46. Prevenar 13® Produces Functional Antibody Titers
PCV 7 VS PCV 13
Prevenar 13® Produced OPA Titers (≥1:8) in 90% to 100%
of Infants for All 13 Serotypes Following the Infant Series
Subjects,%
†
†≥1:2048 for serotype 7F.
Adapted from Kieninger DM, et al. Vaccine. 2010;28:4192-4203.
0
20
40
60
80
100
4 6B9V1418C19F23F1 3 5 6A7F19A
Prev enar 13 % OPA ≥1:8
†
48
47. Serotype Coverage of PCV10 vs PCV13
台灣血清型涵蓋率 PCV10:70% vs PCV13:90%
0 10 20 30 40 50 60 70 80 90 100
Japan₉
Korea₈
China₇
HK₆
Taiwan₅
Thailand₄
Malaysia₃
Singapore₂
Bangladesh₁
PCV10 Prevenar 13
6. Ho PL, et al. Vaccine 22 (2004) 3334–3339
7. Yao K-H, et al. Chin J Evid Based Pediatr. 2008;l 3:426-432.
8. Choi EH, et al. Emerg Infect Dis. 2008;14:275-281.
9. Chiba N, et al. Epidemiol Infect. 2010;138:61-68.
1. Arifeen SE, et al. Clin Infect Dis. 2009;48:S103-S113.
2. Chong CY, et al. Vaccine. 2008;26:3247-3431.
3. Rohani MY, et al. Epidemiol Infect. 1999;122:77-82.
4. Phongsamart W, et al. Vaccine. 2007;25:1275-1280.
5. Hsieh YC, et al. Vaccine. 2009;27:5513-5518. 49
48. Vaccine Coverage for IPD
521 Patients, 2007, Taiwan
%
<2
(34)
2-4
(89)
5-9
(26)
10-64
(173)
65
(199)
All
(521)
Year
PCV-7 PCV-10
PCV-13 PPV-23
Hsieh YC et al. Vaccine 2009;27:5513-8.
50
54. IPD in Children and Older Adults
PCV7 2000年上市且美國小於5歲全面接種
PPV23 1983年上市;1998年美國大於65歲全面接種
Children < 5 years Adults ≥ 65
years
Hicks L, et al. J Infect Dis. 2007;196:1346-1354.
PPV23 in use
55. Pilishvili T, et al. J Infect Dis. 2010;201:32-41.
Cases/100,000population
0
20
40
60
100
80
120
1998 1999 20012000 2002 2003 2004 2005 2006 2007
Year
PCV7 introduced
Age Group 2007 vs baseline
(years) (% reduction)
< 5
5–17
18–49
50–64
≥ 65
76
43
40
18
37
The Changes of IPD after PCV7 in US
56. Direct Effect of PCV7 :
IPD Among Children < 5 Years, 1998/99–2007
Cases/100,000population
0
10
20
30
40
50
60
70
80
90
1998 1999 20012000 2002 2003 2004 2005 2006 2007
Year
PCV7 introduced
Serotype group
PCV7 type
Non-PCV7 type
19A
Pilishvili T, et al. J Infect Dis. 2010;201:32-41.
*100% reduction in PCV7 serotypes, 2007 vs baseline
*
57. IPD Among Adults ≥ 65 Years, 1998/99–2007
Pilishvili T, et al. J Infect Dis. 2010;201:32-41.
Cases/100,000population
0
5
10
15
20
25
30
35
40
1998 1999 20012000 2002 2003 2004 2005 2006 2007
Year
PCV7 introduced
Serotype group
PCV7 type
Non-PCV7 type
19A
*92% reduction in PCV7 serotypes,
2007 vs baseline
*
PPV23 in use
58. PPV23 VS PCV7 (or13)
although 23 > 7 (or 13)
But
Effect ??
PPV23 23-valent Polysaccharide Vaccine
Serotypes 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B,
17F, 18C, 19A, 19F, 20, 22F, 23F, 33F1
Antigen Polysaccharide1
Licensed in 1983(≧2y/o child and adult)
1.Fedson DS, Musher DM. In: Plotkin SA and Orenstein WA, eds. Vaccines. 4th ed. Philadelphia: WB Saunders; 2004:529-588.
59. PCV7 introduced*
Has PPV23 induced a sizeable impact on IPD in the US?
Pilishvili T et al. J Infect Dis. 2010;201:32-41.
