Special Focus Review

Influenza vaccination coverage rate in children

Reasons for a failure and how to go forward

Abstract

Based on an increasingly extensive literature expressing the large interest in the field, this paper gives an overview of different aspects of influenza prevention in children. It relies on paradoxes. First, the heaviest part of the burden is well demonstrated in the youngest infants by numerous epidemiological data elsewhere. On the contrary, with older children, the prevention by influenza vaccines is more efficacious—without notable side effects. Second, the available TIV vaccines are 60 years old and the requests of registration and regulation of vaccines have evolved. There is a specific need in children: it is time to re-discuss the pragmatic utilization of influenza vaccines (full dose in the youngest patient? More flexibility regarding the interval between the two required doses in vaccine-naïve children), and to change from a compassionate use to a targeted research and adapted vaccines considering the limits of TIV in the youngest children. Third, influenza virus transmission is the highest in children in semi-close communities (day-care centers, schools), diffusing to households and more largely to the population. A restricted policy on high risk groups (roughly 10% in a pediatric population, all medical conditions including asthma, for whom influenza vaccine coverage is a 15–75% range) is far below the estimated threshold of 45% coverage rate to limit the virus circulation by an indirect impact during seasonal epidemics. Fourth, public health decisions in the vaccination field are usually taken from top to bottom. The pandemic A/H1N1 has toughly demonstrated that “forgetting” about the perception and expectations of the public and the parents nearly created conflicts and at least a strong resistance impeding the quality of a program worked on for a long time ahead. Fifth, and not the least, HCPs are pivotal in influenza vaccination mostly trusted by the parents. Too often, they are not backed by a national and clear support and they need to reinforce their knowledge on the disease and the vaccines.

Keywords: :

A/H1N1 pandemic children HCPs influenza burden influenza policies influenza rapid diagnosis test influenza social aspects influenza vaccines influenza vaccines coverage rates seasonal influenza

Influenza viruses are the only respiratory viruses for which a vaccine is available thus allowing a prevention of this infectious disease. Despite existing recommendations in industrialized countries, seasonal influenza vaccines are underused in nearly all of them. Though focusing here on seasonal vaccines the experience gained with the 2009 A/H1N1 pandemic allows some useful lessons. We will discuss data on coverage rates, the diverse obstacles to policies and different paths to overcome them. Some statements are specific to children and some overlap with the adult population and the elderly.

Facts on Influenza Vaccine Coverage IVC Rates in Children with Seasonal Vaccines Worldwide

Influenza vaccines are recommended in the pediatric population since the 90s.

Universal program

The Advisory Committee on Immunization Practices ACIP in the US recommended routine influenza vaccination in children, independently from a risk factor, first in children aged 6 to 23 months in 2004, then in the two to four years (2006) and from August 2008 to all children aged five to 18 years. The choice is given between TIV and LAIV within the frame of their indication. The IVC rate achieved in children during the 2009–10 season¹ with at least one seasonal influenza vaccine dose was 26.3%, a 5.5% increase from the 2008–09 season. Per age groups,¹ comparing the 2009–10 and the 2008–09 seasons, almost no change was observed among children aged six to 23 months (55.7% vs. 55.2% respectively) to notable increases among children aged two to four years (38.4% vs. 33.0%), five to 12 years (27.1% vs. 19.0%) and 13 to 18 years (15.3% vs. 10.9%). Full IVC ranged from 34.7% among children aged six to 23 months to 15.3% among those aged 13 to 18 years. Data on annual revaccination are not available. During the 2010–11 season²—the first season the ACIP recommended influenza vaccination for all persons aged at least six months—the preliminary national (43 states and the District of Columbia) IVC rate estimate was 49.0% for children aged six months to 17 years compared with 30.2% for adults aged 18 to 49 years and 68.6% for adults aged at least 65 years.

Finland and Mexico have introduced a routine program in young children more recently.

Influenza vaccine coverage IVC rates in high risk children

In most European Member States, influenza vaccine is recommended from six months of age in high risk patients, as in Australia and several rapidly developing countries in Africa, Asia Pacific, Eastern Europe, Latin America and the Middle East. Underlying medical conditions are the following categories: chronic respiratory and cardiovascular diseases; chronic metabolic disorders; chronic renal and hepatic diseases; immune system dysfunctions (congenital or acquired).

In Spanish children with a chronic medical condition³ a 19.1% IVC rate was achieved compared with 6.8% for all children, 24.2% among HCWs and 22.2% for the overall population. In the region of Madrid, an IVC of 27.1% in chronically ill children⁴^,⁵ aged six months up to 14 years, was higher among diabetics (41.1%) and lower in children with “other pulmonary conditions” (15.2%). In France,⁶ during the season 2003–04, the IVC rate high in risk children was 43.7% increased from 20.4% in 1999–2000, the highest (55.5%) in case of hemoglobinopathy and the lowest (12.8%) in chronic respiratory diseases. Similarly in Italy,⁷ a global 59% IVC rate showed heterogeneity among pathologies. In 2009, Tuppin et al.⁸ identified the IVC rate in French chronically ill subjects: 24.3% in children under ten years old (30.6% in those without asthma), 28.1% in adolescents aged ten to 19 years, compared with 39.2% in the 20 to 64 age range and 63.3% for individuals aged 65 and over (72.3% with a targeted chronic disease and 56.9% without).

Asthma is one of the most frequent chronic condition in children, reported in nearly 9% of those aged less than 18 years (6.5 million, US 2005). An estimation of the IVC rate in asthmatic children in the US⁹ ranges from 10% to 43% for various influenza seasons and more recently 29.0% in children aged two to 17 years with one or more conditions putting them at high risk for complications; in Spain,¹⁰ 18.8% compared with 38% among adults and 32.6% overall; and in France,¹¹ 15.7%, 13.9% and 10.9% for the 2006–07, 2005–06 and 2004–05 seasons respectively.

