Protection of children against influenza: Emerging problems

ABSTRACT

Influenza is a common disease and in children it can be severe enough to lead to hospitalization and death. Protection of all children against influenza, particularly the youngest, is strongly recommended by most health authorities. However, available vaccines cannot be used in the first 6 months of age, a period of life characterized by the highest risk of influenza-related complications. Maternal immunization is an attractive possibility to overcome this problem. For years, protection against influenza has been pursued by administering the trivalent inactivated vaccine given intramuscularly (IIV3). More recently, a trivalent live attenuated influenza vaccine (LAIV3) administered intranasally was licensed and adopted in a number of countries as an alternative to IIV3. In recent years, to increase protection and include a second B strain, quadrivalent inactivated (IIV4) and live attenuated vaccines (LAIV4) were prepared and licensed. However, during the 2015–2016 season the effectiveness of LAIVs was debated, and they were withdrawn from the list of recommended influenza vaccines in the USA. This review presents an update on the evidence related to the protection of infants against influenza through maternal immunization and the effectiveness of LAIV. Available data indicates that despite maternal immunization, a number of children have no protective antibody levels at birth, and in the majority of children with antibody protection, it is limited to the first 8 weeks of the postnatal period. Moreover, data on LAIV effectiveness in the pediatric population must be clarified because this vaccine can significantly improve vaccination coverage in children.

KEYWORDS:

• influenza vaccination
• influenza
• LAIV
• live attenuated influenza vaccine
• maternal immunization

Introduction

Influenza is a common disease. Up to 30% of children, with the highest prevalence among the youngest, are infected by influenza viruses every winter season.¹ Most of the disease cases are mild and spontaneously resolve; however, influenza in children can be severe enough to lead to hospitalization and death.² Lafond et al. estimated that worldwide, influenza is the cause of approximately 374,000 hospitalizations in children <1 year of age (of which 228,000 occur in children <6 months of age) and 870,000 hospitalizations in children <5 years of age annually.^3,4 In the last four influenza seasons in the USA, a total of 515 influenza-associated pediatric deaths have occurred.⁵ However, it is highly likely that the true impact of influenza infection in pediatrics is significantly higher than what is reported in epidemiological studies and official statistics. This is because a great number of patients who are hospitalized and die from severe respiratory problems because of influenza infection are not tested for influenza viruses. Moreover, influenza infection is often not reported as the contributory cause of hospitalization or death when the main signs and symptoms of disease are strictly related to the worsening of an existing chronic underlying illness.⁶

For many years, it was thought that severe influenza cases were only common in children at high risk of influenza-related complications because of a chronic, severe, underlying disease.⁷ Consequently, the prevention of influenza through the use of available influenza vaccines was only recommended to these individuals. However, in recent years, several studies have shown that severe cases can occur in otherwise healthy children. In a study in the USA examining influenza seasons from October 2004 to September 2012, 830 pediatric influenza-associated deaths were reported, and 43% of the children who died had no high-risk medical conditions.⁸ This explains why some countries currently recommend universal influenza vaccinations in children. Because the highest risk of hospitalization and death in otherwise healthy children occurs in the first years of life, a number of countries limit vaccination recommendations to infants, toddlers and preschool children.⁹ In other cases, such as in the USA, influenza vaccine administration is recommended in all pediatric populations from 6 months to 17 years and also in adults of any age.¹⁰

For years, protection against influenza has been pursued by administering the trivalent inactivated vaccine given intramuscularly (IIV3).¹¹ More recently, a trivalent live attenuated influenza vaccine (LAIV3) administered intranasally was licensed and adopted in a number of countries as an alternative to IIV3.¹² In recent years, to increase protection and include a second B strain, quadrivalent inactivated (IIV4) and live attenuated vaccines (LAIV4) were prepared and licensed.¹³ However, because these preparations cannot be used in younger infants, different immunization methods to protect these subjects have been pursued. Maternal immunization is one of these methods, although presently it is not adequately used.^14,15 Moreover, during the last season the effectiveness of LAIV in the USA was debated, and the live vaccine was withdrawn from the list of recommended influenza vaccines in this country. This review presents an update on the evidence related to the protection of infants against influenza through maternal immunization and the effectiveness of LAIV.

