Hexyon - WebEdCafe.com · and reduce vaccine-related costs. In addition to the benefits provided through the use of combination vaccines for paediatric vaccination, changes in vaccine

Hexyon®

A Guide for Healthcare Practitioners in the European Union

Diphtheria, tetanus, pertussis (acellular, component), hepatitis B (rDNA), poliomyelitis (inactivated) and Haemophilus influenzae type b conjugate vaccine (adsorbed)

Monograph from Elsevier

This medicinal product is subject to additional monitoring

Disclosure: The content of this monograph was created with editorial supervision by Elsevier, with funding and review provided by Sanofi Pasteur MSD.

Hexyon® (diphtheria, tetanus, pertussis (acellular, component), hepatitis B [rDNA], poliomyelitis [inactivated] and Haemophilus influenzae type b conjugate vaccine [adsorbed]) is a fully liquid, ready-to-use, paediatric hexavalent vaccine. Hexyon® was granted marketing authorization from the European Commission in April 2013. It was developed by Sanofi Pasteur and is now registered in more than 70 countries worldwide. Hexyon® is commercialized under three brand names: Hexyon® by Sanofi Pasteur MSD in Western Europe, Hexacima® by Sanofi Pasteur in Eastern Europe, and Hexaxim® by Sanofi Pasteur in the rest of the world.

December 2015

COVER ART, TOP TO BOTTOM: DIPHTHERIA, James Cavallini/Science Source; TETANUS, James Cavallini/Science Source; PERTUSSIS, A. Barry Dowsett/Science Source; POLIOMYELITIS, NIBSC/Science Source; HAEMOPHILUS INFLUENZAE, David M. Phillips/Science Source; HBV, Science Source

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Hexyon®: A Guide for Healthcare Practitioners in the European Union

PREFACE As a growing number of new and improved vaccines for the prevention of childhood diseases are developed, healthcare providers are faced with the growing challenges of carrying out complex immunization schedules. Combination vaccines can simplify the vaccination schedule, reduce the numbers of injections needed, and potentially help improve coverage and reduce vaccine-related costs. In addition to the benefits provided through the use of combination vaccines for paediatric vaccination, changes in vaccine formulation can contribute to greater convenience for practice.

Many vaccines require multiple steps, including reconstitu-tion, to prepare for use. Hexyon® (DTaP-IPV-Hep B-Hib) is a fully liquid hexavalent combination paediatric vaccine that combines protection against 6 major infectious diseases included in the national immunization calendars of most countries in Europe: diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis and Haemophilus influenzae type b. Hexyon® is indicated for primary and booster vaccination of infants and toddlers from 6 weeks to 24 months of age in Europe. The overall safety and immunogenicity profile of Hexyon® is similar to other currently available hexavalent combination as well as pentavalent (DTaP/IPV/Hib) plus Hep B paediatric vaccines. Hexyon® uses a new, fully liquid technology so that no reconstitution is needed. The vaccine is ready to use, which may reduce the risk of contamination or handling errors, increase security of use and allow faster preparation, simplifying its use by healthcare practitioners.

1. EXECUTIVE SUMMARYOverview: l Hexyon® (DTaP-IPV-Hep B-Hib) is a hexavalent vaccine indicated

for primary and booster vaccination of infants and toddlers aged 6 weeks to 24 months of age to provide protection against diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis, and invasive diseases caused by Haemophilus influenzae type b.

l Hexyon® is fully liquid and therefore does not require the recon-stitution of the Hib component. All antigens are contained in the pre-filled syringe and thus the vaccine is ready to use.

Immunogenicity:l Hexyon® has been demonstrated to be highly immunogenic for

each of the antigens, in all ethnicities and under various dosing schedules.

l Statistical analysis has confirmed that the immunogenicity of Hexyon® is similar to hexavalent control vaccines or pentavalent DTaP-IPV-Hib plus stand-alone hepatitis B vaccines.

l Hexyon® can be co-administered alongside routine paediatric vaccines, including meningococcal C conjugated vaccine, pneu-mococcal conjugated vaccines, rotavirus vaccines and MMR vaccines.

Safety and experience:l The safety profile of Hexyon® has been established in over

13 clinical trials with over 5000 infants.l Hexyon® is currently available in more than 20 countries

worldwide and more than 3 million doses have been distributed.

CONTENTSPreface ...................................................................................................................................................................................................................................... 3

1. Executive summary ........................................................................................................................................................... 3

2. Serious diseases preventable by hexavalent vaccine .............................................................................................................................................................. 4

Diphtheria ....................................................................................................................................................................................................................... 4Tetanus ................................................................................................................................................................................................................................... 4Pertussis ............................................................................................................................................................................................................................... 4Poliomyelitis ............................................................................................................................................................................................................... 4Haemophilus influenzae type B invasive disease ....................................................................... 5Hepatitis B ....................................................................................................................................................................................................................... 5Conclusions ................................................................................................................................................................................................................. 5

3. Childhood immunization recommendations in the European Union .................................................................................................................................7

4. Sanofi Pasteur MSD acellular pertussis-based combination paediatric vaccine .......................................................................8

Experience with combination paediatric vaccines .............................................................. 8Development of Hexyon® hepatitis B antigen .............................................................................. 8Effectiveness of Tetravac® and Pentavac® against pertussis ........................... 8Effectiveness of combination vaccines against Haemophilus influenzae type B disease ..................................................................................................... 9Use of inactivated poliovirus in the pre- and post-polio eradication eras ......................................................................................................................................................................................... 10Summary ...................................................................................................................................................................................................................... 10

5. Hexyon® immunogenicity profile ......................................................................................12Immune responses after primary and booster vaccination ........................12Persistence of immune responses after primary and booster vaccination ............................................................................................................................................................................................................13Concomitant administration of Hexyon® with other routine paediatric vaccines .............................................................................................................................................................................18Summary .......................................................................................................................................................................................................................18Conclusions .............................................................................................................................................................................................................19

6. Hexyon® safety profile ......................................................................................................20Safety and reactogenicity in primary vaccination ........................................................... 20

Safety of booster vaccination ......................................................................................................................................... 21Safety with concomitant vaccinations ....................................................................................................... 21

Most common adverse events .................................................................................................................................. 21

7. Hexyon® in clinical practice: Benefits of ready-to-use presentation ..................................................................................... 22

Handling errors during vaccine reconstitution ...................................................................... 22Presentation and guidelines for usage...................................................................................................... 23Composition of Hexyon® .......................................................................................................................................................... 23Presentation and shelf life of Hexyon® ...................................................................................................... 23Approved uses of Hexyon® .................................................................................................................................................. 23Recommended vaccination schedule for Hexyon® ....................................................... 23Method of administration ...................................................................................................................................................... 24Contraindications for use of Hexyon® ......................................................................................................... 24Concomitant administration with other vaccines............................................................ 24

8. Conclusions .......................................................................................................................................... 25

Acknowledgements ............................................................................................................................................................................ 25

Glossary.................................................................................................................................................................. 26

List of abbreviations ...................................................................................................................... 27

Disclaimers ....................................................................................................................................................... 27

List of Illustrations .............................................................................................................................. 28

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associated with tetanus have been drastically reduced throughout the world through vaccination with vaccines containing tetanus toxoid (T)11. Nonetheless, according to World Health Organization (WHO) estimates, in 2008 approximately 63 000 worldwide deaths occurred in children aged under 5 years13.

Confirmed cases of tetanus in the EU are rare—123 reported by 26 EU/EEA countries in 2012, a notification rate of 0.03 per 100 000—due to the widespread use of tetanus vaccination in Member States11. Most of the reported cases (80%) occurred in the elderly (≥65 years), probably related to lower coverage or waning immunity. This emphasizes the need to maintain high vaccination rates in all age groups and to employ catch-up/booster strategies in countries with higher rates of disease.

PertussisWhooping cough outbreaks still occur among unvaccinated or incompletely vaccinated children in the EU/EEA.Pertussis (whooping cough) is a highly transmissible respiratory infectious disease caused by the bacterium Bordetella pertussis14. Pertussis first manifests as mild upper respiratory tract symptoms; cough, initially intermittent, becomes paroxysmal. In typical cases paroxysms terminate with a respiratory “whoop”, which may be followed by post-tussive vomiting. Symptoms may take weeks or months to resolve5,14. Childhood vaccination programmes with either acellular pertussis (aP) vaccines or whole-cell pertussis (wP) vaccines have dramatical-ly reduced the incidence of pertussis in developed countries. However, pertussis continues to be a public health concern even in countries with high vaccination coverage5.

In 2011, the number of pertussis cases in Europe showed an increase for the first time since 2008, mainly due to significant increases in some countries such as Norway and The Netherlands1. In 2012 the case rate was more than twice as high as in previous years at 10.93 confirmed cases per 100 000 population (42 525 cases, 38 840 confirmed, reported by 28 EU/EEA countries)11. The disease often goes unrecognized in older children and adults, placing vulnerable young, unvaccinated children at increased risk of infection. Increased awareness of the disease in recent years may account, in part, for the increased incidence in pertussis cases, but the increase likely also reflects of waning immunity among older individuals and unvaccinated or incompletely vaccinated individuals1.

2. SERIOUS DISEASES PREVENTABLE BY HEXAVALENT VACCINE

Routine childhood vaccination programmes have had a large impact on public health in the European Union (EU) Member States, leading to either elimination or excellent control of many preventable infectious diseases1. Vaccination against serious childhood diseases covered by the combination vaccine Hexyon®—diphtheria, tetanus, pertussis, invasive diseases caused by Haemophilus influenzae type b, poliomyelitis and hepatitis B—is recommended by the European Centre for Disease Prevention and Control (ECDC), as well as individually by most Member States2. Despite these recommendations and the clear positive impact of routine vaccination, however, these diseases still occur and can be deadly in developed countries1-8.

DiphtheriaDiphtheria can still be deadly in

developed countries. Diphtheria is an acute infection

affecting the upper respiratory tract and, occasionally, the skin9. The disease is most commonly caused by the bacterium Corynebacteri-um diphtheriae, which produces

a toxin that can cause cardiac and neuronal damage and may lead to

death at any age9. Widespread infant vaccination with vaccines containing

the diphtheria toxoid (D) protects against diphtheria and has dramatically reduced its incidence

globally by more than 90% in the past 2 to 3 decades; nonetheless, over 10% of cases still result in death3. A total of 7321 cases of diphtheria were reported worldwide to the WHO in 201410.

In Europe in 2012, only 27 cases of diphtheria, including 16 caused by C. diphtheriae, were reported within 29 reporting EU/European Economic Area (EEA) countries (a notification rate of 0.01 per 100 000 population), reflecting the high vaccination coverage in the region. Of the reported cases where vaccination status was recorded, most (7 of 11) were not vaccinated11.

TetanusTetanus is often fatal, but because

Clostridium tetani is widespread, it cannot be eradicated.

Tetanus is caused by a toxin produced by the bacterium Clostridium tetani. This bacterial pathogen is widespread in the environment and infection usually

occurs through scratches or wounds in the skin12. Symptoms include

headache, jaw cramping, and muscle spasms (sudden and involuntary muscle

tightening)4. Tetanus is often fatal, but deaths

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Haemophilus influenzae type b (Hib) is a bacterium that can cause a range of diseases including severe pneumonia and meningitis21. Hib disease, particularly invasive disease, can result in substantial morbidity and mortality, mostly in developing countries7,21. The WHO recommends the inclusion of conjugate Hib vaccines in all infant immunization programmes as the only effective means of preventing Hib disease7. Worldwide 192 countries had introduced Hib vaccination into their national immunization programs by the end of 201422. Global coverage with 3 doses of Hib vaccine is estimated to be 52%22. Nonetheless, the WHO estimates that Hib causes 3 million episodes of serious disease and 400 000 deaths annually worldwide23.

During the past 20 years, routine immunization with Hib conjugate vaccines, made from Hib polysaccharide conjugated to tetanus protein, has resulted in a dramatic decrease in the incidence of Hib disease7,21. Between the late 1990s and 2009, all EU/EEA countries introduced routine Hib vaccination in their early childhood vaccination schedules and invasive H. influenzae disease is now rare in the EU/EEA countries24. The most recent data, for 2012, showed rates of invasive Hib at 0.49 cases per 100 000 of the EU/EEA region population24. The highest country-specific rates in Europe in 2012 were in Sweden (2.26 per 100 000) and Norway (1.56 per 100 000)24. Overall, reductions in Hib disease in the WHO European region have fallen from the pre-vaccine era by an estimated 88–100% for Hib meningitis and 78–100% for all invasive Hib disease7. The ECDC follows the WHO recommenda-tion that Hib conjugate vaccine should be included in all routine childhood immunization programmes with a three-dose primary series given at the same time as diphtheria, tetanus and pertussis vaccines, with a booster administered in the second year of life to increase protection7.

Hepatitis BMore than 13 million people in

the WHO Europe region are estimated to live with chronic

hepatitis B, and 36 000 die annually from causes related to hepatitis B infection.

Hepatitis B virus (HBV) accounts for most of the chronic hepatitis

burden caused by viral hepatitis worldwide25. Infection can result in

lifelong chronic infection that can lead to liver cirrhosis, liver cancer, and death. The risk of developing chronic HBV infection is highest in children aged under 5 years, with chronic infection developing in 90% of infants infected during their first year of life compared with 5% of adults infected25. People with chronic HBV infection have a 15–25% risk of dying prematurely from HBV-related cirrhosis and liver cancer8. Ap-proximately 780 000 people die each year from HBV infection, according to the WHO26. In the WHO European Region an estimated 13.3 million people live with chronic hepatitis B (1.8% of adults), which results in death in about 36 000 annually27.

Well-tolerated, effective recombinant hepatitis B vaccines containing the hepatitis B surface antigen have been available

PoliomyelitisAlthough on the verge of eradication

worldwide, poliomyelitis risk persists on the borders of

Europe.Poliomyelitis is a highly infectious and sometimes fatal disease caused by any one of three poliovirus serotypes, designated

types 1, 2 and 315,16. Poliovirus infects the nervous system and can

cause paralysis and other neurologic complications. Although fewer than 1% of

polio patients develop irreversible paralysis, an estimated 5-10% of these patients die because their breathing muscles become immobilized17. The highest case-fatality rates have been reported among adolescents and young adults, but are commonly between 5% and 10%.15. The WHO estimates that since 1988, the year the Global Polio Eradication Initiative (GPEI) was launched18, the number of polio cases worldwide has fallen from 350 000 cases to 359 reported cases in 2014, a decrease of over 99%17. This has been largely due to the widespread use of both oral polio (OPV) and inactivated polio (IPV) vaccines. By March 2014, 80% of the world’s population was certified as living in a WHO-certified polio-free region17. The WHO European Region was declared polio-free in 2002 and it has remained so, according to the recent surveillance report for EU/EEA countries (2012 data)11.

Since 2012, however, the number of polio cases has been increasing globally due to virus importation from polio-endemic countries to other countries17, which the ECDC has identified as a potential threat to Europe11. In 2014 the WHO declared the international spread of wild poliovirus (WPV) a public health emergency and issued recommendations that all residents of and travellers from polio-infected countries should be followed to interrupt WPV transmission as rapidly as possible20. An increasing number of paralytic cases have been associated with OPV use19. Although OPV is no longer used in EU Member States (except in Poland, which still uses an OPV booster dose11), it is still used in many countries worldwide. The GPEI’s Polio Eradication and Endgame Strategic Plan for 2013–2018 calls for progressive withdrawal of OPV and introduction of IPV worldwide17,19. Meanwhile around 12 million people under the age of 29 in the EU are believed to be unvaccinated; the ECDC recommends that they should to be identified and targeted measures taken urgently to increase vaccination coverage in these populations11.

Haemophilus influenzae type b invasive diseaseNational immunization schedules in all

EU/EEA countries include the Hib vaccine, which has led to a marked

decrease in invasive Hib disease. The ECDC emphasizes the need for continued encouragement and promotion of routine vaccination to maintain high

vaccine coverage rates.

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13. World Health Organization. Immunization surveillance, assessment and monitoring. Estimates of disease burden and cost-effectiveness. Available at http://www.who.int/immunization/monitoring_surveil-lance/burden/estimates/en/index.html. Accessed 18 May 2015.

14. Edwards K, Decker M. Pertussis vaccines. In: Plotkin S, Orenstein W, Offit PA, eds. Vaccines, 6th ed. Philadelphia, PA: Saunders Elsevier; 2012:447–492.

15. Sutter RW, Kew OM, Cochi SL, Aylward RB. Poliovirus vaccine—live. In: Plotkin SA, Orenstein WA, Offit P, eds. Vaccines, 6th ed. Philadelphia, PA: Saunders Elsevier; 2012:598–645.

16. World Health Organization, Regional Office for Europe. Poliomyelitis. Available at http://www.euro.who.int/en/health-topics/communica-ble-diseases/poliomyelitis. Accessed 18 May 2015.

