Epidemiologic Characteristics of Recent

Measles Outbreaks in ROK

Park Ok Director, Division of VPD control and NIP,

KCDC

Immunization History for MMR Vaccine

• 1980 MMR was introduced

• 1983 MMR was included in NIP

• 1997 2 dose MMR was recommended by NIP

• 2000-2001 Nationwide huge measles outbreak

• 2001 MR Supplementary immunization activity

• 2002 Immunization registry

• 2005 Web based immunization registry

• Routine MMR vaccine schedule

- MMR 1 at 12-15mo, MMR 2 at 4-6 yr

* MMR Vaccine used in Korea

Reported Cases of Measles (2008-2014. Jul) in Korea

1 2

1 3 2 4 15 3 30

1

94

32

100

328

1 14

19

8

46

0

50

100

150

200

250

300

350

400

450

2008 2009 2010 2011 2012 2013 2014

Imported Import-linked Imported-virus Unknown Under investigation

43

• Measles incidence: 8.2 cases per 1M population • Annual median number: 100.6 cases [range, 2-419 cases]

Cases

Year

17

114 107

419

0

10

20

30

40

50

60

70

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29

Under investigation Imported Import-linked Imported virus Unknown

n % Under investigation 40 9.5

Imported 15 3.6 Import-linked 30 7.2

Imported virus 328 78.3 Unknown 6 1.4

Total 419 100.0

Measles Cases in Korea, by Import Status, Jan-July 2014

Epidemiological week

Cases

Jul 18, 2014 2013 2012 2011 2010

Total 419 107 2 43 114

Imported 15 4 2 3 1

Import-associated 358 103 - 32 94

Endemic - - - - -

Unknown 46 (under

investigation)

- - 8 19

Country Cases No. Details

The Philippines

6 Multicultural family Korean returning from international travel Foreign worker International student, Korean

2 2 1 1

China 5 Multicultural family Korean returning from international travel International student, Korean International student, Chinese International worker, Chinese

1 1 1 1 1

Vietnam 3 Multicultural family Korean returning from international travel

2 1

Singapore 1 Foreign visitor 1

Details of Imported measles cases

0

50

100

150

200

250

B3 D8 H1 Unknown

Cases

Genotype

Genotype n

B3 209

D8 7

H1 5

Unknown* 198

Total 419

* Unknown: includes cases under investigation

Measles Cases in Korea, by Genotype, Jan-July 2014

WHO Measles-Rubella Bulletin, Vol 8 Issue 6 (June 2014)

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9 1011121314151617181920212223242526272829303132333435363738394041424344454647Age (yr)

Cases

Measles Cases in Korea by Age, Jan-July 2014

0

20

40

60

80

100

120

Age Group

Cases (no.)

%

~1yr 100 23.9 unvaccinted

1-3yr 73 17.4 day care

4-6yr 6 1.4 kidergarten

7-12yr 15 3.6 elementary schooler

13-15yr 14 3.3 middle schooler

16-18yr 69 16.5 high schooler

19-29yr 98 23.4 college students

30yr~ 40 9.5

Measles Cases in Korea by Age Group, Jan-July 2014

Cases

Age (yr)

Age (yr) Vaccination History

Total 0 1 2 Unknown

0 99 . . . 99

1~3 44 25 . . 69

4~6 3 1 2 . 6

7~19 4 4 100 23 131

20~ 4 5 27 69 105

Subtotal 156 36 129 90 410

0

20

40

60

80

100

120

140

0 1~3 4~6 7~19 20~

0

1

2

Unknown

Age (yr)

