New perspectives for hexavalent vaccines.

Vaccine xxx (2017) xxx–xxx

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Vaccine journal homepage: www.elsevier.com/locate/vaccine

New perspectives for hexavalent vaccines Pablo Obando-Pacheco, Irene Rivero-Calle, José Gómez-Rial, Carmen Rodríguez-Tenreiro Sánchez, Federico Martinón-Torres ⇑ Translational Pediatrics and Infectious Diseases, Hospital Clínico Universitario de Santiago, Santiago de Compostela, Galicia, Spain GENVIP Research Group, Instituto de Investigación Sanitaria de Santiago, Santiago de Compostela, Galicia, Spain

a r t i c l e

i n f o

Article history: Available online xxxx Keywords: Vaccines Hexavalent vaccines Combination vaccines Infanrix Hexa Hexyon Vaxelis Hexavac

a b s t r a c t With the increase in the number of routine vaccinations the development of pentavalent and hexavalent combination vaccines fitting the routine vaccination schedules became a necessity. In this respect, Europe has taken the lead in comparison with other world regions, and routine vaccination with pentavalent and hexavalent combinations including DTPa, Hib, HepB and IPV has been on European vaccination programs for >15 years. Since the marketing authorization of HexavacÒ and Infanrix HexaÒ in 2000, immunization schedules in most European countries have included hexavalent vaccines. In the last years, two new hexavalent vaccines have been licensed and commercialized worldwide. This paper presents a review of the pharmaceutical profiles of the three hexavalent vaccines currently available. In addition, we aim to review safety, co-administration, tolerability and other practical concerns of their use. Ó 2017 Elsevier Ltd. All rights reserved.

1. Introduction Since the beginning of the vaccination era, the number of vaccine-preventable diseases has continued to increase at a fast rate. Combination vaccines are individual preparations that include two or more antigens of different microorganisms. Combination vaccines have been used in adults and children alike for over half a century; in 1948 the combination of diphtheria, tetanus, and pertussis antigens into a single vaccine was first used to vaccinate infants and children [1–3]. Since then, many new techniques have been developed and the number of components combination into a single product has risen greatly [1–3]. Combination vaccines have not only solved the burden of multiple injections. Other challenges such as the storage and shipment of vaccines, the increasing number of visits, the injection of more adjuvants or the introduction of new vaccines into the calendar have been met owing to the availability of combination vaccines (Fig. 1). Commonly administered combination vaccines include as base the diphtheria and tetanus toxoid, used alone (DT or Td) or with whole cell (DTwP) or acellular (DTaP) pertussis component. To this baseline product, a plethora of components can be added. ⇑ Corresponding author at: Hospital Clínico Universitario de Santiago de Compostela A Choupana, 15706 Santiago de Compostela, Spain. E-mail address: [email protected] (F. Martinón-Torres). URL: http://www.genvip.org (F. Martinón-Torres).

Common combinations include inactivated poliovirus (IPV), Haemophilus influenzae b vaccine (Hib) and/or hepatitis B vaccine (HepB) [1–3]. With the new immunization recommendations made by the WHO, the number of routine vaccinations has grown from the initial 6 recommended EPI antigens – Bacillus Calmette-Guérin, diphtheria, tetanus, pertussis, poliomyelitis and measles – to the current 11 antigens, which additionally include HepB, Hib, pneumococcus, rotavirus, and rubella. This increase meant that the development of pentavalent and hexavalent combination vaccines fitting the routine vaccination schedules became a necessity [1–3]. In this respect, Europe has taken the lead in comparison with other world regions, and routine vaccination with pentavalent and hexavalent combinations including DTPa, Hib, HepB and IPV has been on European vaccination programs for >15 years [4]. Since the marketing authorization of HexavacÒ and Infanrix HexaÒ in 2000 (although HexavacÒ was later withdrawn from the market in 2005 [5]), immunization schedules in most European countries have included hexavalent vaccines (Table 1). In the last years, two new hexavalent vaccines have been licensed and commercialized worldwide [6,7]. This paper presents a review of the pharmaceutical profiles of the three hexavalent vaccines authorized and currently available. In addition, we aim to review safety, co-administration, tolerability and other practical concerns of their use.

http://dx.doi.org/10.1016/j.vaccine.2017.06.063 0264-410X/Ó 2017 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Obando-Pacheco P et al. New perspectives for hexavalent vaccines. Vaccine (2017), http://dx.doi.org/10.1016/j. vaccine.2017.06.063

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P. Obando-Pacheco et al. / Vaccine xxx (2017) xxx–xxx

Fig. 1. Combination vaccines: from challenges to benefits (adapted from Maman K et al. (Ref. [2])). Several key benefits from combination vaccines can be easily identified, with societal and public health & economic categories being the most important. Also important challenges have to be considered.