17. World Health Organization. Poliomyelitis. Fact Sheet N°114. Updated October 2014. Available at http://www.who.int/mediacentre/factsheets/fs114/en/. Accessed October20, 2015.

18. World Health Organization, Global Polio Eradication Initiative. Available at http://www.polioeradication.org/. Accessed 29 May 2015.

19. Moturi EK, Porter KA, Wassilak SG, et al. Progress toward polio eradication--Worldwide, 2013-2014. MMWR Morb Mortal Wkly Rep. 2014;63:468–472.

20. World Health Organization. WHO statement on the meeting of the International Health Regulations Emergency Committee concerning the international spread of wild poliovirus. May 5, 2014. Geneva, Switzerland: World Health Organization; 2014. Available at http://www.who.int/mediacentre/news/statements/2014/polio-20140505/en Accessed 29 May 2015.

21. Chandran A, Watt JP, Santosham M. Haemophilus influenzae vaccines. In: Plotkin SA, Orenstein WA, Offit P (eds). Vaccines. 6th ed. Philadelphia, PA: Saunders Elsevier; 2012:168–182.

22. World Health Organization. Immunization coverage. Fact sheet N°378. April 2015. Available at http://www.who.int/mediacentre/factsheets/fs378/en// Accessed 29 May 2015.

23. European Centre for Disease Prevention and Control (ECDC). Haemophilus influenzae infection: Factsheet for health professionals. Available at http://ecdc.europa.eu/en/healthtopics/Haemophilus_Influenzae_Infection/Pages/healthprofessionals.aspx#sthash.nrYpN0Gs.dpuf Accessed 7 June 2015.

24. European Centre for Disease Prevention and Control (ECDC). ECDC sur-veillance report. Annual epidemiological report: Vaccine-preventable diseases—Invasive bacterial diseases 2014. Stockholm, Sweden: ECDC; 2015. Available at http://ecdc.europa.eu/en/publications/Publications/AER-VPD-IBD-2014.pdf Accessed 29 May 2015.

25. Van Damme P, Ward J, Shouval D, Wiersma S, Zanetti A. Hepatitis B vaccine. In: Plotkin S, Orenstein W, Offit P, eds. Vaccines 6th ed. Philadel-phia, PA: Saunders Elsevier; 2012:205–234.

26. World Health Organization (WHO). Hepatitis B. Fact sheet N°204. Updated March 2015. Available at http://www.who.int/mediacentre/factsheets/fs204/en/ Acessed 29 May 2015.

27. World Health Organization, Regional Office for Europe. Hepatitis: Data and statistics. Available at http://www.euro.who.int/en/health-topics/communicable-diseases/hepatitis/data-and-statistics Accessed 6 June 2015.

28. European Centre for Disease Prevention and Control (ECDC). ECDC surveillance report. Hepatitis B and C surveillance in Europe 2012. Stockholm, Sweden: ECDC; 2014. Available at http://ecdc.europa.eu/en/publications/Publications/101012_TER_HepBandC_survey.pdf Accessed 29 May 2015.

either as stand-alone vaccines or in combination with other vaccines since the early 1980s8. The WHO recommends that all infants receive their first dose of hepatitis B vaccine as soon as possible after birth, preferably within 24 hours. By the end of 2013, hepatitis B vaccine for infants had been introduced nationwide in 183 countries22.

In 2012, 17 329 cases of hepatitis B were reported in 29 EU/EEA Member States (3.5 per 100 000 population), consisting of 16% acute, 71% chronic, and 18% either unknown or unclassi-fied infections28. As the ECDC has observed, while the decrease in acute cases in Europe is reassuring, the large and increasing numbers of diagnosed chronic hepatitis B cases in many countries leaves no room for complacency in national prevention and control programmes28. There is still work to be done in preventing hepatitis B in the region, including working towards more complete vaccine coverage.

References 1. European Centre for Disease Prevention and Control (ECDC). Surveil-

lance report. Annual epidemiological report: Reporting on 2011 surveil-lance data and 2012 epidemic intelligence data. Stockholm, Sweden: ECDC; 2013. Available at: http://www.ecdc.europa.eu/en/publications/Publications/annual-epidemiological-report-2013.pdf. Accessed 29 May 2015.

2. European Centre for Disease Prevention and Control (ECDC). Vaccine schedule. Available at http://vaccine-schedule.ecdc.europa.eu/Pages/Scheduler.aspx. Accessed 1 March 2015.

3. World Health Organization. Diphtheria vaccine: WHO position paper. Wkly Epidemiol Rec 2006;81:24–32. Available at http://www.who.int/entity/wer/2006/wer8103.pdf?ua=1 Accessed 29 May 2015.

4. World Health Organization. Tetanus vaccine: WHO position paper. Wkly Epidemiol Rec 2006;81:198–208. Available at http://www.who.int/entity/wer/2006/wer8120.pdf?ua=1 Accessed 18 May 2015.

5. World Health Organization. Pertussis vaccines: WHO position paper. Wkly Epidemiol Rec. 2010;85:385–400. Available at http://www.who.int/entity/wer/2010/wer8540.pdf?ua=1 Accessed 18 May 2015.

6. World Health Organization. Polio vaccines: WHO position paper, January 2014. Wkly Epidemiol Rec. 2014;89:73–92. Available at http://www.who.int/entity/wer/2014/wer8909.pdf?ua=1 Accessed 3 June 2015.

7. World Health Organization. Haemophilus influenzae type b (Hib) vaccination: Position paper – July 2013. Wkly Epidemiol Rec. 2013;88:413-428. Available at http://www.who.int/entity/wer/2013/wer8839.pdf?ua=1 Accessed 3 June 2015

8. World Health Organization. Hepatitis B vaccines: WHO Position Paper. Wkly Epidemiol Rec. 2009;84:405–420. Available at http://www.who.int/entity/wer/2009/wer8440.pdf?ua=1 Accessed 3 June 2015

9. Tiwari TSP, Wharton M. Diphtheria toxoid. In: Plotkin SA, Orenstein W, Offit P, eds. Vaccines, 6th ed. Philadelphia, PA: Saunders Elsevier; 2012:153–166.

10. World Health Organization, Regional Office for Europe. Immunization, Vaccines and Biologicals: Diphtheria. Available at http://www.who.int/immunization/monitoring_surveillance/burden/diphtheria/en/Accessed 5 June 2015.

11. European Centre for Disease Prevention and Control (ECDC). Surveil-lance report. Annual epidemiological report: Vaccine-preventable diseases 2014. Stockholm, Sweden: ECDC; 2014. Available at: http://ecdc.europa.eu/en/publications/Publications/AER-2014-VPD-FINAL.pdf Accessed: 29 May 2015.

12. Roper MH, Wassilak SG, Tiwari TSP, Orenstein WA. Tetanus toxoid. In: Plotkin SA, Orenstein W, Offit P, eds. Vaccines, 6th ed. Philadelphia, PA: Saunders Elsevier; 2012:746-772.

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analysis, and communication of surveillance data; monitoring adverse events across the EU; and communication and education efforts about the value of vaccination. The ECDC provides an easily accessible guide to primary and booster vaccination schedules for each vaccine-preventable disease in 31 European countries.2

National recommendations for the 31 countries for the 6 vaccine-preventable diseases covered by Hexyon®, outlined in Chapter 2, are summarized in Table 3.1. Recommendations within most countries are aligned with ECDC and WHO guidance. All the countries listed recommend routine childhood immunization for infants from birth to 24 months against diphtheria, tetanus, polio, pertussis, and Haemophilus influenzae type b. Most also recommend routine immunization against hepatitis B. Of the 8 countries that do not, an additional 6 recommend immunization of certain patients at risk for hepatitis B infection2. Healthcare providers should only use Hexyon® or any other vaccine in accordance with local official vaccination recommendations.

References1. European Centre for Disease Prevention and Control (ECDC).

Vaccine-preventable diseases: About the programme. Available at http://ecdc.europa.eu/en/activities/diseaseprogrammes/vpd/Pages/about_the_programme.aspx Accessed 30 May 2015.

2. European Centre for Disease Prevention and Control (ECDC). Vaccine schedule. Available at: http://vaccine-schedule.ecdc.europa.eu/Pages/Scheduler.aspx Accessed 30 May 2015.

A principal aim of the ECDC programme is to provide scientific advice on vaccines to help Member States in making decisions about national vaccination schedules.

The ECDC programme on vaccine-preventable diseases was established in 2006 to investigate issues related to vaccination in general and to promote surveillance and prevention of 14 diseases: diphtheria, human papillomavirus (HPV) infections, measles, mumps, pertussis, poliomyelitis, rabies, rotavirus infection, rubella, tetanus, varicella, invasive bacterial infections with Haemophilus influenzae type b, Neisseria meningitides and Streptococcus pneumoniae. Certain other infectious diseases, including influenza and tuberculosis, are covered by different programmes within the agency1.

A principal aim of the ECDC programme is to provide scientific advice on vaccines to help Member States in making decisions about national vaccination schedules. Many areas of investigation contribute to the ECDC recommendations, including collection,

Table 3.1. Recommendations in EU/EEA countries for routine immunization in infants against 6 infectious diseases.

Member State Diphtheria Tetanus Poliomyelitis* Pertussis**Invasive diseases

caused by HibHepatitis B

Austria • • • • • •Belgium • • • • • •Bulgaria • • • • • •Croatia • • • • • •Cyprus • • • • • •Czech Republic • • • • • •Denmark • • • • • No§

Estonia • • • • • •Finland • • • • • No§

France • • • • • •Germany • • • • • •Greece • • • • • •Hungary • • • • • •Iceland • • • • • NoIreland • • • • • •Italy • • • • • •Latvia • • • • • •Liechtenstein • • • • • No§

Lithuania • • • • • •Luxembourg • • • • • •Malta • • • • • •Netherlands • • • • • •Norway • • • • • NoPoland • • • • • •Portugal • • • • • •Romania • • • • • •Slovakia • • • • • •Slovenia • • • • • No§

Spain • • • • • •Sweden • • • • • No§

United Kingdom • • • • • No§

*Inactivated poliovirus vaccine in all countries except oral poliovirus vaccine booster dose in Poland (6 years of age); **Acellular pertussis vaccine vaccine in all countries except whole-cell pertusiss vaccine for primary vaccination in Poland; §Vaccination against hepatitis B recommended only for risk groups. Adapted from ECDC Vaccine Schedule2.

3. CHILDHOOD IMMUNIZATION RECOMMENDATIONS IN THE EUROPEAN UNION

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l By adding a new hepatitis B antigen valence to the Pentavac® antigen backbone, Hexyon® marked an advance in the development of all-in-one vaccines intended to protect against serious childhood infectious diseases.

Development of Hexyon® hepatitis B antigenHexyon® contains a hepatitis B surface antigen (HBsAg) produced by recombinant DNA technology from an established Hansenula polymorpha yeast expression system (illustration, left) that has been used successfully in the production of other therapeutic products5. This HBsAg is produced exclusively for inclusion in

Hexyon®. Prior to its incorporation into Hexyon®, the H. polymorpha- derived HBsAg was assessed as

a stand-alone vaccine in two clinical trials in adolescents aged 10–15 years (10 g HBsAg

per dose) and adults (20 g HBsAg per dose) in Argentina and Uruguay, respectively6. In both studies, the immunogenicity and safety of a vaccine with the new HBsAg component was compared to those of a Saccharomyces cerevisiae-derived

recombinant hepatitis B vaccine available at that time. In both adolescents and adults

the new H. polymorpha-derived vaccine was well tolerated and highly immunogenic.

Seroprotection rates one month after the third dose of the new hepatitis B vaccine (100%) were

statistically non-inferior to the control vaccine (Figure 4.2) with higher levels of hepatitis B antibody (anti-Hep B) than the control vaccine6. The overall safety profile was comparable to that of the control vaccine6 and other yeast-derived vaccines described in the literature7.

Effectiveness of Tetravac® and Pentavac® against pertussisThe first pertussis vaccines were whole-cell vaccines made from suspensions of killed B. pertussis. Despite their efficacy in reducing pertussis incidence, the frequency of minor local reactions and the rare occurrence of more severe adverse events (such as febrile convulsions) prompted the development of less reactogenic, acellular vaccines8.

Tetravac® (DTaP/IPV) and Pentavac® vaccines, which contain aP components, have demonstrated high effectiveness in the control of pertussis. Long-term studies in the USA and Japan, and regarding Europe, pertussis surveillance data from Sweden9, Austria10, Finland11 and France12 (where acellular pertussis vaccines, including Tetravac® and/or Pentavac®, have been in wide use for over 15 years) have provided sound evidence that the aP valence is effective in protecting against pertussis. In Sweden, a 90% reduction in the number of pertussis cases was seen following the introduction in 1998 of aP vaccine, Tetravac®, replaced by Pentavac® in 1997, and administered on a schedule of 3, 5 and 12 months (Figure 4.3)9.

In contributing to the goal of protecting the greatest number of children against childhood diseases with known public health impacts, combination vaccines play a crucial role by providing an opportunity for improved compliance and reducing healthcare costs through the reduction of the number of consultations and injections. In line with the other members of an acellular pertussis-based family of combination vaccines (Tetravac® and Pentavac®), Hexyon®’s fully liquid, ready-to-use combination vaccine is intended to provide protection against several childhood diseases with a single vaccine, thereby improving comfort for infants and reducing parental anxiety about multiple injections.

Experience with combination paediatric vaccinesHexyon® was developed based on the experience gained with pentavalent combination vaccine Pentavac® (DTaP/IPV/Hib), which was first licensed in Sweden in 1997 and is now used in more than 100 countries worldwide in private practice and/or in public state-funded vaccination programmes1,2, underlining the recognition of its value. Over 25 years of clinical development and postmarketing experience with vaccines (Figure 4.1) has contributed to immunization programmes that have helped reduce the public health burden in Europe of diseases such as diphtheria, tetanus and polio (see Chapter 2 for a discussion of the impact of vaccination implementation on the incidence of serious childhood infectious diseases).

Hexyon® combines all the existing Pentavac® antigens—diphtheria (D) and tetanus (T) toxoids, Bordetella pertussis toxin (PT) and filamentous hemagglutinin (FHA) (both pertussis antigens), IPV, and Hib—with a Hansenula polymorpha- derived recombinant hepatitis B vaccine component (illustrated). This hepatitis B antigen was developed specifically for use in Hexyon®.l The immunogenicity and good safety profile of Pentavac® was

demonstrated through clinical development and pre-licensure clinical experience in nearly 10 000 recipients around the world3, under a range of vaccination schedules, including a challenging schedule that has been recommended by WHO’S Expanded Programme on Immunization (EPI), i.e., at ages 6,10 and 14 weeks3,4.

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4. SANOFI PASTEUR MSD ACELLULAR PERTUSSIS- BASED COMBINATION PAEDIATRIC VACCINES

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Long-term surveillance in Sweden has proven that the aP valence contained in Hexyon® is effective in reducing pertussis incidence.

Overall, extensive data collected from 36 clinical studies performed in 17 countries have established the high and consistent immunogenicity of the aP valence of the combination vaccines that led to the development of Hexyon® 13, which was reconfirmed in all the studies conducted with Hexyon® (see Chapter 5 for a description of the immunogenicity studies).

Effectiveness of combination vaccines against Haemophilus influenzae type B diseaseWhen compared with separate Hib vaccination, DTaP-Hib com-binations have been shown to induce consistently high anti-Hib seroprotection rates (≥0.15 g/mL) but reduced anti-Hib antibody concentrations14-17. However, the strong memory responses observed after booster challenge in the second year of life, even in children with low pre-booster antibody levels (<0.15 g/mL), indicating adequate priming and a good immune memory response, have led to the conclusion that such interference is not clinically relevant14-17. The best supportive evidence comes from effectiveness data collected from active surveillance programmes. Wherever routine Hib vaccination has been successfully implemented, the incidence of Hib meningitis has been dramati-cally reduced18,19 (see Chapter 2).

The effectiveness of the Hib antigen component of Hexyon® has been demonstrated via an extensive (>5-year follow-up) postmar-keting surveillance study in Germany. The vaccine effectiveness (of DTaP and Hib combination vaccines containing same Hib antigen as in Hexyon®) was 96.7% for the full primary series and 98.5% for booster dose (irrespective of priming)20.

Vaccine with new HBsAg component developed for Hexyon®

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Figure 4.1. Development of combination paediatric vaccines leading up to Hexyon® production and registration. M, million; D, diphtheria toxoid; T, tetanus toxoid; aP, acellular pertussis; IPV, inactivated poliovirus; Hib, Haemophilus influenzae type b; Hep B, hepatitis B.