Search strategy and selection criteria

References for this review were identified through two searches. In the first search, PubMed was used for articles published from January 2000 to September 2016 with the terms “influenza vaccine” or “influenza vaccination” and “pregnancy” or “maternal” and “infant” or “neonate.” In the second search, PubMed was used for articles published from January 2000 to September 2016 with the terms “live attenuated influenza vaccine” or “LAIV” and “effectiveness” or “efficacy” and “children” or “child” or “pediatric.” Relevant articles published before 2000 were identified through searches in Google Scholar and Springer Online Archives Collection. Only articles published in English were included.

Protection of the infant through maternal immunization

Children in the first months of life are at increased risk of severe influenza but cannot be protected by available influenza vaccines because these preparations are not licensed for use in children < 6 months of age. In infants, the immunogenicity of the available preparations is generally poor, and the safety and clinical efficacy of IIV3 and IIV4 have not been precisely defined.¹⁶ Moreover, LAIV3 and LAIV4 are not licensed for children < 2 years of age for safety reasons.¹² To overcome these problems and to assure protection against influenza to younger infants, several attempts have been made (Table 1). The use of adjuvant vaccines, intradermal injections and the administration of an increased dose of antigens have been evaluated in controlled clinical trials with good results.¹⁷ However, none of these measures has been definitively accepted by health authorities nor have they been approved for use in current clinical practice. In contrast, a potential preventive measure that has aroused much interest and has been adopted in a number of countries for infant protection is maternal immunization.

Table 1. Attempts to increase the efficacy of the influenza vaccine in infants.

Attempts
Use of adjuvant influenza vaccines
Intradermal injection of influenza vaccine
Administration of an increased dose of antigens

Although LAIV is not recommended for pregnant women because it is based on live viruses, the administration of IIV to pregnant women has long been recommended by many health authorities. Influenza can be more severe during pregnancy than in the general population, and IIV can evoke a significant immune response leading to protection against infection and disease in a large number of pregnant women.^18-24 Moreover, no contraindication to influenza vaccine administration exists; IIV is well tolerated and safe, it does not cause any relevant adverse effects in the mother, and it does not appear to interfere with the normal development of the fetus.^25-28

Evidence that the serum IgG antibodies of pregnant woman actively cross the placenta and reach the fetus²⁹ and that additional IgA antibodies are transferred via breast milk¹⁹ has further increased interest in maternal vaccination. A single administration is presumed to protect both the mother during pregnancy and the conceptus during foetal life and the first period of extra-uterine life. The administration of IIV to pregnant women is presently strongly recommended by the World Health Organization³⁰ and several health authorities worldwide for the protection of mothers and infants against influenza-related complications.^31-33

The relevance of maternal immunization for infant protection against influenza is evidenced by a number of studies, which reported that children born to mothers who had received IIV during pregnancy had significantly higher levels of antibodies against the vaccinated influenza viruses and a reduced risk of influenza infection and influenza-related hospitalization compared to children from unimmunized controls. Both the seasonal IIV3 and the monovalent influenza vaccine specifically prepared for the recent A/H1N12009 pandemic were found to be effective.^{19-23,29,34-37} However, the effectiveness of IIVs in infant protection was not precisely defined because the results of the various studies varied significantly, primarily because of the different methods used to evaluate the impact of vaccine administration. In several cases, only the incidence of influenza-like illness in vaccinated and in untreated populations was compared. In other studies, the surveillance of influenza infection was laboratory-confirmed with rapid tests or with molecular methods.³⁸

