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Vaccine 36 (2018) 5391–5396

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Vaccine

journal homepage: www.elsevier.com/locate/vaccine

Influenza vaccine use to protect healthy children: A debated topic

http://dx.doi.org/10.1016/j.vaccine.2017.09.016 0264-410X/� 2017 Elsevier Ltd. All rights reserved.

⇑ Corresponding author at: Pediatric Clinic, Department of Surgical and Biomed- ical Sciences, Università degli Studi di Perugia, Piazza Menghini 1, 06129 Perugia, Italy.

E-mail address: [email protected] (S. Esposito).

Nicola Principi a, Susanna Esposito b,⇑ a Pediatric Highly Intensive Care Unit, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy b Pediatric Clinic, Department of Surgical and Biological Sciences, Università degli Studi di Perugia, Perugia, Italy

a r t i c l e i n f o a b s t r a c t

Article history: Available online 18 September 2017

Keywords: Children Influenza Influenza vaccine Maternal immunization Pregnancy

At the beginning of this century, a number of studies suggested that in healthy children, particularly those <2 years of age, influenza could have a serious and complicated course, as it frequently led to hos- pitalization and sometimes, albeit rarely, to death. Moreover, pre-schoolers and school-age children were found to be among the most important causes of influenza transmission to the community, as they shed the virus for a longer time than adults and had frequent contact with greater numbers of individuals through day-care and school. These findings led a number of health authorities to modify the official rec- ommendations regarding the use of influenza vaccine in healthy children. Several factors seem to indicate that vaccination against influenza in healthy children of any age and in pregnant women could be effec- tive in preventing the disease in the entire paediatric population and in providing herd immunity in adults and old people as well. The direct advantages of the vaccine seem greater in younger subjects, par- ticularly those <2–3 years of age. Vaccination of older children is considered effective by most experts, but high vaccination coverage of these subjects has been difficult to attain. Similar difficulties have been identified for the vaccination of pregnant women. These challenges can be overcome, at least in part, by appropriate information and accurate evaluations of available data. In addition, further studies specifi- cally designed to clarify unresolved problems regarding vaccine use in paediatric and pregnant popula- tions are needed to convince reluctant health authorities. More effective vaccines for younger children as well as improved availability of data regarding the optimal time period for vaccine administration in pregnant women appear relevant in this regard.

� 2017 Elsevier Ltd. All rights reserved.

1. Introduction

Influenza is a common disease that affects a substantial number of individuals of all ages every winter. Annual influenza epidemics cause relevant medical, social and economic problems [1–3], which is why prevention of the infection through the influenza vaccine has been recommended by health authorities worldwide for sev- eral decades [4–6]. For years, influenza vaccination policies have prioritized the elderly because of the greater number of severe and complicated cases frequently leading to death that occur in this population [7,8]. Children were not included in the list of groups for whom influenza vaccine was recommended unless they suffered from a severe chronic underlying disease that predisposed them to developing influenza-related complications [6–8].

At the beginning of this century, a number of studies suggested that influenza could have a serious and complicated course even in healthy children, particularly those <2 years of age, frequently leading to hospitalization and sometimes, albeit rarely, to death [9,10]. Moreover, pre-schoolers and school-age children were found to be among the most important causes of influenza trans- mission to the community, as they shed the virus for a longer time than adults [11,12] and had frequent contact with greater numbers of individuals at day-care and school [13]. These findings have led a number of health authorities to modify the official recommenda- tions regarding the use of influenza vaccine in healthy children. In some cases, as in the USA, the age limit for vaccination of healthy children initially included only younger subjects and was progressively increased to presently include all subjects between 6 months and 17 years of age [4]. In other countries, only infants and pre-school children were considered for vaccination. However, in most countries, the suggestions arising from epidemiological studies have gone unheeded and healthy children have not been included in the list of subjects for whom influenza vaccination is strongly recommended. A good example of this situation is evident