Table 1 Use of pentavalent and hexavalent vaccines in immunization schemes in Europe (data compiled in Jan 2017). Countries

2+1

3+1

DTPa, VPI, Hib

HepB

Priming age

Booster age

Universal

Schedule

Austria Italy Iceland Denmark Finland Norway Sweden Slovakia France Spain

3,5 m

12 m 11–13 m 12 m 12 m 12 m 12 m 12 m 10–11 m 11 m 11 m

Yes Yes No No, RG No, RG No, RG No, RG Yes Yes Yes

3, 3, – – – – – 2, 2, 2,

Greece Ireland Portugal Romania Lithuania Latvia Cyprus Croatia Switzerland Germany Belgium Netherlands Luxembourg UK Malta Hungary Czech Republic Bulgaria Estonia Slovenia Poland

2, 4, 6 m

15–18 m 13 m (Hib) 18 m (DTPa, Hib) 12 m 18 m 12–15 m 15–18 m 12–23 m 15–24 m 11–14 m 15 m 11 m 13 m 12–13 m (Hib) 18 m 18 m 10 m 16 m 24 m 12–24 m 16–18 m (DTPw, VPI, Hib)

Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes Yes Yes No, RG only Yes Yes Yes Yes Yes No, RG only Yes

2, 4 m

2, 3, 4 m

3,4–5, 6 m

only only only only

5, 12 m 5–6, 11–13 m

4, 10 m 4, 11 m 4, 11 m

2, 4, 6–18 m 2, 4, 6 m 0, 2, 6 m 0, 2, 6 m 0, 1, 6 m 2, 4, 6, 12–15 m 2, 4, 8–12 m 0, 2, 6 m 1, 6, 15–24 m 2, 3, 4, 11–14 m 2, 3, 4, 15 m 2, 3, 4, 11 m 2, 3, 13 m – 12, 13, 18 m Over 2 years 2, 3, 4, 10 m 0, 1, 6 m 0, 1, 6 m Over 2 years 0, 2, 7 m

Use of Hexavalent vaccine

Use of Pentavalent vaccine

3, 5, 12 m 3, 5–6, 11–13 m No 3, 5, 12 m No No 3, 5, 12 m 2, 4, 10 m 2, 4, 11 m 2, 4, 11 m

No 3, 5–6, 11–13 m 3, 5, 12 m 3, 5, 12 m 3, 5, 12 m 3, 5, 12 m 3, 5, 12 m No No No

No 2, 4, No 2, 4, No 2, 4, No 2, 4, No 2, 3, 2, 3, 2, 3, 2, 3, No No No 2, 3, 2, 3, No No No

No No 2, 4, 6 m No 2, 4, 6, 18 m 2, 4, 6 m 2, 4, 6, 15–18 m No 2, 4, 6, 15–24 m 2, 3, 4, 11–14 m No No 4m 2, 3, 4 m 6 w, 3, 4, 18 m 2, 3, 4, 18 m No 2, 3, 4, 16 m 3,4–5, 6 m, 2 y. 3, 4–5, 6, 18 m No

DTPa, VPI, Hib

6m 11 m 6, 12–15 m 6, 12 m 4, 11–14 m 4, 15 m 4, 11 m 13 m

4, 18 m 4m

RG: Risk groups.


3

12 mcg/2–36 mcg 10 mcg/25 mcg* 10 mcg 10 mcg – – – 8 mcg 25 mcg 25 mcg 25 mcg 25 mcg 40 IU 40 IU 20 IU 30 IU Sanofi Pasteur GSK Hexyon InfanrixÒ Hexa DTPa-HB-IPV + Hib (lyophilized)

DT: Diphtheria toxoid, TT: Tetanus Toxoid, B. pertussis antigens -> (PT: Pertussis Toxoid, FHA: Filamentous Haemagglutinin, PRN: Pertactin, FIM: Fimbriae type 2 and 3), HBs: Hepatitis B surface antigen, Hib Antigens -> (PRP-T: Polyribosylribitol phosphate conjugated to tetanus toxoid, PRP-OMPC Polyribosylribitol phosphate conjugated to meningococcal protein), Polio type 1: Poliovirus (Inactivated) Type 1 (Mahoney), Polio type 2: Poliovirus (Inactivated), Type 2 (MEF-1), Polio type 3: Poliovirus (Inactivated) Type 3 (Saukett). * Uses PRP-T as Hib Antigen. ** Uses PRP-OMPC as Hib Antigen.

40 D/8 D/32 D Ò

Sanofi Pasteur and MSD VaxelisÒ

20 IU

40 IU

20 mcg

20 mcg

3 mcg

5 mcg

10 mcg

3 mcg/50 mcg**

*

Polio type 1/2/3 PRP-T PRP-OMPC HBs FIM PRN FHA PT TT DT

DTPa-HB-IPV-Hib (liquid)

A second hexavalent vaccine [8] with slightly different composition was licensed in Europe the same year as HexavacÒ (Table 2). Opposite to HexavacÒ, Infanrix-HexaÒ needs reconstitution as the Hib component is presented in a lyophilized form. As further dis-

