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Update on Pertussis
Dr Gaurav Gupta
Conflict of Interest
• Received grants from various vaccine manufacturers including – Sanofi Pasteur– GSK– Abbott– Novartis
Noel Preston (1988) ‘There must be a few medical subjects that have generated so much controversy & even outright
contradiction, as pertussis’
Today (2014)25 years later than the above statement, pertussis has become even more contentious, more controversial &
more balkanized …
Knowledge is the process of piling up facts,wisdom lies in their simplification
Outline of Presentation
• Pertussis resurgence – background• aP v/s wP – which is better & why• choices amongst wP vaccines – why choose
one over others
Outline of Presentation
• Pertussis resurgence – background• aP v/s wP – which is better & why• choices amongst wP vaccines – why choose
one over others
Reported cases of pertussis in 2008 :: Top 10 countries
7
Australia & USA reported maximum number of cases following India ...
Source: 1. World Health Organization. http://www.who.int/whosis/2010/en/index.html accessed on 12 February, 2014.
Status of global pertussis outbreaks …
8
Source: 1. Available at http://www.cfr.org/interactives/GH_Vaccine_Map/#map (accessed on 24th January, 2014)
2008
9
Source: 1. Available at http://www.cfr.org/interactives/GH_Vaccine_Map/#map (accessed on 24th January, 2014)
2009
Status of global pertussis outbreaks …
10
Source: 1. Available at http://www.cfr.org/interactives/GH_Vaccine_Map/#map (accessed on 24th January, 2014)
2010
Status of global pertussis outbreaks …
11
2011
Status of global pertussis outbreaks …
• Outbreaks also been reported from countries using wP vaccines like from Khairpur District of Sindh province of Pakistan
• However, study conducted between 2005 & 2009 found that B. parapertussis was responsible for outbreakSource: 1. Mughal A, Kazi YF, Bukhari HA, Ali M. Pertussis resurgence among vaccinated children in Khairpur, Sindh, Pakistan. Public Health. 2012; 126:518-22. 2. Bokhari H, Said F, Syed MA, Mughal A, Kazi YF, Kallonen T, et al. Molecular typing of Bordetella parapertussis isolates
circulating in Pakistan. FEMS Immunol Med Microbiol. 2011; 63:373-80. 3. Available at http://www.cfr.org/interactives/GH_Vaccine_Map/#map (accessed on 24th January, 2014).
12
Source: 1. Available at http://www.cfr.org/interactives/GH_Vaccine_Map/#map (accessed on 24th January, 2014)
2012
Status of global pertussis outbreaks …
13
Source: 1. Available at http://www.cfr.org/interactives/GH_Vaccine_Map/#map (accessed on 24th January, 2014)
2013
Status of global pertussis outbreaks …
14
Source: 1. Ali Rowhani-Rahbar, Joan Bartlett, Roger Baxter, Nicola Klein. Pertussis Risk in Children as a Function of Time Since Receipt of the 5th Dose of Acellular Pertussis Vaccine. 29th Annual ESPID Meeting The Hague, The Netherlands June 10, 2011.
Pertussis resurgence in USAIn 2010, California experienced largest pertussis outbreak in 50 years …
Pertussis declined sharply with advent of wP vaccines
Shift from DTwP to DTaP emerged
as the major factor for California outbreak
• Outbreak despite >80% coverage with 3 & 5 component DTaP
• ‘Coincident with this shift in vaccine type, pertussis incidence has been gradually increasing…’
• In November 2012, SAGE expressed concern about the apparent resurgence of pertussis in some industrialized countries despite high vaccine coverage with acellular pertussis (aP) vaccines, which in some settings was associated with an increase in infant pertussis deaths.
• SAGE then established a pertussis working group which presented its report to SAGE.
• Review of epidemiological data on pertussis from 19 developing and industrialized countries in various world regions which have wP- or aP-based programs achieving – high vaccine coverage rates, – effective disease control, – ability to provide high quality data.
