Pnemococcal Vaccines For Elderly

During Covid 19 Pandemi

IGP SUKA ARYANA

DIVISI GERIATRI, BAGIAN/SMF ILMU PENYAKIT DALAM

FK UNUD/RSUP SANGLAH, DENPASAR
OUTLINE
INTRODUCTION

VACCINE IN ELDERLY

PNEUMOCOCCAL VACCINES AND THEIR IMPACT

CAPITA STUDY  GUIDELINES AND RECOMMENDATIONS

CONCLUSIONS
INTRODUCTION
AGING AND
IMMUNOSNESCENE

Inoue et al.
Journal of Intensive Care (2018) 6:65
Michael G. Dorrington and Dawn M. E. Bowdish, FRONTIER IN IMMUNOLOGY, JUNE 2013,
Immunosenescence and novel vaccination strategies for the elderly *
 IMUNOSNESCENCE

IMMUNOSENESCENCE dan akibatnya

Disfungsi Imunitas Inflamasi kronis, Lebih rentan Vaksinasi:

• Penurunan sistem menyebabkan: mengalami: • Penurunan
kekebalan tubuh • Aterosklerosis • Kanker
• Lebih sensitif terhadap • Osteoporosis • Penyakit respon
patogen • Diabetes melitus autoimun antibodi
• Risiko infeksi meningkat • Nyeri sendi
VACCINE IN ELDERLY
LOUKOV DESSY, ET ALL,
Immunosenescence:
implications for vaccination programs
in the elderly.
VACCINE: DEVELOVEMENT AND
THERAPY 2015
 Novel Intervention Vaccine

Michael G. Dorrington and Dawn M. E. Bowdish, FRONTIER IN IMMUNOLOGY, JUNE 2013,

Immunosenescence and novel vaccination strategies for the elderly *
PNEUMOCOCCAL VACCINES IN ELDERLY
AND THEIR IMPACT
History of Pneumococcal Vaccines
1880 1916–1917
Isolation of S pneumoniae Dochez and Avery isolate
by Sternberg and Pasteur pneumococcal capsular
polysaccharides 2000
First approval of
1911–1912 pneumococcal
Wright carries out trials 1929 conjugate vaccine
of whole-cell heat-killed Avery conjugates
pneumococcal vaccine pneumococcal
in several thousand polysaccharides
patients  tetravalent to proteins in
pnemococcal animal models
polysaccharide

1940  penisilin 1991  resistensi AB

1914  vaccine (-)
Lister recognizes 1977 1983
pneumococcal types & PPV14 PPV23
develops first serotype- approved* approved*
specific whole-cell
pneumococcal vaccines
1944–1945
MacLeod and Heidelberger
demonstrate efficacy of
quadrivalent PPSV
*US approval. 1946  hexavalent vaccine
Grabenstein JD, Klugman KP. Clin Microbial Infect. 2012;18(suppl 5):15-24. 11
Use of Conjugate Vaccines Has Increased Over the Past
Few Decades

Pneumococcal Pneumococcal
Meningococcal
heptavalent tridecavalent
polysaccharide
conjugate vaccine conjugate vaccine
vaccine
(PCV7) (PCV 13)

1974 1977 1985 1987 2000 2005 2010

Haemophilus
influenzae type b Meningococcal
polysaccharide quadrivalent
vaccine conjugate vaccine

Pneumococcal
H influenzae type b
polysaccharide vaccine
conjugate vaccine
(PPV23)

Plotkin SA, et al. Nat Rev Microbiol. 2011;9(12):889-893. 12

STUDI EFIKASI PPSV

Daniel P et al. 13-Valent vaccine serotype pneumococcal

community acquired pneumonia in adults in high clinical risk groups.
Vaccine (2018)
Adult Pneumococcal Vaccine

PPV : Substantial health benefit and marginal impact burden of disease

10000
Pneumococcal Pneumonia
(30% of CAP) (nonbacteremic pneumococcal 1000

Cases/100.000/yr
pneumonia)