In cystic fibrosis patients, IVC rates are more satisfactory: 76.4% patients over 6 months of age (1997–1998 flu season),¹² reaching 79.4% in children less than 18 years of age and in France¹³ 79.9%, also higher (85.6%) in children.

No available data of coverage rates are published in children with cancer, leukemia, transplantation and diabetes.

Some comparisons with different populations

The IVC rates of global pediatric population are low all through Europe¹⁴: 4% (France, Poland and Ireland) up to 19% (Germany). IVC rates of global adult population reaches 24–26% in France¹⁵ depending on the years and overall remained stable during past seasons 2008–09 (20.6%) and 2009–10 (20.8%).¹⁶ In elderly IVC rates are close to 70% in many European countries.¹⁴ IVC of chronically ill adult population (Table 1) ranges from 11.1% (Poland) to 56.0% (UK).¹⁴ In Spain⁴ over four recent epidemic seasons, from 2005–06 to 2009–10, an increasing trend (OR 1.03) was noted for the total adult population, especially in HCPs (21.8% in 2005–06; 31.1% in 2009–10) though the IVC in people under 60 with a chronic disease remained low and did not vary significantly during this period: 22.1% overall, 39.1% in heart failure and the lowest in patients suffering neuromuscular diseases (12.8%).

Table 1. From Mereckiene J, Cotter S, D'Ancona F, Giambi C, Nicoll A, Levy-Bruhl D, et al.; VENICE project gatekeepers group. Differences in national influenza vaccination policies across the European Union, Norway and Iceland 2008–2009.¹⁴⁴ “Vaccination coverage for seasonal influenza for clinical risk groups and/or HCW in 11 EU/EEA countries: national seasonal influenza vaccination surveys in Europe, January 2008 and July 2009^a

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Among pregnant women PW despite official recommendations, IVC rates are still low (2-40%). In the US, during the season 2010–11, 49% PW reported a TIV vaccination (12% before pregnancy, 32% during pregnancy and 5% after pregnancy) from 10% in 2003 to 38% in 2008. They are less likely to be smokers and more likely to breast-feed their infants.¹⁷ In another study in the US,¹⁸ IVC estimates were 32.1% for the seasonal vaccination and 45.7% for the 2009 H1N1 vaccine among PW aged 18 to 49 years.

The health care professionals (HCPs) coverage is globally deceitful. Some HCPs in close contact with high risk patients reach 59.4% IVC rate (e.g., HCPs working in cystic fibrosis centers¹²^,¹⁹) or 50% (pediatric setting²⁰). Most of the time IVC rates are inferior: in France,²¹ a mean rate of 42.8%, better in men and medical HCPs; in Spain⁴ an increase from 21.8% in 2005–06 to 31.1% in 2009–10; in Italy,²² from 17.6% in the Emergency Department to 24.3% in the Surgery Department; and in a UK pediatric setting²³ 49.6%, significantly higher among doctors (OR 2.4). During the 2009 A/H1N1 pandemic, several surveys confirm the low IVC rates: In France,²⁴ 22.3% of HCPs in contact with at-risk patients against seasonal influenza and 36.5% against A/H1N1, contrarily to Spain²⁵ where 49.7% of HCPs reported having received the seasonal vaccine and only 16.5% the pandemic vaccine.

These data must be put in perspective with the WHO and national objectives:²⁶ Fifty percent in 2006 and 75% in 2010. The gap between current IVC and European Union recommendations has public health consequences including increased morbidity, hospitalizations and mortality associated with influenza-related complications and costs.

Reasons for a Failure in Children

Failure and obstacles to influenza immunization include a vast and long list of weaknesses and insufficient awareness. We will review successively what is inherent to the disease burden (knowledge), to the vaccine and immunization (protective efficacy and safety) and to inter-relation between doctors, health authorities and population (fear of liability).

Do we know enough about the disease?

An extensive accumulating evidence of the substantial influenza burden has been published since 15 years (see refs. 27–36). In the US, annual rates of hospitalization related to influenza reach nine per 10,000 children aged zero to 59 months (influenza associated) and 45 per 10,000 children aged zero to five months (laboratory-confirmed influenza);³³ recently³⁵ from 2003 to 2008, the hospitalization rate for influenza was the highest in children less than six months of age (30 per 10,000) and the lowest in children aged five to 17 years (0.3–0.8/10 000). Similar ranges were observed in France³⁴ (emergency room), Hong Kong³¹ and Finland.³⁶ Thus in the youngest infants, incidence rates of hospitalization reported or confirmed to influenza are in the same range as what is observed in elderly for whom a routine recommendation is the rule.

The severity of the outcome³⁵ consists in intensive care unit admission (12%), respiratory failure (5%), bacterial co-infection (2%) as found by O’Brien³⁰ and death (0.5%); only 40% of children had underlying high risk conditions.³⁵ European recent studies³⁷^,³⁸ confirm the potential severity in healthy children. Super or co-infection in otitis media and pneumonia³⁰ (confirmed by X-ray) increases strongly out-patients visits and by up to 30% the number of antibiotic prescription to children during an influenza season.²⁹ Both the immaturity of the infant’s immune system and the absence of prior immunity when exposed to a new (for them) influenza strain explain this especially in case of added vulnerability.³⁹

Children with underlying medical condition (asthma, chronic cardiorespiratory disease, neuro-muscular condition…) compared with previously healthy children of the same age have a two- to six- fold increased risk of hospitalization²⁹ and a higher incidence of influenza-related complications (29% vs. 21%) which are more severe.⁴⁰

In children the incidence of deaths due to influenza is very low fortunately (around 100 deaths per year reported in the US by the CDC surveillance network⁴¹) with a mean age of three years, a large number (two in three) occurring in healthy children and the highest (0.88 per 100,000) mortality rate in infants under six months of age.⁴²

The individual burden in children is still (largely?) under-recognized though more pediatricians and GPs are now prone to “think influenza” in children. One caveat is the absence of routine influenza Rapid Diagnosis Test RDT (and its lack of reimbursement) in those under three years of age for whom the disease burden is diluted within other respiratory and digestive overlapping epidemics.

