Virosome influenza vaccine in children

Vaccine 20 (2002) B24–B28

Virosome influenza vaccine in children Christian Herzog a,∗ , Ian C. Metcalfe a , Urs B. Schaad b b

a Berna Biotech Ltd., Rehhagstrasse 79, Berne CH-3018, Switzerland Department of Pediatrics, University Children’s Hospital, Basel CH-4005, Switzerland

Abstract The use of vaccines for the prophylaxis of influenza in children is limited. This is despite high annual rates of influenza in children and despite the complications caused by influenza in children with chronic respiratory illnesses. The disease burden of influenza on infants and young children is reviewed and the potential of recommended influenza vaccination in healthy children, to reduce the direct and indirect health and socio-economic costs, is considered. Clinical experience with a virosome-formulated subunit influenza vaccine in children is presented. These clinical trials in children have shown a virosome-formulated subunit influenza vaccine to be immunogenic and well tolerated, indicating that it might be recommended for immunising healthy infants and children against influenza virus. © 2002 Elsevier Science Ltd. All rights reserved. Keywords: Influenza; Virosome; Immunisation; Children

1. Introduction Influenza is the cause of high morbidity in the general population and high mortality in at-risk groups, namely, individuals with an underlying disease which prevents an adequate immune response to an upper respiratory tract infection, the elderly and young children [1–3]. As a result vaccination is recommended for use in adults over the age of 65, high-risk individuals over the age of 6 months and those that may transmit the virus to high-risk individuals [4]. Several studies have, however, raised the question as to whether healthy children from 6 months of age should be included in the recommended groups for vaccination [4–8]. The use of vaccines has, for some time, been the primary method of influenza prophylaxis. Current influenza vaccines are divided into three categories, whole virus vaccines, which tend to be reactogenic and are recommended only for use in adults [4], and split and subunit formulations made predominantly from the influenza virus surface glycoprotein haemagglutinin [9]. Although the effectiveness of these vaccines is tried and tested they possess limited efficacy in certain groups, such as young children who receive influenza vaccine for the first time. For example, immunisation of infants and young children requires two doses of vaccine spaced 1–2 months apart [4]. This necessity of multiple parenteral vaccinations in infants may have a negative impact on the adoption of influenza vaccination and is com∗

Corresponding author. Tel.: +41-31-980-6111; fax: +41-31-980-6772. E-mail address: [email protected] (C. Herzog).

pounded by the number of vaccinations an infant is subjected to through the first 2 years of life, even taking into account the modern multivalent vaccinations available. In addition current parenteral influenza vaccinations are generally associated with an assortment of local adverse events including redness, swelling, induration and pain [6,10]. These deficiencies have led to the search for alternative antigen delivery systems; one such approach has been the development of virosomes. Previous studies have shown the safety and efficacy of virosomes as delivery systems in influenza vaccination [11,12]. The novelty of this new non-immunogenic biodegradable delivery system lies in the natural presentation of antigens with comparatively low rates of local adverse events. There are currently two licensed virosome-based products on the market, Epaxal® a hepatitis A vaccine and Inflexal® V a vaccine for influenza prophylaxis. Inflexal® V is licensed in eight European countries and has already been shown to be highly immunogenic and safe in healthy adults, the elderly and children [11,12,35,36].

2. Influenza disease burden in children and its reduction by influenza vaccination Young children and infants are specifically at-risk from influenza infection due to a lack of immunological memory to the influenza virus. In recent years, it has become apparent that there is a substantial disease burden caused by influenza infection among otherwise healthy children [13]. Further

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C. Herzog et al. / Vaccine 20 (2002) B24–B28