MEETING OF THE STRATEGIC ADVISORY GROUP OF EXPERTS (SAGE)ON IMMUNIZATION, APRIL 2014
• Pertussis epidemiology• B. pertussis strains have evolved over time
• Inconsistent correlation with vaccine programs and epidemiology
• No evidence to date for diminished effectiveness of vaccines against different allelic variants
• No evidence of emergence of B. parapertussis in aP or wP using countries
• Pertussis vaccination• Main objective of pertussis vaccination is to reduce risk of severe
pertussis in infants• wP and aP very effective in reducing disease with high coverage
• Drastic decline in global incidence and mortality in post-vaccine era
Outline of Presentation
• Pertussis resurgence – background• aP v/s wP – which is better & why• choices amongst wP vaccines – why choose
one over others
FIMbriae
Filamentous Haem-Agglutinin
PeRrtactiN
Pertussis Toxin
Adenylate Cyclase Toxin
Dermo-Necrotic Toxin
Tracheal Cyto-Ttoxin
Bordetella resistance toKilling genetic locus, frame A
Lipo-Oligo-Sachharide
These virulence factors are responsible for pathogenesis of B. Pertussis …
Source: 1. He Q, Makinen J, Berbers G, Bordetella pertussis Protein Pertactin Induces Type-Specific Antibodies: One Possible Explanation for the Emergence of Antigenic Variants? The Journal of Infectious Diseases 2003; 187:1200–5. 2. Crowcroft N. S., Pebody R. G. Recent developments in pertussis. The Lancet 2006;367:1926-1936.
19
20
aP vaccines do not contain many crucial antigens while wP vaccines contain entire complement of all antigens …
Source: 1. Crowcroft NS ,Pebody RG .Recent developments in pertussis.The Lancet 2006;367:1926-1936 2.Preston A. Bordetella pertussis : the intersection of genomics and pathobiology.CMAJ 2005;173(1)55-62.
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The natural immune response involve predominantly Th1 cells ...
Immune response to natural infection by B. pertussis…
Source: 1. Mills K.H.G., McGuirk P. Antigen-specific regulatory T cells: their induction & role in infection. Seminars in Immunology 16 (2004) 107–1.
22
Immunomodulatory responses to these immunogens are complex ...
Immune response induction by wP & aP vaccines …
Source: 1. Mills K. Immunity to Bordetella pertussis. Microbes and Infection, 3, 2001, 655−677.
Comparative efficacy of DTwP & DTaP vaccines
23
Source: 1. Edwards & Decker. In: Vaccines, 4th Edition, 2004. 2. Plotkin & Cadoz. PIDJ, 1997; 16 (5).
Duration of immunity to pertussis
24
wP vaccines provide longer immunity than aP vaccines …
Source: 1. Pediatric Infectious Diseases Journal 2005;24(5) 58-61. 2. Wendelboe et al. PIDJ, 2005.
Duration of protection by wP vaccines
4
Acellular (aP) vs Whole cell (wP) Vaccines
• Acellular vaccines• Lower initial efficacy• Faster waning of immunity• Possible reduced impact on transmission• Likely to result in resurgence
• Magnitude and timing of resurgence difficult to predict• Potential increased risk of death in those too young to be
vaccinated
4
Acellular (aP) vs Whole cell (wP) Vaccines
• Acellular vaccines• Lower initial efficacy• Faster waning of immunity• Possible reduced impact on transmission• Likely to result in resurgence
• Magnitude and timing of resurgence difficult to predict• Potential increased risk of death in those too young to be
vaccinated
• Acellular vaccines• Lower initial efficacy• Faster waning of immunity• Possible reduced impact on transmission• Likely to result in resurgence
• Magnitude and timing of resurgence difficult to predict• Potential increased risk of death in those too young to be
vaccinated• Proposed mechanism
• aP vaccines induce different type of immune response• Higher Th2-promoting antibody responses• Lower Th1 and Th17 responses
• Less effective at limiting and clearing mucosal infections
Safety concerns – wP versus aP
• wP often cause minor (but troublesome) side effects and rarely more serious adverse events. Relatively high incidence of the former is sometimes unacceptable to care-givers and care-providers; this is what prompted the development of aP
• The incidence of frequent side effects (fever, erythema, swelling, fretfulness, drowsiness) is reported to be significantly less with aP as compared to wP.
