The Role of Pneumococcal Conjugate

Vaccine (PCVs) in Infants

Prof.DR.Dr.Hindra Irawan Satari,SpA(K),MTropPaed
Dep IKA FKUI-RSCM
DISCLAIMER
• Paparan sematamata bersifat edukatif dan informasi ilmiah
AGENDA
• Pneumococcal Disease Burden in Children Globally and in Asia
• The Role of Pneumococcal Conjugate Vaccines (PCVs) in Infants
• Currently Available PCVs to Prevent Pneumococcal Disease
• Impact of PCV13
• Pandemic Impact on Pediatric Vaccination Coverage and the Role of
Catch-up Doses
• Wrap up
Pneumococcal Disease Burden in Children
Globally and in Asia
 The Complex Nature of Pneumococcal Infection Is
Underscored by the Variety of Manifestations1-4
Otitis media

Transmission of
pneumococcus from host
Meningitis

100 identified Bacteremia

Pneumococcal strain
Streptococcus pneumoniae establishes itself in
serotypes nasopharynx of host

Pneumonia

1. Centers for Disease Control and Prevention. Pneumococcal disease. In: Hamborsky J, Kroger A, Wolfe S, eds. Epidemiology and Prevention of Vaccine-Preventable Diseases. 13th ed. Washington, DC: Public
Health Foundation; 2015:279-296. 2. Dagan R, et al. J Infect Dis. 2002;185(7):927-936. 5
3. Simell B, et al. Expert Rev Vaccines. 2012;11(7):841-855. 4. Henriques-Normark B, et al. Cold Spring Harb Perspect Med. 2013;3(7):a010215.
 Pneumococcal Disease Presents Differently in Children and Adults1-3

Meningitis
Adults Children
Bacteremia Meningitis

Bacteremic
Bacteremia/
Pneumonia
Sepsis

Nonbacteremic
Pneumonia Pneumonia

Acute Otitis
Media

This is a conceptualized diagram

1. Centers for Disease Control and Prevention. Pneumococcal disease. In: Hamborsky J, Kroger A, Wolfe S, eds. Epidemiology and Prevention of Vaccine-Preventable Diseases. 13th ed. Washington, DC: Public
Health Foundation; 2015:279-296. 2. Huang SS, et al. Vaccine. 2011;29:3398-3412. 3. Said MA, et al. PLoS ONE. 2013;8:e60273. 6
 Risk of IPD Is Highest in the Youngest and Oldest Age Groups

United States England and Wales

20151 2016–20172
IPD incidence (n/100,000 population)

60 35

50 30

25
40
20
30
15
20
10

10
5

0 0
<1 1 2–4 5–17 18–34 35–49 50–64 65–74 75–84 ≥85 <2 2–4 5–14 15–44 45–64 ≥65
Adapted from Centers for Disease Control and Prevention. Active Bacterial Core surveillance (ABCs) Adapted from Ladhani SN, et al. Lancet Infect Dis. 2018;18(4):441-451.
report. Age (years)

IPD, invasive pneumococcal disease

1. Centers for Disease Control and Prevention. Active Bacterial Core surveillance (ABCs) report. Emerging Infections Program Network: Streptococcus pneumoniae, 2015.
http://www.cdc.gov/abcs/reports-findings/survreports/spneu15.pdf. Accessed October 24, 2018. 2. Ladhani SN, et al. Lancet Infect Dis. 2018;18(4):441-451. 7
 LRIs Result in Substantial Mortality Worldwide in Children Aged <5 Years
Global LRI-Related Mortality Rate per 100,000 People for Children <5 Years in 2016: Results From
the Global Burden of Disease (GBD) Study

Rate per 100,000 people

0–4
5–9
10–24
25–49
50–74
75–99
100–249
250–499
500–799
800–1200

• Based on the GBD 2016 estimates, pneumococcal pneumonia caused by S. pneumoniae ~52.3% of LRI-related deaths among children younger
than 5 years of age
LRI=lower respiratory infection.
Adapted from GBD 2016 Lower Respiratory Infections Collaborators (2018). Estimates of the global, regional, and national morbidity, mortality, and aetiologies of lower respiratory infections in 195
countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. The Lancet. Infectious diseases, 18(11), 1191–1210. https://doi.org/10.1016/S1473-3099(18)30310-4
Indonesia: Nasopharyngeal Carriage of Pneumococcal Serotypes in Infants, 2014–2015