Company

2.2. InfanrixÒ Hexa

Commercial name

The first hexavalent [9,18] combination vaccine was introduced in a liquid presentation in the European market in October 2000. The pivotal studies and subsequent comparison with its contemporaneous alternative, InfanrixÒ Hexa, demonstrated that HexavacÒ was capable of producing seroconversion and seroprotective titres against all the antigens included in the product [19]. After the commercialization of HexavacÒ started, studies showed that 1 month after primary immunization, up to 20% of the subjects had less than 100 UI/L antibody titres and the anamnestic response after booster dose was lower than in those children with higher titres after the priming series [20,21]. This observation was also made in studies that analysed the immunogenicity of the vaccine administered concomitantly with PCV7 or MenC [21,22]. Based on the belief that peak antibody levels after immunization condition the immune memory against Hep, the European Medicines Agency (EMA) issued in September 2005 a statement recommending suspension of HexavacÒ marketing authorization [5].

Combination

2.1. HexavacÒ

Table 2 Hexavalent combination vaccines. Summary of characteristics of main hexavalent vaccines available in Europe.

Four hexavalent vaccines have been licensed in Europe in the last 16 years and Europe has been the first region in the world to adopt hexavalent vaccines as part of the routine immunization program (Table 1). As many as 20 out of 33 European countries routinely use hexavalent vaccines in children (Table 1). There are currently three different combination hexavalent vaccine preparations approved for use in the market: InfanrixÒhexa; Hexyon/Hexacima/HexaximÒ; and VaxelisÒ. Their composition is summarized in Table 2 [6–8]. Immune responses to diphtheria, tetanus and polio components of the three different hexavalent combinations that currently are available are non-inferior to that of separate components of the single components [4]. Although there is no serological correlate of protection against pertussis disease, the clinical efficacy of InfanrixÒ Hexa against pertussis has been demonstrated in household contact studies, and the more recent hexavalent vaccines have shown to achieve comparable seroprotective titers for the shared antigens [9–17]. HexyonÒ, Infanrix HexaÒ and VaxelisÒ include 2, 3 and 5 pertussis antigens respectively, with pertussis toxoid and filamentous haemagglutinin common to the three formulations [6–8]. A fourth hexavalent vaccine, HexavacÒ [18], was withdrawn in 2005 because of rapid waning of antibody titres against Hep B component [5]. Currently available hexavalent vaccines induce comparable immune responses to Hep B. InfanrixÒ Hexa contains the same HepB component as used in EngerixÒB- with a different dose compared to HexavacÒ [4]. The three hexavalent vaccines use recombinant DNA technology for B hepatitis antigen production in yeast: Infanrix HexaÒ and VaxelisÒ use Saccharomyces cerevisiae while HexyonÒ produces it in Hansenula polymorpha cells [6–8]. While VaxelisÒ and HexyonÒ are fully liquid, ready-to-use vaccines, InfanrixÒ Hexa requires reconstitution prior to administration [6–8]. Data regarding the long-term persistence of immune response, immune memory, and vaccine effectiveness of VaxelisÒ and HexyonÒ are still needed as compared to InfanrixÒ Hexa.

Adjuvants

2. Hexavalent vaccines

Aluminium phosphate Aluminium hydroxyphosphate sulfate Aluminium hydroxide, hydrated Aluminium hydroxide, hydrated, Aluminium phosphate



4


cussed below, the most significant difference brought about by the new InfanrixÒ Hexa compared to HexavacÒ was the increase in the HepB antigen (from 5 to 10 mg). A meta-analysis performed in 2013 revealed that one of the key factors for persistent seroconversion against HepB is the administration of a high dose of antigen, in agreement with current recommendations. The manufacturer also added a third pertussis antigen to the formula: pertactin (PRN). The main studies of InfanrixÒ Hexa have evaluated various approaches: two- and three-dose priming followed by a booster dose at 12–15 months of age, comparison with pentavalent plus the missing monovalent counterpart, and comparison with the already marketed HexavacÒ [23–31]. All of these studies demonstrated non-inferior immune response and a safety profile similar to comparators. Because of the difficulties experienced with HexavacÒ against HepB, results regarding the response against this antigen were awaited with much expectation. The HepB component of InfanrixÒ Hexa is the same as in EngerixÒ B, for which efficacy and persistence of immune memory for at least 20 years after vaccination have been demonstrated in endemic regions [32,33]. After the primary series and the booster dose, the response was shown to be strong enough in >95% of the subjects [24–30]. Good immunogenicity was also observed in children vaccinated at birth with a monovalent dose of HepB [34,35]. Long term protection to HepB was studied in children of 10–11 years of age. After primary vaccination 48.4% in the hexavalent group and 58.4% in the comparator group had seroprotective antibody levels. After the HepB challenge dose, the percentage with anti-HBs 100 mIU/ml increased to 93.6% in the hexavalent group and 94.4% in the comparator group. GMCs also responded with a great increase. An anamnestic response was recorded in >96% of the infants in both groups [36]. Behre et al. obtained similar results in a study of children of 12–13 years of age completed in 2016, demonstrating that InfanrixÒ Hexa is capable of inducing long term protection against HepB [37]. In addition, Omeñaca et al. carried out studies evaluating the safety, tolerability, and both short and long term antibody response in premature infants vaccinated with InfanrixÒ Hexa, demonstrating success in the majority of subjects [38–41]. As important as short term protection is the persistence of seroprotection, and multiple studies have shown the success of InfanrixÒ Hexa on this front [42–44]. Long term seroprotection was studied in children up to 9 years of age previously vaccinated with InfanrixÒ Hexa [42]. After 6 years, children were tested for antibody response against all the components, and seroprotective levels were obtained for all the antigens but PT. After a second booster dose at 5–6 years, seropositivity was present in >98% of the infants. This finding was further explored by Silfverdal et al., reaffirming the weaning in immunity against PT in 5-year-old children, recommending the administration of a pre-school booster dose in order to ensure continued protection against pertussis [45]. A review conducted by Baldo et al. [46] in Italy, analysing 7 different studies with a 3-5-11 schedule as well as the experience over a twelve-year lapse, showed that adequate immunogenicity was obtained after the primary and the booster dose for all the antigens contained in the vaccine without compromising safety.