( pneumococcal
100
bacteremia)
Invasive Pneumococcal
Disease 10
PPV impact

1
<5 5-9 10- 15- 20- 25- 30- 35- 40- 45- 50- 55- 60- 65- 70- >74
14 19 24 29 34 39 44 49 54 59 64 69 74
PPV impact simulation:
PPV administered at 65 years old; no revaccination
Assumption: 30% of CAP is caused by S. pneumoniae
PPV efficacy of 50% against IPD, 0% against pneumonia
Adapted from Jokinen 1991 (Pneumonia in Eastern Finland in 1981-82)
and Finish Ntl Register (Invasive pneumococcal disease in Finland in 1995-99)
Clinical Effectiveness of pneumococcal vaccination in preventing invasive
pneumococcal disease in observational studies in older adults

From : Fedson D.S., Musher D.S. in « Vaccines », Ed. Plotkin S.A., Orenstein W.A.
Pub. Saunders/Elsevier, 2004, pp. 529-588
Between 1999 and 2016 at least 11 Meta-
analyses of PPV23 Were Conducted

The results of numerous meta-analyses regarding PPV23 effectiveness

in preventing non-invasive (non-bacteremic) disease have been inconsistent
 Rationale for Conjugation

Polysaccharide Vaccines1-3 Conjugate Vaccines1-4

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

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

• T cell–independent • T cell–dependent
immune response immune response

• Memory B cell production has not been studied with PCV13 in adults

1. Siegrist CA. Vaccine Immunology. In: Plotkin SA, et al, eds. Vaccines. 5th ed. Philadelphia, PA: Saunders Elsevier; 2008:17-36. 2. de Roux A, et al. Clin Infect
Dis. 2008;46(7):1015-1023. 3. Clutterbuck EA, et al. Immunology. 2006;119(3):328-337. 4. Pollard AJ, et al. Nat Rev Immunol. 2009;9(3):213-220. 17
67
 FUTURE (Nonconjugate PPV)
• Also under development noncapsular virulence factors.
• Possible advantages to protect against all serotypes and to
stimulate immunologic memory.
• Some pneumococcal proteins that are candidates :
pneumococcal surface protein A (PspA), pneumolysin,
pneumococcal surface adhesin A (PsaA), PspC, and others.
• These protein based vaccines : might be good in elderly adults.
History of PCV13 Licensure and Recommendations in
the United States and European Union
2011 2014
PCV13 licensed for adults aged ≥50 years ACIP recommends PCV13
for prevention of IPD and pneumonia
under accelerated approval pathway 2 for all adults ≥65 years2
US
2010
PCV13 licensed CAPiTA trial
for use in children2 completed2

2009
PCV13 licensed
for use in children1
EU 2011
PCV13 licensed for adults ≥50 years for prevention
of
IPD only, as EMA would not grant an indication for
PCV13 for non-invasive disease based on
serological bridging to PPV23 3,4

ACIP=Advisory Committee on Immunization Practices; CAPiTA=Community-Acquired Pneumonia Immunization Trial in Adults; EMA=European Medicines Agency.
1. Prevenar 13 [summary of product characteristics]. Kent, United Kingdom: Pfizer Limited; 2014. 2. CDC. https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6337a4.htm. Accessed
June 30, 2017. 3. European Medicines Agency. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Procedural_steps_taken_and_scientific_information_after_authorisation/human/001104/WC500096015.pdf. Accessed Oct 31, 2019. 4. European Medicines Agency.
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_-_Variation/human/001104/WC500119784.pdf. Accessed Oct 31, 2019
20
CAPiTA Study:
Impact of Pneumococcal Pneumonia
Vaccine among Aging Population
A Community-Acquired Pneumonia Immunization Trial in Adults
(CAPiTA) to Further Describe the Efficacy and Clinical Benefit of PCV13
Study Design (Netherlands) Demonstrate the Efficacy of PCV13
84,496 Vaccine-Naïve Subjects in the Prevention of a First Episode
Aged >65 Years of