Pneumococcal Carriage Episodes by Serotype in Indonesian Infants,

November 2014 to January 2015

PCV13 serotypes are shown in red (*indicates serotypes not included in PCV10), non-PCV13 capsular serotypes are shown in black, and non-encapsulated pneumococci
(categorized into genetic variants are shown in grey. “Other PCV13” consists of serotypes 1 and 7F (n=2 each). “Other NVT” consists of serotypes 8, 45, 17F, 23B (n=3
each), 38, 39, 18A, 19B, 28F, 35F, 7C (n=2 each), and 40, 10F, 12F, 15F, 17A, and 28A (n=1 each). “Other NESp” consists of non-encapsulated lineages NT4b (n=2) and
NT2/NT3b (n=1).
Adapted from Murad C, et al. Int J Infect Dis. 2019;86:73-81.
 2020 WHO Estimates of Global Immunization Coverage in Children
100%
Pediatric vaccine completion (%) 84%
83% 83% 83%

75%

49%
50% 46%

25%

0%
DTP3 Polio Measles Hepatitis B Pneumococcal Rotavirus
WHO-recommended childhood vaccines

Global coverage with 3 doses of pneumococcal vaccination substantially trails that of other infectious diseases

DTP3=diphtheria-tetanus-pertussis; WHO=World Health Organization.

Adapted from World Health Organization. Immunization coverage. http://www.who.int/news-room/fact-sheets/detail/immunization-coverage. Accessed September 14, 2021. 10
 The Role of Pneumococcal
Conjugate Vaccines (PCVs) in Infants
 Most Common Serotypes Causing IPD in Children <5 Year of Age
Prior to PCV Introduction Globally
Proportion of IPD in Young Children Due to the Most
Common Serotypes Globally

IPD, invasive pneumococcal disease; CI, confidence interval; PD, pneumococcal disease.
Error bars indicate 95% CI for the proportion of invasive PD due to each of the 21 serotypes. Cumulative line indicates the cumulative proportion of invasive PD due to
the 21 serotypes. *Adjusted for regional incidence of cases.
Adapted from Johnson HL, et al. PLoS Medicine. 2010;7(10):e1000348. 12
 Most Common Serotypes Causing IPD in Children <5 Year of Age
Prior to PCV Introduction - Asia
Proportion of IPD in Young Children Due to the Most
Common Serotypes in Asia

Adapted from Johnson HL, et al. PLoS Medicine. 2010;7(10):e1000348

IPD, invasive pneumococcal disease. CI, confidence interval; PD, pneumococcal disease.
.Error bars indicate 95% CI for the proportion of invasive PD due to each of the 21 serotypes. Cumulative line indicates the cumulative proportion of invasive PD due to 13
the 21 serotypes.
Serotypes Contained in Globally Licensed Pneumococcal Conjugate Vaccines

PCV71
4 6B 9V 14 18C 19F 23F PCV7 was the 1st licensed PCV (2000)1
adapted from Wyeth Lederle Vaccines and Pediatric and Pediatric
CRM197

PCV102
4 6B 9V 14 18C 19F 23F 1 5 7F

Protein D TT DT Protein D

PCV133
4 6B 9V 14 18C 19F 23F 1 5 7F 3 6A 19A

CRM197

PCV104
6A 6B 9V 14 19A 19F 23F 1 5 7F
CRM197
CRM=cross-reactive material; DT=diphtheria toxoid; TT=tetanus toxoid. PCV7 as mentioned above is presently not registered in Singapore.
1. Prevenar [summary of product characteristics]. Wyeth Lederle Vaccines and Pedaitric. 2. Synflorix [summary of product characteristics]. GlaxoSmithKline Biologicals. 3. Prevenar 13 [summary of
product characteristics]. Pfizer Ltd. 4. Clarke E, et al. Vaccine. 2020;38(2):399-410. 4. World Health Organization. Public Assessment Summary Report: Pneumococcal Conjugate Vaccine, 14
(adsorbed, 10-valent) Serum Institute of India Pvt. Ltd. World Health Organization; 2019.
 Prevenar 13 Is a Pneumococcal Conjugate Vaccine