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Figure 4.2. Immunogenicity of the HBsAg component developed for Hexyon® compared with control vaccine. Seroprotection rates are for 1 month after the third dose of vaccine containing the new Hexyon® hepatitis B component or a control hepatitis B vaccine in adolescents aged 10–15 years and in adults aged 16–45 years. Vaccines were administered at day 0, 1 month, and 6 months. Seroprotec-tion was defined as an anti-Hep B ≥10 mIU/mL. 95% CIs shown. Adapted from Tregnaghi et al6.

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Wherever routine Hib vaccination has been successfully implemented—mostly as DTaP-containing combination vaccines—the incidence of Hib meningitis has been dramatically reduced.

Use of inactivated poliovirus in the pre- and post-polio eradication erasWhile OPV contributed greatly to bringing about the almost complete eradication of wild polioviruses21-23, the success of OPV relied on both its oral and live features that closely mimic natural infection. Not only does the vaccine provide mucosal immunity that protects from infection and transmission21, but the excretion of OPV strains by vaccinees also provides an indirect means of “vaccinating” an even greater proportion of the population21,22. However, this same capacity of OPV live strains to multiply in the gut of vaccinees is an increasing cause for concern, since it may lead to vaccine-associated poliomyelitis disease and vaccine-de-rived poliovirus-associated outbreaks, may eventually compromise the final goal of eradication.

The use of IPV has not been associated with any risk of vac-cine-associated disease or vaccine-derived poliovirus, and as a result IPV is considered to be safer than OPV23. Extensive records of high immunogenicity under various schedules, even after only 2 doses, in many countries throughout the world23 and proven long-term persistence of antibodies up to 10–15 years after booster vaccination22,23, make IPV the vaccine of choice in the final stages of global polio eradication.

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Figure 4.3. Laboratory confirmed cases of pertussis in Sweden 1986–2007. aP vaccination started in 1996. The number of reported culture and polymerase-chain reaction-confirmed pertussis cases in Sweden per month. DTaP, diphtheria, tetanus, acellular pertussis. Adapted with permission, from Nilsson et al9.

SUMMARYSanofi Pasteur MSD’s long-term experience with combination vaccines has led to the following important features that ultimately have contributed to the development of the 6-in-1 Hexyon® vaccine:

l Good safety profile and high immunogenicity of an H. polymorpha-derived HBsAg produced specifically for Hexyon®;

l Good safety profile of aP-based combination vaccines;

l Proven effectiveness of aP-containing vaccines in controlling pertussis;

l Proven effectiveness of Hib in combination with aP.

IPV HAS: l A better safety profile than OPV;

l High immunogenicity against polioviruses under various vaccination schedules;

l Proven long-term persistence of antibodies against polio after booster vaccination.

11


13. Vidor E, Plotkin SA. Immunogenicity of a two-component (PT&FHA) acellular pertussis vaccine in various combinations. Hum Vacc. 2008;4:328–340.

14. Eskola J, Ward J, Dagan R, Goldblatt D, Zepp F, Siegrist CA. Combined vaccination of Haemophilus influenzae type b conjugate and diphtheria–tetanus–pertussis containing acellular pertussis. Lancet. 1999;354:2063–2068.

15. Vidor E, Hoffenbach A, Fletcher MA. Haemophilus influenzae type b vaccine: reconstitution of lyophilised PRP-T vaccine with a pertus-sis-containing paediatric combination vaccine, or a change in the primary series immunisation schedule, may modify the serum anti-PRP antibody responses. Curr Med Res Opin. 2001;17:197–209.

16. Lagos R, Kotloff K, Hoffenbach A, San Martin O, Abrego P, Ureta AM, Pines E, Blondeau C, Bailleux F, Levine MM.. Clinical acceptability and immunogenicity of a pentavalent parenteral combination vaccine containing diphtheria, tetanus, acellular pertussis, inactivated poliomyelitis and Haemophilus influenzae type b conjugate antigens in two-, four- and six- month-old Chilean infants. Pediatr Infect Dis J. 1998;17:294–304.

17. Hoppenbrouwers K, Kanra G, Roelants M, Ceyhan M, Vandermeulen C, Yurdakök K, Silier T, Dupuy M, Pehlivan T, Özmert E, Desmyter J. Priming effect, immunogenicity and safety of an Haemophilus influenzae type b–tetanus toxoid conjugate (PRP–T) and diphtheria–tetanus–acellular pertussis (DTaP) combination vaccine administered to infants in Belgium and Turkey. Vaccine. 1999;17:875–886.

18. Morris SK, Moss WJ, Halsey N. Haemophilus influenzae type b conjugate vaccine use and effectiveness. Lancet Infect Dis. 2008;8:435–443.

19. Lewis RF, Kisakye A, Gessner BD, Duku C, Odipio JB, Iriso R, Nansera D, Braka F, Makumbi I, Kekitiinwa A.. Action for child survival: elimination of Haemophilus influenzae type b meningitis in Uganda. Bull World Health Organ. 2008;86:292–301.

20. Kalies H, Verstraeten T, Grote V, Meyer N, Siedler A, Schmitt HJ, Breuer T, Moulton LH, von Kries R; Erhebungseinheit für seltene pädiatrische Erkrankungen in Deutschland Study Group. Four and one-half-year follow-up of the effectiveness of diphtheria-tetanus toxoids-acellu-lar pertussis/Haemophilus influenzae type b and diphtheria-tetanus toxoids-acellular pertussis-inactivated poliovirus/H. influenzae type b combination vaccines in Germany. Pediatr Infect Dis J. 2004;23:944–950.

21. Sutter RW, Kew OM, Cochi SL, Aylward RB. Poliovirus vaccine—live. In: Plotkin SA, Orenstein WA, Offit P, eds. Vaccines. 6th ed. Philadelphia, PA: Saunders Elsevier; 2012:598–645.

22. World Health Organization. Polio vaccines: WHO position paper, January 2014. Wkly Epidemiol Rep. 2014;89:73–92.

23. Vidor E, Plotkin SA. Poliovirus vaccine—inactivated. In: Plotkin SA, Orenstein W, Offit P, eds. Vaccines 6th ed. Philadelphia, PA: Saunders Elsevier: 2012;573–597.

References 1. Decker MD, Edwards KM, Bogaerts HH. Combination vaccines. In:

Plotkin S, Orenstein W, Offit PA, eds. Vaccines, 6th ed. Philadelphia, PA: Saunders Elsevier; 2012:981–1007.

2. Sanofi Pasteur MSD. Data on file. 2015.

3. Plotkin SA, Liese J, Madhi SA, Ortiz E. A DTaP-IPV//PRP~T vaccine (Pentaxim™): a review of 16 years’ clinical experience. Expert Rev Vaccines. 2011;10:981–1005.

4. World Health Organization (WHO). Immunization, vaccines and biologicals. WHO recommendations for routine immunization—summary tables. Table 2: Summary of WHO position papers—Recommended routine immunizations for children. Updated February 27, 2015. Available at http://www.who.int/immunization/policy/Immu-nization_routine_table2.pdf?ua=1 Accessed 30 May 2015.

5. Çelik E, Çalik P. Production of recombinant proteins by yeast cells. Biotechnol Adv. 2011;30:1108–1118.

6. Tregnaghi MW, Voelker R, Santos-Lima E, Zambrano B. Immunogenicity and safety of a novel yeast Hansenula polymorpha-derived recombinant Hepatitis B candidate vaccine in healthy adolescents and adults aged 10-45 years. Vaccine. 2010;28:3595–3601.

7. Grotto I, Mandel Y, Ephros M, Ashkenazi I, Shemer J. Major adverse reactions to yeast-derived hepatitis B vaccines—a review. Vaccine. 1998;16:329-334.

8. Edwards KM, Decker MD. Pertussis vaccines. In: Plotkin S, Orenstein W, Offit PA, eds. Vaccines. 6th ed. Philadelphia, PA: Saunders Elsevier; 2012;447- 492.

9. Nilsson L, Grünewald M, Kling A-M. Pertussis surveillance in Sweden; Fifteen year report. Solna, Sweden: Public Health Agency of Sweden; 2013. Available at https:// www.folkhalsomyndigheten.se%2Fpagefiles%2F17379%2Fpertussis-surveillance%2520in-swe-den-fifteen-year-report%25282%2529.pdf&ei=aCNqVamQF-NWgyATSwIOABQ&usg=AFQjCNGBEOkktXvgvOrt-gCToFL0Kl-PAsg&sig2=b4QffD53k9SzIMG2210gqg&bvm=bv.94455598,d.aWw&cad=rja Accessed 30 May 2015.

10. Rendi-Wagner P, Kundi M, Mikolasek A, Vécsei A, Frühwirth M, Kollaritsch H. Hospital-based active surveillance of childhood pertussis in Austria from 1996 to 2003: estimates of incidence and vaccine ef-fectiveness of whole-cell and acellular vaccine. Vaccine. 2006;24:5960–5965.

11. Elomaa A, He Q, Minh NN, Mertsola J. Pertussis before and after the introduction of acellular pertussis vaccines in Finland. Vaccine. 2009;27:5443–5449.

12. Bonmarin I, Levy-Bruhl D, Baron S, Guiso N, Njamkepo E, Caro V; Renacoq participants. Pertussis surveillance in French hospitals: results from a 10 year period. Eurosurveillance. 2007;12:34–38.

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Several key aspects of Hexyon® immunogenicity are explored in the following subsections.

Immune responses after primary and booster vaccinationIn clinical studies Hexyon® was highly immunogenic when administered in a range of primary vaccination schedules.

Immunogenicity under different primary vaccination schedulesThe immunogenicity of Hexyon® was assessed in 8 primary series studies under three different 3-dose primary vaccination schedules: 6-10-14 weeks (1 study)1; 2-3-4 months (1 study)2 and 2-4-6 months (6 studies)3-8 and one study with a 2-dose primary vaccination schedule (3-5 months).10. The immune responses in terms of seroprotection/seroconversion rates and antibody GMTs/GMCs following vaccination with Hexyon® are compiled in Figure 5.1 and Table 5.1, opposite. The 6 studies shown included children who did not receive a dose of hepatitis B vaccine at birth and did not receive any co-administered vaccines; they received only Hexyon® at those visits. Overall, Hexyon® induced a strong immune response to all the antigens under all vaccination schedules used in clinical trials, including the challenging EPI schedule (6-10-14 weeks of age).

5. HEXYON® IMMUNOGENICITY PROFILE

Overall, Hexyon® has been shown to be highly immunogenic in all

schedules, countries, and ethnicities tested.The immunogenicity of a vaccine is its ability to induce a protective immune response in the recipient.

In the case of the diseases covered by Hexyon®, immunogenicity is

typically assessed by the antibody response against the different antigens

included in the vaccine. This can be assessed by the percentage of recipients who achieve certain antibody levels after vaccination, termed seroprotection rate, seroconversion rate, or vaccine response rate or by antibody level, measured as geometric mean titer (GMT) or geometric mean concentration (GMC). Well-established seroprotection levels were used to assess the immune response to Hexyon® antigens against diphtheria, tetanus, poliovirus, hepatitis B and Hib, and provide indicators of protection against disease. A surrogate of protection for pertussis was described by seroconversion rates as the percentage of subjects with ≥4-fold increase, and seroresponse or vaccine response rates.

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Figure 5.1. Vaccine response after three different 3-dose primary series vaccination schedules. Seroprotection/seroconversion rates 1 month after the third dose of Hexyon® are shown using a 6-10-14 week schedule; a 2-3-4 month schedule; a 2-4-6 month schedule (in the absence of hepatitis B immunization at birth or any concomitant vaccine administration)1,2,9. 95% CI shown. D, diphtheria toxoid; T, tetanus toxoid; PT, pertussis toxoid; FHA, filamentous haemagglutinin; PV1,2,3, poliovirus types 1, 2 and 3; Hib, Haemophilus influenzae b; HBsAg, hepatitis B surface antigen. Adapted from Madhi et al1, Ceyhan et al2, Santos-Lima et al9, and European Medicines Agency (EMA)11 and data on file12.

*Vaccine response defined as an antibody level greater than or equal to the lower limit of quantification (LLOQ) in initially seronegative participants, or persistence of the antibody level (post-vaccination ≥ pre-vaccination) in participants who were initially seropositive (≥ LLO Q ). For PT and FHA seroconversion rate defined as a ≥4-fold increase in titer from baseline to 1 month post-3rd vaccination.

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Table 5.1 Antibody levels (GMC/GMT) against all vaccine antigens after 3 doses of Hexyon® under various primary schedules.

StudyMadhi20111

Ceyhan20102

Santos-Lima 201310*

Vesikari 20159

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2-3-4 months

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n 220 145 1270 249

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Anti-D (IU/mL) 0.07 0.07 0.19 0.08

Anti-T (IU/mL) 1.51 0.84 1.95 0.129

Anti-PT (EU/mL) 332 123 213 NA

Anti-FHA (EU/mL) 207 102 224 NA

Anti-Polio 1 (1/dil) 579 102 1340 15.8

Anti-Polio 2 (1/dil) 620 74 1986 14.1

Anti-Polio 3 (1/dil) 975 133 1550 15.7

Anti-Hib (μg/mL) 3.31 2.12 8.62 0.168

Anti-HBsAg (mIU/mL) 330 149 1116 76.5

Adapted from Madhi et al1, Ceyhan et al2, Santos-Lima et al10 and Vesikari et al9 *Pooled data from 4 studies...Antibody levels were measured 1 month after (3+1) or before the third dose (2+1). In all studies, the children did not receive hepatitis B vaccination at birth and did not receive any concomitant vaccines with Hexyon®. GMT, geometric mean titer (used to measure the anti-polio antibodies); GMC, geometric mean concentration; D, diphtheria toxoid; T, tetanus toxoid; PT, pertussis toxoid; FHA, filamentous haemagglutinin; Hib, Haemophilus influenzae type B; HBsAg, hepatitis B surface antigen. Both PT and FHA are pertussis antigens.

Immune protection compared with other licensed hexavalent vaccine and Pentavac® plus a stand-alone hepatitis B vaccine

Hexyon® was shown to induce high immune responses similar to those of other combination vaccines, including another licensed hexavalent vaccine and Pentavac®, regardless of the vaccination schedule used in clinical trials.

Non-inferiority of immune responses with Hexyon® versus control vaccines was demonstrated for each antigen in an assessment of the immunogenicity of Hexyon® versus a reconstituted hexavalent control vaccine (DTaP-IPV-HBV/Hib) in two studies with Hexyon® administered in a 3-dose schedule (Figure 5.2)8 or a 2+1 schedule (Figure 5.3)9-11, as well as in a study that compared Hexyon® with Pentavac® administered with stand-alone hepatitis B vaccine (Figure 5.4).4 In the latter study, non-inferiority of Hexyon® versus a stand-alone hepatitis B vaccine was seen in the hepatitis B response4.

Anti-hepatitis B response after primary and booster vaccinationIn a study conducted in Mexico6, infants received a primary series of either Hexyon® or a control hexavalent vaccine at 2-4-6 months of age, followed by booster vaccination with Hexyon® at 15–18 months of age. High (>99%) hepatitis B seroprotection rates (based on a cutoff of ≥10m IU/mL) were observed one month after booster vaccination with Hexyon® at 15–18 months of age, regardless whether primary vaccination was with Hexyon® or the control vaccine (Figure 5.5).

l Liquid form of Haemophilus influenzae type b (Hib) is stable and immunogenic.

l A lyophilized or freeze-dried vaccine antigen must be reconstituted in a liquid before the vaccine is administered. The Hib component is lyophilized in Pentavac® and in the other licensed hexavalent vaccine, but in the fully liquid formulation, Hexyon®, a liquid component is already included. Studies have shown that the liquid form of Hib in Hexyon® retains the ability to induce a strong immune response.

l The vaccine has a shelf-life of 36 months, similar to that of other pentavalent and hexavalent vaccines that contain lyophilized components.

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Figure 5.2 Comparison of Hexyon® with a control hexavalent vaccine comparator in a 3-dose primary vaccination schedule. Seroprotection/vaccine response* rates post-dose 3 in response to a 3-dose primary series with Hexyon® (left bars) or other licensed hexavalent vaccine comparator (right bars) given at 2, 4, 6 months of age. All children had received a dose of hepatitis B at birth. Both PT and FHA are pertussis antigens. 95% CIs shown. D, diphtheria toxoid; T, tetanus toxoid; PT, pertussis toxoid; FHA, filamentous haemagglutinin; PV1, poliovirus 1; PV2, poliovirus 2, PV3, poliovirus 3; Hib, Haemophilus influenzae type b; HBsAg, hepatitis B surface antigen. Adapted from Lopez et al8. * Vaccine response defined as an antibody level greater than or equal to the lower limit of quantification (LLOQ) in initially seronegative participants, or persistence of the antibody level (post-vaccination ≥ pre-vaccination) in participants who were initially seropositive (≥ LLOQ ).