The collective burden in the whole population is validated by epidemiological data. During seasonal epidemics the peak in children up to 15 years of age usually occurs two weeks before the adults / elderly’s one. The influenza virus transmission, due to high attack rates in children and high titers in the naso-pharyngeal mucosa (“shedding”) of infected children is facilitated in semi-close collectivities (day care centers, schools), households and community. The recent “collective concept” is strongly linked to an added altruist benefit of a large routine vaccination program against any respiratory infectious agent. The indirect positive impact on vulnerable people⁴³ surrounded by children in households and the perspective of diminished circulation and transmission of influenza viruses in a community/population are not reachable with a restricted targeted vaccination policy.

Influenza Vaccines

Trivalent inactivated vaccines TIV history explains at least partly their actual difficulties in the pediatric setting. Since their first registration in the 40s after World War II, they still are mostly egg-culture based, non adjuvanted (without aluminum). Seasonal whole virion vaccines are no more in use. Sub-unit or split formulations are the only TIV available on the market. Life attenuated vaccine LAIV registrated from 2003 in the US and from June 2010 in Europe should be available there for the season 2012–13.

Introduced first in the army, TIV were later on recommended in the elderly due to the recognized high risk of deaths due to influenza (as in the high risk medical adult group), number one public health index. A clear recognition of influenza burden in children is rather “new”—from the mid-90s—with for a long time, the low death rate restraining prevention policy. Thus everywhere in Europe, TIV were only recommended in the targeted high risk pediatric population, in a rather “compassionate” use in absence of their sound pre-registration evaluation in this population.

The position of TIV, seasonal vaccines, is unique among other pediatric recommended vaccines given “all the year around” at any time. Their registration is renewed every year contrarily to most vaccines. Duration of market authorization is roughly 8 months from the beginning of October up to August of the following year.

What about the tolerance? The 1976 swine influenza vaccine—killed, whole virion—raised an issue due to an increased incidence of Guillain-Barre syndrome GBS to approximately one per 100,000 recipients, probably due to a contamination by another infectious agent. The risk of influenza vaccine-associated GBS with sub-unit or split TIV is thought to be approximately one to two cases per one million vaccines: a few studies have found an association, others not; the risk after influenza infection is seven-fold higher (see refs. 44–46). After decades of usage and Millions of doses administered at any age no other signal of any severe undesirable event has been identified. Once the influenza vaccination contra-indicated to true allergy to eggs (in the US: anaphylaxis; in Europe “allergies to egg”) the immediate reactogenicity of TIV is comparable to other recommended vaccines included in national schedules.⁴⁷

Antibody responses to TIV increase with increasing age from six months up to 23 months of age⁴⁸^,⁴⁹ existing though lower in the youngest vaccine-naïve infants aged six to 11 months,³⁹ establishing their value to potential protection.

Effectiveness data, needed in absence of an absolute correlate of protection in adults and the extrapolation to children of what is known in adults, encounter methodological difficulties in the choice of disease criteria (to select specificity or sensitivity) and the interpretation of results⁵⁰ due to capricious epidemics (unpredictable attack rates, circulating strains….). Some randomized, placebo-controlled trials RCTs⁴⁷^,⁵¹ demonstrate solid vaccine effectiveness VE (70–90%) in school age children in preventing laboratory-confirmed influenza LCI when TIV vaccine strains match well with circulating strains. Considering pediatric RCTs in children over two year-old,⁵² TIV and LAIV showed an absolute efficacy of 59% and 82% respectively and a similar VE of 36% and 33%. In another study⁵³ children six to 59 months fully vaccinated against influenza had a lower risk of laboratory-confirmed medically attended influenza illness MAARI (Odds Ratio OR: 0.14) than unvaccinated children; even in the partially vaccinated group the trend continued (OR: 0.27) though the protection provided may be suboptimal.

In children under two years of age for whom the need for a vaccine is the highest, the protective efficacy of TIV is more debatable⁵²^,⁵⁴ with a popular belief that TIV effectiveness data are not fully convincing “similar to placebo.” This is partly due to very few specific studies in this age group and to the difficulty of interpreting results⁵⁰^,⁵² notably in case of mismatch between vaccine and circulating strains.

The match of vaccine strains and epidemic circulating ones is a key factor for VE at any age. A suboptimal match lessens the immune response capacity and vaccine benefit; in healthy adults 18 to 64 years⁵⁵ VE drops from a range of 74–79% down to 44%, in spite of a substantial gain against severe outcomes.

In immune-compromised children VE is lower. Pediatric oncology patients⁵⁶ receiving chemotherapy generate an immune response to TIV, but the potential clinical protection remains unclear. In HIV-infected children⁵⁷^,⁵⁸ compared with non HIV-infected controls, post-vaccination immune response exists, correlated with their pre-vaccination immunological status.

In daily practice TIV implementation is not easy due to their schedule: the two doses at one month interval in vaccine-naïve children less than nine years of age do not facilitate full immunization. TIV are injectable and the calendar during first year of life is already overcrowded. The need for an annual booster is also peculiar among the other immunization schedules. Last but not least the absence of TIV registration in the first six months of life creates a major void.