Polysaccharide Vaccine1,2 Conjugate Vaccine1-4

• Contain polysaccharide
• Contain polysaccharide
antigens covalently
antigens
linked to a carrier protein

• Stimulate T cells to help

• Stimulate B cells to B cells produce
produce antibodies antibodies and generate
immune memory

• T-cell–dependent
• T-cell–independent
immune response and
immune response that
booster response with
cannot be boosted
revaccination

Conjugation allows for stimulation of the T-cell–dependent immune response necessary for immune memory

• Memory B cell production has not been studied with Prevenar 13 in adults
1. Siegrist CA. In: Plotkin et al, eds. Vaccines. 5th ed. Philadelphia, PA: Saunders Elsevier; 2008:17-36. 2. Pollard AJ, et al. Nat Rev Immunol. 2009;9(3):213-220. 3. Clutterbuck EA, et al. Immunology. 2006;119(3):328-337. 4.
de Roux A, et al. Clin Infect Dis. 2008;46(7):1015-1023.
Efficacy of PCV7 — Summary
• Pneumococcal CRM-conjugate vaccines have been shown to be effective in randomized,
double-blind clinical trials1

PCV7 has documented efficacy against

• Vaccine-type IPD (US; N=37,868)2

– 94% efficacy caused by vaccine serotypes (ITT)

• Pneumonia (all-cause and radiologically confirmed; follow-up to IPD trial)3

– 26% radiologically confirmed (ITT)

• Vaccine-type AOM (Finland; N=1,662)4

– 57% estimated efficacy against vaccine serotypes (PP)
AOM, acute otitis media; IPD, invasive pneumococcal disease. PCV7 as mentioned above is presently not registered in Singapore.
1. Black S, et al. Pediatr Infect Dis J. 2000;19:187-195. 2. Black SB, et al. Pediatr Infect Dis J. 2002;21:810-815. 3. Hansen J, et al. Pediatr Infect Dis J. 2006;25:779-781.
4. Eskola J, et al. N Engl J Med. 2001;344:403-409.
 Additional Benefits of PCVs Were Recognized Following PCV7 Introduction

Impact on nasopharyngeal carriage1

Herd effects2

1. Dagan R. et al. J Infect Dis.2002;185(7):927-936 2. Cohen R. et al Pediatr Infect Dis J.2012;31(3)297-301 3. Davis SM et al. Vaccine. 2013;32(1):133-145 2. Pilishivili
T. et al. J Infect Dis.2010;201:32-41.

PCV7 as mentioned above is presently not registered in Singapore. 17

Indirect Protection Extends the Benefits of Vaccination to the Population Level1,2

Population Demographics, Germany, 2017 (N=80,636,124)

7,01M Indirect Effects of Vaccination

6,40M Reduced transmission
6,03M
results in protection of
5,45M unvaccinated populations
5,27M
4,90M 4,94M
4,63M
4,27M 4,33M
3,98M 4,11M
3,90M
3,45M 3,52M
3,38M
(# of individuals)

2,78M
Population

1,45M

0,70M
0,13M

0–4 5–9 10–14 15–19 20–24 25–29 30–34 35–39 40–44 45–49 50–54 55–59 60–64 65–69 70–74 75–79 80–84 85–89 90–94 95–99
Age (years) Adapted from PopulationPyramid.net. Germany 2017

1.PopulationPyramid.net. Germany 2017. https://www.populationpyramid.net/germany/2017/. Accessed September 28, 2018. 2. Dagan R, et al. J Infect Dis. 2002;185(7):927-936. 18
 Different Serotypes Are Associated with Varying Case Fatality Rate
Comparison of the Serotype-specific Risk of Death
Ratios (RRs) Due to Bacteremic Pneumonia

Adapted from Weinberger DM, Harboe ZB, Sanders EA, et al.

Clin Infect Dis. 2010;51: 692-699.

• Risk of death varied by serotype and was stable among studies across time and geography
Nine studies were analyzed; 5 included pediatric patients (1952 to present).Serotype-specific risk of death (RR) were calculated and compared to serotype 14 (a common IPD serotype and only serotype with
nonzero numbers of fatalities in all studies).
The Danish study contributed nearly 70% of patients; the strong correlation with remaining studies suggested estimates were not unduly influenced by the one large study.
19
PCVs Have Been Developed to Target the Serotypes Most Frequently Associated With Disease

PCV13
PCV10
4 6B 9V 14 18C 19F 23F 1 5 7F 3 6A 19A

IPD

Pneumonia

Otitis

Mortality

Antimicrobial resistance

IPD=invasive pneumococcal disease.