Despite the evidence that maternal immunization can protect the mother/child dyad, influenza vaccination coverage among pregnant women has remained significantly lower than desired in all the regions examined. In the USA, coverage for the 2015–2016 season was approximately 50%, and no increase has been reported since the 2012–2013 season.¹⁴ In Europe, where influenza vaccination coverage for pregnant women for the 2012–2013 season was reported by only seven member states (United Kingdom [England, Wales, Scotland, Northern Ireland], Germany, Ireland, Romania, Hungary, Slovenia, and Lithuania), influenza vaccination coverage ranged from 0.2% to 64.6%, with a median value of 25.5%. The highest coverage rates were reported by the United Kingdom and varied from 40.3% in England to 64.6% in Northern Ireland,¹⁵ although coverage rates did not significantly increase with time.³⁹

Several factors may explain the poor compliance with official recommendations (Table 2). Health care providers can influence the use in pregnant women who are cautious about vaccinations because they are assuming responsibility for their fetus.^40,41 Moreover, misperceptions and lack of awareness regarding influenza vaccine efficacy and safety have been identified as barriers to vaccination among health care providers.⁴² It has been shown than more than one third of obstetrician-gynaecologists do not offer the vaccine in their practice.⁴³ Many obstetricians may not be completely convinced of the efficacy of the influenza vaccine owing to a series of problems strictly related to the influenza vaccine itself, such as the best timing of immunization, the real efficacy of IIV and the duration of protection, which have not been completely solved. Regarding the best time of immunization, it is obvious that if the main aim is to protect the mother, vaccine has to be administered in the first period of pregnancy, whereas protection of concept can be better achieved if immunization occurs later, when antibodies can cross the placenta. Serum antibody concentrations in the neonate at birth are proportional to the serum level of the mother at the end of pregnancy, and these levels strictly depend on the moment of maternal immunization. Vaccine administration too close to conception or delivery is probably poorly effective in conditioning protective levels in the child. Vaccine administration between the 32^nd and 36^th week has been suggested to be the optimal time period, but the problem has not been extensively studied and remains unsolved.²⁰ The need to reconcile opposing demands may explain why, with few exceptions,⁴⁴ in most of the official recommendations maternal immunization is suggested during pregnancy without any further detail. Regarding duration of protection, available data indicate that the prevalence of children born to vaccinated mothers protected from influenza is temporally limited, in accordance with the decline of serum influenza antibody concentrations. The proportion of neonates with protective (≥1:40) concentrations of haemagglutinin antibodies has been reported to be less than 80% for the A/H1N1 2009 and B/Victoria strains and less than 60% for the A/H3N2 strain.⁴⁵ Further controls have shown that the percentage of infants with protective antibody titres against all of the vaccine strains decreased from more than 56% in the first week of life to less than 40% at 16 weeks of age and less than 10.0% at 24 weeks of age.⁴⁵ As a consequence, the efficacy of IIV against laboratory-confirmed influenza illness was 85.6% (95% CI: 38.3%-98.4%) among infants 8 weeks of age or younger and decreased to 25.5% (95% CI: −67.9% to 67.8%) among infants 8 to 16 weeks of age and to 30.3% (95% CI: −154.9% to 82.6%) among infants 16 to 24 weeks of age. These findings suggest that to increase the influenza vaccination coverage and convince reluctant obstetricians, a more precise definition of the best timing for maternal immunization and a better understanding of transplacental antibody kinetics during pregnancy are needed. Moreover, the availability of more immunogenic vaccines could significantly improve physician compliance with official recommendations.⁴⁶

Table 2. Explanations for poor compliance with official recommendations for maternal immunization against influenza.

