A review of Haemophilus influenzae disease in Europe from 2000–2014: challenges, successes and the contribution of hexavalent combination vaccines

ABSTRACT

Introduction: The development of diphtheria-tetanus-acellular pertussis-Haemophilus influenzae type b (Hib) conjugate vaccine combinations culminated with hexavalent vaccines, the largest, most complex vaccine combinations in the immunization calendar. Hexavalent vaccines are used widely in Europe and are co-administered with multiple other recommended vaccines. Hib immunogenicity may reduce when combined with acellular pertussis antigens, or in some co-administrations. We reviewed the epidemiology of H. influenzae disease in Europe aiming to evaluate the current level of Hib control and indirectly assess the effectiveness against Hib of GSK’s hexavalent vaccine in 10 countries where it is/has been used almost exclusively.

Areas covered: We reviewed surveillance data from the European Union Invasive Bacterial Infections Surveillance Network and the European Surveillance System database from 1999–2014 and extracted case and incidence/notification rates (per 100,000 population) of invasive H. influenzae disease. We included age and serotype/strains distribution among countries in the European Union/European Economic Area region that reported to the European Centre for Disease Prevention and Control surveillance system.

Expert commentary: The impact of Hib vaccination in Europe is sustained, testifying to continued effectiveness against invasive Hib disease after the implementation of hexavalent vaccines into immunization programs, which, since 2006, has been almost exclusively GSK´s hexavalent DTPa-HBV-IPV/Hib vaccine.

KEYWORDS:

• Booster
• hexavalent vaccine
• Hib disease
• Haemophilus influenzae
• serotype
• surveillance
• vaccine

1. Introduction

Invasive Haemophilus influenzae type b (Hib) disease declined dramatically in young children in countries that implemented universal infant immunization using Hib conjugate vaccines [1]. Historically, Hib was one of the most common causes of meningitis in children under 5 years of age and was also a common cause of pneumonia, epiglottitis, sepsis, and other soft tissue infections. The mean pre-vaccine incidence of Hib meningitis among children younger than 5 years of age was 54/100,000 in the United States and 23/100,000 in Europe [1]. In the United States in 2014, the incidence of invasive Hib disease in children under 5 years was 0.19/100,000, which is well below the Healthy People 2020 target of 0.27/100,000 [2]. In Europe, the notification rate of invasive Hib disease in children under 5 years was 0.19/100,000 in 2012, and only 8% of invasive H. influenzae infections (108 of 1,352 cases with serotype confirmation) in 2012 were Hib [3].

The inclusion of Hib antigen into combination vaccines has reduced the number of injections for babies, reduces health-care professional visits, and has contributed to higher Hib vaccine coverage globally. Nevertheless, the development of combination vaccines was not without challenges. There were originally concerns with the integration of Hib vaccines into combined diphtheria–tetanus–acellular pertussis (DTPa) vaccines due to reduced Hib immunogenicity. An outbreak of invasive Hib disease cases in the United Kingdom between 1999 and 2003 coinciding with a period of introduction and use of DTPa/Hib from late 1999, stimulated debate about the effectiveness of DTPa/Hib combinations [4]. The importance of a booster dose of Hib vaccine in the second year of life and the potential for Hib interference by other vaccines were important insights gained from the United Kingdom vaccination program [5–7].

DTPa/Hib-based combination vaccines culminated in the development of hexavalent vaccines targeting six pediatric diseases: diphtheria, tetanus, pertussis (acellular), hepatitis B, poliomyelitis and Hib (DTPa–HBV–IPV/Hib). Hexavalent vaccines have been used widely throughout Europe and have become the cornerstone of many infant immunization programs. Since hexavalent vaccines were first used, other vaccines; pneumococcal conjugate vaccines (PCV), meningococcal conjugate vaccines (MCV), and most recently, meningococcal serogroup B subunit vaccines, are being progressively added to immunization calendars. In this evolving environment, continued evaluation of Hib vaccine immunogenicity and effectiveness is necessary. Here we review the control of Hib disease in Europe in the aftermath of the United Kingdom experience by reviewing available surveillance data for invasive H. influenzae diseases at the European level. In 2005, the marketing authorization for one of the two hexavalent vaccines available at that time (Hexavac, Sanofi Pasteur) was suspended because of concerns about the low immunogenicity against hepatitis B [8] and not related to effectiveness against Hib disease. As a result, GSK’s hexavalent DTPa–HBV–IPV/Hib vaccine (Infanrix hexa) remained the only hexavalent vaccine available in Europe until 2013. Based on available recommendations and commercially available hexavalent vaccines, GSK’s hexavalent DTPa–HBV–IPV/Hib vaccine is or was, the only, or main, Hib-containing vaccine used in national immunization programs in Austria, Belgium, the Czech Republic, Germany, Ireland, Italy, Luxembourg, the Netherlands, Sweden, and Slovakia. We therefore also examined Hib epidemiology in countries where GSK’s hexavalent DTPa–HBV–IPV/Hib vaccine has been used almost exclusively. These data provide indirect evidence for the effectiveness of hexavalent vaccines, which can be considered the most challenging of the currently licensed combination vaccines in terms of their development and manufacturing.