1. Centers for Disease Control and Prevention. Pneumococcal disease. In: Hamborsky J, Kroger A, Wolfe S, eds. Epidemiology and Prevention of Vaccine-Preventable Diseases. 13th ed. Washington,
DC: Public Health Foundation; 2015:279-296. 2. Simell B, et al. Expert Rev Vaccines. 2012;11(7):841-855. 3. Johnson HL, et al. PLoS Med. 2010;7(10):e1000348. 4. Dagan R, et al. J Infect Dis.
2002;185(7):927-936. 5. Henriques-Normark B, et al. Cold Spring Harb Perspect Med. 2013;3(7):a010215. 6. Fletcher MA, et al. Eur J Clin Microbiol Infect Dis. 2014;33(6):879-910. 7. Prevenar 13
[summary of product characteristics]. Kent, United Kingdom: Pfizer Limited. 8. Synflorix [summary of product characteristics]. Rixensart, Belgium: GlaxoSmithKline Biologicals s.a. 9. Weil-Olivier C, et
al. BMC Infect Dis. 2012;12:207. 10. Cho EY, et al. J Korean Med Sci. 2012;27(7):716-722. 20
 Currently Available PCVs to
Prevent Pneumococcal Disease
Serotypes Contained in Globally Licensed Pneumococcal Conjugate Vaccines

PCV71
4 6B 9V 14 18C 19F 23F
CRM197

PCV102
4 6B 9V 14 18C 19F 23F 1 5 7F

Protein D TT DT Protein D

PCV133
4 6B 9V 14 18C 19F 23F 1 5 7F 3 6A 19A

CRM197

PCV104
6A 6B 9V 14 19A 19F 23F 1 5 7F
CRM197
CRM=cross-reactive material; DT=diphtheria toxoid; TT=tetanus toxoid. PCV7 as mentioned above is presently not registered in Singapore.
1. Prevenar [summary of product characteristics]. Wyeth Lederle Vaccines. 2. Synflorix [summary of product characteristics]. GlaxoSmithKline Biologicals. 3. Prevenar 13 [summary of product
characteristics]. Pfizer Ltd. 4. Clarke E, et al. Vaccine. 2020;38(2):399-410. 4. World Health Organization. Public Assessment Summary Report: Pneumococcal Conjugate Vaccine, (adsorbed, 10- 22
valent) Serum Institute of India Pvt. Ltd. World Health Organization; 2019.
Impact of PCV13
• IPD
• Pneumonia
• Acute otitis media
 Real-World Impact of PCV13 Against All-Cause Pneumonia in Children

USA1*
27% FRANCE4
(<2 years) 32%
(<2 years)

NICARAGUA2*
33%
(<1 year) ISRAEL5
38%
(<5 years)
ARGENTINA3*
PCV13 NIP6 51%
(<5 years)

*Reductions in hospitalizations.
NIP=national immunization program.
1. Griffin MR, et al. MMWR Morb Mortal Wkly Rep. 2014;63(44):995-998. 2. Becker-Dreps S, et al. Pediatr Infect Dis J. 2014;33(6):637-642. 3. López EL, et al.
J Pediatric Infect Dis Soc. 2018;7(1):30-35.. 4. Angoulvant F, et al. Clin Infect Dis. 2014;58(7):918-924. 5. Greenberg D, et al. Vaccine. 2015;33(36):4623-4629. 6. NIP PCV13- Data on File. 24
 Real-World Impact of PCV13 Against All-Cause OM in Children

USA1*
40.5% UK2*
(<2 years) 51%
(<10 years)

ISRAEL3†
60%
(<2 years)

PCV13 NIP4

*All-cause OM.
†Includes complex OM cases.

NIP=national immunization program; OM=otitis media.