1998 200720062005200420032002200120001999
Year
0
120
100
80
60
40
20
Cases/100,000population
PV7 introduced*
Age group
<5
5-17
18-49
50-64
≥65
PPV23 in use
60. Pilishvili T et al. J Infect Dis. 2010;201:32-41.
1998 200720062005200420032002200120001999
Year
0
120
100
80
60
40
20
Cases/100,000population
PCV7 introduced*
Age group
<5
5-17
18-49
50-64
≥65
PPV23 in use
Has PPV23 induced a sizeable impact on IPD in the US?
61. PCV7 introduced
0
5
10
15
20
25
1998 1999 2000 2001 2002 2003 2004 2005 2006
+50%
+64%
+40%
18-49
65+
50-64
Casesper100,000
IPD Serotypes in PPV23 but not in PCV7
(PPV16 Serotypes), adults, US, 1998-2006
PPV23 in use
How about PPV-23 effect??
PPV23 in use
62. Meta-analyses of the Conducted PPV23 Trials Do Not
Indicate a Protective Benefit against CAP
Huss A et al. CMAJ. 2009;180:48-58.
“[This study] supports the notion that further high-quality
trials of the polysaccharide vaccine would fail to show any
protective effect against pneumonia.”
Decreased risk of
clinical outcome
Increased risk of
clinical outcome
0.25 0.5 1 2
Relative risk (95% CI)
Presumptive pneumococcal pneumonia
Double-blind
Adequate concealment of allocation
Pneumonia from all causes
Double-blind
Adequate concealment of allocation
Death from all causes
Double-blind
Adequate concealment of allocation
63. Mortality of Pneumococcal Pneumonia Has
Not Changed despite PPV23 uptake
*90-day mortality in ICU and ward patients.
1. Austrian R, Gold J. Ann Intern Med. 1964;60:759-776.
2. Fine MJ et al. JAMA. 1996;274:134-141.
3. Feikin DR et al. Am J Pub Health. 2000;90:223-229.
4. Restrepo MI et al. Chest. 2008;133:610-617.
13%
Mortality1
(N = 1130)
12.3%
Mortality2
(N = 4432)
12%
Mortality3
(N = 5837)
12.1%
Mortality4
(N = 730)*
Mixed Patient Populations in Different Settings and Countries
1952–1962 1966–1995 1995–1997 1999–2001
PPV23 1983年上市
64. 1. Torling et al. Vaccine, 2003
PPV Reduces the Response to Subsequent Doses of PPV
A: before vaccination; B: 4 weeks after vaccination; C: 1 year after vaccination;
D: 4-7 years after vaccination and revaccination; E: 4 weeks after revaccination
D < A→打完4-7年後抗體比沒打更低;E < B→再補打也回不去(hyporesponsiveness)
Type 1
GMCmicrog/ml
0
5
10
15
20
25
30
A B C D E
Type 4
GMCmicrog/ml
0
5
10
15
20
25
30
A B C D E
Type 7F
GMCmicrog/ml
0
5
10
15
20
25
30
A B C D E
Type 14
GMCmicrog/ml
0
5
10
15
20
25
30
A B C D E
Type 18C
GMCmicrog/ml
0
5
10
15
20
25
30
A B C D E
Type 19F
GMCmicrog/ml
65. Antibody response to PPV23 (GMC)
打完4-7年後抗體比沒打更低 ; 再補打也回不去
6.97
19.06
13.11
4.06
7.47
0
5
10
15
20
25
Before vacc. Postvacc.4w 1 Year 4–7 Years,revacc.Postrevacc.4w
Source: J. Törling et al. / Vaccine 22 (2003) 96–103.
GMCmicrog/ml
85. CAPiTA study
(Community-Acquired Pneumonia immunization
Trial in Adult)
是目前 唯一針對
成人 社區型肺炎預防所進行的大規模臨床試驗
(case number: 84496 and all age≧65y/o)
reported on the 9th ISPPD,
March 9-13,2014
92. 研究成果(1)
PCV13可有效降低65歲以上成年肺炎感染
有效降低45.56% (P=0.0006} 首次發生的疫苗型別
相關的全部肺炎鏈球菌社區型肺炎個案(first
episode of VT-CAP)
有效降低45.00% (P=0.0067} 首次發生的疫苗型別
相關的非侵襲性肺炎鏈球菌社區型肺炎個案(first
episode of NB/NI VT-CAP)
有效降低75.00% (P=0.0005} 首次發生的疫苗
型別相關的侵襲性肺炎鏈球菌疾病個案(first
episode of VT-IPD)
93. Primary and Secondary
Objective, Per Protocol
Population
VT = vaccine-type
CAP = community-acquired pneumonia
NB/NI = nonbacterimic/noninvasive
IPD = invasive pneumonia disease
* 95% CI
M. Bolton presented in 9th ISPPD, March 9-13, Hyderabad, India
94. Cumulative Case Counts, Per Protocol Population Mean
Duration of Follow Up = 3.97 years
M. Bolton presented in 9th ISPPD, March 9-13, Hyderabad, India
45.56%
45%
75%
100. 侵襲性肺炎的高危險群
Risk Factors for IPD
• Extremes of age
– < 2 (or 5) years; ≥ 65 years
• Exposure to cigarette
smoke, multiple children in
household
• Comorbidities
– Alcohol abuse
– Congestive heart failure
– Chronic lung disease
– Cigarette smoking
– Asthma
– Recent influenza infection
– Diabetes mellitus
– Neurological disorders
• Certain ethnic groups
– American Indians, Alaska
Natives, African Americans in
the US
• Immune deficiencies
– B cell defects
– Deficiencies of early
components of classical
pathway of complement
– Asplenia
– Sickle cell disease
– Hematological or solid
malignancies
– Organ transplant recipients
– HIV infection
– Immunosuppressive drugs
Lynch J, Zhanel G. Sem Respir Crit Care Med. 2009;30(2):189-209.
