Hexaxim, Sanofi, May 2017, Patiala. Information about schedules, components, acellular versus wP, and Indian data for using Hexaxim vaccination

1. The new kid on the block
Hexavalent Vaccines!
Dr Gaurav Gupta,
Pediatrician,
21st May 2017, Patiala

2. Conflict of Interest
• Received grants from various vaccine
manufacturers including
– Sanofi Pasteur
– GSK
– Abbott
– Novartis

3. WIIFY
• Need for Combination Vaccines
• Safety, efficacy of Hexavalent Vaccines
• Indian Data
• Scheduling
• Some Unique Features

4. What I won’t be talking about?
• aP versus wP
• Components
• Pricing

5. Approximate duration of immunity after natural
infection and after vaccination

6. COMPONENT COMPANY EFFICACY
1C Amvax, JNIH 71 TO 78%
2C SKB 59%
2C Pasteur Merieux 85%
3C SKB (GSK) 84 %
4C LEDERLE - an european vacc .
not marketed
79 %
5C Connaught (Pasteur) 85 %
DTwP VARIOUS countries 36 TO 96 %
Summary of vaccine efficacy: Cochrane 2012 (and 14)

7. Statements of Vaccines Experts/Health Authorities regarding number of
Pertussis components in licensed vaccines:
• “There are now only 3 broadly distributed acellular pertussis vaccines: the
French 2-component, the Belgian 3-component, and the Canadian 5-
component vaccines. National surveillance data have clearly demonstrated
the ability of each vaccine to accomplish excellent control of pertussis.”
Plotkin et al.
VACCINES 6th
ed.
• The European scientific panel on childhood immunization does not discuss
the number and types of acP vaccines components, since effectiveness data
have not shown any significant differences.”
European CDC
• “Point estimate of vaccine efficacy ranged from 80% to 85% for vaccines
currently licensed in the United States. Confidence intervals for vaccine
efficacy overlap, suggesting that none of the vaccines is significantly more
effective than the other.”
CDC Pink Book
12th ed.
• “long-term large scale use of licensed 2-component aP-containing vaccines
(primarily in Sweden and Japan) and of 1-component aP vaccine in the
national Danish immunization programme, all of these aP-containing vaccines
demonstrated high levels of effectiveness in preventing pertussis irrespective
of antigen content.”
WHO Pertussis
Vaccines
Position Paper 7

8. Indian Pediatrics, Jan 2017

9. Combination Vaccines – Why?
• Simplified Immunization Schedule
• Less injections – Complications
• Better Compliance
• Lesser administration time/ costs/ space

10. Combination vaccines – Why not?
• Adverse effects maybe more common
• Reduced Immunogenicity
• May have lesser shelf life
• Technically difficult
• Expensive

11. Hexavalent Vaccines across the World
• Hexavac – discontinued
• Infanrix Hexa – GSK – with lyophilised Hib
• Hexaxim – Fully liquid 6 in 1 with DPT + Hep B
+ Hib + IPV

12. Hexavalent Vaccines across the World
• Hexavac – discontinued
• Infanrix Hexa – GSK – with lyophilised Hib
• Hexaxim – Fully liquid 6 in 1 with DPT + Hep B
+ Hib + IPV

13. Registered in more than 100 countries

14. Efficacy
• As compared to other aP vaccines
• As compared to wP vaccines, specifically
against Pertussis

15. HEXAXIM® immunogenicity assessment - Overview
● 8 primary series studies
● 3 primary schedules (6, 10 & 14 weeks; 2, 3 & 4 and 2, 4 & 6 months)
● With or without hepatitis B vaccination at birth
● versus different control vaccines:
• wP-based combination vaccines
• PENTAXIM® + standalone hepatitis B vaccine
• INFANRIX-HEXA (DTaP-IPV-HBV//Hib***)
• Concomitantly with other routine pediatric vaccines
*Tritanrix®-HepB/Hib **CombAct-HIB® *** Infanrix Hexa®

16. 0
20
40
60
80
100
D T PT FHA PV1 PV2 PV3 HBsAg Hib
Immunogenicity v/s whole cell-based vaccines
HEXAXIM® induces high immune responses similar
to those of wP-based combination vaccines
Seroprotection/seroconversion rates after the 3rd dose of HEXA or a wP-based combination
vaccine in infants vaccinated at 6,10 &14 weeks of age
(South Africa)1 (No HepB vaccine at birth, no concomitant vaccine)
Seroprotection/
Seroconversionrates(%)
D T PT FHA PV1,2,3 HBsAg Hib
 0.01 IU/mL 4-fold increase
(pertussis antigens)
1/dil  8  10 mIU/mL  0.15 µg/mL
98 96 100 100
94
83
93
58
100
93
99 100 100 98 96 95 95
100
HEXAXIM® 1
n=220
DTwP//Hib* + OPV + Hep B vaccine 1
n=212
* CombAct-HIB® [1] Madhi et al. PIDJ, 2011;30(4)