People	Reason
Pregnant women	Fear for their fetus
Health care providers	Misperceptions and lack of awareness regarding influenza vaccine efficacy and safety
	Doubts regarding the best timing of immunization and duration of protection
Everybody	Product information that limits or even contraindicates the use of influenza vaccines during pregnancy

In addition to these problems, other barriers to maternal immunization to protect the child exist. Product information for several vaccines limits or even contraindicates the use of influenza vaccines in pregnant women. Proveaux et al. studied vaccination information available online, provided by the manufacturer and approved by the regulator regarding the use of influenza vaccines, including package inserts, package labels, package leaflets, patient information labels, product descriptions and summaries of patient characteristics.⁴⁷ A total of 96 vaccines on the market were evaluated. Only 10 of the vaccines had product information that suggested use during pregnancy, and among these, there was a wide variety of information regarding safety data and at what stage of pregnancy administration was preferred. The majority of leaflets contained precautionary language that could discourage use in pregnant or lactating women, and several included contradicting use information. Product information from 4 vaccines indicated that the influenza vaccine should not be used in pregnant women.

To overcome barriers and to increase influenza vaccination coverage in pregnant women, several attempts have been made. Provider-focused interventions and pregnant woman-focused interventions were carried out (Table 3). In the first case, common strategies included notifying providers about the influenza vaccination status of pregnant women, establishing standing orders authorizing nursing staff to administer the vaccine without a medical consultation, giving provider feedback by reporting the influenza vaccination rates of other institutions, and providing education to improve the knowledge and attitudes of healthcare workers toward influenza vaccination in pregnancy. In pregnant woman-focused interventions, the main intent was to disseminate education and the promotion of materials that target pregnant women by mass media campaigns via the Internet, posters and leaflets, lectures and workshops, and personalized reminders and recall systems. A good example of an intervention that targeted both physicians and pregnant women is given by the toolkit distributed by the American College of Obstetricians and Gynecologists.⁴⁸ The toolkit includes materials to help physicians and their staff communicate with patients regarding the importance of receiving the recommended immunizations and how to successfully incorporate immunizations into routine care. A recent systematic analysis of the effectiveness of these interventions reported discordant results, with risk differences (RDs) ranging from −0.15 to 0.03, although in most cases significant increases were observed in influenza vaccine uptake in pregnant women after the interventions.⁴⁹ Unfortunately, most of the studies with favorable results had significant methodologic limitations because they were non-randomized and frequently included a very low number of subjects. Consequently, it was not possible to define the best strategy to significantly improve coverage. However, one randomized controlled trial of moderate quality showed that providing an influenza pamphlet, with or without a verbalized benefit statement, improved the vaccination rate. Based on this finding, the authors recommended that clinicians must provide influenza pamphlets to pregnant women with a verbalized statement about the benefits of influenza vaccines to children.⁴⁹ However, further high-quality studies are needed to plan adequate and effective interventions to increase vaccination coverage among women.

Table 3. Interventions to improve maternal immunization coverage against influenza.

Target	Intervention
Provider-focused	Notifying providers about the influenza vaccination status of pregnant women
	Establishing standing orders authorizing nursing staff to administer the vaccine without a medical consultation
	Giving provider feedback by reporting influenza vaccination rates of other institutions
	Providing education to improve the knowledge and attitudes of healthcare workers toward influenza vaccination in pregnancy
Pregnant women-focused	Disseminating education and promoting mass media campaigns
	Educational activities on the Internet
	Preparation of posters and leaflets
	Lectures and workshops
	Personalized reminders and recall systems

