Influenza vaccination in pediatric age

Abstract

To increase the protective efficacy against influenza in pediatric populations, several attempts to modify the composition or the route of administration of an inactivated influenza vaccine have been made. Adjuvants have been added, vaccines with higher antigen content have been developed and intradermal administration of inactivated influenza vaccine with a variety of devices has been considered. Such attempts to develop universal influenza vaccines will continue to be made. For some time, the knowledge that the licensed influenza vaccines induce strain-specific immunity and may have low efficacy in unexpected outbreaks of new epidemic strains has motivated the development of preparations with broader and longer-lasting protection. Ideally, children would be included early in the evaluation of the efficacy of new vaccines to avoid lengthy delays in making the protection available to this vulnerable population. Moreover, further studies to clarify definitively whether protection of infants <6 months of age can be obtained through vaccination of the pregnant woman have to be performed.

Keywords:

• children
• influenza
• influenza prevention
• influenza vaccine
• pediatric infectious diseases

Every year during the cold months, large numbers of individuals are infected by influenza viruses. Together with the elderly, children under 5 years of age are the subjects with the highest risk of severe disease leading to hospitalization and, although rarely, to death [1,2]. Moreover, children are the most important cause of diffusion of the infection in the community because they shed the virus in greater amounts and for longer periods of time than adults of any age [3]. To reduce the direct and indirect effects of pediatric influenza virus infection, influenza vaccination, universally considered the best measure to prevent and mitigate influenza disease, is recommended worldwide only for children considered at risk due to a severe underlying disease despite, in some cases, the real efficacy of the immunization is yet to be clearly defined. In healthy children, influenza vaccination is recommended in only a small number of countries, although guidelines vary regarding the minimum age [4,5]. In USA, universal influenza vaccination in all the age groups is recommended, including all the children until 17 years of age [6]. In UK, influenza vaccination is recommended in the age group 2–17 years, although the program has been activated only recently [6]. Finally, in Canada and other European countries, in which health authorities recommend the vaccine also in the healthy pediatric population, school-age children and adolescents are excluded [6]. However, the currently available vaccines are not completely satisfactory and have limits that significantly reduce their potential protective efficacy, particularly in younger children. In subjects <2 years of age, the live attenuated influenza vaccine cannot be administered because it can induce broncho-obstruction [5]. Moreover, despite being licensed for older children, it is not marketed in some industrialized countries, such as Italy. The traditional inactivated influenza vaccine (IIV) – both the old formulation containing three viruses and the more recent preparation with four components – is poorly immunogenic in younger subjects; does not protect a significant number of infants, particularly when mismatched viruses are circulating; and is not licensed for those under 6 months of age [4]. Regarding immunogenicity, younger children are quite similar to the elderly, who, because of the senescence of their immune system, respond poorly to immune stimulation [7].

To overcome these problems and to increase the protective efficacy against influenza in pediatric populations, several attempts have been made to modify the composition or the route of administration of IIV. Adjuvants have been added, vaccines with higher antigen content have been developed and intradermal administration of IIV with a variety of devices has been considered [8]. However, almost all of these studies, particularly those sponsored by pharmaceutical companies and specifically designed to collect data in order to obtain marketing authorization, were conducted in adults [9,10]. Studies in children have arisen mainly from spontaneous initiatives of research groups without a commercial objective, and even those designed to obtain data for marketing approval, as the MF59-adjuvanted IIV, did not lead to authorization for pediatric use [11].

In children 6–36 months of age, MF59-adjuvanted vaccine has been found to be not only more immunogenic than traditional IIV but also able to induce significantly higher cross-reactivity against influenza virus mismatched strains without an increase in the incidence of severe adverse events [12]. Moreover, in children between 6 and 71 months of age, it was found to be protective against laboratory-confirmed influenza due to vaccine-matched strains in 79% of the cases compared with 40% with IIV [13].

The positive effect on the immune response of an increased antigen content was demonstrated in unprimed children 6–35 months of age who received two full doses (0.50 ml each) of virosomal-adjuvanted IIV instead of two half doses (0.25 ml each), as usually recommended for children who are immunized for the first time [14]. In comparison to subjects treated with the standard dose, patients who received the double dose had significantly higher seroconversion and seroprotection rates as well as a higher increase in geometric mean titers, with values that persisted for 6 months after the second administration in the protective range for more than 90% of the children, without problems related to safety and tolerability.