1.1. From monovalent to combination vaccines

Four different monovalent Hib conjugate vaccines containing the capsular surface antigen polyribosyl-ribitol phosphate (PRP) became widely available in the late 1980s and early 1990s: (1) PRP conjugated to tetanus toxoid (Hib-TT), (2) PRP conjugated to diphtheria toxoid (Hib-D), (3) oligosaccharide PRP conjugated to a mutated non-toxic diphtheria toxin (Hib-CRM₁₉₇), and (4) PRP conjugated to Neisseria meningitidis outer membrane protein complex (Hib-OMP). Differences in the polysaccharide, carrier protein, and conjugation method produced vaccines with somewhat differing characteristics in terms of their immunogenicity [9]. Primary vaccination with Hib-D induces lower antibody responses than other Hib vaccines; antibody persistence appears to be higher after vaccination with Hib-TT than Hib-OMP; and higher antibody responses are observed after the first dose (but not after completion of the primary series) of Hib-OMP versus Hib-TT or Hib-CRM₁₉₇ [10,11]. Hib-TT and Hib-CRM₁₉₇ induce higher quality anti-PRP antibodies compared to Hib-OMP, as evidenced by higher functional activity [12,13]. All four Hib vaccine types demonstrated efficacy against invasive Hib disease after primary vaccination, with efficacy estimates of between 95 and 100% for Hib-TT, Hib-CRM, and Hib-OMP [9]. Because of its ability to induce a marked antibody response after a single dose, Hib-OMP vaccines have special use in populations at high risk of early-onset Hib disease, such as native Alaskans and Aboriginal Australians [14].

Hib conjugate monovalent vaccine development was rapidly followed by the development of combination vaccines, most commonly based on a DTPa or diphtheria–tetanus–whole cell pertussis (DTPw) backbone. The development and manufacturing of combination vaccines poses particular challenges in ensuring that the potency and immunogenicity, stability, and safety profile are maintained compared to the monocomponent vaccines [15]. Attempts to develop DTPw-based combinations containing inactivated poliovirus vaccine (IPV) failed, for example, because thiomersal used to inactivate the pertussis component adversely impacts the antigenicity of IPV [16], and PRP may be unstable in the presence of aluminum used as adjuvant for other components of hexavalent vaccines. Sometimes such issues may be addressed: Hib component stability can be maintained by presenting the vaccine in a separate lyophilized form, or by changing the adjuvants and adding excipients to liquid-based formulations [17]. However, such measures are not always successful, as evidenced by the suspension of Hexavac.

When Hib vaccines were integrated into DTPa combinations there were concerns that Hib immunogenicity could be affected with potential impacts on efficacy. Strong evidence that DTPa/Hib-containing combinations induce high-quality functional antibodies, immune memory, and high levels of antibodies at levels associated with protection, allayed these concerns, and high vaccine effectiveness was reported in several countries using DTPa/Hib combinations [18,19]. An outbreak of invasive Hib disease in the United Kingdom from 1999 provided important lessons about dosing and scheduling of these combinations, including the importance of the booster dose.

1.2. Hib boosters and vaccine co-administration: lessons learned from the United Kingdom experience

The first European country to introduce infant immunization with monovalent conjugate Hib vaccines was Finland in 1986 [20], followed soon after by Iceland and other countries in Scandinavia. From 1990, the number of countries with routine Hib immunization programs increased steadily in Europe, with associated rapid declines in invasive Hib disease notifications [1].

Hib vaccine was introduced to the United Kingdom infant immunization schedule in 1992. Three priming doses using the early and accelerated 2, 3, and 4 months schedule were recommended without a booster dose [21]. After the introduction of routine vaccination along with an extensive catch-up campaign, the incidence of Hib disease in children fell from 22.9/100,000 in 1990 to 0.65/100,000 in 1998 [22]. From 1998, Hib disease began to increase and reached 4.6/100,000 by 2002. Vaccine effectiveness declined and appeared to be short-lived after infant vaccination, and a higher proportion of vaccine failures had received the DTPa/Hib vaccine than DTPw/Hib [4,22]. The factors believed to have contributed to the increase in Hib disease in the United Kingdom setting were reduced immunogenicity of PRP in DTPa/Hib compared with DTPw/Hib, the loss of the herd protection effects induced by the initial catch-up campaign, the loss of natural boosting due to carriage reduction, and importantly, the absence of a booster dose of Hib vaccine in the second year of life. In response, the United Kingdom ceased use of the DTPa/Hib vaccine and undertook a booster catch-up campaign in 2003. The decrease in Hib cases was immediate and fell to 1.1/100,000 in children under 5 years of age in 2004 [21]. A Hib booster dose was introduced into the routine United Kingdom national immunization schedule in 2006. In 2014, the Hib notification rate was 0.25/100,000 in children less than 1 year of age and 0.03/100,000 in 1–4 year olds.

It is worth noting that a 3-fold increase in invasive Hib disease began in the Netherlands in 2002 (from 0.4 to 1.3/100,000 population among 0–4 year olds), with most cases occurring in fully vaccinated children [23,24]. At that time, children in the Netherlands received primary vaccination with DTPw-IPV + Hib-TT (separate) at 2, 3, and 4 months of age with a booster at 11 months which had been included in the schedule since the inception of the Hib vaccination program in 1993. Unlike the United Kingdom, Hib cases occurred in all ages. No explanation of the increase is apparent. Increased genetic diversity among Hib strains observed in the Netherlands (but not the United Kingdom) may have contributed, potentially reflecting a change from child-to-child to adult-to-child transmission [24,25].

The experience using Hib vaccines in the United Kingdom serves to emphasize the variables that can impact on the success of immunization programs, and the importance of ongoing surveillance in order to allow early detection and detailed analysis of changes that might be observed. Key knowledge gained was the importance of booster vaccination in the second year of life when Hib vaccines are administered in DTPa combinations and with other antigens in infancy. An observational study in Germany estimated that the relative risk of Hib invasive disease for children not receiving a booster dose (and regardless of their priming status) was 6.1 (95% confidence interval [CI] 1.8–20.4) [19]. As well as increasing antibody concentrations, the benefits of the booster dose likely come from an increased impact on nasopharyngeal carriage, and on the expansion of the B memory cell population that helps to maintain serum antibodies at high levels [26].