Study details: Phase III randomized, observer-blind, active-con-trolled, two-centre (Colombia and Costa Rica) study. A total of 1030 subjects were randomised to Hexyon® and 338 to other licensed hexavalent control. Both vaccines were administered at 2-4-6 months of age and 1 month post primary series. All subjects received concomitant PVC7 at 2-4-6 months, and rotavirus vaccine at 2-4 months. Hepatitis B vaccine was given at birth.

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Study details: Phase III randomized, observer-blind, active-con-trolled, multicentre (Finland and Sweden) study. A total of 249 subjects were randomized to Hexyon® and 248 to other licensed hexavalent control. Both vaccines were administered in a 2+1 schedule at 3-5 months and at 11–12 months of age. All subjects received concomitant PVC7 at 2-4-6 months, and rotavirus vaccine at 2 and 4 months of age. No hepatitis B vaccine was given before entry into the trial.

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Figure 5.3. Comparison of Hexyon® with a control hexavalent vaccine comparator in a 2-dose primary vaccination schedule + booster dose. Seroprotection/vaccine response* rates post booster dose in response to a 2-dose primary series + booster dose with Hexyon® (left bars) or a licensed hexavalent vaccine comparator (right bars) given at 3, 5 + 11-12 months of age. No hepatitis B vaccine was administered before entry into the trial. D, diphtheria T; T, tetanus toxoid; PT, pertussis toxoid; FHA, filamentous haemagglutinin; PV1, poliovirus 1; PV2, poliovirus 2, PV3, poliovirus 3; Hib, Haemophilus influenzae type b; HBsAg, hepatitis B surface antigen. Both PT and FHA are pertussis antigens. Adapted from Vesikari et al9.*Vaccine response defined as antibody concentration ≥4 x lower limit of quantitation (LLOQ=2 EU/mL) of the assay if concentration before the first vaccination was <4 x LLOQ.

Figure 5.4. Comparison of Hexyon® to Pentavac® plus stand-alone hepatitis B vaccine. Seroprotection/seroconversion rates 1 month post dose 3 after 3-dose primary series with Hexyon® (left bars) or Pentavac® plus a stand alone hepatitis B vaccine (right bars). Both groups were vaccinated at 2-4-6 months of age. Vaccine response predefined as ≥4-fold increase from baseline in anti-PT and anti-FHA antibody titers 95% CIs are shown. D, diphtheria toxoid; T, tetanus toxoid; PT, pertussis toxoid; FHA, filamentous haemagglutinin; PV1, poliovirus 1; PV2, poliovirus 2, PV3, poliovirus 3; Hib, Haemophilus influenzae type b; HBsAg, hepatitis B surface antigen. Both PT and FHA are pertussis antigens. Adapted from Tregnaghi et al4.

Study details: Infants born in Argentina to HBsAg seronegative mothers were randomized to receive DTaP-IPV-Hep B-PRP-T vaccine or Pentavac® and hepatitis B monovalent vaccine at 2, 4, 6 months of age. Antibody titers were measured before and 1 month after the 3-dose primary vaccination. Objectives were noninferiority based on seroprotection/seroconversion rates and safety up to 1 month after primary vaccination. Of a total of 624 participants enrolled, 312 were randomized to each group, and 604 completed the trial.

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Figure 5.5. High hepatitis B immune response following booster vaccination with Hexyon® regardless of the hexavalent vaccine received during the primary series. Hepatitis B seroprotection rates (≥10 mIU/mL) are shown at 1 month pre- and post-primary vaccination at 2, 4, 6 months of age and pre- and post-booster vaccination at 15–18 months of age with Hexyon® (left panel) or primary vaccination with a licensed hexavalent control vaccine and booster vaccination with Hexyon® (right panel). 95% CIs shown. Adapted from Becerra Aquino et al 20126.

Study details: A total of 1189 healthy Mexican infants were randomized to receive 1 of 3 lots of Hexyon® or a another licensed hexavalent control vaccine for primary vaccination at 2, 4 and 6 months. All participants who completed the primary series and

agreed to participate in the booster part of the study received a dose of Hexyon® at 15–18 months of age. Validated serological assays and parental reports were used to assess immunogenicity and safety, respectively.

Anti-Haemophilus influenzae type b response after primary immunizationClinical studies demonstrated that:l The immunogenicity of Hexyon® administered at 2, 4, 6 months

of age was similar to that of Pentavac® for the Hib seroprotec-tion rate (95% for Hexyon® and 97% for Pentavac®, respectively, based on anti-Hib antibody levels ≥15 g/mL)4.

l Seroprotection rates to the Hib antigen and the levels of anti-Hib antibody produced (GMCs) investigated in several clinical studies were similar for Hexyon® and the control hexavalent vaccine containing a lyophilized Hib component (Figure 5.6).

Clinical studies showed that post primary series seroprotection rates (≥0.15 μg/mL) with Hexyon® were high. When measured, statistical analysis confirmed that Hexyon® immunogenicity is comparable to control hexavalent vaccine in the 2, 4, 6 month schedule.

Kosalaraksa2011

n=189 n=190

Lopez2012

n=935 n=316

Becerra Aquino2012

n=695 n=119

Lanata2012

n=132 n=130

Anti-

Hib

sero

prot

ectio

n ra

tes

(%)

Hexyon® Other licensed hexavalent control vaccine

0

20

40

60

80

100

98 96 95 96 99 99 100 99

Figure 5.6. Haemophilus influenzae type b immune responses in infants primed with Hexyon®. Immunogenicity was measured by seroprotection rates (anti-Hib antibody levels ≥15 μg/mL) and anti-Hib GMCs one month after a primary series at 2-4-6 months of age. Infants were given a 3-dose primary series with Hexyon® (left bars) or a licensed hexavalent comparator (right bars) at 2-4-6 months of age. 95% CIs are shown. Adapted from Kosalaraksa et al5, Becerra Aquino et al6, Lanata et al7 and Lopez et al8.*Infants received a 7-valent pneumococcal vaccine concomitantly with the hexavalent vaccinations.§Infants also received rotavirus vaccine at 2 and 4 months of age. Statistical analysis was not performed in all studies.

16


Persistence of immune responses after primary and booster vaccination

Immunogenicity following primary 3-dose plus booster schedulesAntibody persistence after vaccination with Hexyon® is high for all antigens following primary vaccination prior to booster dose in the second year of life.

High antibody persistence to all antigens (seroprotection rates ≥80%; not applicable to pertussis antigens) was observed after primary vaccination prior to administration of the booster dose during the second year of life.

As shown in Figure 5.7a-c, the antibody persistence was high for studies of a vaccination schedule consisting of primary series given at 2-4-6 months of age, including the challenging EPI schedule, and was similar to control vaccines. As expected, the anti-hepatitis B antibody level was higher in those children who received hepatitis B vaccination at birth (data not shown)1,2. Despite that difference, the proportion of children with seropro-tection rates against hepatitis B (antibody concentration ≥10 mIU/mL) remained high at pre-booster vaccination: at least 80% across all studies regardless of the primary schedule, even without hepatitis B vaccination at birth1,2,6.

The hepatitis B immune response to a booster dose of Hexyon® is high regardless of the primary series vaccination schedule, with or without hepatitis B vaccination at birth.

The immune response to a booster dose of Hexyon® was high with children, almost invariably achieving 97–100% seroprotec-tion rates for all antigens (Figure 5.7), regardless of the primary vaccination schedule, with or without hepatitis B vaccination at birth1,2,6. For pertussis antigens, high seroconversion rates were observed. When measured, statistical analysis confirmed these rates are similar to those of the control vaccines and resemble historical clinical trial data with Pentavac®1. For the diphtheria, tetanus, Haemophilus influenzae type b, and hepatitis B antigens, strong immune responses were observed and high proportions of children reached antibody levels indicative of long-term protection following booster vaccination (Table 5.2) (there are no specific indicators of long-term protection for pertussis and polio antigens)1,2,6.

Table 5.2. Long-term seroprotection after primary and booster vaccination with Hexyon®.

Antibody

Schedule

6-10-14 weeksn=218

(Madhi 2013)13

2-4-6 monthsn=177

(Becerra Aquino 2012)6

Anti-D (≥1.0 IU/mL) 97.9 (94.8, 99.4) 93.2 (88.5, 96.4)

Anti-T (≥1.0 IU/mL) 98.0 (95.5, 99.5) 93.2 (88.5, 96.4)

Anti-Hib (≥1.0 μg/mL) 98.5 (95.7-99.5) 98.3 (95.1, 100.0)

Anti-HBsAg (≥100 mIU/mL) 93.9 (89.6-96.8) 93.2 (88.5, 96.4)

Data are percentage of patients with seroprotection. 95% CI shown. D, diphtheria toxoid; T, tetanus toxoid; Hib, Haemophilus influenza type b; HBsAg, hepatitis B surface antigen. Adapted from Madhi et al13 and Becerra Aquino et al6.

Seroprotection rates measured one month after booster dose (at 15–18 months of age) in children who were primed with Hexyon® at 6, 10, 14 weeks or 2, 4, 6 months of age (without hepatitis B vaccination at birth). For anti-HBsAg levels a cutoff value of ≥100 mIU/mL was used (rather than ≥10 mIU/mL in the previous studies), as this higher level has been found to be indicative of long-term protection against hepatitis B.

Administration of Hexyon® booster dose after primary immunization with other vaccinesBooster vaccination with Hexyon® induced high immune responses against hepatitis B in children primed with Hexyon®, Pentavac® + hepatitis B stand-alone vaccine or another licensed hexavalent vaccine.

Hexyon® has been used as a booster vaccine in toddlers previously vaccinated with Pentavac® plus hepatitis B stand-alone vaccine6, with Hexyon®6 or with another hexavalent licensed vaccine6. In all studies, the immune responses were high, irrespective of the vaccine(s) used in the primary series. High proportions of vaccinated toddlers reached antibody levels indicative of long-term protection against diphtheria, tetanus, and invasive Hib diseases2,6.

In two trials carried out without hepatitis B vaccine given at birth2,6 post booster antibody levels indicative of long-term protection (≥100 mIU/mL) were reached in 87% -100% of toddlers primed, with either Hexyon®2 or Pentavac®6 and stand-alone hepatitis B vaccine or another licensed hexavalent vaccine.

SUMMARYClinical trials have demonstrated that when Hexyon® was used as a booster following different primary vaccination schedules with different vaccines (Pentavac® + standalone hepatitis B vaccine, Hexyon® or another licensed hexavalent vaccine), it provides high immune responses indicative of long-term protection.

17


Figure 5.7a –c. Seroprotection rates in children primed with Hexyon® using 3 different primary immunization schedules (without hepatitis B vaccination at birth). Each schedule (vaccination at 6-10-14 weeks, 2-3-4 months, or 2-4-6 months of age) was assessed in a separate study. In all 3 studies, children were boosted with Hexyon® at 15–+18 months of age following the primary series. The criteria used to define seroprotection rates are shown below the label for each antigen. For PT and FHA, seroconver-sion was defined as a 4-fold increase in antibody level before and after vaccination. Both PT and FHA are pertussis antigens. 95% CIs shown except where not available (*). All measures were performed 1 month after primary and booster vaccination. D, diphtheria toxoid; T, tetanus toxoid; PT, pertussis toxoid; FHA, filamentous hemagglutinin; PV1, poliovirus 1; PV2, poliovirus 2, PV3, poliovirus 3; Hib, Haemophilus influenzae type b; HBsAg, hepatitis B surface antigen. Adapted from Madhi et al1, Ceyhan et al2 and Becerra Aquino et al6.

0

20

40

60

80

100



mIU/mL≥0.15µg/mL

Post-primary series, n=218 Pre-booster, n=218

9398 100

100

100

100

NA*94 95 NA*93 91 97100

100 9899 100 98100

100 8195 100 8096 99

Post-booster, n=218

Sero

prot

ectio

n/va

ccin

e re

spon

se ra

te (%

)

Figure 5.7a. Primary immunization with Hexyon® at 6-10-14 weeks of age (Madhi 2011)1.

Post-primary series, n=145 Pre-booster, n=114

9099 100

100

100

100

NA*94 97 NA*82 92 9998 100

10095 100 8597 100 8591 100 8194 97

Post-booster, n=114

0

20

40

60

80

100



mIU/mL≥0.15µg/mL

Sero

prot

ectio

n/va

ccin

e re

spon

se ra

te (%

)

Figure 5.7b Primary immunization with Hexyon® at 2-3-4 months of age (Ceyhan 2010)2.

9296 99 100

100

100

NA*97 92 NA*98 87 100

100

100

100

100

100 97100

100 8799 100 9098 99

0

20

40

60

80

100



mIU/mL≥0.15µg/mL

Sero

prot

ectio

n/va

ccin

e re

spon

se ra

te (%

)

Post-primary series, n=695 Pre-booster, n=207 Post-booster, n=177

Figure 5.7c Primary immunization at 2-4-6 months of age (Becerra Aquino 2012)6.

18


This supports the value of vaccination at 6-10-14 weeks of age even in infants not vaccinated against hepatitis B at birth1. As would be expected because of a booster effect, levels of antibodies against the HBsAg were higher in infants who received a birth dose of hepatitis B vaccine1.

Hexyon® provides protection against hepatitis B after completion of the primary series with or without hepatitis B vaccination at birth. Hexyon® is indicated in the WHO EPI schedule without a birth dose of hepatitis B. Hepatitis B vaccination at birth using a stand-alone vaccine is recommended in many countries worldwide. In some countries, however, this birth dose is not currently recommended or it is recommended only for babies when the mother is infected (most European countries)12. In addition, some infants may not get vaccinated despite an existing recommendation. Thus, it was important to evaluate the immunogenicity of Hexyon® in infants not vaccinated against hepatitis B at birth to ensure that they are sufficiently protected during their first and most vulnerable months of life.

The immunogenicity of Hexyon® under various immuni-zation schedules with or without hepatitis B vaccination at birth was assessed in several studies according to recom-mendations existing at the time. Since South Africa is one of the countries in which a birth dose of hepatitis B vaccine is not recommended, it was possible to conduct a study in that country to assess hepatitis B immunity in children either primed or not at birth in the same study1.

As shown in Figure, hepatitis B seroprotection rates were high (≥9 6 %) whether or not infants had received a birth dose1. Thus, Hexyon® was shown to provide sufficient protection against hepatitis B after completion of the primary series, even in the absence of hepatitis B vaccination at birth.

Using Hexyon® with or without dose of hepatitis B vaccine at birth

Without Hep Bvaccine at birth

HbsAg ≥10 mIU/mLn=220

With Hep Bvaccine at birth

HbsAg ≥10 mIU/mLn=123

0

20

40

60

80

100

Anti-

HBs

sero

prot

ectio

n ra

tes

(%)

96 99

Concomitant vaccination with other routine paediatric vaccines

The effect of concomitant administration of Hexyon® with other routine paediatric vaccines was evaluated in three primary series studies5,8, one booster study1, and one primary + booster study10.

Concomitant administration of Hexyon® with either pneumococcal polysaccharide conjugated vaccine (7- or 13-serotype), a measles-mumps-rubella vaccine, a rotavirus vaccine, or a pneumoccal vaccine have shown no clinically relevant interference in the antibody response to each of the antigens

Co-administration with pneumococcal conjugate vaccine and rotavirus vaccineDuring clinical development, Hexyon® was administered at 2, 4 and 6 months of age simultaneously with a 7-valent pneumo-coccal conjugate vaccine (PCV7) in two studies5,8. In one of these studies8, Hexyon® was also co-administered with a rotavirus vaccine. In both studies, the immune response to each antigen of Hexyon® was high and similar, when statistical non-inferiority

was measured, to that of the comparator hexavalent vaccine (also co-administered with the rotavirus and/or PCV7 vaccines). Furthermore, in one8, the immune responses (seroprotection/seroconversion rates and GMTs/GMCs) to all PCV7 and rotavirus antigens were high and similar when co-administered with either Hexyon® or control hexavalent vaccine.

In a study of co-administration of Hexyon® with PCV13 in a 2+1 dose schedule, the immune response to Hexyon® was not affected and was consistent with data from previous clinical trials10. The seroprotection response to PCV13 antigens was high and similar following co-administration with Hexyon®.

Co-administration with measles-mumps-rubella vaccineIn the booster study conducted in South Africa11, Hexyon® was co-administered with measles-mumps-rubella (MMR) and varicella vaccines. The immune response to all MMR antigens in terms of both seroprotection/seroconversion rates and GMTs/GMCs was high and not affected by co-administration. The varicella response in this study (73-75%) was slightly lower than would be expected after a single dose of varicella vaccines in healthy children (about 95%).

Hepatitis B seroprotection rates (≥10 mIU/mL) observed in South African infants one month after primary vaccination with Hexyon® at 6-10-14 weeks of age with or without a dose of hepatitis B vaccine at birth. 95% CI are shown. Adapted from Madhi et al1.