Cases

Vaccination History

Measles Cases in Korea, by Age Group and Vaccination History, Jan-July 2014

38%

9% 31%

22% Never

1 dose

2 doses

Unknown

Region Confirmed New cases in

recent 2 weeks

Imported

cases

Genotype

B3 D8 H1

Total 419 6 15 209 7 5

Seoul 93 - 2 71 - -

Incheon 49 1 - 25 - -

North Gyeonggi 32 - 1 17 - -

South Gyeonggi 114 5 4 25 1 2

Gangwon 2 - 1 1 - -

Daejeon 17 - - 11 2 -

Chungbuk 8 - - 4 - -

Chungnam 12 - 2 6 4 -

Gwangju 2 - - 2 - -

Jeonbuk 4 - - 2 - -

Jeonnam 41 - - 27 - -

Daegu 11 - 1 2 - 3

Ulsan 3 - 1 3 - -

Gyeongbuk 16 - 1 6 - -

Busan 13 - 2 7 - -

Gyeongnam 1 - - - - -

Jeju 1 - - - - -

Measles Cases in Korea by Region, Jan-July 2014

* Unvaccinated cases were more likely to present classic manifestations of measles [OR=3.656 (p <0.000)](among 330 measles cases with available data).

Clinical Manifestations of Measles Cases in Korea, Jan-July 2014

Classic measles (F+R+3C)

Non-classic measles

Vaccinated 87 82 169

Unvaccinated 128 33 161

215 115 330

•Rash: mild, atypical H-F-M dz?, acne?, varicella? •Hospitalization rate: 34.8% •Pneumonia, encephalitis, death : not reported so far

0

10

20

30

40

50

60

70

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29

가족 병원 어린이집 지역사회 학교 학원 회사

H중학교

K대학교

B중고교

B병원 D고교

대전,파주

Daejeon, Mokpo, Gyeonggi(Paju,Bundang,Bucheong) hospital

Epidemiological curve of Measles Cases in Korea by Outbreaks, Jan-July 2014

Epidemiological week

Cases

Feb. Mar. Apr. May

A (48)

B (31)

?

C (38)

D (1)

G (19)

J (19)

F (2)

E (2)

H (6m)

I (13m )

A Hospital

B Hospital

C Hospital

K (13)

12 persons (12~13)

D Mid. School

L (10m )

M (17 )

N (33 )

?

O (1 )

P (6m )

Family

Transmission Chain of Outbreaks in Mokpo and Jeonnam Province

Apr May Jun

17 18 19 20 21 22 23 24 25 26 27 28 29 30 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 1 2 3 4 5 6 7

R/O Sepsis, R/O Meningitis

R/O Mycoplasma infection, R/O Viral infection Phillippines

(Cebu)

Deteted during Epi. investigation

Exposure Rash onset

Infective period

Nurse of the ward where E pt admitted

A: 33

B: 32

C: 33

D: 27

E: 2M

F: 30

Worked at emergency room when A pt visited

Hospital visit

Transmission Chain of Outbreaks in Health Care Workers of a Hospital

Feb. Mar. Apr.

K (13m)

B (22m)

G (11m)

F (25)

L (13m)

H (8m)

A (12)

C (9m)

D (18m)

E (11m)

F (9m)

May

G (11m)

H (12m)

I (12m)

From Philippine

L (14m)

A Hospital

B Hospital

C Hospital

O (10m)

M (1)

N (10m)

P (1)

Transmission Chain of Outbreaks in North Gyeonggi Province

Outbreak Name Region Cases No. Import State Genotype Rash onset Duration Age range

S Hospital Daejeon 6 Imported virus B3 2.3 24 days 11M - 31

M Children’s hospital

N. Gyeonggi (Paju)

7 Imported (Philippines)

B3 2.25 23 days 8M – 12

J Hospital S. Gyeonggi (Bundang)

5 Imported virus B3 2.27 55 days 10M – 1

M Children’s hospital

Jeonnam (Mokpo)

5 Imported virus B3 3.5 15 days 6M – 1

S ENT clinic Chungbuk 4 Unknown - 3.10 3 days 35 - 45

D Hospital N. Gyeonggi (Ilsan)

6 Imported (Philippines)

B3 3.13 30 days 9M - 25

G Hospital

Jeonnam (Mokpo)