PCV13 •1○ VT CAP

RANDOMIZED – Invasive or
1:1 non-invasive
Placebo
•2○ VT non-bacteremic (non-
invasive) CAP

•2○ VT invasive pneumococcal

disease

• Safety objectives evaluating the safety profile of PCV13, including:

– Incidence of serious adverse events after vaccination within 28 days (among all participants) and within 6 months (among
participants in the safety subgroup)
– Frequency of solicited adverse events (local reactions and systemic events) within 7 days after vaccination
CAP=community-acquired pneumonia; VT=vaccine-type.
Bonten MJ, et al. N Engl J Med. 2015;372(12):1114-1125. 24
24
CAPiTA Study Enrollment Criteria

Inclusion criteria Exclusion criteria

• Male or female • Any previous pneumococcal vaccination
≥65 years of age • Use of investigational vaccine or medication in
• Registered with the GP last 30 days
referring subjects to study • Resident in nursing home/long-term care facility
• Able to fulfill study • Immune deficiency or suppression*
requirements • History of severe adverse reaction to a vaccine or
component
• Contraindication to influenza vaccination if influenza
vaccine is to be administered at same time
• Contraindication to PCV13

*Immunocompetent subjects with comorbid conditions were included (eg, chronic heart disease, diabetes mellitus, chronic pulmonary disease). Immune-
deficient or immune-suppressed individuals were not eligible for study entry. However, if study subjects became immune-deficient or immune-suppressed after
receipt of study vaccine (ie, during the case-accrual period) and experienced an episode of CAP or IPD, these events were included in the modified intent-to-treat
analyses.
CAPiTA=Community-Acquired Pneumonia Immunization Trial in Adults; GP=general practitioner.
Bonten MJ, et al. N Engl J Med. 2015;372(12):1114-1125. 27
Study Subjects—Baseline Characteristics
(Safety Population)
PCV131 Placebo1
n=42,237 n=42,255

72.8 (5.7) 72.8 (5.6)

Age, years (mean, SD, range)
(61.9–101.1)* (63.3–99.5)*
Male (%, n) 55.5 (23,447) 56.3 (23,801)
Female (%, n) 44.5 (18,790) 43.7 (18,454)
Patient-reported comorbidities (%)
Any 42.3 42.4
Asthma† 4.8 5.0
Diabetes mellitus: insulin use† 3.3 3.2
Diabetes mellitus: no insulin use † 9.1 9.4
Heart disease† 25.3 25.4
Liver disease† 0.5 0.5
Lung disease† 10.1 10.3

Splenectomy† <0.1 <0.1

Smoking 12.3 12.2

*Subjects <65 years of age were excluded from efficacy analyses.2

†
Not mutually exclusive.2
SD=standard deviation.
1. Bonten MJ, et al. N Engl J Med. 2015;372(12):1114-1125. 2. Data on file. Pfizer Inc, New York, NY. 29
CAPiTA Efficacy Results:
Primary and Secondary Objectives

Reduction in Pneumococcal Disease With PCV13

0
10
20 46% 45% 75%
P<0.001 P=0.007 P<0.001
30
Vaccine efficacy (%)

40
50
Primary end point: Secondary end point:
60 Prevention of a first episode of Prevention of a first episode of
70 VT-CAP VT non-bacteremic/non-invasive
80
CAP
Secondary end point:
80 Prevention of a first episode of
100 VT IPD

Statistically significant reductions in first episode of

VT-CAP with PCV13

• Overall, adverse event profile was consistent with that of prior studies in adults

CAP=community-acquired pneumonia; CAPiTA=Community-Acquired Pneumonia Immunization Trial in Adults; VT=vaccine type.