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in the results of a survey regarding the 2014–2015 influenza sea- son conducted by the European Centre for Disease Prevention and Control; in that study, a questionnaire was sent to health authorities of Member States of the European Union and the Euro- pean Economic area (EEA) [14]. Of the 30 Member States that responded to the questionnaire, only Austria, Estonia and Poland recommended influenza vaccine for all paediatric population groups. Latvia and Slovenia recommended vaccination for children aged �6–24 months, whereas Finland, Malta, and Slovakia extended the vaccination period to healthy subjects aged �6– 36 months, �6–59 months, and �6 months–12 years, respectively. A unique situation was reported for the UK; England and Wales recommended the vaccine for children aged �2–4 years and to those 11 years old in Wales only, whereas Northern Ireland and Scotland extended the recommendation to all children �2– 11 years old. In all the other 21 countries of the EU and EEA, influ- enza vaccination of healthy children was not considered a priority.

Differences were also observed in methods for protecting chil- dren <6 months old from influenza for whom an appropriate vac- cine was not licensed. In this case, based on some studies, vaccination of pregnant women was considered a possible solution [15]. However, Bulgaria, Malta and Slovakia did not recommend vaccination for pregnant women, and Croatia and the Netherlands recommended the vaccine only for pregnant women with chronic medical conditions; all other countries indicated that the influenza vaccine had to be administered to pregnant women, although with differences regarding the best period for administration during pregnancy.

In this study, an attempt to evaluate the pros and cons of influ- enza vaccination in otherwise healthy children on the basis of available literature and personal experience will be performed.

2. Vaccination of healthy younger children

Health authorities that recommend influenza vaccination for younger children, although with differences in the defined age limit, have attached great importance to studies showing that influenza is extremely common among children in their first years of life; that it causes a significant increase in the number of medical visits, drug prescriptions, and hospital admissions for respiratory diseases; and that it can lead, although rarely, to death [4– 6,9,10]. Further support for the implementation of vaccination pro- grammes in younger children was provided by the finding that, with few exceptions, studies evaluating the influenza vaccine in clinical practice showed that the administration of both inacti- vated (IIV) and live attenuated (LAIV) vaccines in healthy children was effective in reducing the total burden of influenza, including preventing severe cases (i.e., those requiring admission to the intensive care unit), with an acceptable level of safety and tolera- bility in all cases [16–31]. Moreover, both IIV and LAIV were found to be significantly cost-saving or cost-effective, particularly when both direct and indirect costs due to productivity losses, especially in parents, were considered [32–40].

Many aspects of paediatric influenza that have led health authorities to plan influenza vaccination programmes for younger children have been supported by reliable data from well conducted studies. Approximately 15 years ago, studies found that the hospi- talization rates and antibiotic consumption of younger healthy children significantly increased during periods when the circula- tion of influenza virus predominated over those of other respira- tory viruses [9,10]. In particular, Neuzil et al. reported that in the USA, the number of hospitalizations in excess of the expected num- ber per 10,000 children per year totalled 104, 50, and 19 for sub- jects aged <6 months, 6–12 months, and 13–35 months, respectively [9]. Moreover, an estimated annual average of 6–15

outpatient visits and 3–9 antibiotic courses for every 100 children were ascribable to influenza, with a 10–39% increase in the pre- scription of these drugs in comparison to periods with poor influ- enza virus circulation [9]. Similar data were collected by Izurieta et al., who found that the hospitalization rates among healthy chil- dren <2 years old were approximately 12 times higher than those of healthy school-age children and quite similar to those of chil- dren with chronic health conditions who were 5–17 years old [10].