1.3. Hib vaccination and hexavalent vaccines in Europe

The first Hib-containing combinations introduced in Europe in 1993 were DTPw/Hib vaccines [27], and 1996 saw the introduction of the first DTPa/Hib vaccine combination. IPV was added to these combinations in 1998, and the first DTPa-HBV-IPV/Hib hexavalent vaccines, Infanrix hexa and Hexavac, were licensed in Europe in 2000. Between 2005 after the suspension of marketing authorization of Hexavac and authorization of the first new hexavalent vaccine (Hexyon) for use in Europe in 2013, GSK’s hexavalent DTPa–HBV–IPV/Hib vaccine was the only hexavalent vaccine available in Europe. The new hexavalent vaccines are DTPa2c–HBV–IPV-Hib (2-component pertussis vaccine), licensed in 2012 for use in markets outside of the European Union (EU) as Hexaxim (Sanofi Pasteur) [28], and in 2013 for Europe as Hexyon or Hexacima, and DTPa5c–HBV–IPV–Hib (5-component pertussis vaccine; Vaxelis, MCM Vaccine Co.), which was approved in Europe in 2016 [29]. Unlike the other hexavalent vaccines and the majority of Hib vaccines used in Europe that contain Hib-TT, Vaxelis contains Hib-OMP.

2. Methods

2.1. H. influenzae disease surveillance in Europe

Each country in Europe has its own surveillance system for infectious diseases, including H. influenzae. At the European level, H. influenzae surveillance was conducted by the EU Invasive Bacterial Infections Surveillance Network (EU-IBIS) between 1999 and 2007, and was transferred to the European Centre for Disease Prevention and Control (ECDC) (sector of Invasive Bacterial Diseases coordinated by the Vaccine Preventable Disease group) in 2007 [30]. National surveillance data provided by 29 countries (27 EU countries, Iceland, and Norway) are reported regularly to the ECDC. Surveillance activities have improved over the last decade, with increasing participation of reference laboratories, standardization of laboratory testing methods, and guidelines for serotype and genotype detection [31]. While the enhanced surveillance improves the quality and representativeness of the data, continuing limitations include incomplete serotype information for some countries and differences in reported age intervals for H. influenzae disease, which limits inter-county comparisons.

2.2. Data sources and data extraction

We reviewed surveillance data from EU-IBIS and the European Surveillance System (TESSy) database from 1999 to 2014 [32]. The number of contributing countries was not consistent in each year of the review period. There were 17–20 participating countries within the EU/European Economic Area (EEA) in early years. From 2008, the number of participating countries increased to 29 (including the United Kingdom) [3,30]. We used the TESSy database in preference to national data available on official diseases surveillance websites in order to reduce the diversity and variation in data from the country websites that made it difficult to compare between countries.

Country-specific immunization coverage data (three Hib doses) were obtained from the World Health Organization immunization database [33].

Using pre-defined data extraction tables, case and incidence/notification rates (per 100,000 population) of invasive H. influenzae disease in Europe, the age distribution of H. influenzae disease (age intervals: <1, 1–4, and 65+ years), and the distribution of H. influenzae serotypes (including vaccine serotypes and non-vaccine serotypes) among all countries in the EU/EEA region that reported to the ECDC surveillance system were extracted. Internal data consistency was double-checked, and then pooled for the description of trends. The final data set was verified, discussed, and agreed within the review team.

2.3. Analysis

Our focus was on Hib immunization programs and their impact on the burden of invasive H. influenzae disease for the under 5-year population. Special attention was paid to the impact of GSK´s hexavalent DTPa–HBV–IPV/Hib vaccine on changes in the epidemiological characteristics of invasive H. influenzae disease, including changes in age and serotype distribution of invasive H. influenzae disease in countries where GSK’s hexavalent DTPa–HBV–IPV/Hib vaccine is preferentially used. In these countries, vaccination recommendations use hexavalent vaccines, such that GSK’s hexavalent DTPa–HBV–IPV/Hib vaccine has been the only vaccine available for infant immunization until at least 2013, although the use of other Hib-containing vaccines cannot be entirely ruled out.

Invasive H. influenzae notification rates were calculated per 100,000 population. We pooled data on H. influenzae cases/notification rates by country, by age-group, and through 1999–2014. The descriptive analysis used Microsoft Excel version 2010.

3. Results

3.1. Overall trends of invasiveH. influenzaedisease in Europe following vaccination

Prior to the availability of Hib vaccines, the mean incidence of Hib meningitis among children younger than 5 years of age in Europe was 23/100,000 [1]. In 2015, the average coverage of three doses of (any) Hib vaccine was 77% in Europe as compared with the global level of 64% [34,35]. Hib infections declined in children and the elderly as Hib conjugate vaccine coverage increased across Europe (Figure 1(a)). In children less than 1 year of age, Hib notification rates were between 2.1/100,000 population (2001) and 0.29/100,000 (2014). Similar declines were observed in 1–4 year olds with the lowest rate observed in 2014 (0.10/100,000 population). Hib disease in elderly (65+ years) appears to have remained stable (Figure 1(a)).

Figure 1. Notification rates for invasive H. influenzae disease in the EU/EEA, 1999–2014. (a) Age distribution of Hib invasive disease and vaccine coverage, (b) serotype distribution, (c) Age distribution of all H. influenzae invasive disease.

