Update on Pertussis with special reference to QUINVAXEM in India

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



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.

http://www.who.int/whosis/2010/en/index.html

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


2009


10


2010


11

2011


• 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).

http://www.cfr.org/interactives/GH_Vaccine_Map/

http://www.cfr.org/interactives/GH_Vaccine_Map/

12


2012


13


2013


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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



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.

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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

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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



vaccinated



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.



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 ...

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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

Summary










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

35

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).

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CRM 197 demonstrate better Hib immune response than TT conjugate ...

Summary










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).

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The only pentavalent vaccine which is preservative-free ...

Summary










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










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

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Summary










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

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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



• 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



• 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










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.

50

Summary










Quinvaxem: A new perspective in pentavalent vaccines ...

15

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)

53

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)

54

Health & Medicine

Update on Pertussis with special reference to QUINVAXEM in India