102
103. PCV13/PPV23 Sequential Administration
施打順序建議: 先PCV13→後PPV23
Blood sample obtained.
A
B
0
PCV13 PPV23
12
months
0
PPV23 PCV13
12
months
Favors PCV13 + PPV23Favors PPV23 + PCV13
1
3
4
5
6B
7F
9V
14
18C
19A
19F
23F
One Month After Last Dose
PCV13/PPV23 vs PPV23/PCV13
Study details: Phase 3, randomized, double-blind study in pneumococcal vaccine-naïve 60–64 year-old adults.
Subjects received either PCV13 at Year 0 and PCV13 at Year 1; PCV13 at Year 0 and PPV23 at Year 1; or PPV23 at Year 0
and PCV13 at Year 1. OPA titers were measured before and 1 month after each vaccination.
GMT=geometric mean titre; OPA=opsonophagocytic assay; PPV23=23-valent pneumococcal polysaccharide vaccine.
Adapted from Greenberg RN, et al. Vaccine. 2014;32:2364-2374. 10
5
112. DISCLAIMER
– This event is sponsored by GSK, in the interest of advancing the scientific
knowledge of healthcare professionals.
– GSK does not approve of or recommend the use of medicines in any way
other than that stated in the approved package inserts.
– For full prescribing information, refer to the package inserts approved by TFDA.
115. A型肝炎(Hepatitis A)
1. World Health Organization, 2016. Hepatitis A Factsheet. http://www.who.int/mediacentre/factsheets/fs328/en/ (accessed July 2017); 2. World Health Organization, 2015.
Hepatitis A. http://www.who.int/immunization/diseases/hepatitisA/en/ (accessed July 2017); 3. Armstrong GL. Pediatrics 2002;109:839−845; 4. Van Damme P. Travel Med Infect
Dis 2007;5:79−84; 5. World Health Organization. The immunological basis for immunization series: module 18: Hepatitis A. World Health Organization press; 2011
A型肝炎可引起
輕度至重度疾病1
每年全球約有140萬例
A型肝炎病例2
> 80%的急性A型肝炎
病例是未通報的3–5
發病率與
當地衛生條件和
衛生習慣密切相關1
5
116. 致病原(HAV)
1. Cuthbert JA. Clin Microbiol Rev 2001;14:38−58; 2. Brundage SC. Am Fam Physician 2006;73:2162−2168; 3. Centers for Disease Control and Prevention. Chapter 8:
Hepatitis A. In: The Pink Book: Epidemiology and Prevention of Vaccine-Preventable Diseases. Atkinson W et al (Eds). 12th edn. Washington, DC: Public Health Foundation,
2012. pp. 101–114; 4. Hunt R, 2016. Virology: Chapter 18: Hepatitis viruses. http://www.microbiologybook.org/virol/hepatitis-virus.htm (accessed July 2017)
Picornavirus structure with icosahedral capsid symmetry
外殼
單股RNA
28
nm
病毒蛋白(VPg)
病毒屬微小核糖核酸病毒科(Picornavirus)
肝病毒屬(Hepatovirus)。1
• 無套膜,二十面體的病毒粒子
(28 nm diameter)4
• 內含單股 RNA1
• HAV 病毒株具抗原相似性,
其中四種基因型會感染人類1
Courtesy of Dr
Richard Hunt,
University of
South Carolina
HAV, hepatitis A virus
耐受性極高的病毒:1–3
• 在海水,淡水和土壤中生存數個月。
• 耐冷凍,洗滌劑和酸。
• 需要≥85°C的溫度超過一分鐘以上才會失去活性。
• 它易受消毒劑的影響,例如福爾馬林(formalin)和氯2,3
6
119. 攝入受污染的食物或水
HAV在環境中持續存在,可以抵抗食品生產
過程2
因食物引起的流行主要發生在:
• 貝類攝取過多4,5
• 生食或不完全烹煮的蔬果5
因水而發生的流行較少
• 通常與污水處理不當有關2
• 患者在感染期間自行處理煮熟或未煮熟
食物是A型肝炎爆發的最常見來源5
人與人接觸傳染
大多數感染是由與傳染病人的密切身體接觸
引起的
• 家庭成員(照顧者)和性伴侶1
• 與不洗手的人握手2
孩童扮演重要的角色3
• 他們的感染通常是無症狀的
• 孩童之間的互動通常較不注意衛生習慣
HAV 傳染模式(I)
1. Centers for Disease Control and Prevention, 2016. Hepatitis A FAQs for Health Professionals. http://www.cdc.gov/hepatitis/hav/havfaq.htm (accessed July 2017); 2. World Health Organization, 2016.