studies of the aetiology of influenza-like illnesses (ILI) have shown that influenza viruses in the UK may contribute up to 40% of the ILI in children up to 14 years of age over a winter season [14]. Due to the nature of the disease influenza has a much more pronounced impact on children with chronic medical conditions. It has been shown that during the winter months, affected children aged below 18 years, have 4–21 times more hospitalisations for an acute respiratory disease than healthy children of a comparable age and background [13]. In children younger than 15 years the rates for hospitalisation for treatment of cardiopulmonary disease were comparable to the rate in high-risk elderly patients [15]. In addition this study was able to identify annual counts of 122–202 out patient visits and 65–141 antibiotic courses per 1000 children in Tennessee USA to be directly attributable to influenza. Several studies have considered the impact of influenza vaccination on children with asthma [16–18]. Viral respiratory tract infections, including influenza, can exacerbate asthma, particularly in children [19]. One author extrapolated that influenza vaccination of all children with asthma could prevent 59–78% of asthma hospitalisations and Emergency Department visits during influenza seasons [16]. Although the disease burden of influenza on children suffering from chronic respiratory diseases may be anticipated, the impact of influenza on healthy children is underestimated. As a comparison, influenza immunisation of the elderly is a widely accepted practice with recognised benefits including reduction in morbidity and as a means of cost-effective prophylaxis [4,20]. This is based on the innate decrease in resistance to infection in the elderly population. Often overlooked is the fact that serious influenza-associated morbidity in healthy infants and young children can be as high as in the elderly population [21]. This study identified that for every 100 children, an annual average of 6–15 outpatient visits and 3–9 courses of antibiotics were attributable to influenza in the USA. Children infected with influenza may have further complications. For example, influenza infections have been associated with acute otitis media (AOM). The incidence of influenza-associated AOM in children under 5 years has been shown to equate to an annual rate of 46 per 1000 [22]. Acute otitis media is the leading indication for antibiotic use in children in the USA [23,24]. This is despite the fact that there is a lack of evidence of efficacy for the treatment of AOM with antibiotic agents and that there is a definite risk of development of antimicrobial resistance [25]. In some trials influenza vaccines have shown protection from AOM during respective viral epidemics [26,27]. Influenza vaccination in 6 months to 4 year old children protects against 36% of total AOM and 83% of AOM associated directly with influenza infection [28]. Children are one of the main vectors for the spread of influenza through a community. It has been shown that school age children are the main channel through which influenza is introduced into households [29,30] and that influenza

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attack rates are two to four times higher in school age children than in adults [31]. Furthermore, younger children shed larger quantities of influenza virus over more extended periods of time than other age groups, thus contributing to the spread of influenza [32,33]. As a result of an influenza epidemic in 1957, the Japanese authorities instigated legislation making influenza vaccination of schoolchildren obligatory. From the mid 1970s to the late 1980s the levels of vaccine coverage among Japanese schoolchildren ranged from 50 to 85%. During this period excess mortality rates of the general population dropped from three to four times those in the USA to a comparable level, despite an increase in the proportion of the population over 65 years of age. However, upon cessation of the obligatory influenza immunisations in 1994 the number of excess deaths increased rapidly [34]. The conclusions of this study enforce the belief that routine influenza vaccination of children would lower the transmission of influenza in the entire population.

3. Paediatric experience with virosome influenza vaccine The current recommended vaccination schemes for influenza in infants and children in the European Union (EU) and Switzerland are detailed in Table 1. Children under the age of 3 years (9 years old in the USA) are recommended to have a primer vaccination 1 month prior to a second dose. In the development of influenza vaccines for paediatric use there are currently no accepted criteria for evaluating immune responses. Therefore, for the assessment of influenza vaccine immunogenicity in serum, the EMEA guidelines for young adults have been used: 1. >40% seroconversion (≥4-fold antibody rise and achievement of a titer of ≥1:40 in hemagglutination inhibition (HI) test). 2. >70% seroprotection rate (≥1:40 in HI test). 3. >2.5-fold rise in GMT (HI antibodies). The clinical experience with Inflexal® V in children is mainly based on trials comparing the virosome influenza vaccine with Agrippal Biocine (subunit influenza vaccine) Table 1 Recommended influenza vaccination schemes for infants and young children Age

Influenza vaccine dose

6–35 months ≥3 years

1 or 2a × 0.25 ml i.m.b 1 × 0.5 ml i.m.b

a Two doses with 1 month interval for children under 36 months of age (under 9 years of age in the USA [4]), who are being vaccinated against influenza for the very first time (unprimed) [recommendations for the EU and Switzerland]. b The US Advisory Committee on Immunisation Practices, as well as many other authorities, recommends to use split or subunit vaccines for children under 12 years of age [4].