Strategy of immunization: targeted or universal?

Most European countries with a targeted strategy (Table 1) have retained the objective of an individual prevention. It selects “true” risk groups, is tailored to people and appears cheaper. But the (high) costs of the residual burden (inversely proportional to IVC rates achieved) in terms of severity, consequences and money must be added to the cost of a too often partial program implementation. Moreover, such focused strategies have previously demonstrated their potential for failure (rubella in teenage girls, hepatitis B in high risk only…). Few European countries have recommended a routine immunization program (Latvia and Slovenia up to two years of age, Finland, up to three years; Austria, Estonia and Slovakia up to 18 years).

The US have been the first to recommend a routine influenza vaccination in infants six to 23 months of age, followed by Canada. As in Finland, IVC rates achieved are now globally better than in targeted strategies. In a routine strategy the objectives add to the individual benefit the expectation of an indirect effect, both on vulnerable people and on the circulation/ transmission of viral strains in the community.

A question of price and reimbursement?

In many European Member States, reimbursement of—or free of charge—influenza vaccines and the low price of a vaccine dose (around seven €) are not blocking points for a potential vaccination campaign success. In France⁸ for example, data show the benefit of vouchers sent by the Public insurance system to selected high risk groups (see Table 2) as soon as TIV are available, allowing free of charge vaccine and vaccination up to the end of the campaign (end of January). Reimbursement is fundamental as other examples of failure of recommended and not reimbursed immunization exist (hepatitis A, all travelers’ vaccines). On a global point of view, some other national immunization priorities may also impede the process.

Table 2. Underlying/medical conditions, occupational settings and other groups for which influenza immunization is recommended without regard to age: national seasonal influenza vaccination survey in Europe, July 2009

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What about health care professionals (HCPs) interest?

Vaccination of HCPs is a high priority everywhere. Several studies report their misconceptions and gaps in knowledge⁵⁹^,⁶⁰ contributing to IVC rates below 40% in the US⁶¹ as in many European countries. The lack of perceived personal need was the most common reason for vaccine refusal of pediatric nurses.⁶² During the A/H1N1 pandemic the main arguments for HCPs refusal⁶³^,⁶⁴ were “doubts about vaccine efficacy,” “fear of adverse reactions” and concern about vaccine safety; “I never get the flu” or “getting vaccinated is inconvenient and takes too long,” and “too busy to attend the vaccine clinic.”

Additional issues⁶⁵ include the complex advance purchase planning, predicting appropriate quantities and proper vaccine storage equipment.

Parents’ perception

Influenza belonged to adults for a long time (with the idea that “they get flu” every year…). Parents may have an impression of a benign disease. The absence of popularity of influenza vaccines and the lack of diffusion of sound information in the population –one of the most frequently reported reason for non-vaccination in asthmatic children¹¹—also contribute to the potential negative perception. Wrong beliefs that the vaccine could subsequently cause influenza or ILI or the wrong perception⁶⁶ to have already immunity to influenza impede the acceptance. During the pandemic H1N1 2009, most people⁶⁷ did not believe they were at high risk of acquiring the disease and only half of them indicated that they would accept the vaccine.

The most important factor for patients—and women to decide to be immunized during pregnancy—relies on clear recommendation from their HCPs.⁵⁹^,⁶⁸ The lack of success of annual campaigns is linked to lack of education by HCPs or HCPs’ failure to offer the vaccine.

In pregnant women PW, more targeted since the A/H1N1 2009 pandemic, attitudes and perceived barriers (see refs. 59, 65 and 68–73) were mainly concern with safety issues—fear of side-effects—for the baby or for themselves and vaccine not offered or discussed by HCPs, not available in obstetricians offices (with referral of patients to other physicians or in pharmacies and other clinics) or at a known location or not covered by the health insurance. Though most OB/GYN physicians⁶⁵ said they always recommended influenza immunization to PW—of whom only 28% recalled vaccination to have been discussed—only 50% provided it in their office. Reasons evoked by obstetricians⁶⁵ for not providing the vaccine themselves included the lack of safety and efficacy data, concerns about the medical legal risks of vaccines during pregnancy, poor reimbursement for vaccine administration and the perception that PW would not want to be vaccinated.

The 2009 pandemic season has highlighted many factors—influenza vaccines as a whole, public health decisions, ways and vehicle of communication⁷⁴ involved in the global resistance of the European population to vaccines, more intense in some countries except some (Sweden, The Netherlands). Finally, the deleterious role of rumors, propagated on Internet, had a powerful impact on the public information in terms of mis- or counter-information. To understand how a mass of information⁶⁶ influences individual risk perception in complex, unpredictable and even contradictory ways and how this in turn shapes the evolution of epidemics is important.

How to Go Forward?

A better recognition of the burden of disease in children

(1) A better estimation relies on the improvement of the rapidity—and the sound proof—of influenza diagnosis in ambulatory care and Emergency Department. A casual utilization—and reimbursement—of the influenza rapid diagnosis tests⁷⁵ RDT have proven their interest in children. In a Finnish study⁷⁶ their specificity for all influenza viruses reached 99% and the sensitivity was better for influenza A virus (90%) than for B strains (25%).

(2) A specific interest should focus on children under one year of age, especially on those aged less than six months. They carry the heaviest part of the burden in terms of hospitalization rates and main clinical presentation⁷⁷—sepsis like, 58% of initial diagnosis. This age group, due to the void of any influenza curative treatment and prevention, is a major niche for an indirect protection.