Frequency of Common Side Effects with Pertussis Vaccines
Event Whole cellpertussis vaccine
Acellularpertussis vaccine
Average Average Range
Fever < 38.3°C 44.5% 20.8% 16-29.2%
Fever > 38.3°C 15.9% 3.7% 1.6-5.9%
Erythema 56.3% 31.4% 15-44%
> 2.0 cm 16.4% 3.3% 1.4-5.9%
Swelling 38.5% 20.1% 7.5-24.2%
Drowsiness 62.0% 42.7% 29.4-52.2%
There is a very wide range among various aP with varying frequencies for individual side effects. Impossible to identify an aP with the most (or least) favourable adverse event profile.
Mathew JL. Acellular Pertussis Vaccines: Pertinent Issues, Indian Pediatrics 2008; 45:727-729
Safety concerns – wP versus aP
• Meta-analysis of data from large randomized controlled trials on serious adverse events shows that although the relative risk for some events is less with aP, the absolute risk difference is comparable to wP because such events are very rare with both.
Meta-analysis of Serious Adverse Events with Pertussis vaccines
Event Frequencywith aP
Frequencywith wP
Pooled RR(95% CI)
Interpretation
High fever 227/99323 996/96879 0.18 RR is about (>40°C) (0.23%) (1.03%) (0.08-0.44)
80% less with aP thanwith wP, but the absolutedifference is 2%.
Seizures 58/106204 224/103474 0.28 RR is about (within 48 h) (0.05%) (0.22%) (0.13-0.61)
72% less with aP than with wP, but the absolutedifference is negligible.
Hypotensive- 20/106204 491/103474 0.04 RR is about hyporesponsiveepisode
(0.02%) (0.47%) (0.01-0.19)96% less with aP thanwith wP, but the absolutedifference is negligible.
Mathew JL. Acellular Pertussis Vaccines: Pertinent Issues, Indian Pediatrics 2008; 45:727-729
Relative risk for some events is less with aP, the absolute risk difference is comparable to wP because such events are very rare with both.
Outline of Presentation
• Pertussis resurgence – background• aP v/s wP – which is better & why• choices amongst wP vaccines – why choose
one over others
• Quinvaxem components:– Diphtheria toxoid - ≥30 IU– Tetanus toxoid - ≥60 IU– Whole-cell pertussis - ≥4 IU– HBsAg - 10 mg – Hib (PRPT-CRM197) - 10 mg
- 25 μg of CRM 197– No thiomersal
– No preservatives1
†Thiomersal may be present in traces as a residue of the manufacturing process
Quinvaxem is a fully liquid, pentavalent vaccine
that helps to protect against
diphtheria, tetanus, pertussis, hepatitis B & Haemophilus influenzae type b1
Source: 1. Quinvaxem PI 2006. 2. Data on file 2012.
QuinvaxemFully liquid pentavalent (DTwP-Hep B-Hib) vaccine ...