Hib = Haemophilus influenzae type b; NTHi = non-typeable Haemophilus influenzae. Graphs constructed from surveillance data from EU Invasive Bacterial Infections Surveillance Network (EU-IBIS) and the European Surveillance System (TESSy) database from 1999 to 2014 [32].

By contrast, notification rates for all H. influenzae infections (all Hib, non-type b serotypes and non-capsulated known as non-typeable [NTHi]) gradually increased from 0.27/100,000 population in 1999 to 0.56/100,000 population in 2014 (Figure 1(b)). This increase was mainly driven by changes in invasive H. influenzae disease caused by NTHi strains, and a less pronounced increase in notifications due to non-type b serotypes (Figure 1(b)), among all age-groups. Age-specific data show a consistent increase in all H. influenzae notifications in the elderly (65+ years), from 0.53/100,000 population in 1999 to 1.55/100,000 population in 2014 (Figure 1(c)). Over the 1999–2014 observation period, the range of annual invasive H. influenzae disease notifications remained similar in <1 year olds, and decreased in 1–4 year olds (peak at 2.24/100,000 population in 2002 and trough at 0.54/100,000 population in 2010).

3.2. Overall trends in Hib disease where GSK’s hexavalent DTPa–HBV–IPV/Hib vaccine is used almost exclusively

The large decreases in invasive Hib disease notifications observed when Hib conjugate vaccines were first introduced into national immunization programs have been sustained (Figure 2). Nine countries with complete serotype surveillance data have used GSK’s hexavalent DTPa–HBV–IPV/Hib vaccine predominantly at various times since 2005 (Table 1). The level of Hib control has been sustained in these countries during the periods of high use of GSK’s hexavalent DTPa–HBV–IPV/Hib vaccine (Figure 2).

Table 1. Immunization schedules in countries using GSK’s hexavalent DTPa–HBV–IPV/Hib vaccine.

Country	GSK’s hexavalent DTPa–HBV–IPV/Hib vaccine schedule (age) [36]	Year of Hib vaccine introduction [37]	GSK’s hexavalent DTPa–HBV–IPV/Hib vaccine used almost exclusively from:	Other vaccines scheduled in the first year of life
Austria	3 priming doses, Booster 12–24 months until 2010. Then 3, 5 Booster 12 months	1994	2006	PCV, RV
Czech Republic	2, 3, 4 Booster 10 months	2001	2007–2014	BCG, PCV, RV, MenB
Italy	3, 5–6, Booster 11–13 months	1995 (national schedule from 1999)	2005	PCV
Germany	2, 3, 4, Booster 11–14 months	1990	2006	PCV, RV (MMRV 11–14 months)
Ireland	2, 4, 6, Booster 13–15 months	1992	2008	BCG, PCV (MenC 13–15 months)
The Netherlands	2, 3, 4, Booster 11 months	1993	2011	PCV
Sweden	3, 5, Booster 12 months	1993	2007	PCV
Belgium^a	2, 3, 4, Booster 15 months	1993	2004	PCV, RV
Luxembourg	2, 3, 4, Booster 13 months	1996	2006	PCV, RV
Slovakia	2–3, 4–5, Booster 10–11 months	2000	2005	PCV

PCV: pneumococcal conjugate vaccine; RV: rotavirus vaccine; BCG: Bacillus Calmette-Guérin; MenB: meningococcal serogroup B protein vaccine; MenC: meningococcal serogroup C conjugate vaccine; MMRV: measles–mumps–rubella–varicella vaccine.

^aNo routine surveillance.

Figure 2. Invasive H. influenzae type b (Hib) notification rates among all ages in EU/EEA and in countries where GSK´s hexavalent DTPa-HBV-IPV/Hib vaccine is used and with consistent reporting available, 1999–2014.

Graphs constructed from surveillance data from EU Invasive Bacterial Infections Surveillance Network (EU-IBIS) and the European Surveillance System (TESSy) database from 1999 to 2014 [32].

In contrast to Hib notifications, notification rates for all H. influenzae disease in these nine countries gradually increased between 1999 and 2014 (Figure 2), showing similar trends to those observed in the EU region (Figure 2). In these countries and in Europe overall, this increase is driven by a higher notification rate of NTHi infections, while notifications of non-type b serotypes appear to have changed little. Among these increases, elderly have been more affected than children under 5 years of age.

3.3. H. influenzae infections in countries using GSK’s hexavalent DTPa–HBV–IPV/Hib vaccine

The almost exclusive use of GSK’s hexavalent DTPa–HBV–IPV/Hib vaccine in Austria, Belgium, the Czech Republic, Germany, Ireland, Italy, Luxembourg, the Netherlands, Sweden, and Slovakia permits an indirect assessment of the effectiveness of the vaccine in maintaining control of Hib disease and comparison with overall trends in H. influenzae disease observed across Europe.

3.3.1. Austria

GSK’s hexavalent DTPa–HBV–IPV/Hib vaccine was introduced in Austria in 2004 and has been used almost exclusively since 2006 (Table 1), with coverage rates between 83 and 85% since 2006 (Figure 3(a)). The infant immunization schedule was changed in 2010 from three priming doses and a booster dose in the second year of life, to two priming doses plus booster at 3, 5, and 12 months of age [38]. Primary vaccination also includes coadministration of PCV and rotavirus vaccines.

Figure 3. Notification rates for invasive H. influenzae disease in Austria, Czech Republic, Italy and Sweden from 1999–2014: Age distribution, vaccine coverage, and serotype distribution.