immunogenic as InfanrixÒ hexa. Safety and tolerability were found not to be inferior to comparators [9–14]. Seroprotective levels were achieved in >95% of the infants for all the antigens except Hib and pertussis. For the former, response was enough for disease protection in >91% of the cases. In the case of pertussis, PT and FHA produced a four-fold or greater increase from the baseline in >90% and >82% of cases, respectively. After the booster dose, PT and FHA obtained similar results (>92% and >87%) and the rest of the antigens seroconverted in 100% of the cases [10–13]. With regards to HepB immunogenicity, the study enrolling the largest number of children reported no significant differences in seroprotection after the primary series in comparison with InfanrixÒ Hexa [11]. Notwithstanding this finding, GMCs were lower in Hexyon primed children (1142 mIU/mL) than in those primed with InfanrixÒ Hexa (1576 mIU/mL). Before the booster dose, seroprotection was still present in 89.8% and in 95.4% of infants included in HexyonÒ and InfanrixÒ Hexa groups, respectively [11]. After the booster administration, these values increased to 99.4% and 100%. Comparators showed similar seroprotection values. Lanata et al. obtained comparable results [14]. Other investigators evaluated the response with concomitant vaccination, with comparable results between HexyonÒ and InfanrixÒ Hexa [13]. In Argentina, Tregnaghi et al. [47] compared the use of HexyonÒ in a 2-4-6 months schedule with a DTaP-IPV//PRP-T booster vaccination at 18 months, versus the pentavalent vaccine coadministered with HepB following the same primary series and booster vaccination. After the primary series, both groups obtained similar seroprotective levels or seroconversion. For hepatitis B, the group including the hexavalent vaccine showed only slightly lower seroprotective levels than the comparator. This difference was thought to derive from the slight difference in population sizes for the groups studied. Antibody persistence at 18 months of age was similar between groups, with the exception of anti-HBs (anti–Hep B titer over10 mIU/mL was higher in second group (85.5% vs 99.5%)). This difference was associated with a higher anti–Hep B antibody GMT in this second group 2 (197 mIU/mL vs 87.6 mIU/mL). One month after booster vaccination, high seroprotective or seroconvertive levels were achieved in most participants irrespective of the priming series. A 2+1 posology including concomitant vaccination with PCV13 was studied by Vesikari et al. [48]. HexyonÒ was administered to patients at 3, 5 and 11–12 months of age and compared to InfanrixÒ Hexa in a similar posology. This study indicated similarity in the response to both hexavalent vaccines, although anti-HBs persistence prior to booster dose was lower in the HexyonÒ group (87.6% vs. 97.5% over 10 mIU/mL). On the contrary, anti-PRP levels were higher for HexyonÒ (50.6% vs. 40.8% over 0.15 mg/mL). In any case, non-inferiority was met by both groups for every antigen contained after the primary series and the booster dose. In India, a 6-10-14 weeks old priming schedule with prior administration of oral polio and HepB at birth has been studied [49]. One month after the third dose, seroprotection rates were 100% for all antigens except for diphtheria (99.3%) and for the pertussis antigens (93.8% for anti-PT and 99.3% for anti-FHA).

2.3. HexyonÒ

2.4. VaxelisÒ

The next vaccine to reach the European market was HexyonÒ [6], licensed in 2013 by the European Comission. A liquid form has been adopted for this combination vaccine, with the product prepared in a pre-filled syringe. The quantity of HepB antigen was increased to 10 mg as compared to HexavacÒ. The main trials conducted reviewed a 3-dose priming followed by booster dose. HexyonÒ, which triggered good immune response and long-lasting immune memory against HepB, was deemed as

A new liquid hexavalent vaccine appeared in the market in 2016 (Table 2). VaxelisÒ [7] brought some changes compared to previous vaccines: Hib antigen is based on PRP conjugated to meningococcal protein instead of tetanus toxoid, and 2 more pertussis antigens are added in comparison to InfanrixÒ Hexa: fimbriae 2 and 3 (FIM 2, 3) [50,51]. The clinical trials included four pivotal studies where the immunogenicity and safety of VaxelisÒ were evaluated [51]. As studies were conducted in different