19


References 1. Madhi SA, Mitha I, Cutland C, et al. Immunogenicity and safety of an

investigational fully liquid hexavalent combination vaccine versus licensed combination vaccines at 6, 10, and 14 weeks of age in healthy South African infants. Pediatr Infect Dis J. 2011;30:e68-e74.

2. Ceyhan M, Santos-Lima E. Immunogenicity and safety of an inves-tigational hexavalent fully-liquid DTaP-IPV-Hep B-PRP-T vaccine (Hexaxim™) given at 2, 3, 4 months of age and as a booster at 15-18 months compared with licensed vaccines in Turkish infants. Presented at 5th Asian Congress of Pediatric Infectious Diseases (ACPID), 23–26 September 2010, Taipei, Taiwan.

3. Macías M, Lanata CF, Zambrano B, Gil AI, Amemiya I, Mispireta M, Ecker L, Santos-Lima E. Safety and immunogenicity of an investigational fully liquid hexavalent DTaP-IPV-Hep B-PRP-T vaccine at two, four and six months of age compared with licensed vaccines in Latin America. Pediatr Infect Dis J. 2012;31:e126–e132.

4. Tregnaghi MW, Zambrano B, Santos-Lima E. Immunogenicity and safety of an investigational hexavalent diphtheria-tetanus-acellular pertussis-inactivated poliovirus-hepatitis B-Haemophilus influenzae B conjugate combined vaccine in healthy 2-, 4-, and 6-month-old Argentinean infants. Pediatr Infect Dis J. 2011;30:e88–e96.

5. Kosalaraksa P, Thisyakorn U, Benjaponpitak S, Chokephaibulkit K, Santos-Lima E. Immunogenicity and safety study of a new DTaP-IPVHep B-PRP-T combined vaccine compared to a licensed DTaP-IPVHep B//PRP-T comparator, both concomitantly administered with a 7-valent pneumococcal conjugate vaccine at 2, 4, and 6 months of age in Thai infants. Int J Infect Dis. 2011;15:e249–e256.

6. Becerra Aquino AG, Gutiérrez Brito M, Aranza Doniz CE, Galán Herrera JF, Macias M, Zambrano B, Santos-Lima E. A fully liquid DTaP-IPV-Hep B-PRP-T hexavalent vaccine for primary and booster vaccination of healthy Mexican children. Vaccine. 2012;30:6492–6500.

7. Lanata C, Zambrano B, Ecker L, Amemiya I, Gil A, Santos-Lima E. Immu-nogenicity and safety of a fully-liquid DTaP-IPV-Hep B-PRP-T vaccine at 2-4-6 months of age in Peru. J Vaccines Vaccin. 2012;3:128.

8. Lopez P, Mohs AA, Miranda MC, Zambrano B, Santos Lima E. Immuno-genicity and safety of a primary series of a new fully-liquid DTaP-Hep B-PRP-T hexavalent vaccine (Hexaxim™) co-administered with Prevenar™ and Rotarix™ in healthy children in Latin America. Int J Infect Dis. 2012;16S:e313. Abstract 48.030.

9. Vesikari T, Silfverdal SA, Jordanov E, Feroldi E. Immunogenicity/safety of DTaP-IPV-HB-Hib vaccine versus Infanrix® hexa concomitant with Prevenar 13® (PCV13), at 3, 5, and 11-12 months of age. Presented at the 33rd Annual Meeting of the European Society for Paediatric Infectious Diseases (ESPID), May 13-16 May 2015, Leipzig, Germany. Abstract ESPID-0913.

10. Santos-Lima E, B’Chir S, Lane A. Combined immunogenicity data for a new DTaP-IPV-Hep B-PRP-T vaccine (Hexaxim™) following primary series administration at 2, 4, 6 months of age in Latin America. J Vaccine. 2013;31:1255–1258.

11. European Medicines Agency (EMA). Hexyon – EMEA/H/C/002796 -N/0030. EPAR product information: Annex I - Summary of product characteristics. Updated 16 July 2015. Available at http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002796/WC500145758.pdf

12. Data on file.

13. Madhi SA, Koen A, Cutland C, Groome M, Santos-Lima E. Antibody persistence and booster vaccination of a fully liquid hexavalent vaccine coadministered with measles/mumps/rubella and varicella vaccines at 15–18 months of age in healthy South African infants. Pediatr Infect Dis J. 2013;32:889–897.

14. Vesikari T, Boisnard F, Richard P, Lockhart S. Concomitant administra-tion of a fully liquid, ready-to-use hexavalent vaccine DTaP-IPV-HB-Hib with a meningococcal serogroup C vaccine in infants. Presented at the 33rd Annual Meeting of the European Society for Paediatric Infectious Diseases (ESPID), May 13-16 May 2015, Leipzig, Germany. Abstract ESPID-0330

Co-administration with meningococcal serogroup C vaccineIn a study in Finland14, infants primed at 2-3-4 months with Hexyon® who also received meningococcal serogroup C (MenC) conjugate vaccine co-administered at 2-4 months showed a non-inferior response in terms of seroprotection rate for hepatitis B post third dose. The MenC seroprotection rate demonstrated post second dose was also acceptable. A good immune response to Hexyon® antigens was seen with MenC co-administration.

SUMMARYHexyon® induced high antibody responses to all antigens when co- administered with other routinely administered childhood vaccines: pneumococcal conjugated, rotavirus, MMR or meningococcal C conjugate vaccines.

CONCLUSIONSl Overall, Hexyon® has been shown to be highly

immunogenic in all schedules, countries, and ethnicities tested.

l The immunogenicity profile of Hexyon® is comparable to that of the control hexavalent vaccine and the pentavalent DTaP-IPV- Hib plus stand-alone hepatitis B vaccines.

l Following primary series with Hexyon® and before the booster in the second year of life, antibody persistence against relevant antigens is high.

l A booster dose with Hexyon® induced strong immune responses to all antigens, indicative of appropriate priming and immune memory. The booster responses were high, regardless of the primary vaccination schedule or vaccine used.

l Hexyon® can be administered concomitantly with other routine paediatric vaccines (pneumococcal conjugate, rotavirus, MMR or meningococcal C conjugate vaccines) without altering the immune response to either vaccine.

20


Safety and reactogenicity in primary vaccinationHexyon® is well tolerated and its safety profile is similar to that of other licensed hexavalent or pentavalent aP-based combination paediatric vaccines.

The safety profile of a primary series with Hexyon® was compared to that of another licensed hexavalent vaccine in 4 studies2-5. Both Hexyon® and the control hexavalent vaccine were well tolerated (Table 6.1 and Table 6.2). Overall, the percentage of subjects with solicited injection-site reactions and solicited systemic reactions (regardless of grade or severity) after any dose was similar for both groups. In some studies, a trend toward higher reactogenicity of Hexyon® was observed compared with hexavalent control, especially in cases of injection site reactions.

The tolerability profile of Hexyon® was also compared with Pentavac® plus separate administration of hepatitis B vaccine in additional studies in Argentina6 and Turkey7. In both studies, the incidence of unsolicited vaccine-related AEs was similar and low, and no vaccine-related SAE was reported. In the study conducted

6. HEXYON® SAFETY PROFILE

The safety profile of Hexyon® was evaluated in 8 primary series studies and 5 booster studies (See Chapter 6). The safety profile of Hexyon® has been established in over 13 clinical trials with over 5000 infants1.The choice of control vaccines in the clinical development program was determined by the standards of care in the countries where the studies were conducted. Additionally, the control vaccines selected were representative of those typically used in Europe.

The safety of different vaccination schedules in these studies was evaluated plus the potential impact on safety of an additional dose of hepatitis B vaccine at birth. Adverse events (AEs) were recorded by parents or guardians. Specific solicited AEs (injection site and systemic reactions) were recorded for 7 days after each injection, as well as all unsolicited AEs up to 30 days after each injection, and all serious adverse events (SAEs) throughout the entire study period (up to 6 months after the last vaccination)1.

Table 6.2 Solicited systemic reactions within 7 days of any dose, post primary series of Hexyon® and a control hexavalent vaccine.

Type of event

Severity

Becerra Aquino 2012 Kosalaraksa 2011* Lanata 2012 Lopez 2012† Vesikari 2015

Hexyon®

N=1022ControlN=167

Hexyon®

N=206ControlN=206

Hexyon®

N=132ControlN=131

Hexyon®

N=1030ControlN=338

Hexyon®

N=271ControlN=275

PyrexiaAny Severea

44.62.8

36.33.2

74.12.9

63.63.4

28.00.0

27.52.3

39.31.3

36.90.9

82.3–

69.0–

VomitingAny Severeb

33.81.0

29.30.6

37.60.5

39.81.5

22.00.0

24.40.0

39.1 2.7

40.12.3

37.6–

38.7–

CryingAny Severec

67.23.8

54.81.3

81.13.4

74.32.4

75.80.8

71.00.8

76.29.4

68.67.3

88.9–

88.3–

Somno-lence

Any Severed

43.44.4

33.11.9

68.82.0

60.70.0

55.31.5

62.61.5

60.95.4

57.65.2

83.0–

79.2–

AnorexiaAny Severed

39.52.0

33.12.5

44.40.0

40.30.0

40.90.0

44.30.8

45.64.1

39.02.9

67.2–

66.8–

IrritabilityAny Severee

82.28.2

75.85.1

79.02.0

77.22.9

75.81.5

74.80.8

78.611.0

76.56.4

96.7–

93.1–

Data are percentage of participants experiencing at least one reaction after any vaccination of any vaccine.a≥39.5°C; b≥6 episodes per 24 hours; c>3 hours; dSleeping most of the time; dRefuses 3 feeds/meals; eInconsolable.*Control hexavalent vaccine co-administered at 2- 4- 6- months and **2-4 months, plus hepatitis B vaccine at birth. †Rotavirus vaccine co-administered at 2-4 months.

Table 6.1 Solicited injection-site reactions within 7 days of any dose, post primary series of Hexyon® and a control hexavalent vaccine.

Type of event

Severity

Becerra Aquino 2012 Kosalaraksa 2011* Lanata 2012 Lopez 2012† Vesikari 2015†

Hexyon®

N=1022ControlN=167

Hexyon®

N=206ControlN=206

Hexyon®

N=132ControlN=131

Hexyon®

N=1030ControlN=338

Hexyon®

N=271ControlN=275

PainAny Severea

89.713.1

82.89.6

87.89.8

80.65.8

77.37.6

77.14.6

78.913.1

75.98.7

80.1–

69.3–

Erythema Any Severeb

57.31.5

48.400.6

58.71.5

55.31.0

59.12.3

50.43.8

43.51.2

34.30.3

71.6–

63.5–

Swelling Any Severeb

44.12.0

37.61.3

41.30.5

31.60.5

40.92.3

39.71.7

25.40.9

24.40.3

50.9–

50.7–

Data are percentage of participants experiencing at least one reaction after any vaccination of any vaccine.aCries when injected limb is moved or movement of the injected limb is reduced; b≥5 cm in diameter.*Control hexavalent vaccine co-administered at 2- 4- 6- months and **2-4 months, plus hepatitis B vaccine at birth. †Rotavirus vaccine co-administered at 2-4 months.

21


istered in a 2+1 schedule (at 3 and 5 months of age plus 11-12 months of age) with concomitant administration of penumococcal conjugate vaccine (PCV-13) at 3, 5, 11-12 months of age11.

Co-administration with measles-mumps-rubella and varicella vaccinesThe safety and tolerability profile of Hexyon® given as a booster dose during the second year of life was good when it was co- administered with measles-mumps-rubella (MMR) and varicella vaccines9.

Co-adminstration with a meningococcal serogroup C vaccineWhen Hexyon® was co-administered with meningococcal serogroup C (menC) conjugate vaccine, all vaccines were well tolerated and the safety profile of Hexyon® was consistent with the established product profile12.

Most common adverse eventsAmong the adverse events (AEs) recorded in clinical trials of Hexyon® 13, those classified as “Very common” (≥1/10 of children) included anorexia (decreased appetite); crying; somnolence; vomiting; irritability; pyrexia (body temperature ≥38.0°C); injection-site pain and erythema; and injection-site swelling. Slightly higher solicited reactogenicity was observed after the first dose compared to subsequent doses.

in Argentina, the overall incidence of AEs was similar across the study groups, but the incidence of solicited AEs tended to be higher with Hexyon®6.

The incidence of injection-site and systemic reactions was similar after primary vaccination with Hexyon® whether or not hepatitis B vaccine was given at birth

In studies conducted in Mexico2, Peru4, Colombia and Costa Rica5, Turkey7, South Africa9 and Argentina6, Hexyon® demonstrated a good safety profile with the 2-4 months, 2-3-4 months, and 6-10-14 weeks of age schedules in children who had received a birth dose of hepatitis B vaccine. The study performed in South Africa that demonstrated the safety of Hexyon® when adminis-tered at 6-10-14 weeks of age9 also assessed the potential impact of an additional birth dose of hepatitis B vaccine. As expected, the addition of a birth dose of hepatitis B vaccine did not induce significant changes to the reactogenicity of Hexyon® 9.

In comparative studies of primary vaccination with Hexyon® with similar aP-based paediatric vaccines that are used in Europe (i.e., another hexavalent vaccine or Pentavac® plus hepatitis B vaccine), the incidences of solicited injection-site and systemic AEs (any and severe) were generally similar

Safety of booster vaccinationThe incidence of injection-site and systemic reactions was similar in children boosted with Hexyon® regardless of the primary vaccination schedule.

The safety of Hexyon® as a booster dose was evaluated in more than 1500 children primed with Hexyon® or other control vaccines1,2,7.

l Overall, Hexyon® was well tolerated when administered as a booster dose during the second year of life, regardless of the primary vaccination.

l After a booster, the incidence of grade 3 reactions was similar for Hexyon® and controlled vaccines10.

l Most unsolicited AEs were systemic and mainly associated with common medical conditions of infancy. No SAEs were considered by the Investigators to be related to vaccination2,7,9.

Safety with concomitant vaccinationsOver the past decades, there has been a steady increase in the number of vaccines included in routine immunization programs. The concomitant administration of Hexyon® with other childhood vaccines has been evaluated in several studies.

Co-administration with pneumococcal conjugate vaccine and rotavirus vaccineTwo studies conducted in Thailand3 and Colombia and Costa Rica5

demonstrated that the safety and tolerability profile of Hexyon® given as a primary vaccination (at 2, 4 and 6 months of age) was good when Hexyon® was co-administered with pneumococcal conjugate vaccine and rotavirus vaccine. A good safety profile was also demonstrated in a Finnish/Swedish study of Hexyon® admin-

KEY POINTS ON HEXYON® SAFETY PROFILEl Overall, Hexyon was well tolerated as a primary series

and booster vaccination in all schedules, countries and ethnicities tested.

l The primary series and booster safety profile of Hexyon® is generally similar to that of a licensed hexavalent vaccine and to that of another aP-based vaccine.

l A booster dose of Hexyon® does not further increase the reactogenicity, regardless of the vaccine used for the primary series, even in those children who received a dose of hepatitis B vaccine at birth.

l Concomitant administration of Hexyon® with other routine paediatric vaccines (pneumococcal conjugate vaccine, rotavirus vaccine, or MMR vaccines) is well tolerated.

References 1. European Medicines Agency (EMA), Committee for Medicinal Products

for Human Use (CHMP). Assessment report: Hexyon. EMA/373968/2013. London, UK: European Medicines Agency; 5 March 2013. Available at http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002796/WC500145760.pdf Accessed 1 June 2015.

2. Becerra Aquino AG, Gutiérrez Brito M, Aranza Doniz CE, Galán Herrera JF, Macias M, Zambrano B, Santos-Lima E. A fully liquid DTaP-IPV-Hep B-PRP-T hexavalent vaccine for primary and booster vaccination of healthy Mexican children. Vaccine. 2012;30:6492-6500.

22


7. HEXYON® IN CLINICAL PRACTICE: BENEFITS OF A READY-TO-USE PRESENTATION

Hexyon® is a fully liquid, ready-to-use vaccine, which

simplifies administration compared with vaccines that need reconstitution, and helps to increase security of use. It reduces

the risk of contamination or handling errors

and it ensures that each inoculation contains all the

components and that the Hib component is not omitted.Data from the Hexyon® clinical development program have shown that primary and booster vaccination with Hexyon® is a well-tolerated and immunogenic option for the prevention of several serious childhood diseases. Importantly, Hexyon®’s formulation and presentation provide new benefits for healthcare professionals.

Handling errors during vaccine reconstitutionHandling errors during reconstitution can lead to misuse, ineffective immunization or adverse events. The WHO has identified a number of handling errors related to vaccine reconstitution preparations that can lead to adverse events following vaccination1, including:

l Vaccine reconstituted with incorrect or wrong amount of diluting agent.

l Vaccine prepared incorrectly for use, e.g., not being shaken properly before use, or vaccine component missed.

l Vaccine or diluting agent contaminated.

l Reconstituted vaccine used beyond 6 hours after reconstitution.