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Table 2 Summary of the methodology of the comparative Inflexal® V influenza trials in children Study Study 1 Inflexal® V (n = 43) Influvac (n = 21) Study 2 Inflexal® V (n = 25) Agrippal (n = 24) Study 3 Inflexal® V (n = 36)

Influvac (n = 28) Study 4 Inflexal® V (n = 23)

Age range of subjects (years)

Dose regimen (i.m.)

Day of immunisation

Immunogenicity population

Immunogenicity evaluated

Specific inclusion criteriaa

≥1 ≥1

1 × 0.5 mla 2 × 0.25 mla

Day 0 Day 0 and 28

n = 18 n = 22

Day 0 and 28 Day 0, 28 and 56

Clinically stable for cystic fibrosis

>6 1–6

1 × 0.5 mlb 2 × 0.25 mlb

Day 0 Day 0 and 28

n = 18 n =1

Day 0 and 28 Day 0, 28 and 56

3–12 6–12

2 × 0.25 ml 2 × 0.5 ml

Day 0 and 30 Day 0 and 30

n = 11 n = 11

Day 0, 30 and 60 Day 0, 30 and 60

3–12 6–12

2 × 0.25 ml 2 × 0.5 ml

Day 0 and 30 Day 0 and 30

n = 12 n = 11

Day 0, 30 and 60 Day 0, 30 and 60

1–5 1–5

1 × 0.5 ml 1 × 0.5 ml

Day 0 Day 0

Unprimed n = 29 Primed n = 6

Day 0 and 28 Day 0 and 28

1–5 1–5

2 × 0.25 mlc 1 × 0.5 ml

Day 0 and 28 Day 0

Unprimed n = 19 Primed n = 6

Day 0, 28 and 56 Day 0 and 28

1–5

1 × 0.5 ml

Day 0

n = 19

Day 0 and 28

No specific health criteria

No specific health criteria

No specific health criteria

i.m.: intramuscularly administered. Tolerability and safety was monitored through diaries (solicited) for 4 days following each vaccination and then unsolicited until study end. a Population randomised into one and two dose regimens irrespective of age. b Population randomised into one and two dose regimen according to age (>6/≤6 years). c Two doses for children under 36 months of age vaccinated against influenza for the very first time (unprimed) with 1 month interval.

and Influvac (subunit influenza vaccine) (Table 2). These studies assessed, in 1–12 year old children, the efficacy and tolerability of Inflexal® V (n = 104) in comparison to the two subunit influenza vaccines (n = 73), detailed here as studies 1, 2 and 3 (Table 3). Study 4 evaluated the safety and immunogenicity of Inflexal® V in 1–5 years old children (n = 23). The humoral immune parameter (HI-antibody titers) was evaluated in all studies according to the EMEA criteria already outlined and tolerability was reported descriptively in terms of rates of solicited and unsolicited adverse events (Table 4). Study 1, an open, randomised, parallel group, multicentre trial in five study centres in Switzerland compared the immunogenicity and safety of Inflexal® V and the subunit vaccine Influvac in children and adolescents with cystic fibrosis [35]. Descriptive statistics were used for the comparison of immunogenicity and for adverse event rates. Study 2, a double-blind, comparative, parallel group, single-centre trial compared in two age groups (one versus two dose regimens) the immunogenicity and safety of Inflexal® V with that of the subunit vaccine Agrippal Biocine. Study 3, an open, randomised, comparative, parallel group, multicentre trial in Switzerland compared the immunogenicity and safety of Inflexal® V with the subunit influenza vaccine Influvac. Children who had never received influenza vaccination (unprimed children) and those

who had received at least one dose of influenza vaccine in a previous season (primed children) were allocated into separate groups. Within a group, children were randomised to receive either Inflexal® V or Influvac, respectively. The children were vaccinated and monitored as shown in Table 2. An additional trial, study 4, was an open, non-comparative, multicentre trial based in Switzerland evaluating the safety and efficacy of Inflexal® V in healthy children. Overall the novel trivalent virosome-based influenza vaccine, Inflexal® V, was comparable with the immunogenicity results of all the vaccines used, in that it satisfactorily fulfilled all of the EMEA criteria (Table 3), in the case of study 3 even when using a single dose only, also in unprimed children (Table 3). The distinction of the virosome-based influenza vaccine is represented by its excellent local tolerance, especially important in the vaccination of children and infants (Table 4). The tolerability of the vaccines compared in the clinical trials were based on solicited questions covering a variety of local and systemic adverse events (Table 4). Overall it can be seen that Inflexal® V produces far fewer local adverse events, especially where pain and tenderness were concerned (37%), in contrast to the comparator vaccine used (51%). Taking into consideration the number of cystic fibrosis (CF) patients included in the integrated groups for comparison (Inflexal® V, n = 43, Comparator, n = 21) the