Bonten MJ, et al. N Engl J Med. 2015;372(12):1114-1125. 32
32
CAPiTA: Safety of PCV13 Reported Within 7 Days Post-
Vaccination, Safety Subgroup
PCV13 group (n=881– Placebo group
914) (n=859–878)
Redness 4.9% 1.2%
Local Swelling 6.8% 1.2%
adverse
events Pain 36.1% 6.1%
Limitation of arm movement 14.1% 3.2%
Fever (≥38°C) 2.9% 1.3%
Fatigue 18.8% 14.8%
Headache 15.9% 14.8%
Chills 9.4% 8.4%
Rash 3.3% 0.8%
Systemic Vomiting 0.3% 0.9%
adverse
events Decreased appetite 5.3% 3.7%
Diarrhea 5.7% 8.7%
New generalized muscle pain 18.4% 8.4%
Aggravated generalized muscle pain 9.1% 4.4%
New generalized joint pain 7.4% 5.4%
Aggravated generalized joint pain 5.2% 4.2%

Bonten MJ, et al. N Engl J Med. 2015;372(12):1114-1125. 33

In a Post-hoc Analysis, PCV13 Was Protective Throughout the Duration of the
CAPiTA Study, With No Waning of Efficacy Observed

Cumulative Episodes of VT-CAP

Cumulative Number of Episodes

PCV13
Placebo

Years Since Vaccination

Years since vaccination plots from post hoc analysis
CAP=community-acquired pneumonia; CAPiTA=Community Acquired Pneumonia Immunization Trial in Adults; VT=vaccine-type.
Patterson S, et al. Trials Vaccinol. 2016;5:92-96. 34
 In a Post-hoc Analysis, PCV13 Was Protective Over the Duration of the CAPiTA
Study, With No Waning of Efficacy Observed

Cumulative Episodes of NB/NI VT-CAP Cumulative Episodes of VT-IPD

Cumulative No. of Episodes

Cumulative No. of Episodes

Years Since Vaccination Years Since Vaccination

Years since vaccination plots from post hoc analysis

CAP=community-acquired pneumonia; CAPiTA=Community Acquired Pneumonia Immunization Trial in Adults; NB=non-bacteremic; NI=non-
invasive; VT=vaccine type.
Patterson S, et al. Trials Vaccinol. 2016;5:92-96. 35
Post Hoc Analysis: PCV13 Efficacy by Stratification of
Participants in the CAPiTA Trial (Adults ≥65 Years of Age)
Based on Their At-Risk* Status
Study (CAPiTA, Netherlands): parallel group, randomized, placebo-controlled, double-blind trial in 84,496 subjects
≥65 years of age1,2,†

84,064† immunocompetent adults ≥65 years of age with no prior history

of pneumococcal vaccination were included in the post hoc analysis

At risk* Without known risk

(n=41,385) (n=42,679)

PCV13 Placebo PCV13 Placebo

(n=20,680) (n=20,705) (n=21,339) (n=21,340)

PCV13 VE against vaccine-type CAP and Sp CAP was evaluated in both

participants with at-risk conditions and those without known risk

*At-risk classification was based on self-identification of one of the following conditions: heart disease, lung disease, asthma, diabetes with or
without insulin use, liver disease, smoking, and history of spleen removal.
†
In the post hoc analysis 432 of 84,496 participants were excluded.
CAPiTA=Community-Acquired Pneumonia Immunization Trial in Adults; CAP=community-acquired pneumonia; Sp=Streptococcus pneumoniae;
VE=vaccine efficacy.
Suaya JA, et al. Vaccine. 2018;36(11):1477-1483. 36
Post Hoc Analysis: Efficacy in At-Risk Subjects in the
CAPiTA Trial
Risk Reduction in Prevention of First Episode of VT-CAP
PCV13 Placebo VE (%) (95.2 CI)
Entire study population (n) 42,019 42,045
# cases 49 90 45.6 (21.9–62.5)
At-risk group (n) 20,680 20,705
# cases 43 72 40.3 (11.4–60.2)
Without known risk (n) 21,339 21,340
# cases 6 18 66.7 (11.8–89.3)