32
Summary
• Only pentavalent vaccine with CRM197 Hib conjugate – better tolerability & titers than TT conjugate
• The only pentavalent with no preservative / no added thiomersal in India
• Optimal aluminum phosphate (adjuvant) levels
• Extensive clinical database (>4000 subjects) across different schedules & interchangeability
• Well documented immunogenicity & safety profile & low post injection reactogenicity including Indian data
• 1st WHO pre-qualified, fully liquid pentavalent vaccine, with sustained WHO PQ since 2006
• The most widely used pentavalent vaccine globally (>418 million doses :: till Sep 2012)
• Protecting 25% of the global newborn cohort from 5 deadly disease every year#
• Registered in >30 countries & distributed by UNICEF & PAHO in > 90 countries
Quinvaxem
Summary
• Only pentavalent vaccine with CRM197 Hib conjugate – better tolerability & titers than TT conjugate
• The only pentavalent with no preservative / no added thiomersal in India
• Optimal aluminum phosphate (adjuvant) levels
• Extensive clinical database (>4000 subjects) across different schedules & interchangeability
• Well documented immunogenicity & safety profile & low post injection reactogenicity including Indian data
• 1st WHO pre-qualified, fully liquid pentavalent vaccine, with sustained WHO PQ since 2006
• The most widely used pentavalent vaccine globally (>418 million doses :: till Sep 2012)
• Protecting 25% of the global newborn cohort from 5 deadly disease every year#
• Registered in >30 countries & distributed by UNICEF & PAHO in > 90 countries
Quinvaxem
Evolution of Hib conjugates2CRM197 is a modern Hib conjugate ...
Tetanus Toxoid (TT)
Diphtheria Toxoid(DT)
Outer Membrane Protein of
meningitidis (OMP)
Cross Reactive Material
of C. diptheria (CRM197)
Derived from Clostridium tetani
Inactivated with formalin
Purified with ammonium sulfate and filter sterilized prior to conjugation process
Derived from C. diphtheriae
Detoxified with formaldehyde
Purified by ammonium sulfate fractionation & filtration
Outer membrane protein complex derived from N. meningitidis serogroup B strain11Purified by detergent extraction, ultracentrifugation,filtration & sterile filtration
Enzymatically inactive, nontoxic mutant of diphtheria toxin
Requires no formaldehyde detoxification
Obtained at near 100% purity
* M.Wt. 140 kD 63 kD 37 kD 63 kD
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Experience of CRM197 conjugated vaccines
used in modern conjugate vaccines2
• Prevnar, Menveo
• demonstrated efficacy & safety
positive effect on preexisting immunity of CRM197 & TT than DT and TT which have negative effect to pre- or concomitant immunization with other conjugate vaccines3
shows highest immune responses after the 3rd dose5
better tolerated than TT conjugate4
Hib CRM197 vs Hib TT
Better local reactogenecity profile than Hib-TT Conjugate
Vaccines6,7
P <0.05
P <0.05
Source: 1. Based on: Harrison LH. Clin Microbiol Rev. 2006;19:142-164. 2. Bröker M, et al. Vaccine 2009; 27:5574–5580. 3. M. Tontini et al. / Vaccine 31 (2013) 4827– 4833. 4. Decker MD et al. J Pediatr. 1992; 120 (2 pt 1):184-9. 5. Kanra G, Viviani S, Yurdakok K, Özmert E et. al. Clinical Microbiology and Infection. Vol.6 Sup 1.2000. Abstract WeP 296 p.236-7. 6. Decker MD, et al. J Pediatr. 1992;120(2 pt 1):184-189. 7. Knuf M et al. Vaccine 2011; 29: 4881-90 based on: Decker MD et al. J Pediatr 1992; 120 (2 pt 1) 184-189.
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CRM197 conjugate proteinCRM 197 demonstrates better local reactogenicity than TT conjugate ...
CRM197 conjugate protein
Pentavalent Vaccine Hib conjugate Hib GMT’s µg/ml
(1 month after 3rd dose)
Pentavac1 (Serum Institute of
India)
TT (Tetanus Toxoid)
7.55
Comvac (Bharat Biotech)2
TT (Tetanus Toxoid)
7.01
Pentaxim3 (Sanofi Pasteur)
TT (Tetanus Toxoid)
4.17*
Quinvaxem4 (Novartis Vaccines)
CRM197 (Cross Reactive Material 197)
15*In aP pentavalent vaccine aP antigens interfere with Hib response, leading to
lower GMTs compared with monovalent Hib vaccines5
Source: 1. Sharma HJ et al. Human Vaccines 7:4, 451-457; April 2011; c 2011. 2. SPC Comvac 2012. 3. Ortiz et al. INDIAN PEDIATRICS. VOLUME 46__NOVEMBER 17, 2009. 4. Eregowda A et al. Human Vaccines & Immunotherapeutics 9:9, 1903–
1909; September 2013; c 2013 5. Plotkin SA et al. Expert Rev. Vaccines 10(7), 981–1005 (2011).