5


countries of the EU and in the US, different schedules were monitored. The first schedule studied consisted of a three-dose primary immunization at 2, 4, and 6 months, with HepB at birth [15,16]. Seroprotection was achieved in >97% of the cases for all the antigens in the vaccine except pertussis. Vaccine response against PT achieved criteria for protection in 98.9% of the cases, but values for other pertussis antigens ranged from 84 to 90%. This response was deemed not inferior to the comparators [15,16]. In regards to GMCs, FHA did not meet the threshold for non-inferiority, while meeting criteria for post-infant series response rate and for both response rate and GMC after the toddler dose [15,16]. In the study where the schedule was 2, 3, and 4 months without HepB at birth, with booster dose at 12 months, antibody responses after the primary series and after the booster satisfied all acceptability criteria and met all non-inferiority comparisons to InfanrixÒ Hexa [17]. In almost all cases (>97%), the vaccine response was enough to produce protection in the infants for D, T, PT, FIM, IPV, HepB and PRP. For FHA the response was adequate in 89% of the cases and for PRN in 86.7%. The booster response was adequate for all antigens [17]. The last pivotal study conducted reviewed a two-dose priming schedule (2 and 4 months without HepB at birth) and booster dose at 11–12 months [52]. More than 92% of the infants showed a robust immunogenic response against most of the antigens in the vaccine. FHA and PRN were seroprotective in an 89% and 80.3% of cases, respectively. The booster dose was effective for all antigens [52]. Although non-inferiority criteria were met, in comparison with InfanrixÒ Hexa, GMCs were inferior after booster dose against PRN, HepB, IPV and PRP. Nevertheless, levels reached are considered sufficient for long term protection. Hib responses for this hexavalent vaccine were superior to InfanrixÒ Hexa [52], consistent with prior studies showing that PRP-OMPC included in VaxelisÒ induces protective responses sooner than PRP-T [53].

3. Co-administration of hexavalent vaccines with other vaccines There is substantial experience with hexavalent vaccines co-administered with other pediatric vaccines routinely recommended, showing adequate immune response and safety. These include PCVs, rotavirus, meningococcal conjugate, measles, mumps, rubella, and varicella vaccines (Table 3) [46]. 3.1. Pneumococcus Hexavalent vaccines have been studied in concomitant use with PCV7 and PCV13 vaccines [54]. A study compared a group of infants where PCV7 was administered at the same time as an hexavalent vaccine, to another group where only the hexavalent vaccine was injected; no significant changes in immunogenicity were observed [55,56]. After the three-dose priming, antibody titres remained at seroprotective levels, although GMCs were diminished in the co-administration group after the booster dose, but not significantly [55]. Vaccine response after the booster dose was still adequate [56]. In the Netherlands [57] a study focused on the immunogenicity of the HepB component of a hexavalent vaccine co-administered with PCV7. The serologic response was not inferior, however GMCs against the FHA component of the hexavalent were lower than in the control group. Tapiéro et al. [58] randomized infants into three groups that received, respectively, a three-dose primary series of VaxelisÒ plus PCV7; VaxelisÒ with PCV7 administered 1 month later; or VaxelisÒ plus HepB plus PCV7. A similar immunological response was found between groups; when PCV7 was co-administered, diphteria antibodies were found to be lower but still over the threshold of seroprotection. GMCs were all high and similar between groups [58]. A subsequent study of the same group after a booster dose at 15 months of age found adequate seroresponse/seroprotection rates for all antigens [59]. A comparison between concomitant

Table 3 Summary of clinical trials evaluating co-administration of hexavalent vaccines with other antigens [91]. Antigen

Vaccine

Author

Hexavalent Schedule

Reference

Pneumococcus

PCV7

Tichmann-Schumann et al. Knuf et al. Whelan et al. Tapiéro et al. Halperin et al. Berner et al. Esposito et al. Block et al. Tichmann-Schumann et al. Vesikari et al. Esposito et al.

2, 3, 4/12–23 months 2, 3, 4/12–15 months 2, 3, 4/11 months 2, 4, 6 months 2, 4, 6/15 months 11–18 months 3,5/11 months 2, 4, 6/15 months 2, 3, 4/12–23 months 3, 5/11–12 months 3, 5/11 months

55 56 57 58 59 60 61 16 55 48 61

Schmitt et al. Tejedor et al. Tejedor et al. Schmitt et al. Vesikari et al. Oliver et al. Martinon-torres et al. Knuf et al.

2, 3, 4/12 – 15 months 2, 4, 6 months 17–20 months 2, 3, 4/12 months 2, 3, 4 months 2, 3, 4 months 2, 4, 6 months 12–23 months

62 64 63 65 66 67 68 69

Silfverdal et al. Vesikari et al. Marshall et al. Block et al. Silfverdal et al.