The WHO has concluded that adverse events following vaccination due to errors in storage, handling, or administration of vaccines are more common than are adverse events due to the properties of vaccines1.

A “time and motion” study measured the preparation time with Hexyon® versus a paediatric hexavalent vaccine that requires reconstitution2. In this study 96 healthcare professionals (HCPs) prepared each vaccine in a cross-over manner. Both vaccine preparations were recorded using video equipment allowing for time capture. An independent nurse assessed the time taken for vaccine preparation and immunization errors by systematic review of the videos.

Hexyon® ready-to-use vaccine was associated with a decrease in preparation time of almost 50% compared with the reconstitut-ed hexavalent vaccine. The study also showed a higher number of mishandlings, including one missing reconstitution of Hib component when reconstitution was required.

3. Kosalaraksa P, Thisyakorn U, Benjaponpitak S, Chokephaibulkit K, Santos-Lima E. Immunogenicity and safety study of a new DTaP-IPVHep B-PRP-T combined vaccine compared to a licensed DTaP-IPVHep B//PRP-T comparator, both concomitantly administered with a 7-valent pneumococcal conjugate vaccine at 2, 4, and 6 months of age in Thai infants. Int J Infect Dis. 2011;15:e249–e256.

4. Lanata C, Zambrano B, Ecker L, Amemiya I, Gil A, Santos-Lima E. Immu-nogenicity and safety of a fully-liquid DTaP-IPV-Hep B-PRP-T vaccine at 2-4-6 months of age in Peru. J Vaccines Vaccin. 2012;3:128.

5. Lopez P, Mohs AA, Miranda MC, Zambrano B, Santos Lima E. Immuno-genicity and safety of a primary series of a new fully-liquid DTaP-Hep B-PRP-T hexavalent vaccine (Hexaxim™) co-administered with Prevenar™ and Rotarix™ in healthy children in Latin America. Int J Infect Dis. 2012;16S:e313. Abstract 48.030

6. Tregnaghi MW, Zambrano B, Santos-Lima E. Immunogenicity and safety of an investigational hexavalent diphtheria-tetanus-acellular pertus-sis-inactivated poliovirus-hepatitis B-Haemophilus influenza B conjugate combined vaccine in healthy 2-, 4-, and 6-month-old Argentinean infants. Pediatr Infect Dis J. 2011;30:e88-e96.

7. Ceyhan M, Santos-Lima E. Immunogenicity and safety of an investiga-tional hexavalent fully-liquid DTaP-IPV-Hep B-PRP-T vaccine (Hexaxim™) given at 2, 3, 4 months of age and as a booster at 15-18 months compared to licensed vaccines in Turkish infants. Presented at 5th Asian Congress of Pediatric Infectious Diseases (ACPID), 23-26 September 2010, Taipei, Taiwan. Poster.

8. Macías M, Lanata CF, Zambrano B, Gil AI, Amemiya I, Mispireta M, Ecker L, Santos-Lima E.. Safety and immunogenicity of an investigational fully liquid hexavalent DTaP-IPV-Hep B-PRP-T vaccine at two, four and six months of age compared with licensed vaccines in Latin America. Pediatr Infect Dis J, 2012;31:e126–e132.

9. Madhi SA, Koen A, Cutland C, Groome M, Santos-Lima E. Antibody persistence and booster vaccination of a fully liquid hexavalent vaccine coadministered with measles/mumps/rubella and varicella vaccines at 15–18 months of age in healthy South African infants. Pediatr Infect Dis J. 2013;32:889–897.

10. McCormack PL. DTaP-IPV-Hep B-Hib vaccine (Hexaxim®). Pediatr Drugs. 2013;15:59–70.

11. Vesikari T, Silfverdal SA, Jordanov E, Feroldi E. Immunogenicity/safety of DTaP-IPV-HB-Hib vaccine versus Infanrix® hexa concomitant with Prevenar 13® (PCV13), at 3, 5, and 11-12 months of age. Presented at the 33rd Annual Meeting of the European Society for Paediatric Infectious Diseases (ESPID), May 13-16 May 2015, Leipzig, Germany. Abstract ESPID-0913

12. Vesikari T, Boisnard F, Richard P, Lockhart S. Concomitant administra-tion of a fully liquid, ready-to-use hexavalent vaccine DTaP-IPV-HB-Hib with a meningococcal serogroup C vaccine in infants. Presented at the 33rd Annual Meeting of the European Society for Paediatric Infectious Diseases (ESPID), May 13-16 May 2015, Leipzig, Germany. Abstract ESPID-0330

13. European Medicines Agency. Hexyon: EPAR product information. Updated 16 July 2015. London, UK: 2015. Available at http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002796/WC500145758.pdf. Accessed 18 July 2015.

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Presentation and guidelines for usage of Hexyon®The recommended use of Hexyon®, in accordance with official recommendations, is flexible, providing options of a range of administration schedules3. Thus, Hexyon® can be used in many situations that healthcare professionals face when trying to ensure that their patients receive all of their recommended vaccinations on time. The details of Hexyon® presentation and use are provided below. The information provided in this chapter is consistent with the EMA product information for Hexyon®2.

Hexyon® is a fully liquid, ready-to-use vaccine against several serious childhood diseases that does not require reconstitution and has a flexible administration schedule.

Composition of Hexyon® Active substances of Hexyon®

The quantities of D, T, poliomyelitis antigens, and pertussis antigens (PT and FHA) contained in Hexyon® are identical to those contained in Pentavac®. The sole common antigen that differs in quantity is Hib capsular polysaccharide (polyribosylribitol phosphate conjugated to tetanus toxoid, PRP-T), which is increased from 10 μg to 12 g per dose. The hepatitis B antigen (10 g) is the only additional active component. All the antigens included in Hexyon® are manufactured by Sanofi Pasteur. Each unit dose (0.5 mL) contains antigens against several diseases in the concentrations or potencies shown in Table 7.1:

Adjuvants in Hexyon®

Each unit dose (0.5 mL) is adsorbed on aluminium hydroxide, hydrated (0.6 mg Al3+).

Presentation, storage and shelf-life of Hexyon®Hexyon® is a whitish, cloudy suspension for injection that is dispensed in unidose presentations (Figure 7.1), as either:

l Pre-filled syringes without needles (packs of 1, 10 or 50) with double detachable labels for easy documentation; or

l Pre-filled syringes with one or two separate needles (packs of 1 and 10).

All vaccine valences of Hexyon® are in liquid form, including Hib; therefore no reconstitution is necessary prior to vaccine administration.

Table 7.1. Antigens included in Hexyon® and their potencies.

Purified dyphtheria toxoid ≥20 IU

Purified tetanus toxoid ≥40 IU

PT 25 g

FHA 25 g

Type 1 poliovirus (Mahoney) 40 units

Type 2 poliovirus (MEF-1) 8 units

Type 3 poliovirus (Saukett) 32 units

Haemophilus influenzae type b polysaccharide 12 g

Purified recombinant HBsAg 10 g

PT, pertussis toxoid; FHA, filamentous haemagglutinin; HBsAg, hepatitis B surface antigen.

Figure 7.1. Hexyon® packaging.

Hexyon® should be refrigerated at 2–8°C. Hexyon® should never be frozen.

Hexyon® has a shelf-life of 3 years.

Approved use of Hexyon®The approved indication of Hexyon® is for primary and booster vaccination of infants and toddlers from 6 weeks to 24 months of age against diphtheria, tetanus, pertussis, poliomyelitis, hepatitis B, and invasive diseases caused by Haemophilus influenzae type b3. The vaccine should be used in accordance with official recommen-dations.

Recommended vaccination schedule for Hexyon®Hexyon® can be administered in a range of schedules with or without a hepatitis B birth dose (Table 7.2):

Primary vaccination:l The primary vaccination consists of 2 doses (with an interval of

at least 8 weeks) or 3 doses (with an interval of at least 4 weeks), in accordance with official recommendations.

l All vaccination schedules including the WHO Expanded Programme on Immunization (EPI) at 6, 10, 14 weeks of age can be used whether or not a dose of hepatitis B vaccine has been given at birth.

l Where a dose of hepatitis B vaccine is given at birth, Hexyon® can be used for supplementary doses of hepatitis B vaccine from the age of 6 weeks. If a second dose of hepatitis B vaccine is required before this age, monovalent hepatitis B vaccine should be used.

Booster vaccination:l After a 2-dose primary vaccination with Hexyon®, a booster dose

must be given.

l After a 3-dose primary vaccination with Hexyon®, a booster dose should be given.

l Booster doses should be given at least 6 months after the last priming dose and in accordance with the official recommendations. At the very least, a dose of Hib vaccine must be administered.

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l Pertussis vaccine should not be administered to individuals with uncontrolled neurologic disorder or uncontrolled epilepsy until treatment for the condition has been established, the condition has stabilized and the benefit clearly outweighs the risk

Concomitant administration with other vaccinesHexyon® can be co-administered with other routinely adminis-tered childhood vaccines:

l Data on concomitant administration of Hexyon® with a pneu-mococcal polysaccharide conjugated vaccine have shown no clinically relevant interference in the antibody response to each of the antigens.

l Data on concomitant administration of rotavirus vaccines have shown no clinically relevant interference in the antibody response to each of the antigens.

l Data on concomitant administration of a booster dose of Hexyon® with measles-mumps-rubella vaccines have shown no clinically relevant interference in the antibody response to each of the antigens.

l There may be a clinically relevant interference in the antibody response of Hexyon® and a varicella vaccine and these vaccines should not be administered at the same time.

l Data on concomitant administration of Hexyon® with a menin-gococcal C conjugate vaccine have shown no clinically relevant interference in the antibody response to each of the antigens

l If co-administration with another vaccine is considered, immuni-zation should be carried out on separate injections sites.

l Hexyon® must not be mixed with any other vaccines or other parenterally administered medicinal products.

References1. World Health Organization. Global vaccine safety. Information for

health-care workers – managing adverse events. Available at http://www.who.int/vaccine_safety/initiative/detection/managing_AEFIs/en/index2.html. Accessed 20 April 2015.

2. De Coster I, Fournie X, Faure C, et al. Assessment of preparation time with fully-liquid versus non-fully liquid paediatric hexavalent vaccines. A time and motion study. Vaccine. 2015;33:3976-3982.

3. European Medicines Agency. Hexyon: EPAR product information. Updated 16 July 2015. London, UK: 2015. Available at http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002796/WC500145758.pdf. Accessed 18 July 2015.

In addition:

l In the absence of hepatitis B vaccination at birth, it is necessary to give a hepatitis B vaccine booster dose. Hexyon® can be considered for the booster.

l After a 3-dose WHO EPI schedule with Hexyon® (6-10-14 weeks) and in the absence of hepatitis B vaccination at birth, a hepatitis B vaccine booster must be given. At the very least, a booster dose of polio vaccine should be given. Hexyon® can be considered for the booster.

l When a hepatitis B vaccine is given at birth, after a 3-dose primary vaccination, Hexyon® or a pentavalent DTaP-IPV/Hib vaccine can be administered for the booster.

l Hexyon® may be used as a booster in individuals who have previously been vaccinated with another hexavalent vaccine or a pentavalent DTaP-IPV/Hib vaccine associated with a monovalent hepatitis B vaccine.

Method of administrationHexyon® should be administered intramuscularly. Never inject by the intravascular route. The recommended site of injection is the antero-lateral aspect of the upper thigh in infants and toddlers and the deltoid muscle in older children.

Contraindications for use of Hexyon®There are some infants and children who should not be vaccinated with Hexyon®. Hexyon® is contraindicated in cases of:

l History of an anaphylactic reaction after a previous administra-tion of Hexyon®

l Hypersensitivity to the active substances, to any of the excipients listed in Section 6.1 of the EMA product information2, to trace residuals (glutaraldehyde, formaldehyde, neomycin, streptomycin and polymyxin B), to any pertussis vaccine, or after previous administration of Hexyon® or a vaccine containing the same components or constituents.

l If the individual has experienced an encephalopathy of unknown etiology, occurring within 7 days following prior vaccination with a pertussis containing vaccine (whole cell or acellular pertussis vaccines).

In these circumstances pertussis vaccination should be dis-continued and the vaccination course should be continued with diphtheria, tetanus, hepatitis B, poliomyelitis and Hib vaccines.

Table 7.2. Examples of Hexyon® vaccination schedules.

EPI schedule 6 weeks 8 weeks 10 weeks 12 weeks 14 weeks 12 months 12-24 months

+/- hepatitis B vaccine at birth X X X X

Other schedules 2 months 3 months 4 months 5 months 6 months 12 months 12-24 months*




+/- hepatitis B vaccine at birth X X X

+/- hepatitis B vaccine at birth X X X

*Booster dose should be given in accordance with official local recommendations in accordance with official recommendations and at least 6 months after last priming dose. A booster dose of Hib vaccine must be given.

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8. CONCLUSIONSHexyon® is an important new tool for healthcare practitioners in their continued efforts to ensure high vaccination coverage against preventable infectious paediatric diseases in Europe.Combination vaccines can simplify immunization schedules, reduce the numbers of injections needed and help improve coverage and reduce vaccine-related costs.

Hexyon® is a fully liquid hexavalent combination paediatric vaccine indicated for primary and booster vaccination of infants and toddlers from 6 weeks to 24 months of age in Europe. Hexyon®, which contains Hansenula polymorpha-derived HBsAg specifically developed for hexavalent vaccination, has demon-strated high seroprotection and seroconversion rates against diphtheria, tetanus, pertussis, poliovirus, hepatitis B virus, and Haemophilus influenzae type b that are and comparable to rates with a hexavalent control vaccine and a pentavalent vaccine. The safety profile of Hexyon® is generally similar to paediatric combination vaccines of standard doses of licensed vaccines that provide prevention against the same infectious diseases.

In addition to the benefits provided through the use of combination vaccines for paediatric vaccination, Hexyon® uses a new, fully liquid technology so that no reconstitution of the Hib component is needed and all injections contain the Hib component. The vaccine is ready to use, which improves security by reducing the risk of contamination or handling errors. It also simplifies the practice and allows faster preparation.Hexyon® is important new tool for healthcare practitioners in their continued efforts to ensure high vaccination coverage against preventable infectious paediatric diseases in Europe.

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Pathogen A microorganism, such as a bacterium, a fungus, or a virus that causes disease or illness in an infected host.

Pentavalent Having a valency of 5. A pentavalent combination vaccine immunizes against 5 different diseases.

Pertussis Also known as whooping cough, caused by the bacterium Bordetella pertussis.

Poliomyelitis (“polio”) An acute neurologic disease caused by one of three poliovirus serotypes (P1, P2 or P3), usually affecting children and young adults. The disease can cause permanent paralysis and other neurologic complications.

Primary vaccination/immunization First or principal intro-duction of a vaccine into the body for the purpose of inducing immunity.

Reconstitution Return to a liquid state by adding water or another diluting agent.

Seroprotection After vaccination, the achievement of an antibody titer above the defined threshold of protection. Usually interpreted as a moderate to high probability of protection against a disease.

Surveillance program A deliberate, continuous effort by an agency to monitor the occurrence, prevalence, and development of a particular disease.

Tetanus Infection caused by the bacterium Clostridium tetani, which is widespread in the environment. Infection usually occurs through wounds. Case fatality rate is high.

Toxoid An inactivated form of a toxin, often used as a vaccine against the toxin. A toxoid is derived from a toxin by inactivating (chemically) the toxic property without altering the antigenic qualities that induce antibodies.

Vaccination Administration of a vaccine to induce immunity against a specific pathogen.

Vaccination schedule The age at which primary or booster doses of vaccine are administered.

Vaccine coverage Estimate of the number of people who have received particular vaccines.

Vaccine response An antibody level greater than or equal to the lower limit of quantification (LLOQ) in initially seronegative participants (<LLOQ), or persistence of the antibody level (post vaccination ≥ pre vaccination) in participants who were initially seropositive (≥ LLOQ) .

Valency (valence) The number of antigens of a single microorganism (pathogen) that a vaccine is designed to protect against.

GLOSSARYAntigen A molecular structure that can be recognized by the adaptive immune system (i.e., through a specific B cell receptor or a T cell receptor).

Booster vaccination An additional dose of an immunizing agent, such as a vaccine, given after the initial dose to sustain the immune response elicited by the previous administration of the same agent.

Correlates of protection Immune markers that correlate with protection against infection or disease after vaccination (or natural infection).

Diphtheria An acute infectious disease affecting the upper respiratory tract and occasionally the skin that is caused by the bacterium Corynebacterium diphtheria.

Effectiveness Treatment results in usual or routine care in a real-world setting that may or may not be controlled for research purposes. Differs from efficacy, which denotes treatment results in a group of patients participating in ideal conditions such as a controlled, clinical trial.