C. Herzog et al. / Vaccine 20 (2002) B24–B28

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Table 3 Overview of immunogenicity results of comparative Inflexal® V influenza vaccination trials in children Study

Study 1 Inflexal® V Influvac Study 2 Inflexal® V Agrippal Study 3 Inflexal® V Influvac Study 4 Inflexal® V

Dose regimen (i.m.)

Immunogenicity population

H1N1

GMT-fold increase H3N2

B

Seroconversion H1N1

H3N2

B

Seroprotection H1N1

H3N2

B

1 × 0.5 ml 2 × 0.25 ml

n = 18 n = 22

P P

P P

P P

P P

P P

P P

P P

P P

P P

1 × 0.5 ml 2 × 0.25 ml

n = 18 n =1

P P

P F

P P

P P

P F

P P

P P

P P

P P

2 × 0.25 ml 2 × 0.5 ml

n = 11 n = 11

P P

P P

P P

P P

P P

P P

P P

P P

P P

2 × 0.25 ml 2 × 0.5 ml

n = 12 n = 11

P P

P P

P P

P P

P P

P P

P P

P P

P P

1 × 0.5 ml 1 × 0.5 ml

Unprimed n = 29 Primed n = 6

P P

P P

P P

F P

P F

P P

F P

P P

P P

2 × 0.25 ml 1 × 0.5 ml

Unprimed n = 19 Primed n = 6

P P

P P

P P

P P

P P

P P

P P

P P

P P

1 × 0.5 ml

n = 19

P

P

P

P

P

P

P

P

P

The sections under each EMEA criteria correspond to the three virus groups H1N1, H3N2 and B respectively. The letters F and P represents failure and pass, respectively, of the EMEA criteria.

results for systemic adverse events showed good tolerability of Inflexal® V [35]. In addition, a study investigating the use of Inflexal® V in HIV-infected children (n = 23, mean age = 7.2 years) showed the vaccination to be well tolerated with no

influenza-like illness during 3 months follow-up. No significant changes were observed in the CD4+ count and the viral load. The conclusions of this study were that influenza vaccination should be recommended in HIV-infected children [36].

Table 4 Integrated solicited safety data from the comparative studies 1, 2, 3 and the open study 4

4. Conclusions

Adverse event

Systemic event Coryza Coughing Fatigue Headache Irritability Malaise Nausea Shivering/rigors Dizziness/vertigo Temperature ≤38 ◦ C Temperature >38 ◦ C Total vaccinees with ≥1 AE Local event Pain/tenderness Induration Redness Ecchymosis Swelling Total vaccinees with ≥1 AE

Inflexal® V (n = 127) (%)

Comparator (n = 73) (%)

31 30 34 25 6 12 8 2 6 98 2

32 34 29 13 5 15 2 0 4 99 1

54

55

37 17 8 0 4

51 23 12 0 7

44

59

Serious influenza-associated morbidity in healthy infants is equivalent to that of the elderly. The use of influenza vaccinations in infants and young children may drastically reduce the morbidity and mortality related to the disease in addition to the socio-economic costs. As children are one of the main vectors of influenza the positive effects of child immunisations may not only be evident in the individuals immunised but throughout the community. In addition, immunisations of children with chronic respiratory illnesses are likely to result in a reduction of exacerbation of the chronic disease, hospitalisations and subsequent use of antibiotics. The use of an influenza vaccine may therefore have an impact not only on the associated respiratory tract symptoms and infections but also on the current over subscription of unnecessary antibiotics. Inflexal® V is an efficacious and well tolerated influenza vaccine in children. Clinical trials have shown that use of this novel virosome-based trivalent influenza vaccine produces a strong immunogenic effect and results in fewer and more moderated local and systemic adverse events. Inflexal® V is currently licensed in eight European countries for use in infants and children from the age of 6 months.

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