Hepatitis A Factsheet. http://www.who.int/mediacentre/factsheets/fs328/en/ (accessed July 2017); 3. Centers for Disease Control and Prevention. Chapter 8: Hepatitis A. In: The Pink Book: Epidemiology
and Prevention of Vaccine-Preventable Diseases. Atkinson W et al (Eds). 12th edn. Washington, DC: Public Health Foundation, 2012. pp. 101–114; 4. World Health Organization, 2011. The immunological
basis for immunization series: module 18: Hepatitis A; 5. Fiore AE. Clin Infect Dis 2004;38:705−715
傳播的主要方法是通過糞 - 口途徑1
9
HAV, hepatitis A virus
120. 在大約50%的病例中,HAV感染的來源仍然未被識別3
HAV傳染模式(II)
1. Hunt R. Chapter 19: Hepatitis: Part 1-Disease transmitted enterically hepatitis A and E. In: Virology. http://www.microbiologybook.org/virol/hepatitis-disease.htm (accessed July
2017); 2. Centers for Disease Control and Prevention. Chapter 8: Hepatitis A. In: The Pink Book: Epidemiology and Prevention of Vaccine-Preventable Diseases. Atkinson W et al
(Eds). 12th edn. Washington, DC: Public Health Foundation, 2012. pp. 101–114; 3. Fiore AE. Clin Infect Dis 2004;38:705−715
性行為(特別是同性之間)1
靜脈注射藥物1
血液傳播(如輸血)
較少發生,因為1,2
• 血液中HAV顆粒的濃度低於糞便
中的濃度
• HAV僅在血中存在相對短的時間
有時候,A肝也會經由以下傳染:
HAV, hepatitis A virus
10
121. 風險較高的職業3
A型肝炎危險族群
凝血不完全的病患2
前往疫區旅行的人2
長期肝病1
同性戀1,2
藥物(毒品)注射2
生活衛生不佳的環境,
中低收入戶1,2
有A型肝炎的性伴侶1
1. World Health Organization, 2016. Hepatitis A Factsheet. http://www.who.int/mediacentre/factsheets/fs328/en/ (accessed July 2017); 2. World Health Organization, 2011.
The immunological basis for immunization series: module 18: Hepatitis A. http://apps.who.int/iris/bitstream/10665/44570/1/9789241501422_eng.pdf (accessed July 2017);
3. Grzeszczuk A et al. Med Sci Monit 2003;9:PH11-14
HIV的患者2
♂♂
11
Household contacts of
infected individuals1,2
托育中心的幼童2
食物處理者2
123. A型肝炎全球疾病負擔1
1. Murphy T et al. Hepatitis A vaccines. Vaccines, 6th edition. Edited by Plotkin SA, Orenstein W, Offit P, 2013:183–204; 2. Steffen R et al. J Travel Med 2015;22:1–12
從2000年到2010年,每8000名旅行者每月的A型肝炎發生率為12
Adapted from Vaccines (Sixth Edition), Murphy T et al, Hepatitis A vaccines,
pages 183–204, Copyright 2013, with permission from Elsevier
High
Transitional
Low/very low
Intermediate
Anti-HAV prevalence
HAV, hepatitis A virus
13
124. 通常,成年人患有更多症狀性疾病,疾病嚴重程度隨年齡增長而增加7
疾病負擔:
HAV感染的臨床結果與年齡相關1–3
1. Centers for Disease Control and Prevention. Chapter 8: Hepatitis A. In: The Pink Book: Epidemiology and Prevention of Vaccine-Preventable Diseases. Atkinson W et al (Eds). 12th edn. Washington, DC:
Public Health Foundation, 2012. pp. 101–114; 2. World Health Organization. The immunological basis for immunization series: module 18: Hepatitis A. WHO press; 2011; 3. Hollinger FB and Ticehurst JR.