Live attenuated influenza vaccine (LAIV) effectiveness

LAIV is a live attenuated influenza vaccine for administration by intranasal spray authorized for use in people 2–59 years of age (Table 4). The influenza strains used in LAIV are attenuated, cold-adapted, and temperature-sensitive, so they replicate in the nasal mucosa rather than in the lower respiratory tract and do not cause influenza.¹² LAIV was found to be effective in influenza prevention in several controlled trials conducted in children before the A/H1N12009 pandemic. Compared with conventional IIV3, LAIV was found to be superior in most studies.^50-52 Superiority was more evident in children <6 years of age than in older children. Moreover, for children <6 years of age, the evidence for the superiority of LAIV was of higher quality. Based on these findings, the Advisory Committee on Immunization Practices (ACIP) of the USA included LAIV, initially as LAIV3 and later as LAIV4, on the list of influenza vaccines recommended for influenza prevention in children. Furthermore, in the USA in 2014, health authorities suggested the preferential use of LAIV, when immediately available, for healthy children 2–8 years old who did not have contraindications to the vaccine.^53-55 Several other countries have licensed LAIV for use in children.^53,54 In the UK, health authorities that had previously recommended IIV only for the prevention of influenza in at-risk children planned to initiate a universal childhood influenza vaccination program using LAIV because of its efficacy, safety and easy administration.⁵⁶ As expected, LAIV efficacy estimates carried out in the USA during the 3 influenza seasons from 2010–2011 to 2012–2013 evidenced that the vaccine provided statistically significant protection with a reduction of medically attended, laboratory-confirmed influenza illness.⁵⁷ Influenza occurrence, independent of the viral strain, was similar for participants vaccinated with LAIV or IIV. However, beginning in 2013–2014, a year in which the A/H1N1pdm09 strain predominated worldwide, contrasting results of LAIV effectiveness were reported. All three test-negative studies carried out in the 2013–2014 influenza season in the USA reported low to negative and statistically non-significant vaccine effectiveness estimates for LAIV against any influenza strain and against A/H1N1pdm09.^58,59 In particular, in the study by Caspard et al., in which a total of 1,033 children and adolescents were included, influenza was detected in 14% of all children, with 74% of the influenza cases due to A/H1N1pdm09 strains, 21% to influenza B, and 4% to influenza A/H3N2. LAIV did not show significant effectiveness against A/H1N1pdm09 (VE 13% [95% CI: −55 to 51]) but was effective against B/Yamagata strains (82% [95% CI: 12–96]).⁵⁹ In contrast, results from studies in children vaccinated with IIV revealed that vaccine effectiveness against A/H1N1pdm09 strains was 74% (95% CI: 50–86). Furthermore, effectiveness against B/Yamagata strains in children vaccinated with IIV was 70% (95% CI: 18–89). These results were surprising because in 2009–2010, when monovalent vaccines were administered during the A/H1N1pdm09 pandemic, the LAIV strain was shown to be effective in children 2–9 years of age, with a vaccine effectiveness of 82% (95% CI: 14–96) when cases that occurred within 7 days of vaccination were excluded, and 55% (95% CI: −270 to 95) when cases occurring within 14 days of vaccination were excluded.⁵⁹ However, 2013–2014 USA results varied from those of different geographic areas. Two studies conducted in Canada in 2013–2014 suggested that LAIV was effective, although estimates were based on small sample sizes with wide confidence intervals.^60,61 Furthermore, a study carried out in the UK revealed a lower, although not statistically significant, incidence of influenza illness in communities in which school-aged children were vaccinated with LAIV.⁶²

Table 4. Main characteristics of live attenuated influenza vaccines.

Characteristics
Attenuated, cold-adapted, and temperature-sensitive influenza strains
Replication of influenza strains in the nasal mucosa rather than in the lower respiratory tract without causing influenza
Intranasal administration
Availability of trivalent and quadrivalent formulations
Authorized for use in people 2–59 years of age
Superior efficacy in influenza prevention compared to inactivated influenza vaccine in several controlled trials conducted in children before the A/H1N12009 pandemic
Optimal efficacy observed in children <6 years of age
Safety problems because of wheezing-related risks in children <2 years of age

The 2014–2015 influenza season was not only dominated by A/H1N1pdm09 but also by antigenically drifted A/H3N2 viruses. The data collected in the USA and in the UK revealed that both LAIV and IIV were poorly effective against all strains of influenza and influenza due to the dominating virus. In the USA, it was reported that LAIV and IIV effectiveness against any influenza was 3% and 15%, respectively, whereas that against A/H3N2 was −5% for LAIV and 13% for IIV.⁵⁷ In the UK, LAIV effectiveness against A/H3N2 was 35% (95% CI: −29.9 to 67.5), whereas for influenza B it was 100% (95% CI: 17.0 to 100.0). IIV was less effective against both viral strains, although differences did not reach statistical significance.⁶³