Endemic A disease or condition regularly found among a particular population or in a certain country or area.

Epidemiology The study of the frequency, distribution and deter-minants of health- related states or events (including disease).

Haemophilus influenzae type b A type of Gram-negative cocco-bacillus (bacterium) that causes for invasive infections in humans that are often severe, particularly among infants.

Hepatitis B virus The virus that is a major cause of acute and chronic hepatitis (inflammation of the liver), which can lead to liver cirrhosis, liver cancer, or death.

Hexavalent Having a valency of 6. A hexavalent combination vaccine immunizes against 6 different diseases.

Immune response A bodily response to an antigen that occurs when lymphocytes identify the antigenic molecule as foreign and induce the formation of antibodies and lymphocytes capable of reacting with it and rendering it harmless. Triggered by vaccination (immunization).

Immunogenicity The property of being able to elicit an immune response.

Invasive disease Disease caused when bacteria or viruses spread to parts of the body that are normally sterile, such as the blood or the central nervous system.

LLOQ Lower limit of quantification within the validated quantita-tive range of an assay. (LLOQ); See Vaccine response.

Memory (anamnestic) response An enhanced and rapid adaptive immune response raised on re-exposure to a previously encountered antigen.

Morbidity The rate of a diseased state or symptom or the incidence of a disease in a specified community or group.

Mortality The number of deaths in a given time or place or (also mortality rate) the proportion of deaths to population.

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DISCLAIMERSThis document is intended for healthcare professionals only. For approved product information consult the manufacturer’s prescribing information at the end of this publication.

ACKNOWLEDGMENTSThe authors would like to thank Amy Yellen-Shaw, PhD for providing editorial support.

ABBREVIATIONSAE adverse event

aP acellular pertussis

CI confidence interval

D diphtheria toxoid

DTaP diphtheria, tetanus, acellular pertussis.

ECDC European Centre for Disease Prevention and Control

EEA European Economic Area

EMA European Medicines Agency

EPAR European Public Assessment Reports

EPI Expanded Programme on Immunization (WHO)

EU European Union

FHA filamentous haemagglutinin

GMC geometric mean concentration

GMT geometric mean titre

GPEI Global Polio Eradication Initiative (WHO)

HBV hepatitis B virus

HCP health care professional

Hep B hepatitis B

Hib Haemophilus influenzae type b

HBsAg hepatitis B surface antigen

IPV inactivated polio vaccine

LLOQ lower limit of quantification

MMR measles-mumps-rubella

OPV oral polio vaccine

P pertussis

PCV-7 Seven-valent pneumococcal conjugate vaccine

PRP-T polyribosyl ribitol phosphate conjugated to tetanus toxoid

PT pertussis toxoid

PV1, 2, 3 poliovirus type 1, 2, 3

SAE serious adverse event

T tetanus toxoid

WHO World Health Organization

wP whole-cell pertussis vaccine

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Cover and Chapter 2Page 4 Corynebacterium diphtheriae. James Cavallini/Science Source

Clostridium tetani. James Cavallini/Science Source

Bordetella pertussis., A. Barry Dowsett / Science Source

Page 5 Poliovirus. NIBSC/Science Source

Haemophilus influenzae. David M. Phillips/Science Source

Hepatitis B. Science Source

Chapter 4Page 8 Hansenula polymorpha protein expression vector. (Tőzsér J et al. Protein Biotechnology. University of Debrecen, Hungary: 2011.

(http://www.tankonyvtar.hu/en/tartalom/tamop425/0011_1A_Proteinbiotech_en_book/ch12.html)

Page 9 Figure 4.1. Development of combination paediatric vaccines leading to Hexyon® production and registration.

Figure 4.2. Immunogenicity of the HBsAg component developed for Hexyon® compared with control vaccine. Seroprotection rates are for 1 month after the third dose of vaccine containing the new Hexyon® hepatitis B component or a control hepatitis B vaccine in adolescents aged 10–15 years and in adults aged 16–45 years. Adapted from Tregnaghi MW et al. Imunogenicity and safety of a novel yeast Hansenula polymorpha-derived recombinant hepatitis B candidate vaccine in healthy adolescents and adults aged 10-45 years. Vaccine. 2010;28:3595–3601.

Page10 Figure 4.3. Laboratory confirmed cases of pertussis in Sweden 1986–2007. Adapted from Nilsson L et al. Pertussis surveillance in Sweden; Fifteen year report. Solna, Sweden: Public Health Agency of Sweden; 2013. https://www.folkhalsomyndigheten.se%2Fpagefiles%2F17379%2Fpertussis-surveillance%2520in-sweden-fifteen-year-report%25282%2529.pdf&ei=aCNqVamQF-NWgyATSwIOABQ&usg=AFQjCNGBEOkktXvgvOrt-gCToFL0KlPAsg&sig2=b4QffD53k9SzIMG2210gqg&bvm=bv.94455598,d.aWw&cad=rja

Chapter 5Page 12 Figure 5.1. Vaccine response after three different 3-dose primary series vaccination schedules. Adapted from Madhi SA et al. Im-

munogenicity and safety of an investigational fully liquid hexavalent combination vaccine versus licensed combination vaccines at 6, 10, and 14 weeks of age in healthy South African infants. Pediatr Infect Dis J. 2011;30:e68-e74; Ceyhan M, Santos-Lima E. Immunogenicity and safety of an investigational hexavalent fully-liquid DTaP-IPV-Hep B-PRP-T vaccine (Hexaxim™) given at 2, 3, 4 months of age and as a booster at 15-18 months compared with licensed vaccines in Turkish infants. Presented at 5th Asian Congress of Pediatric Infectious Diseases (ACPID), 23–26 September 2010, Taipei, Taiwan; and Santos-Lima E et al. Combined im-munogenicity data for a new DTaP-IPV-Hep B-PRP-T vaccine (Hexaxim™) following primary series administration at 2, 4, 6 months of age in Latin America. J Vaccine. 2013;31:1255–1258.

Page 14 Figure 5.2 Comparison of Hexyon® with a control hexavalent vaccine comparator in a 3-dose primary vaccination schedule. Adapted from Lopez P et al. Immunogenicity and safety of a primary series of a new fully-liquid DTaP-Hep B-PRP-T hexavalent vaccine (Hexaxim™) co-administered with Prevenar™ and Rotarix™ in healthy children in Latin America. Int J Infect Dis. 2012; 16S:e313. Abstract 48.030.

Figure 5.3. Comparison of Hexyon® with a control hexavalent vaccine comparator in a 2-dose primary vaccination schedule + booster dose. Adapted from Vesikari T et al. Immunogenicity/safety of DTaP-IPV-HB-Hib vaccine versus Infanrix® hexa concomitant with Prevenar 13® (PCV13), at 3, 5, and 11-12 months of age. Presented at the 33rd Annual Meeting of the European Society for Paediatric Infectious Diseases (ESPID), May 13-16 May 2015, Leipzig, Germany. Abstract ESPID-0913.

Page 15 Figure 5.4. Comparison of Hexyon® to Pentavac® + stand-alone hepatitis B vaccine. Seroprotection/seroconversion rates in response to a 3-dose primary series with Hexyon® or Pentavac® + a standalone hepatitis B vaccine . Adapted from Tregnaghi MW et al. Immunogenicity and safety of an investigational hexavalent diphtheria-tetanus-acellular pertussis-inactivated poliovi-rus-hepatitis B-Haemophilus influenzae B conjugate combined vaccine in healthy 2-, 4-, and 6-month-old Argentinean infants. Pediatr Infect Dis J. 2011;30:e88–e96.

ILLUSTRATIONS

29


Figure 5.5. High hepatitis B immune response following booster vaccination with Hexyon® regardless of the hexavalent vaccine received during the primary series. Hepatitis B seroprotection rates (≥10 mIU/mL) are shown pre- and post-primary vaccination at 2, 4, 6 months of age and pre- and post-booster vaccination at 15–18 months of age with Hexyon® or primary vaccination with a licensed hexavalent control vaccine and booster vaccination with Hexyon® Adapted from Becerra Aquino AG et al. A fully liquid DTaP-IPV-Hep B-PRP-T hexavalent vaccine for primary and booster vaccination of healthy Mexican children. Vaccine. 2012;30:6492–6500.

Page 16 Figure 5.6. Haemophilus influenzae type b immune responses in infants primed with Hexyon®. Adapted from Kosalaraksa P et al. Immunogenicity and safety study of a new DTaP-IPVHep B-PRP-T combined vaccine compared to a licensed DTaP-IPVHep B//PRP-T comparator, both concomitantly administered with a 7-valent pneumococcal conjugate vaccine at 2, 4, and 6 months of age in Thai infants. Int J Infect Dis. 2011;15:e249–e256; Becerra Aquino AG et al. A fully liquid DTaP-IPV-Hep B-PRP-T hexavalent vaccine for primary and booster vaccination of healthy Mexican children. Vaccine. 2012;30:6492–6500; Lanata C et al. Immuno-genicity and safety of a fully-liquid DTaP-IPV-Hep B-PRP-T vaccine at 2-4-6 months of age in Peru. J Vaccines Vaccin. 2012;3:128; and Lopez P et al. Immunogenicity and safety of a primary series of a new fully-liquid DTaP-Hep B-PRP-T hexavalent vaccine (Hexaxim™) co-administered with Prevenar™ and Rotarix™ in healthy children in Latin America. Int J Infect Dis. 2012;16S:e313. Abstract 48.030.

Page 17 Figure 5.7a –c. Seroprotection rates in children primed with Hexyon® using 3 different primary immunization schedules (without hepatitis B vaccination at birth). Adapted from Madhi SA et al. Immunogenicity and safety of an investigational fully liquid hexavalent combination vaccine versus licensed combination vaccines at 6, 10, and 14 weeks of age in healthy South African infants. Pediatr Infect Dis J. 2011;30:e68-e74; Ceyhan M, Santos-Lima E. Immunogenicity and safety of an investigation-al hexavalent fully-liquid DTaP-IPV-Hep B-PRP-T vaccine (Hexaxim™) given at 2, 3, 4 months of age and as a booster at 15-18 months compared with licensed vaccines in Turkish infants. Presented at 5th Asian Congress of Pediatric Infectious Diseases (ACPID), 23–26 September 2010, Taipei, Taiwan.; and Becerra Aquino AG et al. A fully liquid DTaP-IPV-Hep B-PRP-T hexavalent vaccine for primary and booster vaccination of healthy Mexican children. Vaccine. 2012;30:6492–6500.

Page 18 Hepatitis B seroprotection rates (≥10 mIU/mL) observed in South African infants one month after primary vaccination with Hexyon® at 6-10-14 weeks of age with or without a dose of hepatitis B vaccine at birth. 95% CI are shown. Adapted from Madhi SA et al. Immunogenicity and safety of an investigational fully liquid hexavalent combination vaccine versus licensed combination vaccines at 6, 10, and 14 weeks of age in healthy South African infants. Pediatr Infect Dis J. 2011;30:e68-e74.

Chapter 7Page 19 Figure 7.1. Hexyon® packaging.

Page 22 Child, Corbis Photography

i

should be given. Hexyon can be considered for the booster. When a hepatitis B vaccine is given at birth, after a 3-dose primary vaccination, Hexyon or a pentavalent DTaP-IPV/Hib vaccine can be administered for the booster. Hexyon may be used as a booster in individuals who have previous-ly been vaccinated with another hexavalent vaccine or a pentavalent DTaP-IPV/Hib vaccine asso-ciated with a monovalent hepatitis B vaccine. Other paediatric population: The safety and efficacy of Hexyon in children over 24 months of age have not been established. Method of ad-ministration Immunisation must be carried out by intramuscular (IM) injection. The recommended injection site is preferably the antero-lateral area of the upper thigh and the deltoid muscle in older children (possibly from 15 months of age). For instructions on handling see section 6.6. 4.3 Contraindications History of an anaphylactic reaction after a previous administration of Hexyon. Hypersensitivity to the active substances, to any of the excipients listed in section 6.1, to trace residuals (glutaraldehyde, formaldehyde, neomycin, streptomycin and polymyxin B), to any pertussis vaccine, or after previous administration of Hexyon or a vaccine containing the same components or constituents. Vaccination with Hexyon is contraindicated if the individual has expe-rienced an encephalopathy of unknown aetiology, occurring within 7 days following prior vaccina-tion with a pertussis containing vaccine (whole cell or acellular pertussis vaccines). In these circum-stances pertussis vaccination should be discontinued and the vaccination course should be contin-ued with diphtheria, tetanus, hepatitis B, poliomyelitis and Hib vaccines. Pertussis vaccine should not be administered to individuals with uncontrolled neurologic disorder or uncontrolled epilepsy until treatment for the condition has been established, the condition has stabilised and the benefit clearly outweighs the risk. 4.4 Special warnings and precautions for use Hexyon will not prevent disease caused by pathogens other than Corynebacterium diphtheriae, Clostridium tetani, Bordetella pertussis, hepatitis B virus, poliovirus or Haemophilus influenzae type b. Howev-er, it can be expected that hepatitis D will be prevented by immunisation as hepatitis D (caused by the delta agent) does not occur in the absence of hepatitis B infection. Hexyon will not protect against hepatitis infection caused by other agents such as hepatitis A, hepatitis C and hepatitis E or by other liver pathogens. Because of the long incubation period of hepatitis B, it is possible for unrecognised hepatitis B infection to be present at the time of vaccination. The vaccine may not prevent hepatitis B infection in such cases. Hexyon does not protect against infectious diseases caused by other types of Haemophilus influenzae or against meningitis of other origins. Prior to immunisation Immunisation should be postponed in individuals suffering from moderate to severe acute febrile illness or infection. The presence of a minor infection and/or low-grade fever should not result in the deferral of vaccination. Vaccination should be preceded by a review of the person’s medical history (in particular previous vaccinations and possible adverse reactions). The adminis-tration of Hexyon must be carefully considered in individuals who have a history of serious or se-vere reactions within 48 hours following administration of a vaccine containing similar compo-nents. Before the injection of any biological, the person responsible for administration must take all precautions known for the prevention of allergic or any other reactions. As with all injectable vaccines, appropriate medical treatment and supervision should always be readily available in case of an anaphylactic reaction following administration of the vaccine. If any of the following events are known to have occurred after receiving any pertussis containing vaccine, the decision to give further doses of pertussis containing vaccine should be carefully considered: • Temperature of ≥ 40°C within 48 hours not due to another identifiable cause; • Collapse or shock- like state (hypo-tonic-hyporesponsive episode) within 48 hours of vaccination; • Persistent, inconsolable crying lasting ≥ 3 hours, occurring within 48 hours of vaccination; • Convulsions with or without fever, occurring within 3 days of vaccination. There may be some circumstances, such as high incidence of pertussis, when the potential benefits outweigh possible risks. A history of febrile convulsions, a family history of convulsions or Sudden Infant Death Syndrome (SIDS) do not constitute a contraindication for the use of Hexyon. Individuals with a history of febrile convulsions should be closely followed up as such adverse events may occur within 2 to 3 days post vaccination. If Guillain-Barré syndrome or brachial neuritis has occurred following receipt of prior vaccine contain-ing tetanus toxoid, the decision to give any vaccine containing tetanus toxoid should be based on careful consideration of the potential benefits and possible risks, such as whether or not the prima-ry vaccination has been completed. Vaccination is usually justified for individuals whose primary vaccination is incomplete (i.e. fewer than three doses have been received). The immunogenicity of the vaccine may be reduced by immunosuppressive treatment or immunodeficiency. It is recom-mended to postpone vaccination until the end of such treatment or disease. Nevertheless, vacci-nation of individuals with chronic immunodeficiency such as HIV infection is recommended even if the antibody response may be limited. Special populations: No data are available for premature infants. However, a lower immune response may be observed and the level of clinical protection is unknown. Immune responses to the vaccine have not been studied in the context of genetic polymorphism. In individuals with chronic renal failure, an impaired hepatitis B response is ob-served and administration of additional doses of hepatitis B vaccine should be considered accord-ing to the antibody level against hepatitis B virus surface antigen (anti-HBsAg). Precautions for use

▼This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1. NAME OF THE MEDICINAL PRODUCT Hexyon suspension for injection in pre-filled syringe. Diphtheria, tetanus, pertussis (acellular, component), hepatitis B (rDNA), poliomyelitis (inactivated) and Haemophilus influenzae type b conjugate vaccine (adsorbed). 2. QUALITATIVE AND QUANTITATIVE COMPOSITION One dose1 (0.5 ml) contains:

Diphtheria Toxoid not less than 20 IU2

Tetanus Toxoid not less than 40 IU2

Bordetella pertussis antigens

Pertussis Toxoid 25 micrograms

Filamentous Haemagglutinin 25 micrograms

Poliovirus (Inactivated)3

Type 1 (Mahoney) 40 D antigen units4

Type 2 (MEF-1) 8 D antigen units4

Type 3 (Saukett) 32 D antigen units4

Hepatitis B surface antigen5 10 micrograms

Haemophilus influenzae type b polysaccharide(Polyribosylribitol Phosphate)conjugated to Tetanus protein