(3) More data in specific high risk pediatric groups on immune responses are needed although some—with small effectives—are already available in children receiving chemotherapy,⁵⁶ pediatric patients with cancer,⁷⁸ cystic fibrosis⁷⁹ though no study reported VE data. During the 2009 A/H1N1 pandemic, the monovalent Influenza A (H1N1) vaccine—either AS03(B)-adjuvanted⁸⁰ or not⁸¹—administered to HIV-infected children⁸⁰ and to transplant children⁸¹ demonstrated its immunogenicity while appearing to be safe in those children.

(4) More attention should be given to the socio-economic burden—absenteeism from school (children) and work (parents, close contacts)—major consequence of an influenza epidemic for the households.⁵² In a Finnish study,⁸² for every 100 influenza-infected children less than three years old, 195 days of parental work were lost with a mean duration of 3.2 days. In Italy,⁸³ healthy children with influenza had a significant absenteeism—due to duration of fever—from day care or school and needed help at home by members of the household contacts. These often underestimated non-medical costs should be added to the direct medical costs in the economic evaluation of the burden when discussing a strategy of immunization. As in Europe, vaccination strategies are on a national basis, every country should implement cost-effectiveness studies.

Better use of the existing vaccines

(1) A worldwide collaborative effort

WHO⁸⁴ insists on the improvement of strains identification and on the efforts needed to increase the reliability and timeliness of the global influenza vaccine supply; collaboration with vaccine manufacturers is a key point.

(2) Half dose or full dose of TIV in children less than 36 months of age?

The reactogenicity encountered with the whole virion inactivated vaccine, led to sub-unit or split TIV, recommended with a half dose per injection in children six to 35 months of age thought to improve the tolerance. Of note, the United Kingdom recommends for young children a full dose of TIV (0.5 mL). Interestingly, a prospective Finnish study⁸⁵ demonstrates a significant VE of 66% in children from nine months of age up to two years of age receiving a full 0.5 ml dose per injection. Skowronski et al.⁸⁶ also found that 2 full TIV doses may improve immunogenicity in infants (aged six to 11 months) but not in toddlers (aged 12 to 23 months), without increasing reactogenicity in both groups. This could lead to an abandon of the half doses given in this age group as recommended in most countries. Additionally such a change would not require an additional medical visit and the only incremental cost associated would be limited to that of the vaccine.⁸⁶

(3) To accumulate evidence on vaccine effectiveness VE

The benefit of influenza vaccines has to be evidence-based.⁸⁷ Some—too rare—publications already contribute. In Mexico⁸⁸ the influenza vaccination routine program in children has significantly reduced the impact of influenza related hospitalizations from 7.5% down to 3.4%. In Spain⁸⁹ during the 2010–11 season, in a case control study, the adjusted TIV VE in preventing laboratory-confirmed influenza LCI due to any type of influenza virus was 50%. In a Spanish cohort of people with major chronic conditions⁹⁰ during the season 2010–11, the adjusted TIV VE was 31% in preventing medically attended influenza-like illness ILI and 58% in preventing LCI.

Data from the A/H1N1 2009 season emphasize the high pandemic VE. In children aged six to 36 months given two doses of an ASO3-adjuvanted vaccine⁹¹ a high immunogenicity was found (higher than with a whole virion pandemic vaccine) but the reactogenicity was also higher. In Swedish children and adults⁹² with 54% vaccine coverage the range of a weekly VE was 87–95% with a single dose of an AS03 adjuvanted vaccine. In a UK case control study,⁹³ the adjusted VE was 72% in preventing confirmed pandemic influenza infection. In a Canadian case-control study⁹⁴ the adjusted VE after one dose of ASO3 adjuvanted A/H1N1 vaccine given to children and adults mostly less than 50 years was overall at 93% with high estimates of at least 90% of vaccine protection. In a European multi-center case-control study⁹⁵ from seven countries the 2009–2010 pandemic VE against medically attended ILI laboratory-confirmed as pandemic strain achieved 71.9% overall, 78.4% in patients less than 65 years and 72.9% in individuals without chronic disease; no specific pediatric data are available. Nevertheless the risk of narcolepsia reported in children post immunization with the AS03-adjuvanted pandemic vaccine though not with the MF59-adjuvanted pandemic vaccine⁹⁶ impedes its future use in children up to 20 years of age.

(4) To promote the universal vaccination

The idea runs in Europe since 2004, based on influenza substantial large health burden and socioeconomic consequences for the children—everyday activities disrupted, number of school days lost—and their household contacts. Principi et al.⁹⁷ promoted an extended recommendation to infants aged six to 23 months, children with recurrent acute otitis media or respiratory-tract infections and healthy children attending day-care centers or elementary schools. In 2006 a group of European experts⁹⁸ also discussed the benefits of a routine immunization in children. Esposito et al.⁹⁹^,¹⁰⁰ emphasized in 2008 and 2009 the benefit of a universal childhood influenza vaccination as a low-cost preventive intervention. The CEVAG from central Europe¹⁰¹ promoted in 2010 the benefits of routine vaccination of infants and children at greatest risk from the age of six months up to 60 months of age, adding an indirect protection to other high-risk groups in the community. Herd effect¹⁰²—or herd immunity—increases the prevalence of immunity by the vaccine, thus preventing the circulation of infectious agents in susceptible populations and unvaccinated persons. The impact on reduction of influenza transmission depends on the amplitude of vaccines uptake. Grijalva et al.¹⁰³ estimates at 45% the mean IVC rate to reach both direct and indirect impacts on the population. Interestingly, in Madrid¹⁰⁴ a global recommendation in adults 60–64 y resulted in a significantly higher vaccination uptake compared with the rest of Spain (40.1% vs. 29.1%), especially in high risk persons of this age group (59% vs. 43.5%) with a nearly two-fold (OR = 1.95) probability to get vaccinated.