Different and conflicting results of surveillance studies were also reported for the 2015–2016 influenza season, in which the A/H1N1pdm09 virus predominated. Moderate and statistically significant LAIV effectiveness against any influenza infection (46%–58%) was observed among children and adolescents 2–17 years of age in two American studies,⁶⁵ in the UK,⁶⁶ in Canada,⁶⁷ and in Finland.⁶⁸ Compared to IIV, LAIV was slightly less effective, but differences did not reach statistical significance. In contrast, in the same age group, the US Flu Vaccine Efficacy Network found very low, if any, LAIV effectiveness against any influenza (3%), with statistically significant differences compared to IIV, for which vaccine effectiveness was 63%.⁶⁹ Effectiveness against A/H1N1pdm09 was −15% for LAIV and 54% for IIV.

Data regarding LAIV effectiveness led to different conclusions by health authorities in different countries. In the USA, the authorities considered all of the data collected by the US Flu Vaccine Efficacy Network in the seasons 2013–2014, 2014–2015, and 2015–2016 and concluded that LAIV4 did not have any statistically significant benefit in preventing influenza (all 95% CIs spanned zero).⁷⁰ On the contrary, IIV was considered effective, although seasonal variations were observed. Children who received LAIV4 had a 2.5-fold greater chance of developing influenza, attributable to any virus, compared to children who received IIV. Consequently, during its June 2016 meeting, the American Advisory Committee on Immunization Practices (ACIP) recommended that LAIV should not be used during the 2016–2017 influenza season.⁷⁰ However, the US Food and Drug Administration decided that LAIV4 had to remain licensed for use in the USA⁷¹ because of the limitations of observational studies in estimating vaccine effectiveness. In contrast, Canada,⁵⁴ the UK,⁷² and Finland⁷³ have not withdrawn LAIV from the list of influenza vaccines recommended for use in children by health authorities because current evidence indicates a protective effect of LAIV, although it is lower than expected.

The low LAIV effectiveness during the 2014–2015 influenza season was evidenced in several countries and can be explained by several factors, including the presence of antigenically drifted A/H3N2 viruses. The effectiveness of IIV during that period was also shown to be low. In contrast, the poor vaccine effectiveness during the 2013–2014 and 2015–2016 influenza seasons in which A/H1N1pdm09 dominated and the discordant vaccine effectiveness estimates between studies carried out in different countries during this period are difficult to explain. These findings have been suggested to reflect biological mechanisms, methodological issues or both, including biases in the design of observational studies and statistical considerations, which limit the precision of vaccine effectiveness estimates.⁵⁷ In 2013–2014, the test negative design was used in the USA⁵⁹ and in Canada,⁶¹ but opposite results were obtained. The two studies carried out in Canada in the same influenza season used different methods but led to the same conclusions.^60,61 Poor LAIV effectiveness against A/H1N1pdm09 may depend, as previously observed with IIV,⁷⁴ on reduced immunogenicity of the vaccine as a result of a more highly vaccinated population in recent years compared with populations of earlier studies, in which a higher proportion of children were vaccine-naïve. The importance of this problem is not defined, but the use of LAIV in countries that have recently introduced this preparation and have maintained its use despite the ACIP decision may offer adequate data to inform this question. Potential interference among viruses included in the LAIV4 cannot be excluded but is not consistent with the results reported when the immunogenicity of LAIV4 was compared with that of LAIV3.⁷⁵ Heat susceptibility may have played a role, at least for the poor vaccine effectiveness in 2013–2014. During that influenza season, LAIV was prepared with the A/California/7/2009pdm09 strain. This virus has an increased susceptibility to degradation compared with other live viruses, although degradation occurs at a temperature well above what is recommended for storage and handling (2-8°C).^76,77 A study carried out in the USA regarding the association between vaccine shipping conditions and LAIV lot effectiveness revealed that from 2013 to 2014, the proportion of LAIV recipients who tested positive for the A/H1N1/2009 pandemic virus among children who received a lot released between August 1 and September 15, 2013 was significantly higher than that in children who received a lot shipped either earlier or later (21% vs. 4%; p<0.01).⁷⁸ A linear relationship was observed between the proportion of positive subjects and outdoor temperature during truck unloading at distributor locations. The importance of outdoor temperature on the effectiveness of LAIV was further supported by evidence that a reduction similar to that found in 2013 against the A/H1N12009 pandemic virus was reported in the 2010–2011 season when most LAIV doses were shipped before mid-September. In contrast, significant effectiveness was observed in 2009–2010 when LAIV was shipped in the USA after mid-September and in 2013–2014 in Canada when the vaccine was shipped starting in November. However, heat susceptibility cannot explain the poor vaccine effectiveness found in 2015–2016 because in that season, the A/California/7/2009pdm09 strain was substituted in LAIV by the A/Bolivia/559/2013/H1N1 strain, a virus that is significantly more stable. Unfortunately, the real immunogenicity of this strain has not been specifically evaluated in randomized controlled trials, and it cannot be excluded that poor vaccine effectiveness may be linked to the relatively reduced immunogenicity due to reduced replicative fitness of both viral strains.^78,79 However, differences among studies carried out in 2015–2016 do not appear to support this hypothesis. Table 5 summarizes possible reasons for reduced LAIV4 effectiveness.