• At-risk classification was based on at least 1 of 7 self-identified medical conditions

reported prior to vaccination: heart or lung disease, asthma, diabetes with or
without insulin use, liver disease, splenectomy, and smoking
• Subjects were excluded from the analysis if they self-identified with a history of
splenectomy or had missing answers for the medical history questionnaires
• Self-identified medical conditions were not verified by medical record review
CAP=community-acquired pneumonia; CAPiTA=Community-Acquired Pneumonia Immunization Trial in Adults; VE=vaccine efficacy; VT-
CAP=vaccine-type community-acquired pneumonia.
Suaya JA, et al. Vaccine. 2018;36(11):1477-1483. 37
 Efficacy vs Effectiveness

Vaccine effectiveness – ability of vaccine to prevent

outcomes of interest in the “real world
 Primary care settings.
 Less stringent eligibility.
 Assessment of relevant health outcomes.
 Clinically relevant treatment selection and follow-up
duration.
 Assessment of relevant adverse events.
 Adequate sample size to detect clinically relevant
differences.
 Intention to treat analysis.

Agency for healthcare Research and Policy, US Dept HHS, 2006

 Assessment of 1-Year Survival Following Pneumonia Hospitalization,
Based on Vaccination Status, in Friuli Venezia Giulia Region of Italy
Adults aged ≥65 years hospitalized for CAP, with no CAP-related admissions
in the previous year, January 2012–December 2013 (N=4766) were included in the study

Excluded: PCV13
vaccination after
hospitalization, n=736
N=4030

PPV23* PCV13 Not vaccinated†

Pneumococca
N=583 N=206 N=3241
l
14.5% 5.1% 80.4%
vaccination
status

Influenza
526/583 204/206 2251/3241
vaccination
(90.2%) (99.0%) (69.5%)
status

*Vaccinated within 5 years before hospitalization.

†
Never vaccinated and those vaccinated with PPV23 >5 years prior to hospitalization.
CAP=community-acquired pneumonia.
Baldo V, et al. PLoS One. 2016;11(11):e0166637. 62
Assessment of 1-Year Survival Following Pneumonia Hospitalization,
Based on Vaccination Status, in Friuli Venezia Giulia Region of Italy

1.0

0.9

Cumulative survival
0.8

0.7
The 1-year survival rate after
hospitalization for pneumonia PCV13
0.6 was significantly higher by ~7% PPV23
for PCV13-immunized patients Not vaccinated
than for the other 2 groups
0.5
-1 0 1 2 3 4 5 6 7 8 9 10 11 12
Months
• PCV13 was determined to be an independent protective factor against
mortality due to pneumonia (adjusted OR: 0.599; 95% CI: 0.390, 0.921)
• The limitations of this study include:
o Small number of patients in the PCV13 vaccinated group
o Only 1-year follow-up of mortality following pneumonia hospitalization
CI=confidence interval; OR=odds ratio. 63
Baldo V, et al. PLoS One. 2016;11(11):e0166637.
 Pendahuluan dan Tujuan

Infeksi saluran nafas akibat virus  rentan

untuk terjadinya ko-infeksi bakteri 
berhubungan dengan morbiditas dan
motalitas yang tinggi, terutama selama
pandemi

Meta-analisis memperkirakan 3,5% pasien dengan

COVID-19 memiliki koinfeksi virus dan 14,3%
koinfeksi bakteri

Mencari pengaruh pandemic COVID-19 dan konsekuensinya (lockdown) terhadap invasive

pneumococcal disease untuk memperkirakan resiko SARS-CoV-2 dan koinfeksi IPD, serta
menilai potensi vaksin pneumonia dalam menurunkan morbiditas dan mortalitas IPD selama
pandemic COVID-19
 Peningkatan resiko
kematian sebesar
2,55 kali lebih
tinggi pada pasien
COVID-19 dengan
koinfeksi
pneumonia yang
serotipnya sesuai
dengan serotip
pada PCV13