Recently, more precise estimates of the total burden of influ- enza in healthy children were obtained using laboratory confirmed diagnoses. These figures showed that in full-term infants aged 1 year or younger, the annual incidence of symptomatic seasonal influenza could be significantly higher than 50 per 1000 children [41]. Moreover, it was shown that seasonal influenza plays a rele- vant role in the occurrence of lower respiratory tract infections requiring medical assistance among children �36 months of age, with an annual incidence of 1.1 per 100 children-years [42]. Similar data were reported when the impact of the 2009 pandemic on younger children was evaluated. A series of studies showed that infants and toddlers had either the highest risk of hospitalization or the highest proportion of severe respiratory cases ascribed to influenza [43–53]. Finally, several reports indicate that children with influenza can die [54–56]. For example, data collected in the USA for the four influenza seasons between 2012–2013 to 2015–2016 [56] indicate that during this period, a total of 517 influenza-associated paediatric deaths were reported to the Cen- ters for Disease Control and Prevention (CDC), and of them, only approximately half occurred in at-risk children, thereby highlight- ing the risk of healthy subjects [56]. To support the relevance of influenza in healthy younger children, supporters of vaccination have highlighted that it is highly likely that the official data regard- ing the number of medical visits, drug prescriptions, hospitaliza- tion rates and deaths due to influenza underestimate the true importance of the disease. In clinical practice, laboratory tests for detecting influenza virus are not commonly performed. Moreover, even when they are conducted, many cases of patients actually infected by the influenza virus will test negative because the virus is no longer present in the respiratory secretions at the time they were collected. Finally, influenza as a cause of death is very rarely reported. This could explain why, in contrast to what was found in the USA [54], death due to influenza was never or only rarely reported in Europe during both pandemics and seasonal epidemics, even in children aged 0–4 years [57–61].

Some of the conclusions of the studies cited above have been criticized by experts, and these criticisms convinced some health authorities around the world to not recommend the influenza vac- cine for younger children. The most relevant observations were raised in response to data regarding the true efficacy and effective- ness of the influenza vaccine in younger patients. As reported in a meta-analysis [62], the general methodological quality of a great number of studies that positively evaluated the impact of influenza vaccines in children was considered very poor. Moreover, even when studies with the lowest risk of bias such as randomized con- trolled studies, cohort studies and case-control studies were con- sidered, a certain degree of efficacy and effectiveness could be demonstrated only for children �2 years of age, in whom the effi- cacy and effectiveness reached 80% and 33% for LAIVs and 59% and 36% for IIVs, respectively [62]. In contrast, both vaccines were found to be inadequate in providing even minimal protection to children <2 years old: LAIVs because they were not licensed for children in that age range, and IIVs because their efficacy and effec- tiveness did not differ from that of placebo. Further doubts regard- ing the use of influenza vaccines in younger children were raised when their efficacy and effectiveness were found to significantly vary from year to year and, in some years, to be even lower than that reported in the meta-analysis by Jefferson et al., even among

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children >2 years [62]. The dependence of the efficacy and effec- tiveness on the degree of matching between the pre-determined influenza strains in the vaccine and the circulating vaccine types is only one of the factors that can affect vaccine activity. Occasion- ally, undefined reasons can significantly reduce the impact of influ- enza vaccines, as recently evidenced in the USA. In this country, for three consecutive influenza seasons from 2013–2014, LAIVs were found to be ineffective, which led the USA Advisory Committee for Immunization Practices (ACIP) to recommend not using this vaccine [63]. Moreover, criticisms of studies on the cost-savings and cost-efficacy of influenza vaccination for younger children have been raised. Some studies have found that influenza vaccines are cost-saving only under certain conditions [64–66] or that they have no economic advantages at all [67,68]. Finally, safety has been considered a possible reason for debating influenza vaccination of younger children. Generally, IIVs are considered safe and well tol- erated. However, the possible association between the emergence of an autoimmune/inflammatory syndrome and the administration of influenza vaccines containing adjuvants such as squalene and aluminium hydroxide has been mentioned by some opponents to vaccinations as a possible reason for refusing to administer the influenza vaccine [69]. The potential development of narcolepsy, observed during an influenza pandemic after the administration of adjuvanted IIVs, was also a negative factor considered [70].