Table 5. Possible reasons for reduced quadrivalent live attenuated influenza vaccine (LAIV4) effectiveness.

Possible reasons
Reduced immune response against A/H1N1pdm09 as a result of a more highly vaccinated population during the influenza seasons 2013–2014 and 2015–2016
Antigenically drifted A/H3N2 viruses during the 2014–2015 influenza season
Biological mechanisms
Methodological issues in studies (i.e., biases in the design, statistical limits)
Potential interference among viruses included in the LAIV4
Heat susceptibility

Conclusions

Protection of all children against influenza, particularly the youngest, is mandatory for most health authorities. However, how this protection can be achieved has not been defined. Currently available vaccines cannot be used in the youngest children, a group of subjects at the highest risk of influenza-related complications. Maternal immunization is an attractive possibility to overcome this problem. However, several problems concerning the best time of immunization, the number of children protected and the duration of protection have not been solved. Available data indicate that despite maternal immunization, a number of children have no protective antibody levels at birth and that in most cases the duration of protection is limited to the first 8 weeks of the postnatal period. Therefore, infants remain unprotected for an extended period before vaccines can be administered. The availability of more immunogenic and effective preparations may evoke a stronger immune response in the mother, resulting in a longer efficacy period in the infant. Worldwide, the influenza vaccination coverage of pregnant women is very low, and only strong initiatives to improve coverage will favor infant protection.

Moreover, the best influenza vaccine to use in children has not been precisely defined. LAIV has raised interest because it avoids intramuscular injection. However, it is licensed only for children ≥2 years of age, and its real efficacy is debated. The ACIP of the USA has recently decided that for the 2016–2017 influenza season, LAIV could not be used because it was found to be ineffective in the previous 3 influenza seasons. This decision was not accepted by several other health authorities because LAIV vaccine effectiveness was considered adequate in their countries. The reasons for the differences in vaccine effectiveness are unknown. However, data on LAIV effectiveness must be clarified because LAIV can significantly improve vaccination coverage in children. Parents are reluctant to accept immunization by intramuscular injection, and the availability of an intranasally administered, effective and safe vaccine may significantly improve compliance with recommendations. Further studies are needed to improve our knowledge and solve all the problems to assure the best protection of children against influenza, a common frequently under evaluated disease.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Funding

This review was supported by a grant from the Italian Ministry of Health (Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico 2016 850/01). The funding source had no impact on the literature search or in the preparation of the manuscript.