Menandakan pentingnya peranan dari vaksinasi PCV13 

Harapan dapat menurunkan mortalitas
• Koinfeksi SARS-CoV-2 dengan infeksi bakteri dan pathogenesisnya masih belum diteliti
secara luas  satu studi, koinfeksi SARS-CoV-2 dan IPD berhubungan dengan resiko
kematian 7 kali lipat lebih tinggi dibandingkan pada IPD tanpa SARS-CoV-2.
• infeksi SARS-CoV-2 28 hari setelah terkena IPD berhubungan dengan peningkatan
mortalitas sebesar 4 kali lipat

• PCV13 mencegah pneumonia yang berkaitan dengan serotip yang terkandung pada
vaksin ini

• RCT pada anak-anak dan dewasa menemukan bahwa PCV melindungi dari terjadinya
pneumonia yang terkait virus respiratori, termasuk SARS-CoV2, sebesar 23-49%

Lewnard JA, Et all. 2021.

Resiko yang lebih rendah dari masing-masing outcome (A, B, dan C) untuk yang
mendapat PCV13
 PNEUMOCOCCAL VACCINE:
GUIDELINES AND RECOMMENDATIONS
Indication of PCV13
Children 6 Weeks through Adult 50 Years of Age
5 Years of Age and Older

Is indicated for active immunization for

Active immunization for the prevention of
invasive disease, pneumonia, and acute
otitis media caused by Streptococcus
pneumonia in infants and children from 6
weeks to 5 years
of age
prevention of pneumococcal disease
(including pneumonia and invasive
disease) in adults 50 years of age and
older caused by Streptococcus
pneumoniae 1,3,4,5,6A,6B, 7F, 9V, 14,
18C,19A,19F and 23F

Latest BPOM approved Prevenar 13 local product document. 2019

 Pneumococcal Vaccination for Hajj
According to recommendations of Saudi Arabia government,
meningococcal vaccination is mandatory and influenza and
pneumococcal vaccines are optional
Country Meningococcal Pneumococcal Influenza
Indonesia Mandatory Optional/ recommended for Frequently used (self-
>65 years pay)
Malaysia Mandatory (free) Optional (self-pay) Optional (self-pay)
Pakistan Mandatory Not recommended (PPV23 -
and PCV13 are available)
Philippines Mandatory Recommended for high-risk -
individuals
Singapore Mandatory Recommended for >60 years Required
and those with chronic risk
illnesses
Thailand Mandatory Recommended as part of Mandatory
routine adult immunization
schedules

Disclaimer: In Indonesia, PCV13 is approved for adults 50 years of age and older
Rashid H et al. Travel Med Infect Dis 2013; 11: 288-294
Satgas Imunisasi Dewasa PAPDI. Pedoman Imunisasi Pada Orang Dewasa 2017. Interna Publishing Pusat Penerbitan Ilmu Penyakit Dalam. 2017. Pg.461. 5
 TAKE HOME MESSAGES

• Pneumococcal disease is responsible for significant morbidity and

mortality, much of which is preventable by use of the available vaccines
• Conjugate vaccine evokes T cell-dependent immune response
• PCV13 vaccine shows efficacy of pneumococcal pneumonia (invasive and
non-invasive) in adults ≥65 years old in CAPiTA study
• Adult age recommended 1 dose of PCV13
• However, despite the accessibility of effective vaccines, immunization of
eligible adults is underused.
• Clinicians must take a proactive role in recommending the vaccine to
eligible adults and elderly.
THANK YOU

Email: ptsuka_aryana@unud.ac.id
Scopus ID: 37062993600
Orchid ID : 1-8582-2254