37
CRM 197 demonstrate better Hib immune response than TT conjugate ...
Summary
• Only pentavalent vaccine with CRM197 Hib conjugate – better tolerability & titers than TT conjugate
• The only pentavalent with no preservative / no added thiomersal in India
• Optimal aluminum phosphate (adjuvant) levels
• Extensive clinical database (>4000 subjects) across different schedules & interchangeability
• Well documented immunogenicity & safety profile & low post injection reactogenicity including Indian data
• 1st WHO pre-qualified, fully liquid pentavalent vaccine, with sustained WHO PQ since 2006
• The most widely used pentavalent vaccine globally (>418 million doses :: till Sep 2012)
• Protecting 25% of the global newborn cohort from 5 deadly disease every year#
• Registered in >30 countries & distributed by UNICEF & PAHO in > 90 countries
Quinvaxem
Quinvaxem
• The world is moving away from Thiomersal1
• Growing global trends towards thiomersal-free vaccine usage
– European Medicines Agency in 2007 recommends reducing exposure to mercury2
– The US FDA is continuing its efforts to reduce the exposure to Thiomersal3
– AAFP, AAP, ACIP and PHS recommend vaccines free from Thiomersal3
Quinvaxem is the only pentavalent vaccine which is preservative-free with no added Thiomersal
USA: 30 & France: 2
childhood vaccines with thiomersal
1999 2002
USA & Europe All childhood vaccines are
thiomersal free or contain only traces
2012
USA & Europe Almost all vaccines are thiomersal-free
Source: 1. Hessel L. Bull Acad Natl Med. 2003;187(8):1501-10. 2. The European Medicines Agency Evaluation of Medicines for Human Use , London, 11 January 2007 EMEA/CHMP/VWP/19541/2007; CHMP Position Paper on Thiomersal Implementation of the Warning Statement Relating to Sensitisation. 3. http://www.fda.gov/biologicsbloodvaccines/safetyavailability/vaccinesafety/ucm096228.htm (accessed Aug. 2013).
39
The only pentavalent vaccine which is preservative-free ...
Summary
• Only pentavalent vaccine with CRM197 Hib conjugate – better tolerability & titers than TT conjugate
• The only pentavalent with no preservative / no added thiomersal in India
• Optimal aluminum phosphate (adjuvant) levels
• Extensive clinical database (>4000 subjects) across different schedules & interchangeability
• Well documented immunogenicity & safety profile & low post injection reactogenicity including Indian data
• 1st WHO pre-qualified, fully liquid pentavalent vaccine, with sustained WHO PQ since 2006
• The most widely used pentavalent vaccine globally (>418 million doses :: till Sep 2012)
• Protecting 25% of the global newborn cohort from 5 deadly disease every year#
• Registered in >30 countries & distributed by UNICEF & PAHO in > 90 countries
Quinvaxem
Safety Profile2 :
Adverse reactions that have been reported with high aluminum containing vaccines include
Sterile abscesses
Erythema
Subcutaneous nodules
Granulomatous inflammation
Contact hypersensitivity
Production of IgE antibodies
Regulations
US FDA (21 CFR 610.15)
• aluminum content of a vaccine shall not exceed 0.85 mg of aluminum per dose
WHO technical guidelines
• aluminum content of a vaccine shall not exceed 1.25 mg of aluminum per dose
Optimal aluminium adjuvant content for favourable tolerability ...