2, 3, 2, 2, 2,

52 76 15 16 52

Vesikari et al. Zepp et al. Madhi et al. Deichmann et al.

12 months 12–23 months 15–18 months 12–23 months

PCV13

Meningococcus

MenC

A, C, W135 and Y Rotavirus

RV1 RV5

MMRV

MMRV

4/11–12 months 5/11–12 months 4, 6/15 months 4, 6/15 months 4/11–12 months

17 71 72 73


6


use of PCV7 and hexavalent vaccine, versus a pentavalent comparator vaccine as a booster dose at 11–18 months was the subject of a study by Berner et al. [60]. Both groups achieved seroprotective levels against PRP, diphtheria, tetanus, and polioviruses and an adequate booster effect. Pertussis also elicited a booster response with generally similar results in both groups. Similar seroprotection rates and increases in post-vaccination GMCs were also observed for all PCV7 serotypes [60]. Both comparators showed similar systemic and local reactions when co-administered with PCV7. Studies have also investigated the concomitant use of PCV13, demonstrating no significant interaction between vaccines [16,48,55,61]. Esposito et al. studied the concomitant use of a routine hexavalent vaccine with either PCV7 or PCV13, comparing both groups [61]. The immunogenicity results from this study showed no significant differences between PCV13 and PCV7 in the responses to concomitantly administered hexavalent vaccine [61]. Slight differences were observed in diphtheria GMCs, which rose after booster dose, meeting non-inferiority criteria both after primary and booster dose. The GMTs for polio after the booster dose were slightly lower in the PCV13 group, but met noninferiority requirements [61]. Regarding serotypes, 6B and 23F IgG levels were lower after the infant series but increased well after the third dose. The rest of the serotypes evoked an adequate response in both groups with no interferences [61]. Recently, in the pivotal study conducted in the US for VaxelisÒ, co-administration of hexavalent with PCV13 showed a lack of immune interference for the majority of the PCV13 serotypes [16]. Only the 6B serotype did not meet the prespecified GMC non-inferiority criteria; however, it would have satisfied GMC non-inferiority criteria used in an earlier pivotal study of the 13-valent pneumococcal vaccine. Pertussis antigens showed a diminished response, nonetheless, seroconversion rates were similar and the synergic effect of the multiple pertussis antigens, especially PT, is likely to suffice for protection against pertussis [16]. Another recent study [48] has shown that after a 2 + 1 schedule with either HexyonÒ or InfanrixÒ Hexa, immune response after the third dose to each of the PCV13 serotypes achieved seroprotective levels in both groups, with no significant difference between them. Even though GMCs were slightly lower in the HexyonÒ group, no clinical repercussion is expected. No major issues were reported with regards to tolerability, with a similar frequency of local reactions and a higher frequency of systemic reactions (fever, irritability), although not clinically relevant [16,54,55,58,59].

3.2. Meningococcus InfanrixÒ Hexa has been administered in different studies concomitantly with different formulations of meningococcal C vaccine (MenC) [54]. No major differences in seroprotection and tolerability were found between the co-administration group and that where the vaccines were injected at different points in time [62–64]. The Spanish group of Tejedor et al. showed a mild increase in the antibody titres against Meningococcus C if the vaccines were administered separately, but this was attributed to the priming effect of the diphteria toxoid [63,64]. Evaluation of a two-dose MenC regime versus a three-dose regime was also assessed, finding similar profiles of immunogenicity and reactogenicity between groups [65]. Immunogenicity and safety analyses showed that co-administration of HexyonÒ and MenC vaccines did not impact the immune response to the antigens of either of the two vaccines [66]. Additional studies support co-administration of MenC vaccine with VaxelisÒ in the specific schedules employed in the UK and Spain [67,68].

