Nasal spray live attenuated influenza vaccine: the first experience in Italy in children and adolescents during the 2020–21 season

Influenza virus is responsible for nearly 30% of the infectious disease burden in Europe: every year up to 50 million people contract symptomatic flu and the high number of mild to moderate infections leads to loss in production and pressure on health services [1, 2]. In Italy the average annual frequency of influenza cases in the general population is estimated around 9%. In the age group 0–14, which is the most affected, the incidence is around 26% (12–40%) [3].

The purpose of a vaccination programme for all children is to provide them with direct protection, thereby creating indirect protection to the adult population, since children are the major propagators of influenza [4, 5] and represent a crucial reservoir of the virus [6‐9].

Live attenuated influenza vaccine (LAIV) is approved for use in Europe [10], US [11] and Canada [12]. Fluenz Tetra™, in particular, is a non-invasive intranasal quadrivalent LAIV (qLAIV) used in children and adolescents aged 2 to 17 years. A recent comparative study of LAIV vs inactivated influenza vaccine (IIV) concluded that LAIV is more effective in preventing influenza in children [4, 13] and one of its advantages is the capacity to induce immune responses at the site of infection [14]. The most common adverse event reported after LAIV administration was nasal congestion [15]. A large phase III trial with LAIV recorded an increased incidence of medically significant wheezing in vaccine-naive children aged less than 24 months and an increase of hospitalizations in children aged 6–11 months as compared with the trivalent inactivated vaccine (TIV). Belshe RB et al. concluded that LAIV was highly effective and safe for children aged 12 through 59 months with no previous history of asthma or wheezing [16]. In the UK a universal childhood vaccine programme with LAIV was introduced in 2012 [15] and in 2018/19 flu season it was estimated that the overall adjusted vaccine effectiveness for 2 to 17 years olds receiving LAIV was 48.6% [17].

In Italy the coverage in children and adolescents has always been very low, reaching a peak of 4.2% in children aged 2 to 4 and a minimum of 1.9% of the 9–17 population (2019/20 flu season) [18].

For the 2020/21 season, flu vaccination has been extended to all children aged 6 months through 6 years and the Lombardy region chose to introduce Fluenz Tetra™ for the first time in Italy, in addition to the IIV (Vaxigrip Tetra®) [19]. (Fluenz Tetra™) was administered by nurses, health care assistants, medical specialists and resident physicians in various vaccination centres in Milan.

The primary outcome of the study was to assess the number of adverse reactions, their severity, and the possible presence of factors influencing them. Demographic data of vaccinated children and their families were collected in order to evaluate uniformity of access to care. Finally, the degree of satisfaction with the vaccination and the intention to repeat it in the following year for both parents and health care providers was measured, with the aim of identifying factors that could help planning the 2021–22 vaccination campaign.

This survey confirms the safety of qLAIV (Fluenz Tetra™) administered to children and adolescents aged 2 to 17 years, considering both the type and the severity of the adverse events observed [15].

In fact in our study rhinitis was the most common side effect, followed by fever and malaise; on the other hand, in contrast to reports in other similar studies [15, 20], in our population cough and respiratory distress were not relevant. No immediate adverse reactions were documented.

As reported in literature [15], in the week following vaccination, most of the side effects we observed proved to be mild to moderate in severity. Moreover, the small number of subjects enrolled in our study that experienced significant adverse events didn’t require hospitalization and none reported delayed adverse reactions.

As we expected, children aged 2–5 years, being closer to the (Fluenz Tetra™) utilization age limit, had the majority of adverse events, whereas the risk of developing side effects decreased nearly two-fold in children aged 6–11+ years and adolescents. These data show intranasal qLAIV is particularly well tolerated by the latter.

Our study also showed that besides preschoolers, those with chronic diseases excluding allergies, and those who had at least one acute infectious disease in the previous year, experienced a significantly higher risk of developing side effects. On the other hand prematurity was not associated with a higher frequency of side effects.

We were pleased to observe that allergies, which represent the most common chronic disease in childhood, did not increase the risk of adverse events. To be noted that children with severe asthma or anaphylaxis to egg proteins did not receive qLAIV, according to AIFA’s indication and (Fluenz Tetra™) leaflet [21].

We also collected interesting information from the questionnaires that lead to important considerations that will help program the vaccination campaigns in Italy in the years to come.

For instance, while the proportion of foreign parents was in line with the foreign population in Milan (11.9% vs 14.1%) [22], other factors were peculiar to our study population. In particular we had a very high proportion of parents with university degrees compared to the Italian population (69.6% vs 28%) [23]; we had a high percentage of parents who were vaccinated themselves (26.2% compared to 2.2% of all subjects aged 18–44 in the Lombardy region in 2019–20) [18]; and finally a very high proportion of children that had attended day care before the age of three (90% in our study compared to 30% of children in the North of Italy, with a peak of 47% in children of parents with higher education) [24].

These data lead us to believe that the 2020–21 influenza vaccination campaign failed to reach all sections of the population, and that those with a higher education and with established knowledge regarding vaccination were favoured.

Parents interviewed affirmed that they learned about the vaccination campaign through word of mouth, consisting of informal social media communications among parents of the same school group. The school therefore played an important role, not so much as an institution, as through its social role. Interestingly, the school has been mentioned in several studies as a possible place to check the immunization status and promote educational programmes for families [25].

Although in several studies health professionals are considered the most important source of information for parents, influencing the decision to vaccinate their children or not [26, 27], only 30% of the parents interviewed declared that they had heard about the vaccination campaign through their doctor, but this percentage increases to 50% if we consider parents of children with chronic diseases. In the latter, the role of the physician was decisive in the parents’ choice to have their children vaccinated against influenza.

Despite the ongoing Covid19 pandemic, most parents chose to vaccinate their children “to protect them”, indicating that they had grasped the real indication for flu vaccination and wanted to take advantage of the opportunity offered, this year for the first time, to vaccinate healthy children and young people free of charge with an easy-to-administer vaccine. The decision to vaccinate for this particular reason, as well as the decision by parents to undergo flu vaccination themselves, is associated with a stronger desire to repeat the vaccination next year, as reported in literature [28].

Instead, having their children vaccinated because “they were concerned about Covid19”, which was the second most frequent reason given by parents, makes families hesitant about reconfirming the vaccination next year.

Adverse reactions, however, were the main factor influencing parents’ decision not to repeat the vaccine.

(Fluenz Tetra™) proved to be non-invasive, easy and practical to administer even for inexperienced operators, such as most of those who took part in this flu campaign. This entailed that the degree of satisfaction was high among both health workers and parents, with the former mostly willing to repeat the experience in future years, and the latter mostly intending to have their children vaccinated again.

The study conducted leads us to conclude that the substantial safety of the vaccine, especially in school-age children and adolescents, the ease of administration and the high level of acceptance by families make the nasal qLAIV suitable for widespread vaccination of these subjects.

We therefore believe that it is important to inform and involve families extensively, especially through the school setting, and that it is desirable for physicians to be actively involved in the vaccination education of their patients.