Finally, skin administration of IIV with a microinjection system was found effective in children aged ≥3 years [15]. Compared with virosomal-adjuvanted intramuscular IIV, intradermal IIV resulted in similar seroconversion and seroprotection rates and geometric mean antibody titers for A/H1N1 and A/H3N2 antigens, but it was significantly more immunogenic against the B strain, for which the immune response is usually the weakest. Local adverse events were more common in subjects with intradermal vaccination, but they were mild and transient. Systemic adverse events were rare, and their frequency did not differ between groups [15].

Further studies are needed to definitively establish whether the new modalities to prepare and use IIV might be truly effective in younger children, overcoming the problem of the poor immunogenicity of the traditional IIV.

Moreover, it has to be clarified how to protect children <6 months for whom IIV is presently not recommended. Together with studies specifically planned to evaluate whether the new IIVs can be effective in these subjects, more data are needed to establish whether a possible solution to protect these infants is to administer IIV to pregnant women [16]. Immunization in the second and third trimesters has been extensively studied and found to be safe and effective. Not only does it provide protection for the pregnant woman and her infant in the first months of life with a 50% reduction of the risk of influenza infection, but it also decreases the infant’s risk of low birth weight [17–19]. Unfortunately, rates of maternal influenza vaccination have historically been low, possibly reflecting ongoing concerns about vaccine safety [20,21].

In conclusion, although it is well known that influenza can be a severe clinical problem in the first years of life, the development of prophylactic measures for younger children is proceeding at a very slow pace. Moreover, alternative measures, such as vaccine administration to pregnant women, encounter unjustified prejudices that can be overcome only with education and continued efforts to encourage clinicians to strongly recommend and offer influenza vaccination to their pregnant patients.

Expert commentary & five-year view

Improved IIVs were developed and licensed for use in the elderly in recent years. The same preparations were not systematically evaluated in children, for whom the poorly immunogenic traditional IIV, licensed for subjects in the first years of life, remained the only prophylactic measure against influenza. To overcome this problem, it should be mandatory that all the attempts made to increase immunogenicity and efficacy of new IIVs are tested not only in adults but also in children in order to evaluate which of them offers adequate protection against influenza in the first years of life. This means that pediatric studies on the different doses, route of administration and types of vaccine are needed. Unfortunately, performing adequate clinical trials with influenza vaccines in pediatrics is not easy because, as previously demonstrated for drug development [21], the ethics of conducting placebo-controlled studies in children remains a matter of great concern and hampers meaningful investigations in many areas of pediatric prophylaxis and therapy. Moreover, although regulatory agencies in both Europe and the USA have increased the incentives to develop drugs for pediatric conditions, the pharmaceutical industry generally considers clinical studies in children unattractive, non-viable or non-profitable [21]. The pediatric market is significantly smaller than that for the elderly. Moreover, influenza vaccination is recommended worldwide only for children at risk, a group that constitutes only a minority of the entire pediatric population. Vaccination of healthy subjects is recommended in only a few countries [6]. Consequently, it is not surprising that the industry has little interest in the development of new influenza vaccines for the pediatric population. It is likely that the problem would be solved if influenza vaccine were recommended worldwide for pediatric populations. Unfortunately, this is a difficult aim because the poor immunogenicity of the traditional IIV is the major reason that many health authorities believe that influenza vaccination of healthy children is unnecessary.

In the near future, further attempts to develop universal influenza vaccines will be made. For some time now, the knowledge that the licensed influenza vaccines induce strain-specific immunity and may have low efficacy in unexpected outbreaks of new epidemic strains or the emergence of pandemic viruses has motivated the development of preparations with broader and long-lasting protection and, ultimately, universal vaccines based on conserved viral proteins or domains that are able to protect against all the influenza viruses regardless of their subtypes [22]. Further studies are needed to resolve the difficulties regarding the relatively low immunogenicity of the hemagglutinin stalk domain and the potential infection-enhancing effect, which could become pronounced against antigenically distant influenza viruses, thereby reducing or eliminating the protective potency of the vaccination. Ideally, provided that safety problems have been addressed, children would be included early in the evaluation of the efficacy of new vaccines to avoid a long delay before these vulnerable individuals can take advantage of an available protective measure.

Financial & competing interests disclosure

The authors were supported by a grant from the Italian Ministry of Health (Bando Giovani Ricercatori 2009). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.