Hepatitis A Virus. In Fields Virology. 3rd edition. Fields BN, Knipe DM, Howley PM et al (Eds). Philadelphia: Lippincott – Raven Publishers 1996:735–782; 4. Centers for Disease Control and Prevention,
2016. The ABCs of hepatitis fact sheet. https://www.cdc.gov/hepatitis/resources/professionals/pdfs/abctable.pdf (accessed July 2017); 5. Brundage SC. Am Fam Physician 2006;73:2162−2168; 6. World
Health Organization. Wkly Epidemiol Rec 2012;87:261−276; 7. World Health Organization, 2016. Hepatitis A Factsheet. http://www.who.int/mediacentre/factsheets/fs328/en/ (accessed July 2017)
Aged
<6 years
Aged
6–14 years
Aged
>14 years
<10% 40–50% 70–80%
發病率
0
20
40
60
80
100
Asymptomatic
infection
Symptomatic
infection
Complete
recovery
Children <6 years Adults
Percentage
猛爆性肝炎很少發生 (<1% overall),下列患者的發病率較高:1,2,5,6
按年齡組劃分的黃疸機率4
Underlying chronic liver disease ImmunosuppressionAdvanced age
HAV, hepatitis A virus
14
125. 猛爆性肝炎
Fulminant hepatitis
• HAV最嚴重的併發症5
• 導致80%~85%患者死亡5,6
• 死亡率與年齡增長高度相關3
• >70%的死亡發生在大於49歲的
患者中3
疾病負擔
絕大多數(> 99%)A型肝炎患者會完全康復1,2
1. World Health Organization. The immunological basis for immunization series: module 18: Hepatitis A. WHO press; 2011; 2. World Health Organization. Wkly Epidemiol Rec 2012;87:261−276;
3. Hollinger FB and Ticehurst JR. Hepatitis A Virus. In Fields Virology. 3rd edition. Fields BN, Knipe DM, Howley PM et al (Eds). Philadelphia: Lippincott – Raven Publishers 1996:735–782; 4. World Health
Organization, 2012. International travel and health. Chapter 6: Vaccine-preventable disease and vaccines. http://who.int/ith/ITH_EN_2012_WEB_1.2.pdf (accessed July 2017); 5. Centers for Disease Control
and Prevention. Chapter 8: Hepatitis A. In: The Pink Book: Epidemiology and Prevention of Vaccine-Preventable Diseases. Atkinson W et al (Eds). 12th edn. Washington, DC: Public Health Foundation, 2012.
pp. 101–114; 6. Ichai P & Samuel D. Liver Transpl 2008;14:S67–S79
Mortality
0.1 0.3
2.1
4.0
0
1
2
3
4
5
≤14 years 15-39 years 40 years ≥60 years
HAV相關死亡風險隨年齡增長而增加3,4
死亡率(%)
老年人群中的A型肝炎相關死亡人數增加3,4
猛爆性肝炎與高死亡率有關5
3
4
3
3
HAV, hepatitis A virus
15
135. 按時程接種兩劑疫苗能有效預防A型肝炎感染5
HAV:暴露前的預防措施
• 第一支核准的A型肝炎疫苗(1992)1
• Sterile suspension containing formaldehyde-inactivated
HAV (HM175 HAV strain) adsorbed onto aluminium
hydroxide2–4
• 兩種劑型2–4
• HAVRIX 成人
• HAVRIX 孩童
1. Andre F et al. Expert Rev Vaccines 2002;1:9–23; 2. GSK, 2016. HAVRIX Monodose SmPC. http://www.medicines.org.uk/emc/medicine/2041/SPC/Havrix+Monodose+Vaccine/
(accessed July 2017); 3. GSK, 2016. HAVRIX Junior EU SmPC. http://www.medicines.org.uk/emc/medicine/2040 (accessed July 2017); 4. GSK, 2016. HAVRIX US PI.
https://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM224555.pdf (accessed July 2017); 5. Centers for Disease Control and Prevention, 2016.