*Blank years indicate years without available data. Purple (dark) arrows represent the year when GSK´s hexavalent DTPa-HBV-IPV/Hib vaccine was introduced; green (light) arrows represent the year since GSK´s hexavalent DTPa-HBV-IPV/Hib vaccine was used almost exclusively. Panels A, C, E and G show Hib notification rates. Hib = Haemophilus influenzae type b; NTHi = non-typeable Haemophilus influenzae. Graphs constructed from surveillance data from EU Invasive Bacterial Infections Surveillance Network (EU-IBIS) and the European Surveillance System (TESSy) database from 1999 to 2014 [32].

Notification rates of Hib infections have declined to levels that are lower than the average EU/EAA rate since 2006 (range 0.00–0.02 per 100,000 population vs. 0.07–0.02 per 100,000 population). Hib disease continues to be well controlled in all age groups in Austria. There is a trend toward increased notifications of invasive disease caused by NTHi, although the data are incomplete (Figure 3(b)). The notification rate of NTHi disease increased to 0.25/100,000 population in 2014 from 0.0–0.16/100,000 in the years prior.

3.3.2. Czech Republic

Hib vaccination was introduced into the Czech Republic in 2001. Notification rates show a marked and rapid decrease in invasive Hib disease in children under 5 years of age after vaccine introduction (Figure 3(c)), with a change in the number of notifications from more than 100 annually in 1999 and 2000 to fewer than 5 cases annually after 2007. GSK’s hexavalent DTPa–HBV–IPV/Hib vaccine was introduced in 2007 and recommended for use at 2, 3, and 4 months of age with a booster dose at 10 months of age, and was the vaccine in predominant use until 2014 with high coverage rates of 99–100% (Table 1, Figure 3(c)). Between 2007 and 2014, Hib notification rates continued to fall, indicating ongoing disease control through vaccination with GSK’s hexavalent DTPa–HBV–IPV/Hib vaccine. Infants in the Czech Republic receive a birth dose of Bacillus Calmette-Guérin vaccine, as well as rotavirus vaccine, PCV, and from 2014, Neisseria meningitidis serogroup B vaccines in the first year of life (Table 1).

The notification rate of non-type b and NTHi appears to be increasing slightly in the Czech Republic. NTHi notifications increased from 2005 from 0.00/100,000 population prior to 2005, to 0.07–0.11 between 2010 and 2014. Non-type b notifications increased from 2007, from 0.00/100,000 prior to 2007 to 0.06/100,000 in 2014 (Figure 3(d)).

3.3.3. Italy

Surveillance of invasive H. influenzae disease began in 1997 and was extended nationally in 2002 [39]. From 2003 to 2006, cases of invasive H. influenzae disease were detected through the National Surveillance Network of Bacterial Meningitis. As from January 2007, data have been collected under the National Surveillance of Invasive Bacterial Disease and reported to the ECDC surveillance system.

Voluntary Hib vaccination was introduced in Italy in 1995 and included in the national vaccination program in 1999 (Table 1). GSK’s hexavalent DTPa–HBV–IPV/Hib vaccine was introduced in Italy in 2001. Since then, Hib vaccine coverage rates increased from 55% in 2000 to 94% or higher from 2004. Three doses are scheduled at 3, 5, and 11–13 months co-administered with PCV (Figure 3(e)). GSK’s hexavalent DTPa–HBV–IPV/Hib vaccine has been used almost exclusively in Italy since 2005.

Prior to the introduction of Hib vaccination, the incidence of invasive Hib disease in Italy was 8–11 cases/100,000 children under 5 years of age, varying regionally from 2.6/100,000 in the south to 23.8/100,000 in the north, with low Hib vaccination coverage rates between 4 and 34% during the same period [40]. After the introduction of GSK’s hexavalent DTPa–HBV–IPV/Hib vaccine, the incidence of Hib invasive disease in children under 5 years of age decreased to 0.07/100,000 in 2009 [39]. This suggests improved disease control as vaccine coverage increased (Figure 3). The impact of Hib vaccination on the disease notification rates was also reported by Terracciano et al. [41], who noted that Hib cases occurring between 2007 and 2014 were in unvaccinated or partially vaccinated children, as well as adults.

Along with the decrease of invasive Hib disease following vaccination, a statistically significant increase in the proportion of invasive infections caused by NTHi was observed in 2007–2009 (mainly in adults 65+ years of age) compared to 1997–2002 [39]. Surveillance conducted by l’Istituto Superiore di Sanità also indicated that most invasive disease notifications are now due to NTHi [42,43]. Each year between 2007 and 2015, 0–24.1% of serotyped H. influenzae isolates were Hib, whereas up to 82.6% were NTHi. Between 1 and 7 non-type b serotypes were reported annually (2007–2015), with only 1 case reported in 2014 [42,43].

Data reported to the ECDC for Italy is only available from 2006 (Figure 3). Since 2006, the annual number of invasive Hib notifications in children less than 1 year of age has been either 0 or 1 case (incidence 0.00 to 0.20/100,000 population), except for 3 cases in 2012 (0.56/100,000 per population) (Figure 3(e)). The Hib notification rate in 1–4 year olds was between 0.00–0.05/100,000 population annually. Notifications of NTHi infections appear to increase in 2013 and 2014, peaking at 0.07/100,000 population in 2013, but still remains well below the European average incidence of 0.33/100,000 population in 2014. However, the available data do not allow assessment of long-term trends and the notification rate.

3.3.4. Sweden

Sweden introduced Hib conjugate vaccines in 1993 [44] and vaccine coverage increased rapidly and has remained very high (98% to 99% between 1999 and 2014) (Figure 3(g)). GSK´s hexavalent DTPa–HBV–IPV/Hib vaccine was introduced in 2003 and has been used almost exclusively since 2007 according to the recommended 3, 5, and 12 months vaccination schedule, co-administered with PCV (Table 1).