17. 0
20
40
60
80
100
D T PT FHA PV1 PV2 PV3 HBsAg Hib
The immune response to all HEXAXIM® antigens is high and similar
to that of PENTAXIM® co-administered with standalone hepatitis B vaccine
Seroprotection/
Seroconversionrates(%)
D T PT FHA PV1,2,3 HBsAg Hib
 0.01 IU/mL 4-fold increase
(pertussis antigens)
1/dil  8  10 mIU/mL  0.15 µg/mL
100 100 100 100
92 93 93 90
100 100 100 100 100 100 99 100
95 97
HEXAXIM®
n=260
PENTAXIM® + Hep B vaccine
n=271
[5] Tregnagui et al. PIDJ, 2011;30(6)
Seroprotection/Seroconversion rates after the 3rd dose of HEXA or PENTA
in infants vaccinated at 2, 4 & 6 months of age
(Argentina)5 (No Hep B vaccine at birth, no concomitant vaccine)
Immunogenicity Vs PENTAXIM®

18. Completion of a 3-dose primary series and a booster administration in the first 2 years of life with the investigational
DTaP-IPV-HB-Hib vaccine in toddlers induced strong Ab responses towards the antigens included in the
investigational vaccine which persisted in significant percentages of children at 3.5 years of age

19. Safety

20. HEXAXIM® safety assessment - Overview
Evaluated in 20 clinical trials in more than 6000 infants and toddlers
● 18,000 doses administered to > 6000 infants in 20 clinical trials
● With or without hepatitis B vaccination at birth
● versus different control vaccines:
• wP-based combination vaccines
• PENTAXIM® + standalone hepatitis B vaccine
• INFANRIX-HEXA (DTaP-IPV-HBV//Hib***)
• Concomitantly with other routine pediatric vaccines
[19] Sanofi Pasteur. Data on file

21. Solicited reactions after any dose of HEXAXIM® or DTwP-HepB//Hib*
in infants vaccinated at 2,4 & 6 months of age (Mexico & Peru)3 (No concomitant vaccine)
0
20
40
60
80
100
Pain Red Swell A Fever Vom Crying Somnol Anor Irr
The reactogenicity of HEXAXIM® is consistently lower than that of
wP-based combination vaccines
Gr3: grade 3 *Tritanrix®-HepB/Hib [3] Macias et al. PIDJ, 2012;31(8)
78 94
59 71
17 36
3 6
43 67
1 6
75 93
4 6
30 31
2 3
78 92
3 5
57 69
5 6 3 5
82 92
46 59
6 10
Reactionincidence(%)
HEXAXIM®
n=1422
DTwP-HepB//Hib*
n=711
Any Gr3 Any Gr3 Any Gr3 Any Gr3 Any Gr3 Any Gr3 Any Gr3 Any Gr3 Any Gr3
Pain Redness Swelling Fever Vomiting Crying Somnolence Anorexia Irritability
Tolerability Vs. wP-based combination vaccines

22. Safety in primary and booster series
Key points
Well tolerated under various primary schedules (6-10-14 weeks, 2-3-4
and 2-4-6 months)
Better tolerated than wP-based combination vaccines
Comparable to other licensed aP-based combination vaccines
(PENTAXIM®, Infanrix Hexa)
The safety and reactogenicity - not affected by the administration of
hepatitis B vaccine at birth
* Infanrix® Hexa

23. Indian Data

24. IMMUNOGENICITY AND SAFETY OF
DTaP-IPV-HB-PRP-T COMBINED
VACCINE GIVEN AT 6, 10 AND 14
WEEKS OF AGE IN INFANTS FROM
INDIA, WHO PREVIOUSLY RECEIVED
A DOSE OF HEP B VACCINE AT BIRTH
Presenting Author: Prof Sanjay Lalwani
Date : 23 January 2016
Venue : PEDICON – Hyderabad
WHO Universal Trial Number (UTN): U1111-1127-6936

25. Immunogenicity (Primary objective): % Seroprotection
and Vaccine Response one month after 3 doses
99.30% 100%
93.80%
99.30% 100% 100% 100% 100% 100%
0.00%
10.00%
20.00%
30.00%
40.00%
50.00%
60.00%
70.00%
80.00%
90.00%
100.00%
Anti-D (≥
0.01 IU/mL )
Anti-T (≥
0.01 IU/mL )
Anti-PT
(Vaccine
response)
Anti-FHA
(Vaccine
response)
Anti-Polio 1
(≥ 8 (1/dil)
Anti-Polio 2
(≥ 8 (1/dil)
Anti-Polio 3
(≥ 8 (1/dil)
Anti-Hep B
(≥ 10
mIU/mL)
Anti-PRP (≥
0.15 μg/mL)
25