Hepatitis A FAQs for Health Professionals. http://www.cdc.gov/hepatitis/hav/havfaq.htm (accessed July 2017)
Formulation HAV
(antigen)
Aluminum hydroxide
(adjuvant) (mg)
Dose volume
(mL)
Dosing schedule
(months)
Age indication
(years)
HAVRIX
成人2 1440 EL.U 0.5 1.0 0, 6/12 ≥19
HAVRIX
孩童3 720 EL.U 0.25 0.5 0, 6/12 1−18
主動免疫
EL.U, ELISA units; HAV, hepatitis A virus
25
136. HAVRIX具有可接受的安全性
HAVRIX安全性
*For more information on the safety profile of HAVRIX, please refer to SPCs of HAVRIX 1440 and 720
1. GSK, 2016. HAVRIX Monodose SmPC. http://www.medicines.org.uk/emc/medicine/2041/SPC/Havrix+Monodose+Vaccine/ (accessed July 2017); 2. GSK, 2016. HAVRIX Junior Monodose SmPC.
http://www.medicines.org.uk/emc/medicine/2040 (accessed July 2017); 3. Schmidtke P et al. Vaccine 2005;23:6127–6132; 4. Briem H et al. J Med Virol 1994;44:443−445; 5. Van Damme P et al. J Travel
Med 1996;3:83−90; 6. Findor JA et al. J Travel Med 1996;3:156−159; 7. Poovorawan Y et al. Vaccine 1996;14:1092−1094; 8. Poovorawan Y et al. Asian Pac J Allergy Immunol 1998;16:111−117
HAVRIX的安全性是累積
> 5300名受試者的數據
*1,2
未出現嚴重不良事件3–8
最常通報的不良事件:1,2
• 注射部位的疼痛/紅腫(HAVRIX
720: 18.2% doses; HAVRIX 1440:
>50% doses)
• 頭痛
• 過敏 (HAVRIX 720 only)
• 疲勞 (HAVRIX 1440 only)
26
137. Annualincidenceper
100,000population
0
20
40
60
80
100
120
1985 1990
,
Universal
immunisation
1995 2000
HAV:疫苗接種策略與建議
1. World Health Organization. Wkly Epidemiol Rec 2012;87:261–276; 2. Dagan R et al. JAMA 2005;294:202−210
通用常規疫苗接種
Total infectious hepatitis
Hepatitis AYear
1999年以色列開始執行了針對18-24個月兒童的常規A型
肝炎疫苗接種
2002- 2004年,發生率降至每10萬人有2.5人
與疫苗接種前相比,每年A型肝炎病例減少≥95%2
WHO建議將HAV的疫苗接種納入國家免疫接種計劃,針對年齡≥1歲的兒童若於以下條件:1
• 急性A型肝炎的發生率
• 流行病從高到中改變
• 考慮成本效益
以色列通報的A型肝炎年發生率
27
HAV, hepatitis A virus; URV, universal routine vaccination
Reproduced from Dagan R et al. 20052
138. HAV:疫苗接種策略與建議
1. World Health Organization. Wkly Epidemiol Rec 2012;87:261–276; 2. AIDSinfo, 2015. https://aidsinfo.nih.gov/drugs/503/hepatitis-a-and-hepatitis-b--recombinant--
vaccine/0/patient (accessed July 2017)
慢性肝病的患者1
與非人靈長類動物接觸
的工人1
男男同性關係1
需要終身用血液製品治
療的人1
去高流行區旅行的人1
在低流行地區,應考慮對高風險個體進行針對性的免疫接種
靜脈藥物注射者1
某些HIV患者2
♂♂
28
HAV, hepatitis A virus
142. HAV:暴露後預防
Recommendations
1. Public Health Agency of Canada, 2012. Canadian Immunization Guide. Part 4: Active Vaccines; 2. Australian Department of Health, 2014. The Australian Immunisation
Handbook, 10th edition. http://www.health.gov.au/internet/immunise/publishing.nsf/Content/Handbook10-home (accessed July 2017); 3. Centers for Disease Control and
Prevention. MMWR Weekly 2007;56;1080−1084; 4. World Health Organization. Wkly Epidemiol Rec 2012;87:261−276
– ≥12個月大的健康人1–3
接觸後2週內接種一劑A型
肝炎疫苗
免疫球蛋白(IG)是
推薦的免疫預防劑
<12個月的兒童中1–3
如果不能接種疫苗或有禁忌症1,2
• 包括那些患有慢性肝病的人3
年齡> 40歲(美國)的人3
當以下狀況時,控制社區範圍爆發以疫苗接種為最成功:4
• 社區很小
• 注射疫苗的行為從很早就開始了
• 在多個年齡層有高的疫苗覆蓋率
• 除了接種疫苗防護,健康教育及生活環境衛生也積極改善
32
HAV, hepatitis A virus
Immunocompromised patients should receive both hepatitis A vaccine and IG because they may not respond fully to the vaccine
– 在免疫功能低下的患者中1,2 除A型肝炎疫苗外,
建議使用IG
150. HAVRIX 1440的免疫生成性
四個回溯性研究的分析比較了
年齡≥40歲的成人HAVRIX 1440(0,6個月)與20-30歲受試者(對照組)的免疫生成性和安全性1
HAV, hepatitis A virus; PI, post-dose 1; PII, post-dose 2
1. Van der Meeren O et al. Hum Vacc Immunother 2015;11:1729–1734; 2. Van Der Meeren O et al. 14th Conference of the International Society of Travel Medicine (ISTM), 2015.