Most of these criticisms can be rejected in light of the most recent studies and of objective assessments of the available data. Some recent studies not included in the meta-analysis of Jefferson et al. that were conducted with appropriate methods seem to indi- cate that IIVs can have a satisfactory efficacy and effectiveness in younger children [71–74]. A good example of these results can be observed from data collected in several studies [72,73]. In the first study, authors conducted an observational evaluation of chil- dren presenting to a paediatric hospital with influenza-like illness from 2008–2012 [72]. Vaccination status was confirmed via the national immunization register and/or vaccine providers, and a test-negative design was used to estimate vaccine effectiveness. The global vaccine effectiveness was 64.7% (95% confidence inter- val [CI]: 33.7–81.2%), and the vaccine efficacy for children <2 years was 85.8% (95% CI: 37.9–96.7%). In the second study, which was performed with the same methods, the effectiveness of IIVs in reducing the risk of severe disease in children aged 6–59 months with or without risk factors was evaluated [72]. The authors found that in both groups of children, vaccine effectiveness was �70%. Moreover, most experts considered the safety concerns regarding aluminium hydroxide a non-scientific way of undermining vacci- nation programmes, as they introduced a theoretical risk that was almost impossible to prove. Finally, narcolepsy was demon- strated to occur in subjects with a highly susceptible genetic pre- disposition (HLA-DBQ-1⁄602) who received one of the vaccines specifically produced for the recent 2009 pandemic, which con- tained high quantities of the strongly immunogenic polymerized form of influenza nucleoprotein antigen NP (Pandemrix containing the adjuvant ASO3) [75]. Consequently, narcolepsy could not be considered a risk for subjects not using that vaccine. Based on these findings, most paediatricians and infectious disease special- ists have supported the vaccination of younger children, at least those between 6 and 24 months of age [76].

3. Universal vaccination in paediatric populations

Some health authorities not only recommend influenza vaccina- tion for healthy younger children based on the previously cited reasons but also extend vaccine administration to the entire paedi- atric population, regardless of age. Vaccination of school-age chil- dren should reduce the incidence of infection in these subjects,

thus limiting their disease-related problems, including school absenteeism [4–6]. Moreover, vaccination should limit the diffu- sion of viruses into the community, thereby reducing the risk of influenza for the most vulnerable individuals, mainly the elderly [4–6]. Finally, universal vaccination of children could increase influenza vaccination coverage of at-risk subjects who, despite being included worldwide among the individuals for whom influ- enza vaccine is strongly recommended, remain frequently unvacci- nated [77,78].

The direct and indirect effects of school-based influenza vacci- nation have been demonstrated by several studies. Vaccination of school-aged children has repeatedly been reported to be effective in reducing the number of class cancellation days and absenteeism in school [79–81]. Moreover, for every 20% increase in the vaccina- tion rate of elementary school-aged children, a 4% decrease in absenteeism rates was calculated to occur during influenza out- break periods, including in upper class unvaccinated children [82].

Regarding the general population, it was demonstrated in 1969 that the incidence of influenza-like illness in the general popula- tion was significantly lower in areas where most of the children had received influenza vaccine than in areas without a paediatric influenza vaccination programme [83]. Some years later, it was reported that the implementation of a universal vaccination pro- gramme for children was associated with a significant reduction in the number of all-cause deaths and deaths attributed to pneu- monia or influenza, particularly in the elderly [84]. Moreover, the opposite trends occurred when the programme was suspended [84]. In recent years, mathematical models and field research have confirmed the importance of influenza vaccination in older chil- dren to ensure optimal influenza control in the entire population. When large school-based influenza vaccination campaigns were implemented, a significant reduction in the community risk of influenza- and influenza-like illness-associated emergency care visits was observed [85–95]. Interestingly, the impact of school- based vaccination strategies is considered potentially higher than that of strategies targeting people aged �65 years [96]. This belief emerged because in the USA, despite a rise in elderly vaccination rates from 15% to 65% between 1985 and 2000, elderly influenza mortality rates remained largely unaffected [97]. Moreover, both IIV and LAIV administration in older children has been demon- strated to be cost-saving and cost-effective [36].