Adoption of alternative vaccine technologies

An extensive set of data (see refs. 105–111) demonstrates the potential benefit in the pediatric population of the live-attenuated trivalent vaccine LAIV and opens expectation. The absolute efficacy (over placebo) and the relative efficacy (over TIV) are both in favor of the utilization of LAIV in children with clinical protection against LCI, to a lesser extent against ILI and a positive impact on acute otitis media. LAIV encounters some limits: it cannot be administered before 2 y of age due to tolerance (higher hospitalization rate in children under one year of age and increased wheezing) and only in healthy children. Recommended in the US since 2003, in a large school based program¹⁰³ in children five to 17 years old VE consisted in a decrease of approximately five fewer influenza-associated ED visits per 1,000 annually of MAARI attributable to influenza and of hospitalizations. Administered by nasal spray it would not interfere with injectable vaccines schedules and could be given easily by HCPs and maybe not only by doctors and nurses.

Research is on the way to develop more effective seasonal influenza vaccines with the major objectives to provide long-lasting immunity and broad protection against strains that differ antigenically from vaccine viruses. Most vaccines are in the initial phase of research and development: naked HA with a universal antigen; non-HA-based vaccines; virosomal and adjuvanted vaccines; quadrivalent vaccines with two B strains. Such technologies will probably have significant implications for the vaccine virus selection, as well as for vaccine regulatory and manufacturing processes.⁸⁴

Different strategies with TIV in children

(1) Efforts to increase the suboptimal and challenging compliance to two doses of influenza vaccines at least four weeks apart in vaccine-naïve children less than nine years are warranted. Two doses are necessary in those children as demonstrated by Neuzil et al.:¹¹² the proportion of children with protective Ab responses was significantly higher after two doses than after one dose of TIV for each antigen. To start influenza vaccination at any time in children—accepting an increased interval between the two doses—could help. For example initiating TIV immunization in spring at the time of routine office visits may facilitate the full immunization of children during early fall before the epidemic wave when the vaccine components do not change between years¹¹³ and could still be better than nothing in case of change of some of the three antigenic components.

(2) School based policy is one strategy to reduce the spread of influenza in households and communities.¹¹⁴ A large metanalysis¹¹⁵ and a study on the field in the US¹¹⁶ demonstrate its efficiency in reducing the absenteeism.¹¹⁷ In a large county school-based¹⁰³ a significant decrease of disease coincided temporally with an LAIV vaccination campaign in children aged five to 17 years.

Cocooning strategy for close contacts in households surrounding vulnerable newborns

The objectives of such a strategy are to reduce the risk of transmission and circulation of the infectious agent around vulnerable subjects by vaccinating members of the household, caregivers and close contacts. Already promoted and recommended for pertussis¹¹⁸ cocooning is well accepted and successfully implemented in a high-risk population by using standing orders and providing vaccinations on-site. To overcome the practical and logistical barriers needs extended vaccination hours, one limit being an inaccurate recall of vaccination history.¹¹⁹^,¹²⁰

Immunization of pregnant women PW with TIV

This strategy has the double advantage (1) to protect women against the increased risks from influenza in pregnancy; and (2) to provide indirect protection after birth to newborns and infants less than six months of age by decreasing their risk of exposure (highest hospitalization rate; void of vaccine).

(1) After naturally acquired maternal infections, the resulting trans-placental maternal antibodies Ab protect infants and last probably less than six months.³⁹^,¹²¹^,¹²²

(2) Several studies with TIV immunization of PW during the third trimester of pregnancy demonstrate the immunogenicity and/or a VE for them and their infants comparing the latter with those born to unvaccinated mothers. In infants born to vaccinated mothers, a significant increase in Ab levels to influenza virus was found in the cord blood¹²³ and protective Ab titers from birth until 20 weeks of life—progressively declining until 26 weeks of life.¹²⁴ During the pandemic 2009 A/H1N1, both H1N1 adjuvanted vaccine¹²⁵ and MF59-adjuvanted vaccine¹²⁶ induced protective Ab titer in mothers and newborns, persisting in most infants for at least 5 mo.¹²⁶ On the field trials showed a significant trend in newborn infants of PW receiving seasonal TIV by comparison with infants born to unvaccinated mother. A Bangladesh randomized trial¹²⁷ showed a 63% reduction of the rate of laboratory confirmed influenza LCI during the first six months of life. Similarly, Poehling et al.¹²⁸ reported that hospitalized infants of vaccinated mothers were 45–48% less likely to have LCI during their first influenza season. Among Native Americans from 2002 to 2005, Eick et al.¹²⁹ in a prospective observational study found a reduction by 41% of LCI and by 39% of hospitalization for ILI; the reduced risk of influenza infection in young infants correlated with higher Ab titers; in a matched case control study, among infants aged less than six months of vaccinated mothers, the prevention of hospitalization for LCI was highly effective (92%).

Health care professionals (HCPs)

(1) Higher vaccination rates correlate significantly and directly with knowledge¹³⁰^,¹³¹ (11% among low-level, 16% in intermediate and 42% in the highest knowledge) and education reduce misconceptions about influenza and influenza vaccine.¹³⁰

(2) Understanding the reasons and behavioral patterns of HCPs¹³¹ has a major impact, often significant on their vaccination rates. The willingness of GPs to accept immunization against influenza is due to the following main factors: previous receipt of influenza vaccine in the prior three years (adjusted OR = 4.38),⁶⁴ belief in the vaccine's effectiveness, older age, being on call for emergencies and work representing a high risk condition,⁶³^,⁷⁴ “to avoid getting sick” and “to protect the patient” or “non-vaccination places their patients at a higher level of risk.”¹³²

In pediatric nurses previous vaccination strongly predicts future vaccine acceptance. An adequate and achievable coverage requires an intensive voluntary immunization program, using best-known practices.⁶² Organizational barriers could be overcome with a flexible program convenience and workplace vaccine delivery.¹³²