Quinvaxem
Quinvaxem contains 0.3 mg aluminium adjuvant for desired immunogenicity & low local reactogenicity1
Source: 1. Quinvaxem prescribing Information 2013. 2. Krewski, Yokel, Nieboer, et al. Human Health Risk Assessment for Aluminum, Aluminum Oxide, and Aluminium Hydroxide. JJ Toxicol Environ Health B Crit Rev. 2007; 10(Suppl 1): 1–269.
41
Summary
• Only pentavalent vaccine with CRM197 Hib conjugate – better tolerability & titers than TT conjugate
• The only pentavalent with no preservative / no added thiomersal in India
• Optimal aluminum phosphate (adjuvant) levels
• Extensive clinical database (>4000 subjects) across different schedules & interchangeability
• Well documented immunogenicity & safety profile & low post injection reactogenicity including Indian data
• 1st WHO pre-qualified, fully liquid pentavalent vaccine, with sustained WHO PQ since 2006
• The most widely used pentavalent vaccine globally (>418 million doses :: till Sep 2012)
• Protecting 25% of the global newborn cohort from 5 deadly disease every year#
• Registered in >30 countries & distributed by UNICEF & PAHO in > 90 countries
Quinvaxem
QuinvaxemSummary of clinical evidence ...
Study Phase Design Primary objective Schedule Quinvaxem (n) Comparator
Kanra et al. (Turkey) II
Open label, randomized, comparative
Compare immunogenicity of HBV component of Quinvaxem® with that of a separate HepB vaccine
(Hepavax-Gene®) when concomitantly administered with Quattvaxem®
2-3-4 (months)
152 151
(separate DTwP-Hib & Hep B)
Gentile et al. (Argentina) II
Open label, single center, non-randomized
Evaluate immunogenicity of HBV component of Quinvaxem® given to infants who may or may not have
received 1 dose of HepB vaccine at birth
2-4-6 (months) 218 -
Aspinall et al. (South Africa) III
Double blind, multicenter, randomized
Demonstrate clinical equivalence of 3 consecutive production lots of Quinvaxem® given to infants with
regard to seroprotection rates for HepB
6-10-14 (weeks) 360 -
Aspinall et al. (South Africa) III
Open label, multicentric, randomized
Evaluate antibody responses to HBsAg, PRP, Bordetella pertussis, diphtheria, and tetanus after a booster
vaccination in infants receiving the booster dose of Quinvaxem® 1 month prior to, or concomitantly with, a
measles vaccine
18 ± 3 (months)(booster)
227 -
Suárez et al.(El Salvador)
III
Open label, multicentric, randomized,
parallel group
Demonstrate that antibody response to PRP (anti-PRP titer >1.0 μg/mL) 1 month after booster dose of
Quinvaxem® is as good as after separate administration of DTwP and Hib vaccines when received as a primary
immunization course with the commercially available DTwP-HepB/Hib vaccine
15–24 (months)(booster)
150 149
(separate DTwP & Hib)
Asturias et al. (Guatemala) IV
Open label, observational,
post-authorization safety study
Investigate the incidence of clinically relevant AEs and all serious AEs in infants vaccinated with Quinvaxem®, administered according to the national schedule for
routine vaccination
2-4-6 (months) 3000 -
Eregowda et al. (India) III
Open label, multicenter, randomized
Demonstrate immunogenicity and safety of three doses of Quinvaxem® in Indian infants
6-10-14 (weeks) 175 -
AE = adverse event; DTP = diphtheria, tetanus, pertussis; DTwP = diphtheria, tetanus, whole-cell pertussis; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HepB = hepatitis B; Hib = Haemophilus influenzae type b; PRP = polyribosylribitol phosphate
43
Summary
• Only pentavalent vaccine with CRM197 Hib conjugate – better tolerability & titers than TT conjugate
• The only pentavalent with no preservative / no added thiomersal in India
• Optimal aluminum phosphate (adjuvant) levels
• Extensive clinical database (>4000 subjects) across different schedules & interchangeability