1. Marom T, et al. JAMA Pediatr. 2014;168(1):68-75. 2. Lau WC, et al. Vaccine. 2015;33(39):5072-5079. 3. Ben-Shimol S, et al. Clin Infect Dis. 2014;59(12):1724-1732. 4. NIP PCV13- Data on File. 25
 Global Total of Averted Cases of Pneumococcal Disease and
Pneumococcal-Associated Deaths in Children in the PCV13 Era (2010–2019)

•Overall, 20.8M cases have been averted and 625K lives have been saved since 2010

2M cases averted and 250K lives

IPD
saved in children <5 years of age

14.8M cases averted and 375K lives saved in Pneumonia

children <5 years of age

Globally, an estimated 286.5

million children were Nasopharyngeal carriage†
vaccinated with PCV13
between 2010–2019

*Study assumes no AOM fatalities.

†Study analysis did not include reductions in nasopharyngeal carriage and associated indirect effects in unvaccinated children or adults.

AOM=acute otitis media; IPD=invasive pneumococcal disease.

Adapted from Chapman R, et al. Vaccine. 2020;38(45):7138-7145. 26
 Three Levels of Protection Against Disease Caused by Streptococcus pneumoniae

Adapted from Dagan R. (2019). Relationship between immune response to pneumococcal conjugate vaccines in infants and indirect protection after vaccine
implementation, Expert Review of Vaccines, DOI: 10.1080/14760584.2019.1627207
PCV13 Is Included in Over 130 NIPs, With Exclusivity in 127 Countries Worldwide1,2

PCV13 Only* = 127

PCV13 / PCV10† Shared = 5
(PCV13 covers >50% of total BC)

PCV13 / PCV10† Shared = 1

(PCV13 covers <50% of total BC)

PCV10 Only = 31

As of Nov 2020

*Canadian province of Quebec and Italian region of Piemonte have initiated PCV vaccination programs with PCV10.
†Both PCVs are available/reimbursed in the NIP or the NIP consists of different PCVs by region.
BC=birth cohort.
NIP=national immunization program.
1. Gavi Alliance Annual Progress Report 2017. http://www.gavialliance.org/results/gavi-progress-reports/. Accessed May 16, 2019.
2. Data on file. Pfizer Inc, New York, NY. 2020.
28
Pandemic Impact on Pediatric Vaccination Coverage
and the Role of Catch-up Doses
 Impact of Pandemic on Routine Immunization
in South-East Asia and Western Pacific
Number of Antigens By Country and By Age

AU, Australia; BN, Brunei; CN, China; HK, Hong Kong; ID, Indonesia; IN, India; JP, Japan; KH, Cambodia; KR, South Korea; MM, Myanmar; MY, Malaysia; NP, Nepal; NZ, New Zealand; PH, Philippines;
PK, Pakistan; SG, Singapore; TH, Thailand; TW, Taiwan; VN, Vietnam.
Adapted from Harris RC, et al. Lancet Reg Health West Pac. 2021;10:100140. doi:10.1016/j.lanwpc.2021.100140.
 Impact of Pandemic on Routine Immunization in
South-East Asia and Western Pacific
Proportion of Countries Impacted, By Antigen

Adapted from Harris RC, et al. Lancet Reg Health West Pac. 2021;10:100140. doi:10.1016/j.lanwpc.2021.100140.
 The Majority of Children Missing Doses From the Peak of the Pandemic
Will Be Nearly Two Years of Age Today
South Asia Monthly Vaccine Coverage*
for DTP3 and MCV1, from January to
December 20201 • Health authorities have recognized the need to protect
those children that have missed pediatric vaccine doses
for any reason1

• Catch-up vaccination, as defined by the WHO, “refers to

the action of vaccinating an individual, who for
whatever reason (e.g. delays, stockouts, access,
hesitancy, service interruptions, etc.), is missing/has
not received doses of vaccines for which they are
eligible, per the national immunization schedule”2

• Developing and educating stakeholders on a clear

Feb–June 20201 Sept–Nov 20211 catch-up vaccination strategy will be critical to closing
Cohort Cohort
the gaps in vaccination rates created by the current
2–6 mths of age 20–24 mths of age pandemic1

Represents ~ 2 to 4 million children with missed

doses of pediatric vaccines1

Adapted from Causey K, et al. Lancet. 2021;398:522-534. 2. World Health Organization. Leave no one behind : guidance for planning and implementing catch-up vaccination (who.int). Accessed 6 October 2021.
 The WHO identified catch-up vaccination policy and catch-up schedules
“as an essential component of a well-functioning immunization program”