Last but not least, Knuf et al. showed in their study that a meningococcal vaccine against serogroups A, C, W135 and Y could be administered concomitantly with good immunogenicity [69]. 3.3. Rotavirus Two rotavirus vaccines are currently available in the market in both Europe and the US: RotarixÒ (RV1) and RotateqÒ (RV5). Concomitant vaccination with hexavalent vaccines has been implemented in different studies. Vesikari et al. [52,70] demonstrated that co-administration of RV1 or RV5 did not impair in any way the immune response to the antigens, elucidating antibody titres concordant with seroprotective levels. No safety issues were reported in this study. In the US, two studies evaluating immune response to a fully liquid hexavalent vaccine included concomitant vaccination with RV5 in all groups, and observed no noteworthy interference [15,16]. 3.4. Measles-Mumps-Rubella-Varicella Evaluation of the primary series followed by a booster dose of the Measles-Mumps-Rubella-Varicella vaccine (MMR-V) six weeks after co-administration showed no disruption of the immune response. Local reactions were slightly higher, but clinically well tolerated [71]. In South Africa, a comparison was performed between two groups of infants, one receiving a liquid hexavalent vaccine at 6, 10 and 14 weeks, and a control group receiving a tetravalent plus monovalent HepB and OPV at the same ages; both were followed by the same vaccine as booster dose at 15–18 months co-administered with MMR+V. All doses were well tolerated, with no significant interference in immune response [72]. Deichmann et al. also demonstrated that concomitant administration of MMR-V with the booster dose of an hexavalent vaccine was safe and immunogenic [73]. A recent report analysing VaxelisÒ given at 2, 3, and 4–12 months found that responses to MMR-V given concomitantly at 12 months were all non-inferior compared to InfanrixÒ Hexa [17]. 4. Safety of hexavalent vaccines Hexavalent vaccines, either as primary vaccination or as booster dose, have been well tolerated in general [7,74,75], with no major issues reported in the studies or in the follow-up after commercialization. In general, with the exception of a higher rate of fever and local symptoms (mild to moderate and transient) in comparison with control vaccines, all unlikely to be clinically significant, hexavalent vaccines did not show significant differences in tolerability [7,74,75]. Irritability on the day of injection was also frequent [7,74,75]. Tolerability issues generally arose in the first days post injection, independently of the series [7,74,75]. Co-administration with other approved vaccines although it may possibly increase reactogenicity, remains acceptable in children [32,15,16,32,52,48, 55,58–66,69–72]. A study conducted in Germany [76] to assess the need of prophylactic paracetamol when administering a hexavalent vaccine determined that paracetamol effectively prevented fever and other reactions, mainly during the infant series. However, given the generally mild nature of this events and lack of clinical concern, this practice is not routinely recommended. Association between hexavalent vaccination and the occurrence of sudden unexpected death (SUD) was suspected when a series of three SUDs happened within 48 h of the administration of the booster dose of HexavacÒ in Germany between 2000 and 2003 [4,77]. An alarm was raised and further investigation began. The Committee for Proprietary Medicinal Products (CPMP) issued a


7

P. Obando-Pacheco et al. / Vaccine xxx (2017) xxx–xxx Table 4 Posology specified in the summary of product characteristics of the different hexavalent vaccines available. Full-term infants

Ò

Infanrix Hexa

Primary Vaccination (minimum 6 weeks old) 3-dose (at least 1 month intervals between doses)

2-dose (at least 2 month intervals between doses)

HexyonÒ

VaxelisÒ

* ** ***

3-dose (at least 1 month between doses) 2-dose (at least 2 month between doses) 3-dose (at least 1 month between doses) 2-dose (at least 1 month between doses)

intervals intervals intervals intervals

Booster Vaccination At least 6 months after priming and preferably before 18 months* At least 6 months after priming and preferably before 11– 13 months* At least 6 months after priming** At least 6 months after priming** At least 6 months after priming*** At least 6 months after priming***

Preterm infants >24 weeks

HepB

Primary Vaccination 3-dose (at least 1 month intervals between doses)

In the absence of hepatitis B vaccination at birth, it is necessary to give a hepatitis B vaccine booster dose. Hexavalent vaccines can be considered for HepB booster dose. When a hepatitis B vaccine is given at birth, hexavalent vaccines can be used as replacement for supplementary HepB doses after week 6.

Booster Vaccination At least 6 months after priming and preferably before 18 months.

No data available

Can be given

Can be given

Can be given

Can be given

Not later than 36 months. Not later than 24 months. Not later than 15 months.

statement in 2003 after a statistical analysis based on the German data was performed. No plausible biological cause for association between hexavalent vaccines and SUD in the second year of life was found [4,77]. In Italy, a cases series study of neonates born in the period 1999–2004 reported that the association between hexavalent vaccine administration and risk of SUD in the first 14 days after vaccine administration was significantly lower than that estimated in Germany, and was limited to the first vaccine dose, at an age when the incidence of SUD is also the highest [4]. It was concluded that the limited increase in relative risk appeared to be confined to the first dose and may be partially explained by the confounding effect of age [4]. Other studies have confirmed so far that none of the hexavalent vaccines used at the moment had any distinct effect on SUD.

able. Recent data also supports the administration of DTaP5-IPVHB-Hib in a mixed primary series schedule (hexa/penta/hexa) including PRP-OMPC/PRP-T/PRP-OMPC, with no concerns over immunity response or safety [67]. With pertussis, there is always difficulty, as there is no correlation of serological protective levels. Due to this fact, there has not been a clear answer regarding the interchangeability of pertussis-containing hexavalent vaccines. Nevertheless, no contraindication has been stated [79]. However, it is always preferable to use the same vaccine, at least in the priming schedule. Vaccination with different vaccines containing similar antigens is deemed acceptable only if the timeliness of the immunization of the child may be affected, or if the vaccine administered previously is unknown [79].