Poster PO03.11
Age
group
Pre
(%)
Day 15
(%)
Month 1
(%)
Month 6
(%)
Month 7
(%)
≥40 years 0 79.7 97.5 88.8 100
20–30 years 1.4 92.3 97.4 92.3 100
Anti-HAV seropositivity rates1,2 Anti-HAV antibody GMC1
年齡≥40歲的成年人的標準時間表
兩組均無通報嚴重不良事件
(SAE)
接種兩劑的HAVRIX 1440在≥40歲的受試者中的總體免疫反應和安全性與年輕受試者相似1,2
較年輕的受試者可能在第一次給藥後15天表現出更快速和更高的血清轉化1,2
0
20
200
PRE PI(D15) PI(M1) PI(M6) PII(M7)
10.0 126.5 329.1 144.2 2378.9
10.4
age ≥40
age ≤30 219.4 469.2 140.5 4370.9
2,000
20,000
Anti_HAVGMC
(log10mIU/mL)
40
152. HAVRIX 720的長期保護效力
在兩份長期追蹤研究中嬰兒接種疫苗後長達10年的抗HAV抗體濃度測量1,2
≥12 個月的孩童
*Seropositivity (cut-off ≥5 mIU/mL for reference 1 and cut-off ≥10 mIU/mL for reference 2);
†Within each group infants were randomised by maternal anti-HAV status; only data about infants born to anti-HAV negative mothers is shown
GMC, geometric mean concentration; HAV, hepatitis A virus
1. Bian G et al. Vaccine 2010;28:4798−4801; 2. Sharapov UM et al. Hepatology 2012;56:516−522
99.1 100 100
0
20
40
60
80
100
Average 2.1 yrs 12, 18 m 15, 21 m
61.59
107
97
0
40
80
120
160
Average 2.1 yrs 12, 18 m 15, 21 m
Seropositivity (%)
Age of administration
GMC (mIU/mL)
Seropositivity10years
aftervaccination(%)
GMC(mIU/mL) Age of administration
N=110 N=21 N=27 N=110 N=21 N=27
42
Seronegative
before vaccination1
Born to anti-HAV-negative mothers2 †
Seronegative
before vaccination1
Born to anti-HAV-negative mothers2 †
無論是否有來自母體的抗體,
若給予2歲以下兒童的A型肝炎疫苗所誘導的血清陽性率至少持續10年2
153. HAVRIX 1440的長期保護效力
在兩份長期追蹤的研究中,連續在成人接種疫苗後每年測量抗HAV抗體濃度至17年
1,2
*Seropositivity cut-off ≥15 mIU/mL
CI, confidence interval; GMC, geometric mean concentrations; HAV, hepatitis A virus; LT-ATP, long-term according-to-protocol cohort (the LT-ATP cohort for immunogenicity included
all subjects who were included in the ATP immunogenicity analysis in the primary study, for whom serology results were available for that blood sampling visit and who had not been
eliminated due to any protocol violations); m, month
1. Van Herck K et al. J Med Virol 2011;83:1885−1891; 2. Van Herck K et al. Hum Vaccin Immunother 2012;8:323−327
Enrolled1
Year 172
Study A
Healthy adults 17–40 years
(HAVRIX Adult at 0, 6 months)
N=63 (45 in LT-ATP cohort)
N=119
Study B
Healthy adults 21–40 years
(HAVRIX Adult at 0, 12 months)
N=124 (91 in LT-ATP cohort)
N=194
GROUP
Anti-HAV response at year 172
Long-term total cohort LT-ATP cohort
Seropositivity* GMC (mIU/mL) Seropositivity* GMC (mIU/mL)
% 95% CI Value 95% CI % 95% CI Value 95% CI
Study A 100 94.3−100 331 250−439 100 92.1−100 278 207−374
Study B 100 97.1−100 406 333−494 96.7 90.7−99.3 369 294−464
17-40歲的成人
43
154. HAVRIX 1440 的長期保護效力
在所有長期追蹤的結果中,抗HAV抗體濃度在17年內都保持高水平
Serum samples up to Year 11 were tested with ELISA kits, while serum samples from Years 12 to 17 were tested with EIA kits