(3) To increase in HCPs the IVC needs the crucial participation of institutions—hospitals, long-term care facilities and other health agencies. Development of comprehensive infection control programs to protect patients and staff will improve yearly influenza vaccination of their staff.⁶¹ For example, the estimated relative risk of hospital-acquired ILI according to in-hospital exposures to contagious individuals varied from 5.48 (patients exposed to at least one contagious HCP), to 17.96 (patients exposed to at least one contagious patient) and to 34.75 (patients exposed to at least one contagious patient and one contagious HCP) compared with patients with no documented exposure in the hospital.¹³³ In The Netherlands,¹³⁴ a survey determined a list of independent predictors of influenza vaccination uptake in hospital-based HCPs: age over 40 years, presence of a chronic illness, awareness of personal risk and of the risk of infecting patients, trust in the vaccine effectiveness to reduce the risk of infecting patients, HCPs' duties—to do no harm and to ensure continuity of care, finding vaccination useful despite the constant flow of visitors and having knowledge of the Health Council's advice, social influence and convenient time for vaccination. During the pandemic A/H1N1 2009, were in favor of vaccine uptake the high risk of contact with H1N1 virus (88%) and responsibility to protect patients (71%).¹³⁵

New ways of communication?

WHO is supportive and recommends strategies¹³⁶ for reducing the morbidity and mortality associated with annual influenza epidemics. To increase public knowledge of the health and economic burden of influenza is the second among the agenda four main strategies.

(1) Implementation of strategies for improving vaccination coverage could rely on Health departments and other non office-based vaccination providers to increase access to vaccination at work and school locations, pharmacies and stores and other nonmedical sites. In addition, physicians and clinics should implement proven strategies (e.g., office-based protocols, including reminder/recall notification and standing orders).²

(2) Understanding and responding to the parents’ perception lead to better acceptance of the public and are major drivers of a vaccination campaign success. Parents of children attending day care¹³⁷ were significantly more favorable to their child influenza vaccination when the HCPs support for the vaccine was stronger, when they tended to view it safer and to know more about preventing influenza than other parents.

Perception of influenza vaccination efficacy is one of the most influential factors determining vaccine acceptance¹³⁸ as shown in previous studies of populations from diverse countries and of various ethnicities. During the pandemic A/H1N1 2009, the knowledge and perceived extent of agreement about VE were significantly associated with the highest probability of vaccination in all age groups (children OR = 10.5; adults OR = 8.85; elderly OR = 19.9).¹³⁹ In Australia,¹⁴⁰ the willingness to accept vaccination was high (67%) though significantly lower than when pandemic vaccination uptake was investigated in 2007 (88%). Parents who had the perception that A/H1N1 infection may become severe were significantly more prone to accept vaccination for their children. Subjects whose family member(s) was/were vaccinated were significantly more likely to be vaccinated (OR = 26.3 for children, OR = 5. For adults and OR = 3.72 for elderly). Similarly, Poland et al.¹⁴¹ retained a lack of concern about the individual risk of influenza to explain a lack of willingness or urgency to be vaccinated.

(3) Several studies⁶⁵^,⁷¹ have assessed the effect of information campaign consisting of physician education program and distribution of posters advertising influenza vaccines in various places offering care. To reach the WHO coverage rate objective of 75% information campaigns are essential targeting both HCPs and the general population. Yudin et al.⁷¹ reported increased awareness and rates of influenza vaccination after the intervention.

(4) The interest of media and the position and support of health authorities are key factors. The reluctance of the public and the parents is amplified in case of mistrust of information provided by public health or governmental authorities. A link between (un)willingness to be vaccinated against seasonal and/or pandemic influenza appeared, due to some similarities in decision-making for this infection.

A renewal of interest is needed with more promotion, publication and communication on the effective results. A focus on households (which family wouldn’t take care of their small infants) would be beneficial on an individual point of view, but also for the cocooning and the indirect impact.

Sources of information on influenza vaccination have a significant effect on the probability of vaccination. In Japan¹³⁹ sites providing both information and influenza vaccination were significantly associated with better coverage rates: medical facilities for children (odds ratio OR = 4.21), workplaces for adults (OR = 2.40) and medical facilities, town office and family for elderly people (OR = 6.18, OR = 5.59 and OR = 3.29 respectively). Other sources include television, radio, newspapers, internet (public website and official governmental website);⁷⁰^,⁷¹ in Japan¹⁴¹ TV/radio were the next commonly utilized for children and adults though newspaper/magazine and TV/radio showed a significantly inverse association with vaccination.

(5) Specific actions should target high risk population: Payaprom et al.¹⁴² comparing the effect of a theory-based educational leaflet, based on the Health Action Process Approach, and action planning intervention with a standard government information leaflet demonstrate greater changes on intentions (risk perception, outcome expectancies, self-efficacy) in the former without significant difference in vaccination rates between the two groups.