Prior to vaccination, the incidence of invasive H. influenzae disease was 34.4/100,000 in children under 5 years of age (1987–1992), of which 95% were due to Hib [44]. After the introduction of Hib vaccination, the incidence of invasive Hib disease in children decreased to 3.5/100,000 in 1994, and ranged from 0.8 to 1.8/100,000 population between 2005 and 2008 [44]. The incidence of Hib disease appears to show more long-term variation in Sweden than in other countries; ranging in children less than 1 year of age from 0.0/100,000 population in some years to more than 3.0/100,000 in others (2002 and 2010) (Figure 3(g)). However, no more than four cases were reported annually in <1 year olds between 1999 and 2014.

Trends for non-type b and NTHi invasive infections appear to have increased, which is in-line with trends observed elsewhere in Europe (Figure 3(h)). NTHi notifications increased from 0.00/100,000 prior to 2005 to 1.27/100,000 in 2012. The non-type b notification rate was 0/100,000 prior to 2005 and has ranged between 0.12 and 0.35/100,000 since then.

3.3.5. Germany

Hib conjugate vaccines were introduced in Germany in 1990. GSK’s hexavalent DTPa–HBV–IPV/Hib vaccine was introduced in Germany in 2000 and it became the only hexavalent vaccine in use in Germany after 2006 (2, 3, and 4 months schedule with 11–14 month booster dose, Table 1) with coverage rates between 93 and 94% (Figure 4(a)). GSK´s hexavalent DTPa–HBV–IPV/Hib vaccine is co-administered with PCV and rotavirus vaccines in primary vaccination.

Figure 4. Notification rates for invasive H. influenzae disease in Germany, Ireland and the Netherlands from 1999–2014: Age distribution, vaccine coverage, and serotype distribution.

*Blank years indicate years without available data. Purple (dark) arrows represent the year when GSK´s hexavalent DTPa-HBV-IPV/Hib vaccine was introduced. Panels A, C, and E show Hib notification rates.Hib = Haemophilus influenzae type b; NTHi = non-typeable Haemophilus influenzae. Graphs constructed from surveillance data from EU-IBIS and the European Surveillance System (TESSy) database from 1999 to 2014 [32].

Active surveillance of Hib disease in Germany was performed within the ECDC surveillance framework by two independent national surveillance programs conducted by the German Pediatric Surveillance Unit (ESPED) from 1992: active hospital-based surveillance and active laboratory-based surveillance. Reporting of non-type b H. influenzae disease commenced in 1998 [45]. ESPED data have been used to provide serial estimates of the effectiveness of different Hib vaccines in preventing invasive Hib disease in children. The effectiveness of three vaccine doses of different Hib-combination vaccines used in Germany was estimated to be 98.8% (95% CI 98.2–99.3) between 1998 and 1999 [46], and 96.7% (95% CI 87.7–99.1) between 1998 and 2002 [19].

Using ESPED data, the effectiveness of hexavalent vaccines (including Hexavac and GSK’s hexavalent DTPa-HBV-IPV/Hib vaccine) in preventing invasive Hib disease over a 5-year follow-up period between 2000 and 2005 was 90.4% (95% CI 70.6–96.8) for a full 3-dose primary series and 100% (95% CI 52.7–100) for a full primary series plus booster dose [47].

ECDC data confirmed ongoing control of Hib disease in Germany (Figure 4(a)). In 2014, the notification rate of invasive Hib disease was 0.00/100,000 in children less than 1 year of age and 0.11/100,000 in children aged between 1 and 4 years (Figure 4(a)). Consistent with other countries and Europe as a whole, the rate of non-Hib disease has increased over the last decade, with most of this increase being due to NTHi (Figure 4(b)). In 2014, the notification rate was 0.05/100,000 for non-type-b H. influenzae serotypes, and 0.29/100,000 NTHi.

3.3.6. Ireland

Primary vaccination using Hib conjugate vaccines was introduced for routine immunization in the Republic of Ireland in 1992 (Table 1). Children in Ireland also receive Bacillus Calmette-Guérin and PCV vaccines during the first year of life. Hib notifications decreased from approximately 2.8/100,000 total population prior to Hib vaccination, to 0.26/100,000 by 2002 [48]. An increase in Hib cases in vaccinated children under 5 years of age was observed between 2002 and 2005, which led to a catch-up campaign that began in 2005 and the introduction of a booster dose in 2006 (Figure 4(c)). Hib notifications subsequently declined to 0.11/100,000 population before GSK’s hexavalent DTPa–HBV–IPV/Hib vaccine introduction (Figure 4(d)).

GSK’s hexavalent DTPa-HBV-IPV/Hib vaccine was introduced in Ireland in 2008 and has been used almost exclusively since then with primary immunization at 2, 4, and 6 months of age and a booster dose at 13 months of age (Table 1), the coverage rate exceeding 93% (Figure 4(c)). According to ECDC data, invasive Hib disease has remained well controlled in Ireland since 2008, with a low notification rate of 0.02/100,000 population across all ages, and 0.0/100,000 (no cases were reported) in children under 5 years of age in 2014 (Figure 4(c)), indicating continued efficacy of GSK’s hexavalent DTPa–HBV–IPV/Hib vaccine and effectiveness of the primary and booster regimen introduced in 2006.

Notifications of invasive infections caused by NTHi have increased in the last decade, with a less marked increase in non-type b infections. In 2014, the notification rate was 0.83/100,000 population for NTHi versus less than 0.25/100,000 annually prior to 2006 (Figure 4(d)).