Regarding the vaccination of younger children, some of the find- ings used to support vaccination of school-aged children have been debated, leading to declines in immunization. First, it was stated that the direct advantages of vaccinations in these subjects could be marginal or too complicated to be attained. It was emphasized that the flu is generally mild in older healthy children, and thus prevention cannot be considered a priority for subjects in this age group in the absence of risk factors. Second, vaccine efficacy and effectiveness, despite being better than in younger patients, were considered inadequate to justify universal vaccination [62]. Third, reaching high vaccination coverage in older children, partic- ularly adolescents, can be very difficult because they have low uti- lization of primary and preventive care. Higher levels of coverage can be obtained by immunizing children at school [98]. However, this strategy also seems to be problematic. A study conducted by Lind et al. found that by implementing a school-based programme, older children might be less likely to attend school and be immu- nized; parents can perceive a loss of parental control over informa- tion, choices and decisions; and teachers can complain about a loss of instructional time [99]. Finally, studies that found that signifi- cant advantages could be obtained from the use of influenza vac- cine in older children may have been overly optimistic. The calculations were frequently found to be based on high influenza attack rates, low estimates of vaccine costs or both, thereby limit- ing the use of the final results in policy decisions [98,100].

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However, vaccine administration in younger children and in school-aged subjects seems to be a reliable measure for reducing the total burden of influenza in all vaccinated and unvaccinated subjects. Most likely, more efforts have to be made to implement school-based vaccination programmes and to overcome the limita- tions of the possible poor adherence among children, parents and teachers to experts’ recommendations.

4. Protection of infants with maternal immunization

Vaccination of pregnant women has been recommended by many health authorities worldwide for several years because influ- enza can be more severe in these subjects than in the general pop- ulation [101–106]. Moreover, the fact that influenza can be a severe disease in infants and that currently available vaccines are not licensed for use in the first six months of life have further high- lighted the importance of administering influenza vaccines during pregnancy [1–5]. IIVs, which are the only vaccines that can be given to pregnant women because LAIVs are based on live viruses, have been demonstrated to be immunogenic and safe for both the mother and the conceptus [107–110]. Antibodies produced by the mother actively cross the placenta and protect the foetus and infant from influenza for at least the first weeks of life, as demon- strated by some well conducted studies. In studies that confirmed influenza infection with rapid tests or molecular methods, a vac- cine effectiveness of approximately 50% was shown [111–116].

Despite these findings, maternal immunization coverage against influenza has remained significantly lower than desired, even in countries where health authorities have recommended influenza vaccine for pregnant women for several years. Several factors might explain this situation, including misperceptions and lack of awareness regarding the efficacy and safety of influenza vaccine among health care providers and the poor definition of the strategy used to obtain the longest protection of the infant. Moreover, information on the use of influenza vaccines during pregnancy, including package inserts, labels and leaflets, patient information labelling, product descriptions and summaries of patient characteristics, frequently limit or even contraindicate the administration of this preventive measure in pregnant women despite its approval by regulators [117–120].

Several attempts have been made to overcome these barriers and increase the influenza vaccination coverage in pregnant women. Provider-focused and pregnant women-focused interven- tions have been conducted, but in most cases, the results have been disappointing; however, when health authorities have strongly supported the information and recommendations, a slight but steady increase in vaccination coverage of pregnant women has been shown.

5. Conclusions

Several factors seem to indicate that vaccination against influ- enza of healthy children of any age and of pregnant women can be effective in preventing the disease in the entire paediatric pop- ulation and in providing herd immunity in adults and old people. The direct advantages seem greater in younger subjects, particu- larly those <2–3 years of age, and this explains why most countries that recommend influenza vaccination in healthy children limit vaccine administration to younger subjects. Vaccination of older children is considered effective by most experts, but high vaccina- tion coverage of these subjects has been difficult to attain. Similar difficulties have been found for vaccination of pregnant women. The belief that influenza is a disease with little clinical relevance, especially in older children, that influenza vaccines have poor effi- cacy and effectiveness, and that they can be associated with the

development of adverse events are the most common reasons pre- cluding the use of influenza vaccine in healthy children and preg- nant women. All these limitations can be overcome, at least in part, by appropriate information and accurate evaluations of the avail- able data. In addition, further studies specifically designed to clar- ify unresolved problems regarding vaccine use in paediatric and pregnant populations are needed to convince reluctant health authorities. More effective vaccines for younger children as well as improved availability of data regarding the optimal time period for vaccine administration in pregnant women appear relevant in this regard.

Acknowledgments

This review was supported in part by the IMI grant Flucop.

Conflict of interest

The authors declare that there are no conflicts of interest.

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