During the A/H1N1 2009 pandemic the factors independently associated influencing a pregnant woman's PW acceptance of influenza vaccination (and higher coverage estimates) included the receipt of a HCP's recommendation for vaccination, a perceived effectiveness of influenza vaccinations, an explanation of the vaccine safety for the fetus, a perceived high chance of influenza H1N1 infection and complications associated.⁷²^,⁷³ In many countries, obstetricians act as primary physicians during a woman’s pregnancy and are the main if not the only one capable of promoting educational interventions concerning influenza vaccination. This is reflected by the statement of 84% of PW that they would seek medical information about pandemic influenza vaccine from their obstetrician.¹⁴³

Conclusion

This overview of different aspects of influenza prevention in children relies on several paradoxes. First, the heaviest part of the burden is in the youngest infants; but the more the children are growing, the more the prevention by influenza vaccines is efficacious—without notable side effects. Second, TIV vaccines are 60 years old and the requests of registration and regulation of vaccines have evolved (in a good sense); there is a specific need in children: it is time to challenge their pragmatic utilization (full dose in the youngest? more suppleness about the interval between the two required doses in vaccine-naïve children under nine years?) and to change from a compassionate use to a targeted research and adapted vaccines, considering TIV limits in children under two years. Third, influenza virus transmission is the highest in children in semi-close communities (day-care centers, schools), diffusing to households and the population; the coverage rate achieved with a restricted policy on high risk groups (roughly 10% of pediatric population, all medical conditions together including asthma)—range of 15 to 75%—is far below the estimated threshold of 45% to achieve an indirect impact limiting the virus circulation during seasonal epidemics. Fourth, public health decisions in the vaccination field are usually taken and applied from top to bottom; the pandemic A/H1N1 has toughly demonstrated that “forgetting” about the perception and expectations of the public and the parents nearly created conflicts and at least a strong resistance impeding the quality of a program thoroughly worked on. Fifth, and not the least, HCPs are pivotal in influenza vaccination, mostly trusted by the parents; too often, they are not backed by a clear national support and there is a need to reinforce their knowledge on the disease and the vaccines.

Table 1. From Mereckiene J, Cotter S, D'Ancona F, Giambi C, Nicoll A, Levy-Bruhl D, et al.; VENICE project gatekeepers group. Differences in national influenza vaccination policies across the European Union, Norway and Iceland 2008–2009.¹⁴⁴ “Vaccination coverage for seasonal influenza for clinical risk groups and/or HCW in 11 EU/EEA countries: national seasonal influenza vaccination surveys in Europe, January 2008 and July 2009^a

	Vaccination coverage for clinical risk groups (%)		Vaccination coverage for HCW (%)
	Survey 2008	Survey 2009	Survey 2008	Survey 2009
the Netherlands	75.2	71.1	-	-
Norway^b	50	50	-	-
Germany	48.5	49	27	23
Belgium	47	-	-	-
UK	42.1	45.3	14	13.4
France	35	52	48	-
Hungary	-	32.9	23.7	23.5
Ireland	27.6	-	20	-
Romania	-	-	-	89.4
Portugal	-	-	40	26
Spain	-	-	34.9	28.1

EEA, European Economic Area; EU, European Union; HCW, Healthcare workers; ^aEU target for influenza season 2014–15, 75%; ^bVaccine coverage was calculated for the ≥65 age group and clinical risk groups together. Influenza season provided for clinical groups for Survey 2008: Belgium, 2003–4; Germany, Ireland, 2005–6; the remaining countries, 2006–7. Influenza season provided for HCW for Survey 2008: France, 2004–5; Germany, Ireland, 2005–6; the remaining countries, 2006–7. All countries reported vaccination coverage data for Survey 2009 for the 2007–08 influenza season.

Table 2. Underlying/medical conditions, occupational settings and other groups for which influenza immunization is recommended without regard to age: national seasonal influenza vaccination survey in Europe, July 2009

Medical/Underlying conditions	Number of countries where vaccination is recommended	(%)
Chronic pulmonary diseases	27	(100)
Cardiovascular disease	27	(100)
Renal disease	25	(93)
Hepatic diseases^a	15	(58)
Haematological or metabolic disorders	26	(96)
Diseases of the immune system	25	(93)
HIV/AIDS^a	24	(92)
Children taking aspirin^a	18	(69)
Pregnancy	10	(37)
Any condition that may compromise respiratory function	12	(44)

^a Twenty six countries responded to these questions. Percentage calculated from reference 26. From Mereckiene J., Cotter S., D'Ancona F., Giambi C., Nicoll A., Levy-Bruhl D., et al.; VENICE project gatekeepers group. Differences in national influenza vaccination policies across the European Union, Norway and Iceland 2008–2009.¹⁴⁴

Disclosure of Potential Conflicts of Interest

Participation to experts meetings, international congresses and lectures sponsored by the following companies: Baxter, GSK, Novartis, SP-MSD, Pfizer, Roche.

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Human Vaccines & Immunotherapeutics

Influenza vaccination coverage rate in children

Reasons for a failure and how to go forward

Special Focus Review

Influenza vaccination coverage rate in children

Reasons for a failure and how to go forward

Abstract

Facts on Influenza Vaccine Coverage IVC Rates in Children with Seasonal Vaccines Worldwide

Universal program

Influenza vaccine coverage IVC rates in high risk children

Some comparisons with different populations

Reasons for a failure and how to go forward

Published online:

Reasons for a Failure in Children

Do we know enough about the disease?

Influenza Vaccines

Strategy of immunization: targeted or universal?

A question of price and reimbursement?

Reasons for a failure and how to go forward

Published online:

Table 2. Underlying/medical conditions, occupational settings and other groups for which influenza immunization is recommended without regard to age: national seasonal influenza vaccination survey in Europe, July 2009

What about health care professionals (HCPs) interest?

Parents’ perception

How to Go Forward?

A better recognition of the burden of disease in children

Better use of the existing vaccines

(1) A worldwide collaborative effort

(2) Half dose or full dose of TIV in children less than 36 months of age?

(3) To accumulate evidence on vaccine effectiveness VE

(4) To promote the universal vaccination

Adoption of alternative vaccine technologies

Different strategies with TIV in children

Cocooning strategy for close contacts in households surrounding vulnerable newborns

Immunization of pregnant women PW with TIV

Health care professionals (HCPs)

New ways of communication?

Conclusion

References

Related research

Information for

Open access

Opportunities

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