• Well documented immunogenicity & safety profile & low post injection reactogenicity including Indian data
• 1st WHO pre-qualified, fully liquid pentavalent vaccine, with sustained WHO PQ since 2006
• The most widely used pentavalent vaccine globally (>418 million doses :: till Sep 2012)
• Protecting 25% of the global newborn cohort from 5 deadly disease every year#
• Registered in >30 countries & distributed by UNICEF & PAHO in > 90 countries
Quinvaxem
Investigators:
Dr. Sanjay Lalwani, HoD, Dept. of Pediatrics, Bharati Vidyapeeth Medical College, Pune
Dr. Sukanta Chatterjee, HoD, Dept. of Pediatrics, Medical College, Kolkata
Dr. Adarsh Eregowda, HoD, Dept. of Pediatrics, Rajarajeshwari Medical College and Hospital, Bangalore
45
Quinvaxem – Indian study
Source: 1. Human Vaccines and Immunotherapeutics 2013;9(9):1-7. (Sept 2013 issue)
0
20
40
60
80
100
2%
Tetanus
100%100%
Diphtheria
99%
18%
Hepatitis B
98%
11%
Hib (Long Term Protection)
95%
23%
Hib (Short Term Protection)
100%
68%
Pertussis
99%
Post Vaccination Baseline N = 161
Minimum Protective Levels:• D : ≥ 0.1 IU/mL• T : ≥ 0.1 IU/mL• wP : 4-fold increase or 20
EIU/mL• Hib : Short term: ≥ 0.15
mcg/mL• Long term: ≥ 1.00 mcg/mL• Hep B : ≥ 10 mIU/mL
46
Seroprotection rates at Baseline & 1 month after 3rd vaccine dose ...
Quinvaxem – Indian study
Source: 1. Human Vaccines and Immunotherapeutics 2013;9(9):1-7. (Sept 2013 issue)
Most of the solicited local reactions were mild to moderate in intensity
Most of the unsolicited AEs were also mild to moderate in intensity.
There were no vaccine-related serious adverse events (SAEs) or deaths reported during the study period
Results – Safety (4)
1310
4
11
0
20
40
60
80
100
Fever ≥ 38°CErythema TendernessInduration
3rd Vaccination (N = 165)
AD
R (
%)
Comparison of available pentavalent vaccines
Pentavalent Vaccine
Composition
Seroprotection (%)Reactogenecity
(%)
RemarkDiphtheria
Pertussis
Tetanus
HibHepatitis B
PainRedness
Swelling
Fever
Quinvaxem1
• Hib conjugated to CRM197*
• No Thiomersal#,
• Optimal aluminum content$
99 99 100 100 98 10 11 4 13
• Sustained WHO prequalification since 2006
• Most widely used pentavalent vaccine globally (>418 million doses till Sep 2012)
• Extensive Clinical database (>11000 doses in >4000 infants & toddlers) demonstrating high immunogenicity & safety
Pentavac2
• Hib conjugated to TT
• Contains thiomersal
• High content of alumInum
100 95 100 100 100 22 39 20 18 • Estimated 40 million doses• Poor reactogenecity profile
Comvac3
• Hib conjugated to TT
• Contains thiomersal
• Optimal aluminum content
98 76 98 100 98 9.2 4 4 24
• Not WHO prequalified• Hep B component WHO delisted• No supply to UNICEF• No published clinical data
Easyfive-TT4
• Hib conjugated to TT
• Contains thiomersal
• Optimum aluminum content
9566 - 76
99 95 94 NA NA 42 73
• WHO delisted in 2011 & relisted in 2013
• No published clinical data
Pentaxim5
Hib conjugated to TT, Preservative added and optimal content of alum
100PT - 85
FHA - 93
100 99
IPV 100% For all strain 14 4 5 17
• Extensive clinical database• > 85 Million doses distributed
since last 15 years
Source: 1. *CRM197 : Better immunogenicity & tolerability profile than TT conjugate # Thiomersal: absence of scientific consensus on safety of thiomersal $ Alum adjuvant forms depot at site of injection and causes increased local reactogenecity. 1. Eregowda A et al, Human Vaccines & Immunotherapeutics Sep 2013: Vol 9(9), 1903–1909, 2.Sharma H et al.Vaccine 29 (2011) 2359–2364 3.Comvac prescribing information 4.Easyfive TT prescribing information. 5. Pentaxin prescribing information. ****They are independent studies and Definitions/ Scales used may differ 48
Summary