26. Safety: Solicited reactions from D0 to D7, any
grade, after each injection (in %)
26
19%
4.60%
10.30%
13.80%
3.40% 3.40%
11.90%
0.60%
6.50%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Tenderness Erythema Swelling
Post Dose 1 Post Dose 2 Post Dose 3
7.5%
9.8%
16.1%
9.8%
6.9%
22.4%
8.6%
3.4%
9.8%
3.4% 3.4%
16.7%
7.1%
3.0%
7.7%
3.0% 3.0%
12.5%
0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
70.0%
80.0%
90.0%
100.0%
Fever Vomiting Abnormal
Crying
Drowsiness Loss of
appetite
Irritability
Post Dose 1 Post Dose 2 Post Dose 3
 54.6% experienced at least 1 solicited
systemic reaction.
 Most frequently reported systemic
reaction was irritability (36.2%)
 19.0% of subjects reported fever ; no
Grade 3 fever reported
Injection site reactions
 37.9% experienced at least 1 solicited
injection site reaction, most frequent being
tenderness (30.5%).
 2.9% of subjects reported Grade 3 reactions
 The incidence lowered with successive
doses with no Grade 3 reaction reported
after the third dose
Systemic reactions

27. What Schedule works?

28. HepB seroprotection rates (%≥10mIU/ml) and GMT
(IU/mL) following different HepB immunization regimen
HB
regimen
Infant series
product &
regimen
Post Infant series
responses
Toddler
product
Pre
toodler
booster
Post
toddler
booster
0 + 2 + 1 HXM 3-58 97,2% - 401 HXM (11/12) 87,6% - 76 96,4% - 1,370
0 + 3 + 0
HXM 2-4-611 99,2% - 1,148 -
HXM 2-4-612 99,2% - 986 -
0 + 3 + 1
HXM 2-3-45 94,0% - 149 HXM (15/18) 80,7% - 44 97,3% - 1,379
HXM 2-3-49 97,5% - 242
96,1% - 267
HXM (12)
90,1% - 76
91,4% - 95
98,9% - 2,230
98,9% - 2,233
HXM 2-3-410 95,7% - 207 HXM (11/18) Ongoing Ongoing
HXM 2-4-62 98,3% - 1,142 HXM (15/18) 89,8% - 93 99,4% - 2,553
HXM 6-10-143,4 95,7% - 330 HXM (15/18) 78,9% - 51 98,5% - 4,630
1 + 3 + 0
HXM 6-10-147 100% - 2,491 -
HXM 2-4-66 99,5% - 2,477 -
1 + 3 + 1
HXM 6-10-143,4 99,0% - 1,913 HXM (15/18) 94,7% - 228 100% - 44,893
HXM 2-4-61 99,7% - 3,013
HXM (12/18) 97,5% - 386 99,7% - 8,462
IH (12/18) 97,7% - 406 99,5% - 11,218
IH 2-4-62 100% - 2,766 HXM (15/18) 99,2% - 336 100% - 9,688
1. Lopez P & al. ICID 2012 & ESPID 2014 2. Aquino A & al. Vaccine 2012 3. Madhi S & al. PIDJ 2011
4. Madhi S & al. PIDJ 2013 5. Ceyhan M & al. ACPID 2010 6. Kosalaraska P & al. Int JID 2011
7. Lalwani S & al. PEDICON 2016 8. Vesikari T & al. ESPID 2015 9. Vesikari T & al. ESPID 2015 and 2016
10. Prymula R & al. ESPID 2016 11. Tregnaghi MW & al. PIDJ 2011 12. Lanata C & al. Vaccine & Vaccinations 2012

29. HepB immunization and use of hexavalent vaccines
The use of Hep-B containing combination vaccines in the first year
of life primary series offers below possibility:
●To adopt Hep B immunization regimen by using an hexa-only infant
primary series regimen
●Lead to a “0” (birth) + 3 +/- 1 (second year of life) regimen: “birth + 3 +
1” or “birth + 3 + 0”

30. Recommendations
WHO
IAP

31. Features

32. Hepatitis B antigen: Source
Produced using the patented Hansenula
polymorpha yeast expression system:
● Consistent high quality and reliable supply
● No need for methanol as solvent (used with
other yeast expression system)5
Manufactured and controlled in Sanofi
Pasteur’s state-of-the-art facility in Argentina
● Completely dedicated to this new hepatitis B
antigen
Produced exclusively for use in HEXAXIM®
[5] Celik. Biotechnol Adv, 2012;30(5) [6] Shouval. J Hepatol, 2003;39(Suppl1)

33. Presentations
HEXAXIM® is available as FULLY LIQUID:30
● Needleless pre-filled syringes (box of 1 and 10) with two needle
lengths for optimal flexibility (16 mm 25G, 25 mm 23G)
• With double detachable labels for easy documentation
[30] Sanofi Pasteur. HEXAXIM®. Summary of Product Characteristics

34. Registered in more than 100 countries

35. Technological innovation

36. THANK YOU
docgaurav@gmail.com
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Acknowledgement: Dr Sujatha Shetty, Dr Vibhas,
Sanofi Pasteur
Comments/ Questions