The WHO developed guidance to assist countries “to lay out strategies for
continuously implementing catch-up vaccination as a component of routine
immunization and as an integral part of the healthcare system”, helping to:
• Ensure eligible individuals who miss routine vaccinations can be identified and vaccinated at
the earliest opportunity and

• Describe intensified strategies to close “immunization gaps” following a significant disruption

in immunization services

World Health Organization. Leave no one behind : guidance for planning and implementing catch-up vaccination (who.int). Accessed 6 October 2021.
 Catch-up Vaccination Strategies
Following an Interruption of Services
WHO Recommendations for Interrupted or Delayed Routine Immunization*

*simplified table

BCG-Bacillus Calmette Guerin Vaccine, boPV- Bivalent Oral Polio virus, IPV- inactivated polio vaccine, DTPCV- diptheria-tetanus toxoids containing vaccine
Adapted from World Health Organization. https://www.who.int/publications/i/item/leave-no-one-behind-guidance-for-planning-and-implementing-catch-up-vaccination. Accessed 25 October 2021.
(Page 35) b: In polio-endemic countries and in countries at high risk for importation and subsequent spread of poliovirus, WHO recommends a birth dose of bOPV (“bOPV0”), followed by a primary series of 3 bOPV doses and
at least 1 dose of IPV.c: In certain situations, MCV can be given from 6 months of age. This dose should be considered a zero dose (“MCV0”) and two subsequent doses (MCV1 and MCV2) should still be provided according
to the national schedule.
 Special Catch-up Vaccination Strategies
Following an Interruption of Services
WHO Recommendations for Interrupted or Delayed Routine Immunization*

*simplified table
Adapted from World Health Organization. https://www.who.int/publications/i/item/leave-no-one-behind-guidance-for-planning-and-implementing-catch-up-vaccination. Accessed 25 October 2021.
 Catch-Up Guidelines for Healthy Children <5 Years of Age
That Have Missed A Recommended Dose of PCV
The CDC recommends healthy children aged 24–59 months age with any
incomplete PCV series* receive 1 dose of PCV13

*Incomplete series includes not having received all doses in either the recommended series or an age-appropriate catch-up series.
Adapted from Centers for Disease Control and Prevention. https://www.cdc.gov/vaccines/schedules/downloads/child/job-aids/pneumococcal.pdf. Accessed 29 September 2021.
 Wrap-up
• PCV13 serotypes continue to exert a sizeable burden of disease in Asia and around the world1

• Introduction of PCV13 into pediatric NIPs has led to substantial reductions in invasive and mucosal
pneumococcal disease in children, led to reductions in disease in unvaccinated populations via indirect effect,
and reduced the prevalence of antimicrobial-resistant strains2-5

• The emergence of NVTs has highlighted the varying capacity of different serotypes to colonize the nasopharynx
and to cause disease — reinforcing the importance of protecting populations with a broad coverage PCV5,6

• Maintaining routine immunization schedules and implementing catch-up strategies for those children
who have missed doses is critical to protecting vulnerable populations from vaccine-preventable
disease7,8
NIP=national immunization program; NVT=non-vaccine serotype.
1. Chen C et. al. Lancet Global Health 2019; 7:e58-67; 2. Hanquet G, et al. Thorax. 2018. doi:10.1136/thoraxjnl-2018-211767. 3. Chapman R, et al. Vaccine. 2020;38(45):7138-7145. 4. Tomczyk S, et al. Clin Infect Dis.
2016;62(9):1119-1125. 5. Dagan R. Exp Rev Vaccines. 2019;18:641-661. 6. Garcia Quesada, M. Microorganisms 2021;9, 738. https://doi.org/10.3390/microorganisms9040738. 7. WHO/UNICEF joint statement–
Maintaining routine immunization services vital during the COVID-19 pandemic. http://www.euro.who.int/en/media-centre/sections/statements/2020/whounicef-joint-statement-maintaining-routine-immunization-services-
vital-during-the-covid-19-pandemic. Accessed May 15, 2020. 8. World Health Organization. Leave no one behind : guidance for planning and implementing catch-up vaccination (who.int). Accessed 6 October 2021.