Seventeen-year antibody persistence in adults primed with two doses of an inactivated hepatitis A vaccine, Van Herck K et al, Human Vaccines & Immunotherapeutics, 2012,
Taylor & Francis, reprinted by permission of Taylor & Francis
GMC, geometric mean concentration; HAV, hepatitis A virus; LT-ATP, long-term according-to-protocol cohort; Y, year
Van Herck K et al. J Med Virol 2012;8:323−327
0
0 2 4 6 8
Annual time points (Years)
10 12 14 16 18
10
100
1,000
10,000
GMCs(mIU/ml)
0,6 months regimen (up to Y11)
0,6 months regimen (Y12 to Y17)
0,12 months regimen (up to Y11)
0,12 months regiment (Y12 to Y17)
Evolution of anti-HAV antibody GMCs up to 17 years post-primary vaccination, LT-ATP cohort
17-40歲的成人
44
155. 模擬接種疫苗17年之後的數據能預測40年後會有90%的受試者仍保持血清反應陽性
(≥15mIU/ mL)
HAVRIX 1440的長期保護效力(模擬)
Model 4.2 is based on all available data (obtained using the initial and currently used laboratory tests)
HAV, hepatitis A virus ; seropositive (≥15 mIU/mL)
Hens N et al. Vaccine 2014;32:1507−1513
60
70
80
90
100
15 20 25 30 35 40
Study A (N=194) Study B (N=120)
Years
Anti-HAVseropositivity(%)
45
157. 兩劑HAVRIX兒童常規接種已被證明具有免疫生成性,可有效減少A型肝炎感染病例的數量
HAVRIX 720 的常規疫苗接種保護力
1999年,以色列是第一個實施全國童年URV政策的國家,
在18和24個月時使用兩劑HAVRIX 7201,2
The start of the routine vaccination programme is marked by an arrow
URV, universal routine vaccination
1. Dagan R et al. JAMA 2005;294 202−210; 2. Levine H et al. Eurosurveillance 2015;20:pii=21040
0
10
20
30
40
50
60
70
80
1993 1995 1997 1999 2001 2003 2005 2007 2009 2011
Incidenceper100,000inhabitants
URV initiated
在執行後的2 - 3年內,A型肝炎發生率急劇下降
2008年至2012年間,每100,000人平均<1.0例2
與未執行疫苗接種政策前相比,表示持續減少>
98%2
48
Adapted from Levine H et al. Eurosurveillance 2015;20:pii=21040
158. 普遍常規接種使A型肝炎發生率明顯下降,
免疫反應持續5-17年
Incidence and persistence
49
*Two performed in Argentina, one in Belgium, two in China, one in Israel and four in the USA
GMC, geometric mean concentration; HAV, hepatitis A virus; URV, universal routine vaccination
Stuurman AL et al. Hum Vacc Immunother 2017;13:3:724–736
9/10 studies showed a marked decline
in incidence of acute hepatitis A before
and after URV
0
40
80
120
160
Before URV After UMV
Incidenceper100,000
6–142.4
0.4–7.9
URV 使HAV incidence 在
US, Israel, Argentina 和
Panama各年齡層均顯著下降
• 在接種疫苗最多的兒童的年齡組中,發生
率下降率普遍最高。
• 年齡最大的組別下降率最低。
10項研究顯示了疫苗接種後≥5年的抗體持
續性*
17年後(在follow-up時間最長的研究中)
,87-100%的個體受到血清保護
anti-HAV antibodies 的GMC會受到以下因
素影響:
接種的dose數
接種年齡
疫苗接種時程
母親的抗體狀態
159. 普遍常規疫苗接種顯著減少併發症,住院和死亡率
普遍常規接種所帶來的影響
50
*Private market
URV, universal routine vaccination
Stuurman AL et al. Hum Vacc Immunother 2017;13:3:724–736
Argentina (URV
initiated in 2006)
2000–2003 2008–2011
17
0 cases
猛爆性肝炎病例數
United States (URV initiated from 1999)
1996–1997 2004
20.9
8.7
門診數
1995–1999 2000–2004
0.51
0.28
年齡校正後的死亡率
2004–2005 2010–2011
0.64
0.29
住院率
2011年,美國的A型肝炎
發生率是有史以來最低的
Greece (vaccine
introduced* in 1999)
1999 2013
77.3
住院數
18.5