• Only pentavalent vaccine with CRM197 Hib conjugate – better tolerability & titers than TT conjugate
• The only pentavalent with no preservative / no added thiomersal in India
• Optimal aluminum phosphate (adjuvant) levels
• Extensive clinical database (>4000 subjects) across different schedules & interchangeability
• Well documented immunogenicity & safety profile & low post injection reactogenicity including Indian data
• 1st WHO pre-qualified, fully liquid pentavalent vaccine, with sustained WHO PQ since 2006
• The most widely used pentavalent vaccine globally (>418 million doses :: till Sep 2012)
• Protecting 25% of the global newborn cohort from 5 deadly disease every year#
• Registered in >30 countries & distributed by UNICEF & PAHO in > 90 countries
Quinvaxem
Product Manufacturer
2006 2007 2008200
92010 2011 2012 2013
# of doses supplied
Quinvaxem Crucell / Novartis
WHO - PQ
418 million
(till Sep 2012)
Shan 5Shantha
Biotechnics
WHO -
PQ
Delisted
X
SII Penta / Pentavac
Serum Institute of India
WHO -
PQ
40 million doses
Easyfive TTPanacea Biotec
WHO -
PQ
Delisted
Delisted
Relisted
55 million doses
Combi FiveBiological Evans
WHO - PQ
Data not available
ComvacBharat biotech
No WHO prequalificationNo supply to international
agencies
PentaximSanofi Pasteur
No WHO prequalificationNo supply to international
agencies
Quinvaxem®: Only pentavalent vaccine sustained WHO prequalification status since
introduction in 2006Demonstrating consistent quality & safety profile ...
Source: 1. Source: http://www.who.int/immunization_standards/vaccine_quality/pq_consultation_2013/en/index.html.
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Summary
• Only pentavalent vaccine with CRM197 Hib conjugate – better tolerability & titers than TT conjugate
• The only pentavalent with no preservative / no added thiomersal in India
• Optimal aluminum phosphate (adjuvant) levels
• Extensive clinical database (>4000 subjects) across different schedules & interchangeability
• Well documented immunogenicity & safety profile & low post injection reactogenicity including Indian data
• 1st WHO pre-qualified, fully liquid pentavalent vaccine, with sustained WHO PQ since 2006
• The most widely used pentavalent vaccine globally (>418 million doses :: till Sep 2012)
• Protecting 25% of the global newborn cohort from 5 deadly disease every year#
• Registered in >30 countries & distributed by UNICEF & PAHO in > 90 countries
Quinvaxem: A new perspective in pentavalent vaccines ...
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General Recommendations (1)• All children should be immunized against
pertussis• Maintain high levels of coverage (≥90%)
• Minor reductions can lead to an increase in incidence
• Goal is early and timely vaccination in all countries
• As soon as possible ≥ 6 weeks of age• ≥ 3 doses of assured quality vaccine
• 1 dose (~50%+) 2 doses (~ 80%+) effective against severe disease
• wP vaccines preferred when:• Program target is prevention of infant disease• Limited number of pertussis doses delivered /
affordable
• aP vaccines should only be considered when:
• Program objectives include older children and adults• Large numbers of doses may be included in a
national immunization schedule• Cost implications (higher unit cost & number of required
doses)
General Recommendations (2)
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Supplemental Strategies may be considered toPrevent Infant Mortality
• Maternal immunization• aP vaccines safe & effective (via transfer of maternal
antibodies)
• Cocooning• Potential reduction in severe morbidity; timing crucial;
requires high coverage
• Adolescent/adult boosters• Health care workers should be priority group
General Recommendations (3)
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