12 micrograms

22-36 micrograms1 Adsorbed on aluminium hydroxide, hydrated (0.6 mg Al3+)2 As lower confidence limit (p= 0.95)3 Produced on Vero cells4 Or equivalent antigenic quantity determined by a suitable immunochemical method5 Produced in yeast Hansenula polymorpha cells by recombinant DNA technology

The vaccine may contain traces of glutaraldehyde, formaldehyde, neomycin, streptomycin and polymyxin B which are used during the manufacturing process (see section 4.3). For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM Suspension for injection in pre-filled syringe. Hexyon is a whitish, cloudy suspension. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Hexyon (DTaP-IPV-HB-Hib) is indicated for primary and booster vaccination of infants and toddlers from six weeks to 24 months of age against diphtheria, tetanus, pertussis, hepatitis B, poliomy-elitis and invasive diseases caused by Haemophilus influenzae type b (Hib). The use of this vac-cine should be in accordance with official recommendations. 4.2 Posology and method of administration Posology Primary vaccination: The primary vaccination consists of two doses (with an interval of at least 8 weeks) or three doses (with an interval of at least 4 weeks) in accordance with the official recommendations. All vaccination schedules including the WHO Ex-panded Program on Immunisation (EPI) at 6, 10, 14 weeks of age can be used whether or not a dose of hepatitis B vaccine has been given at birth. Where a dose of hepatitis B vaccine is given at birth, Hexyon can be used for supplementary doses of hepatitis B vaccine from the age of six weeks. If a second dose of hepatitis B vaccine is required before this age, monovalent hepatitis B vaccine should be used. Booster vaccination: After a 2-dose primary vaccination with Hexyon, a booster dose must be given. After a 3-dose primary vaccination with Hexyon, a booster dose should be given. Booster doses should be given at least 6 months after the last priming dose and in accordance with the official recommendations. At the very least, a dose of Hib vaccine must be administered. In addition: In the absence of hepatitis B vaccination at birth, it is necessary to give a hepatitis B vaccine booster dose. Hexyon can be considered for the booster. After a 3-dose WHO EPI schedule with Hexyon (6, 10, 14 weeks) and in the absence of hepatitis B vaccine at birth, a hepatitis B vaccine booster must be given. At the very least, a booster dose of polio vaccine

SUMMARY OF PRODUCT CHARACTERISTICS

ii

General disorders and administration site conditions

Very common Injection-site pain, injection- site erythema, injection-site swellingIrritabilityPyrexia (body temperature ≥ 38.0°)

Common Injection-site induration

Uncommon Injection-site nodulePyrexia (body temperature ≥ 38.0°)

Rare Extensive limb swelling†

* Adverse reactions from spontaneous reporting.† See section c

c- Description of selected adverse reactions Extensive limb swelling: Large injection-site reactions (>50 mm), including extensive limb swelling from the injection site beyond one or both joints, have been reported in children. These reactions start within 24-72 hours after vaccination, may be associated with erythema, warmth, tenderness or pain at the injection site and resolve sponta-neously within 3-5 days. The risk appears to be dependent on the number of prior doses of acellu-lar pertussis containing vaccine, with a greater risk following the 4th and 5th doses. d- Potential ad-verse events (i.e. adverse events which have been reported with other vaccines containing one or more of the components or constituents of Hexyon and not directly with Hexyon). Nervous system disorders - Brachial neuritis and Guillain-Barré Syndrome have been reported after administration of a tetanus toxoid containing vaccine. - Peripheral neuropathy (polyradiculoneuritis, facial paral-ysis), optic neuritis, central nervous system demyelination (multiple sclerosis) have been reported after administration of a hepatitis B antigen containing vaccine. - Encephalopathy/encephalitis. Respiratory, thoracic and mediastinal disorders: Apnoea in very premature infants (≤ 28 weeks of gestation) (see section 4.4). General disorders and administration site conditions: Oedematous reaction affecting one or both lower limbs may occur following vaccination with Haemophilus influenzae type b containing vaccines. If this reaction occurs, it is mainly after primary injections and within the first few hours following vaccination. Associated symptoms may include cyanosis, redness, transient purpura and severe crying. All events should resolve spontaneously without sequel within 24 hours. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions. Suspected adverse events should be reported via the appropriate national reporting system. In the UK, reporting forms and information can be found at www.mhra.gov.uk/yellowcard. Suspected adverse events should also be reported to Sanofi Pasteur MSD. In the UK, reporting forms can be found at www.spmsd.co.uk/AE or via telephone at (0)1628 785291. In other countries, please use the appropriate local national reporting system. 4.9 Overdose No cases of overdose have been reported. 5. PHARMACOLOGICAL PROPER-TIES 5.1 Pharmacodynamic properties Pharmaco-therapeutic group: Vaccines, Bacterial and viral vaccines combined, ATC code: J07CA09. Results obtained for each of the components are summarised in the tables below:

Antibody Thresholds

Two doses Three doses

3-5 MonthsN=249**

6-10-14Weeks

N=123 to 220†

2-3-4MonthsN=322††

2-4-6MonthsN=934 to

1270‡

% % % %

Anti-diphtheria (≥ 0.01 IU/ml)

99.6 97.6 99,7 97.1

Anti-tetanus (≥ 0.01 IU/ml)

100.0 100.0 100.0 100.0

Anti-PT(Seroconversion‡‡) 93.4 93.6 88.3 96.0

(Vaccine response§) 98.4 100.0 99.4 99.7

Anti-FHA

(Seroconversion‡‡) 92.5 93.1 90.6 97.0

Do not administer by intravascular, intradermal or subcutaneous injection. As with all injectable vaccines, the vaccine must be administered with caution to individuals with thrombocytopenia or a bleeding disorder since bleeding may occur following an intramuscular administration. The po-tential risk of apnoea and the need for respiratory monitoring for 48 to 72 hours should be con-sidered when administering the primary immunisation series to very premature infants (born ≤ 28 weeks of gestation) and particularly for those with a previous history of respiratory immaturity. As the benefit of vaccination is high in this group of infants, vaccination should not be withheld or delayed. Interference with laboratory testing Since the Hib capsular polysaccharide antigen is ex-creted in the urine, a positive urine test can be observed within 1 to 2 weeks following vaccina-tion. Other tests should be performed in order to confirm Hib infection during this period. 4.5 Interaction with other medicinal products and other forms of interaction Data on concomitant administration of Hexyon with a pneumococcal polysaccharide conjugated vaccine have shown no clinically relevant interference in the antibody response to each of the antigens. Data on concomitant administration of a booster dose of Hexyon with measles-mumps-rubella vaccines have shown no clinically relevant interference in the antibody response to each of the antigens. There may be a clinically relevant interference in the antibody response of Hexyon and a varicella vaccine and these vaccines should not be administered at the same time. Data on concomitant administration of rotavirus vaccines have shown no clinically relevant interference in the antibody response to each of the antigens. Data on concomitant administration of Hexyon with a meningococcal C conjugate vaccine have shown no clinically relevant interference in the antibody response to each of the antigens. If co-administration with another vaccine is considered, immuni-sation should be carried out on separate injections sites. Hexyon must not be mixed with any other vaccines or other parenterally administered medicinal products. No significant clinical inter-action with other treatments or biological products has been reported except in the case of immu-nosuppressive therapy (see section 4.4), no significant clinical interaction with other treatments or biological products has been reported. Interference with laboratory testing: see section 4.4. 4.6 Fertility, pregnancy and lactation Not applicable. This vaccine is not intended for administration to women of child-bearing age. 4.7 Effects on ability to drive and use machines Not applicable. 4.8 Undesirable effects a- Summary of the safety profile In clinical studies in individuals who received Hexyon, the most frequently reported reactions include injection-site pain, irritability, crying, and injection-site erythema. Slightly higher solicited reactoge-nicity has been observed after the first dose compared to subsequent doses. b- Tabulated list of adverse reactions. The following convention has been used for the classification of adverse reac-tions: Very common (≥1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1,000); Very rare (<1/10,000); Not known (cannot be estimated from available data).

System Organ Class Frequency Adverse Events

Immune system disorders Uncommon Hypersensitivity reaction

Rare Anaphylactic reaction*

Metabolism and nutrition disorders

Very common Anorexia (decreased appetite)

Nervous system disorders Very common Crying, somnolence

Common Abnormal crying (prolonged crying)

Rare Convulsions with or without fever*

Very rare Hypotonic reactions or hypotonic- hyporesponsive episodes (HHE)

Gastrointestinal disorders Very common Vomiting

Common Diarrhea

Skin and subcutaneous tissue disorders

Rare Rash

Table 1: Adverse Reactions from clinical trials and reported during commer-cial use

Table 1: Seroprotection/Seroconversion rates* one month after a primary-vaccination with 2 or 3 doses of Hexyon

iii

Anti-HBs With hepatitis B vaccina-tion at birth

/ 100.0 / 99.7

(≥ 10 mIU/ml)

Without hepatitis B vaccina-tion at birth

96.4 98.5 97.3 99.4

Anti-Polio type 1 (≥ 8 (1/dilution))

100.0 100.0 100.0 100.0


100.0 100.0 100.0 100.0


99.6 100.0 100.0 100.0

Anti-PRP (≥ 0.15 μg/ml))

93.5 98.5 98.2 98.3

* Generally accepted surrogates (PT,FHA) or correlates of protection (other components)N = Number of individuals analysed (per protocol set)** 3, 5 months without hepatitis B vaccination at birth (Finland, Sweden)† 6, 10, 14 weeks with and without hepatitis B vaccination at birth (Republic of South Africa)†† 2, 3, 4 months without hepatitis B vaccination at birth (Turkey)‡ 2, 4, 6 months without hepatitis B vaccination at birth (Mexico) and with hepatitis B vaccina-tion at birth (Costa Rica and Colombia)‡‡ Seroconversion: minimum 4-fold increase compared to pre-vaccination level (pre-dose 1)§ Vaccine response: If pre-vaccination antibody concentration (pre-dose 1) <8 EU/ml, then the post-booster antibody concentration should be ≥8 EU/ml. Otherwise, post-booster antibody concentration should be ≥ pre- immunisation level (pre-dose 1)

The immune responses to Hib (PRP) and pertussis antigens (PT and FHA) were evaluated after 2 doses in a subset of subjects receiving Hexyon (N=148) at 2, 4, 6 months of age. The immune responses to PRP, PT and FHA antigens one month after 2 doses given at 2 and 4 months of age were similar to those observed one month after a 2-dose priming given at 3 and 5 months of age: anti-PRP titers ≥ 0.15 μg/ml were observed in 73.0% of individuals, anti-PT vaccine response in 97.9% of individuals and anti-FHA vaccine response in 98.6% of individuals. Vaccine efficacy of the acellular pertussis (aP) antigens contained in Hexyon against the most severe WHO-defined typical pertussis (≥ 21 days of paroxysmal cough) is documented in a randomised double-blind study among infants with a 3 dose primary series using a DTaP vaccine in a highly endemic country (Senegal). The need for a toddler booster dose was seen in this study. The long term capability of the acellular pertussis (aP) antigens contained in Hexyon to reduce pertussis incidence and control pertussis disease in the childhood has been demonstrated in a 10-year national pertussis surveil-lance on pertussis disease in Sweden with the pentavalent DTaP-IPV/Hib vaccine using a 3, 5, 12 months schedule. Results of long term follow-up demonstrated a dramatic reduction of the pertus-sis incidence following the second dose regardless of the vaccine used. The vaccine effectiveness against Hib invasive disease of DTaP and Hib combination vaccines (pentavalent and hexavalent including vaccines containing the Hib antigen from Hexyon) has been demonstrated in Germany via an extensive (over five years follow-up period) post-marketing surveillance study. The vaccine effectiveness was of 96.7% for the full primary series, and 98.5% for booster dose (irrespective of priming). 5.2 Pharmacokinetic properties. No pharmacokinetic studies have been per-formed. 5.3 Preclinical safety data. Non-clinical data reveal no special hazard for humans based on conventional repeat dose toxicity and local tolerance studies. At the injection sites, chron-ic histological inflammatory changes were observed, that are expected to have a slow recovery. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Disodium hydrogen phos-phate; Potassium dihydrogen phosphate; Trometamol; Saccharose; Essential amino acids including L-phenylalanine; Water for injections. For adsorbent: see section 2. 6.2 Incompatibilities. In the absence of compatibility studies, this vaccine must not be mixed with other vaccines or medicinal products. 6.3 Shelf life. 3 years. 6.4 Special precautions for storage. Store in a refrigerator (2°C – 8°C). Do not freeze. Keep the container in the outer carton in order to protect from light. 6.5 Nature and contents of container. 0.5 ml suspension in pre-filled syringe (type I glass) with plunger stopper (halobutyl) and tip cap (halobutyl), without needle. 0.5 ml suspension in pre-filled syringe (type I glass) with plunger stopper (halobutyl) and tip cap


Anti-HBs(≥ 10 mIU/ml)

With hepatitis B vaccination at birth

/ 99.0 / 99.7

Without hepatitis Bvaccination at birth

97.2 95.7 96.8 98.8


90.8 100.0 99.4 99.9


95.0 98.5 100.0 100.0


96.7 100.0 99.7 99.9

Anti-PRP (≥ 0.15 μg/ml))

71.5 95.4 96.2 98.0

* Generally accepted surrogates (PT, FHA) or correlates of protection (other components)N = Number of individuals analysed (per protocol set)** 3, 5 months without hepatitis B vaccination at birth (Finland, Sweden)† 6, 10, 14 weeks with and without hepatitis B vaccination at birth (Republic of South Africa)†† 2, 3, 4 months without hepatitis B vaccination at birth (Turkey)‡ 2, 4, 6 months without hepatitis B vaccination at birth (Argentina, Mexico, Peru) and with hepatitis B vaccination at birth (Costa Rica and Colombia)‡‡ Seroconversion: minimum 4-fold increase compared to pre-vaccination level (pre-dose 1)§ Vaccine response: If pre-vaccination antibody concentration <8 EU/ml, then the post-vac-cination antibody concentration should be ≥ 8 EU/ml. Otherwise, post-vaccination antibody concentration should be ≥ pre- immunisation level.

Antibody Thresholds

Booster vaccination at 11-12 months of age after a two doses primary course

Booster vaccination during the second year of life following a three dose primary course

3-5MonthsN=249**

6-10-14WeeksN=204†

2-3-4MonthsN=114††

2-4-6MonthsN=177 to

396‡

% % % %

Anti-diphtheria (≥ 0.01 IU/ml)

100.0 100.0 99,1 97.2

Anti-tetanus (≥ 0.01 IU/ml)

100.0 100.0 100.0 100.0

Anti-PT(Seroconversion‡‡) 94.3 94.4 96.3 96.2


Anti-FHA(Seroconversion‡‡) 97.6 99.4 94.4 98.4


Table 2: Seroprotection/Seroconversion rates* one month after booster vaccination with Hexyon

iv

(halobutyl), with 1 separate needle. 0.5 ml suspension in pre-filled syringe (type I glass) with plunger stopper (halobutyl) and tip cap (halobutyl), with 2 separate needles. Pack size of 1 or 10 pre-filled syringes with or without needle. Pack size of 50 pre-filled syringes without needle. Multipack of 50 (5 packs of 10) pre-filled syringes without needle. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling. Prior to adminis-tration, the pre-filled syringe should be shaken in order to obtain a homogeneous, whitish, cloudy suspension. The suspension should be visually inspected prior to administration. In the event of any foreign particulate matter and/or variation of physical aspect being observed, discard the pre-filled syringe. For syringes without an attached needle, the needle must be fitted firmly to the syringe, rotating it by a one-quarter turn. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER Sanofi Pasteur MSD SNC, 162 avenue Jean Jaurès, 69007 Lyon, France. 8. MAR-KETING AUTHORISATION NUMBER(S) EU/1/13/829/002, EU/1/13/829/003, EU/1/13/829/004, EU/1/13/829/005, EU/1/13/829/006, EU/1/13/829/007, EU/1/13/829/008 9. DATE OF FIRST AUTHORISATION /RENEWAL OF THE AUTHORISATION Date of first authorisation: 17 April 2013. 10. DATE OF REVISION OF THE TEXT 11/2015. Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

Copy distributed by Sanofi Pasteur MSD – SNC au capital de €60,000,000 – RCS Lyon B 392 032 934 – CO01086 – December 2015 – CORP000000128

This document is intended for healthcare professionals only.

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Hexyon - WebEdCafe.com · and reduce vaccine-related costs. In addition to the benefits provided through the use of combination vaccines for paediatric vaccination, changes in vaccine