	869 (0·6%)	4966 (0·5%)
High (>75%)	1 742 840 (98·5%)	133 517 (99·4%)	1 058 069 (99·5%)
Municipality urbanisation *
Urban	593 602 (33·6%)	50 181 (37·3%)	393 357 (37·0%)
Semi-urban	869 499 (49·2%)	64 878 (48·3%)	515 086 (48·5%)
Rural	305 396 (17·3%)	19 327 (14·4%)	154 592 (14·5%)

	Number of infections	Person-days	Rate per 100 000 person-days	Crude IRR (95% CI)	Vaccine effectiveness (95% CI)	Adjusted vaccine effectiveness * (95% CI)
Infection
Unvaccinated group	562 083	131 656 589	426·9	1	NA	NA
Partly vaccinated group	83 441	25 860 465	322·7	0·76 (0·75-0·76)	24·4 (23·9-24·9)	27·4 (26·4-28·4)
Fully vaccinated group	121 232	51 699 305	234·5	0·55 (0·55-0·55)	45·1 (44·8-45·4)	29·4 (28·5-30·2)
Severe disease
Unvaccinated group	510	89 464 006	0·57	1	NA	NA
Partly vaccinated group	75	22 169 941	0·34	0·59 (0·46-0·76)	40·7 (24·3-54·1)	38·1 (20·9-51·5)
Fully vaccinated group	59	23 094 584	0·26	0·45 (0·34-0·59)	55·2 (41·2-66·4)	41·1 (22·2-55·4)