3.3.7. The Netherlands

Hib conjugate vaccines were introduced in the Netherlands (3-dose priming plus booster) in 1993, followed by a marked reduction in invasive Hib disease in children under 5 years of age, from 28.7/100,000 population in 1992 to 0.8/100,000 in 2002 [24]. Following the increase in Hib disease from 2002 [23], notification rates of Hib disease remain higher in the Netherlands compared to the EU/EEA: mean rate 2.92/100,000 population in children less than 1 year of age and 0.41/100,000 population in 1–4 year olds in the Netherlands, versus 0.29/100,000 and 0.10/100,000 population, respectively, for the whole of the EU/EEA in 2014. No explanation is readily forthcoming.

GSK´s hexavalent DTPa-HBV-IPV/Hib vaccine was introduced in the Netherlands in 2007 in a primary schedule recommended at 2, 3, and 4 month of age with a booster dose at age 11 months, and has been used almost exclusively since 2011 (Table 1). Children in the Netherlands also receive PCV during the first year of life. Notification rates for Hib disease have remained comparatively stable in all ages since the introduction of GSK’s hexavalent DTPa–HBV–IPV/Hib vaccine (Figure 4(e)).

Notification rates of all H. influenzae disease have been higher than the EU/EEA average in most years between 1999 and 2014: range 0.43–0.95/100,000 in the Netherlands and 0.27–0.56/100,000 in the EU/EEA (Figure 2). Notification rates of NTHi have increased over time, reaching 0.7/100,000 in 2014, whereas non-type b H. influenzae notifications appear to have remained stable, between 0.07–0.10/100,000 population since 2007 (Figure 4(f)).

3.3.8. Other countries where GSK’s hexavalent DTPa–HBV–IPV/Hib vaccine is used almost exclusively

GSK’s hexavalent DTPa–HBV–IPV/Hib vaccine has been used almost exclusively in Belgium since 2004, Luxembourg since 2006, and Slovakia since 2005 (Table 1). National Hib notification data for these countries are less robust than the countries reported above, but the available information is provided for completeness.

Belgium introduced Hib conjugate vaccines in 1993 with coverage estimated to be 92–98% from 2004. Belgium has a voluntary laboratory notification system that reports to ECDC. According to ECDC surveillance reports, the majority of H. influenzae infections in 2012 were in 65+ year olds (41/74, 55.4%) [3]. No information on the serotype distribution was available.

Luxembourg introduced vaccination with GSK’s hexavalent DTPa–HBV–IPV/Hib vaccine in 2001 in a 2, 3, 4 months primary schedule with a booster dose recommended at 13 months of age. The vaccine is co-administered with PCV and rotavirus vaccine. Hib vaccine coverage rates reached 98% in 2002 and have remained at 98–99% since then. No Hib cases have been reported during the 1999–2014 period, reflecting the small population of Luxembourg and likely good ongoing control of Hib disease.

Hib vaccination commenced in Slovakia in 2000 and GSK’s hexavalent DTPa–HBV–IPV/Hib vaccine has been used almost exclusively since 2005. Primary vaccination with co-administered PCV is recommended at 2–3 and 4–5 months of age with booster at age 10–11 months (Table 1). The Hib vaccine coverage rate has been 97–99% since 2003. There were 0–5 cases of invasive H. influenzae disease in Slovakia between 2008 and 2012, compared to 19 cases in 1999 [3,37], suggesting ongoing control of Hib disease.

3.4. Limitations of the surveillance data

The available Hib surveillance data are influenced by country-specific health policies and disease surveillance systems, diagnostic and case detection methods, and reporting processes. These factors, as well as possible changes in the case-definition of invasive H. influenzae disease and laboratory testing methods over the years between 1999 and 2014, can all influence the accuracy and completeness of reporting, particularly when the number of cases is very low. Because of these variations, comparisons of Hib disease incidence between countries and trends over time should be interpreted with caution.

3.5. Breakthrough disease and administration errors: GSK’s hexavalent DTPa–HBV–IPV/Hib vaccine post-marketing surveillance

Post-marketing surveillance of GSK’s hexavalent DTPa–HBV–IPV/Hib vaccine includes regular review of all spontaneous reports of adverse events, including breakthrough cases of Hib disease in vaccinated children and drug administration errors, reported to GSK’s worldwide safety database. Breakthrough cases are specifically monitored as any change over time could be a signal of decreasing vaccine effectiveness. Drug administration errors are of interest because GSK’s hexavalent DTPa–HBV–IPV/Hib vaccine consists of a pre-filled syringe containing the DTPa–HBV–IPV component and a separate vial containing the lyophilized Hib component that requires reconstitution (with the DTPa–HBV–IPV component) prior to administration.

Since launch in October 2000 until October 2015, the rate of Hib breakthrough cases was estimated to be 0.027 cases per 100,000 doses distributed. Over a 12-month period from October 2014 until October 2015, product preparation errors resulting in the Hib dose being missed were reported at a rate of 0.39/100,000 doses distributed. Despite the recognized limitations of passive adverse event reporting [49], these data provide reassurance that the occurrence of reported breakthrough cases is rare, and that errors in administration due to the requirement for reconstitution occur very infrequently.

4. Expert commentary

Hexavalent vaccines are the backbone of pediatric immunization programs in many countries in Europe. Initially administered alone, hexavalent vaccines are now frequently co-administered with PCVs, MCVs, and/or human rotavirus vaccines. Meningococcal serogroup B subunit vaccines have also been recently introduced into some schedules. Our review of ECDC surveillance data indicate that invasive Hib disease is generally well controlled in Europe where the majority of Hib vaccines administered are Hib-TT. Within the limitations of the data, sustained control is observed in countries where GSK’s hexavalent DTPa–HBV–IPV/Hib vaccine is used almost exclusively and co-administered with PCV, suggesting ongoing effectiveness against invasive Hib disease in this setting. Rates of Hib disease appear similar in countries using GSK’s hexavalent DTPa–HBV–IPV/Hib vaccine where the primary schedule is two priming doses with booster, and in countries where three priming doses and booster are administered.