5. Practical considerations

Rapid waning of hepatitis B vaccine induced antibodies was the reason for the withdrawal of the hexavalent combination vaccine, HexavacÒ, by the EMEA in 2005. Although >95% of children vaccinated with HexavacÒ had seroprotective antibody levels after primary vaccination, up to 20% of them were relatively low (100 IU/L) and these subjects had a lower response to booster dose [5]. This observation was also reflected in studies where HexavacÒ was co-administered with pneumococcal vaccine or meningococcus C conjugate vaccine. It was assumed that these children might not have assured protection against hepatitis B during adolescence and adulthood [5]. This theory notwithstanding, no increase in Hepatitis B infection has been recorded in those countries where HexavacÒ was widely used. In a subsequent study Zanetti et al. showed that even though 60% of the 5 to 6-year-old children studied did not have seroprotective levels against HepB prior to booster dose, a protective antibody response was induced in 92.1% of the participants. The authors concluded that HexavacÒ-vaccinated children maintained T-cell memory and were able to trigger antiHBs production by B cells when exposed to the viral antigen [82]. This data has recently been confirmed by the same group, observing a high percentage of children (>80%) with persistence of immune memory against HepB at least 10 years after a twodose primary and booster vaccination schedule with either HexavacÒ or InfanrixÒ Hexa [83]. At the same time, it has been shown that vaccine dosage and the length of the gap between the last and preceding doses in

5.1. Schedules and specific posology Schedules may differ when priming with hexavalent vaccines, but good antibody titres have been obtained regardless of the posology used (Table 4). The different schedules regarding pentavalent/hexavalent vaccines used in Europe can be summarized as either 2 + 1 or 3 + 1 approaches (Table 1). Both schemes have proved to be effective in protecting against all the immune preventable diseases recommended by the WHO, without altering other immunizations or reemergence in European countries of any diseases that could be explained by the use of different schedules [78]. 5.2. Interchangeability Given the existence of multiple vaccine manufacturers, several combination vaccines containing slightly different components are available. This raises questions as to how to proceed if the previously administered vaccine is unknown or not available at the moment of administration of the next dose [79–81]. Several studies have compared immunization with schedules containing vaccines of different manufacturers, demonstrating good immunological response [80,81]. Vaccines containing diphtheria, tetanus, poliovirus, HepB and Hib antigens are interchange-

5.3. Immunogenicity against HepB


8


the primary series, are the main determinants of immune persistence in HepB vaccination. The new generation of hexavalent vaccines increased the amount Hep B antigen to avoid this issue [84]. 5.4. Pertussis immunogenicity The main components of the aP pertussis vary between different vaccines and include PT, FHA, PRN and Fimbriae type 2 and 3 (FIM). Out of these, only the PT component is deemed essential for conferring protection against pertussis infection [85], as demonstrated for example in Denmark, where a monovalent pertussis vaccine containing only PT has been in use for >15 years with no pertussis outbreak since 2002 [86,87]. Conversely, several published papers have shown that other components such as FHA or pertactin do not protect against pertussis infection. Regardless of the inclusion or exclusion of the different components, no inferiority in immune response, immune duration, efficacy or safety has been reported in any of the commercialized DTaP combination vaccines. 5.5. Liquid versus reconstitutable vaccines Manufactures of hexavalent vaccines have produced two different vaccine presentations: on the one side, we have a vaccine that requires reconstitution of its components (InfanrixÒ Hexa) and on the other hand we have the more recent fully ready liquid vaccines, which can be administered directly (HexyonÒ, VaxelisÒ). Several studies report that fully liquid preparations can increase time efficiency [88–91]. In Germany, a survey was undertaken among professionals with regards to their preferences. Five key attributes were analysed: type of device, experience of this hexavalent vaccine in the market, preparation time, probability of handling errors, and dosage errors. Healthcare providers preferred overall the fully liquid preparation, mainly because it reduced the probability of dosage error and also diminished the preparation time [92]. In comparable contexts of immunogenicity, tolerability and safety, it would seem safe to assume that manufacturers will lean towards fully liquid vaccines in the future.

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6. Conclusions [19]

According to our literature review of the evidence available, we can state that the hexavalent vaccines currently available have shown in the pre-marketing trials and the posterior follow-up a fair amount of data supporting good immunogenicity, safety and tolerability. Concerns with long term protection, especially against HepB and pertussis, have been addressed. These vaccines will, however, need to be kept under surveillance for medium and long term effectiveness and safety, especially the most recent formulations. Considering the recent success of hexavalent vaccines, the development and licensing into the market of even more valence vaccines seems a matter of time. References [1] Skibinski D, Baudner B, Singh M. O0 Hagan D. Combination vaccines. J Global Infectious Diseases 2011;3(1):63. [2] Maman K, Zöllner Y, Greco D, Duru G, Sendyona S, Remy V. The value of childhood combination vaccines: from beliefs to evidence. Human Vaccines Immunotherapeutics 2015;11(9):2132–41. [3] Decker MD. Principles of pediatric combination vaccines and practical issues related to use in clinical practice. Pediatr Infect Dis J 2001 Nov;20(11 Suppl): S10–8. [4] Esposito S, Tagliabue C, Bosis S, Ierardi V, Gambino M, Principi N. Hexavalent vaccines for immunization in paediatric age. Clin Microbiol Infect 2014;20:76–85. [5] European Medicines Agency - - European Medicines Agency recommends suspension of Hexavac [Internet]. Ema.europa.eu. 2017 [cited 13 February 2017]. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/

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