The impact of Hib vaccination in Europe is sustained across different settings, testifying to the continued effectiveness against invasive Hib disease after the implementation of hexavalent vaccines into immunization programs, which, since 2006, has been almost exclusively GSK’s hexavalent DTPa–HBV–IPV/Hib vaccine. The stable, low reporting rate of vaccine failure cases further supports ongoing effectiveness. Maladministration has been raised as a concern due to the need for reconstitution of the Hib component, with possible impacts on the immunogenicity of the incorrectly prepared dose. The sustained impact on invasive disease and the low spontaneous reporting rate of maladministration and vaccine failure cases in GSK’s worldwide safety database do not give rise to concerns.

Serotype replacement may potentially occur after implementation of all conjugate vaccines. However, it is not easy to unravel the potential contributions of Hib vaccines and PCVs to any observed trends. Notification rates of capsulated non-type b strains appear to have changed only slightly over time in Europe, whereas an increase in NTHi notifications is more apparent. NTHi is increasingly recognized as an emerging pathogen causing diseases of the respiratory tract as well as invasive disease including meningitis and septicemia [50]. Most of the increase in NTHi invasive disease has been observed in adults aged 65+ years, although NTHi continues to affect young children. Similar observations have been made in the United States and Canada [51,52].

5. Five-year view

After an 8-year period where the only hexavalent vaccine available to providers was GSK’s hexavalent DTPa-HBV-IPV/Hib vaccine, new hexavalent vaccines are now becoming available. As new hexavalent vaccines are introduced into vaccination calendars, and as immunization programs continue to expand with additional vaccines to be co-administered with the hexavalent vaccine backbone, Hib surveillance needs to remain an important goal in Europe to ensure that the current level of Hib disease control is sustained. Further work is needed to improve surveillance methods, with more countries performing serotype analyses in the future.

Key issues

• Early Hib control in Europe was achieved with Hib monovalent conjugate vaccines that were gradually replaced with combination vaccines that contribute to higher acceptance and coverage. Hexavalent vaccines are the most complex combinations in terms of formulation and manufacturing.

• Initially administered as monovalent vaccines, Hib vaccines are nowadays often given as hexavalent vaccines co-administered with additional recommended vaccines. It is important to document sustained Hib control as infant vaccination schedules evolve.

• In 2014, the average European coverage of three doses of (any) Hib vaccine was 85%. In children < 1 year of age the Hib notification rate in Europe in 2014 was 0.29/100,000.

• Hib disease continues to be well controlled in Europe where most Hib conjugate vaccines are conjugated to TT.

• GSK´s hexavalent DTPa-HBV-IPV/Hib vaccine was the only hexavalent vaccine available in Europe from 2005 until 2013, and has accumulated 16 years of clinical and safety experience since its launch in 2000.

• Hib control has been sustained in nine countries with comparable serotype surveillance data that used GSK´s hexavalent DTPa-HBV-IPV/Hib vaccine almost exclusively at various times since 2005. In these countries the vaccine is co-administered with PCV, and is used in a 2-dose priming or 3-dose priming schedule. Within the limitations of the data, continuing low rates of invasive Hib disease suggest ongoing vaccine effectiveness in these different settings.

Contributorship

J Dolhain developed the concept of the review paper and provided Hib disease background. S Wang collected all country data and performed data analysis, and drafted the outline of the manuscript. All authors were involved in data interpretation, reviewed the manuscript critically for important intellectual content and approved the final version to be published. All authors take accountability for all aspects of the published manuscript.

The views and opinions of the authors expressed herein do not necessarily state or reflect those of ECDC. The accuracy of the authors’ statistical analysis and the findings they report are not the responsibility of ECDC. ECDC is not responsible for conclusions or opinions drawn from the data provided. ECDC is not responsible for the correctness of the data and for data management, data merging and data collation after provision of the data. ECDC shall not be held liable for improper or incorrect use of the data.

Trademarks

Infanrix hexa is a trademark of the GSK group of companies. Hexaxim and Hexacima are trademarks of Sanofi Pasteur. Hexavac and Hexyon are trademarks of Sanofi Pasteur MSD S.N.C. Vaxelis is a trademark of MCM Vaccine Co.

Declaration of interest

J Dolhain and M Tafalla declare they are employed by the GSK group of companies. L Hanssens was a GSK employee during the manuscript development; she is now an independent expert. S Wang was working as a consultant (Novellas Healthcare c/o GSK) at the time the manuscript was prepared. J Dolhain, L Hanssens and M Tafalla hold shares in the GSK group of companies. 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.

Acknowledgments

European Haemophilus influenzae surveillance data were obtained from information made public by the European Center for Disease Prevention and Control. Data from The European Surveillance System – TESSy was provided by Austria, Czech Republic, Italy, Sweden, Germany, Ireland, The Netherlands, Belgium, Luxembourg and Slovakia and released by ECDC.

The authors thank Frederik Fierens (GSK, Belgium) for critically reviewing the manuscript. Writing support services were provided by Joanne Wolter (independent medical writer c/o GSK); editing and publication co-ordinating services were provided by Iudit-Hajnal Filip (XPE Pharma & Science c/o GSK).

Additional information

Funding

GlaxoSmithKline Biologicals SA supported all costs associated with the development of this manuscript.