6 Imported virus B3 3.19 33 days 1-47

S children’s hospital

S. Gyeonggi (Pucheon)

22 Imported virus B3 3.20 ongoing (7.13) 5M – 1

G Hospital Incheon 16 Imported virus B3 4.4 58 days 7M - 30

H Hospital Jeonnam (Mokpo)

5 Imported virus B3 5.1 45 days 14 - 33

S Hospital Gyeongnam (Andong)

13 Imported virus B3 5.1 ongoing (6.28) 5M - 35

S Hospital S. Gyeonggi (Pucheon)

23 Imported virus B3 5.12 22 days 2M - 47

B Hospital Busan 7 Imported (Philippines)

/Imported virus

B3 5.9 24 days 11M - 33

Measles Outbreaks in Health Care Setting, Korea, 2014

* Outbreak: cluster of more than two cases

# Outbreaks in Korea, Jan-July 2014 Total 21 measles outbreaks Hospital(13), School(7), and Office(1) Average size: 12 cases [ranges, 3-85 cases] Average duration: 31 days [ranges, 3-58 days]

Outbreak Name

Region Cases No. Import State

Genotype Setting Rash onset

Duration Age range

G Residence Academy

S. Gyeonggi (Kwangmyeog)

9 Imported virus

B3 Boarding school

2.27 58 days 18 - 20

H Middle school

Jeonnam (Mokpo)

15 Imported virus

B3 School 3.14 37 days 12 - 13

K Univ Seoul 85 Imported virus

B3 University 4.8 51 days 18 - 44

G Company Chungnam 3 Imported D8 Office 4.21 30 days 26 – 38

B Upper school

Seoul 17 Imported virus

B3 School 5.13 23 days 13 - 17

Y High school Seoul 4 Imported virus

B3 School 5.18 6 days 15 - 17

S High school Daegu 3 Imported (China)

H1 School 5.23 26 days 17 - 18

D High school Daegu 4 Imported (China)

H1 School 6.16 Ongoing (7.4) 17 - 18

Measles Outbreaks in other than Health Care Setting, in Korea, Jan-July 2014

* Outbreak: cluster of more than two cases

1 1 5

19

43

11

3 3 0

5

10

15

20

25

30

35

40

45

50

3.23-29 3.30-4.5 4.6-4.12 4.13-19 4.20-26 4.27-5.3 5.4-10 5.11-17 5.18-24 5.25-31 6.1-6.7 6.8-6.14 6.15-6.16

Cases

Week

Catch-up(5.15-17)

An Outbreak in K University and Catch Up Campaign

• There are bimodal peaks; aged <1 year and aged 17-20 years.

• The main outbreak settings were hospitals and schools.

• Significant proportion of measles cases in Korea, Jan-July 2014 was vaccinee (40.0%).

• Among 419 confirmed measles cases, there were 15 (3.6%) imported cases; 14 (93.9%) occurred in Korean residents returning from international travel, and 1 (6.1%) occurred in foreign visitor.

• Measles importation were associated with travel from 4 countries: the Philippines, China, Vietnam, and Singapore.

• Outbreak-related cases comprised 265 (63.2%) of total measles cases.

• Predominant measles genotype was B3.

Summary of Surveillance Data of Measles Cases in Korea, Jan-July 2014

Continuous import from abroad

Hospital infections among infants

Outbreaks in previously vaccinated youth

• Overseas travels during vacations (students for language course in abroad,

international students from abroad, multicultural families)

• Diagnosis failure due to atypical symptoms at the first visit to clinics

• Delayed notice of outbreaks after transmissions of several generations

through hospitals, families, and schools

• Imports from abroad hospital infection through contacts to imported cases

transmission among family members and in community

transmission through infections at schools

Characteristics of the Recent Measles Outbreaks in Korea

WHO Measles-Rubella Bulletin, Vol 8 Issue 6 (June 2014)

Huge Outbreaks in Neighbor Countries

Huge outbreaks in neighbor countries transmission by travellers

Continuous Imports from Abroad

Transmission routes of measles cases in 2013

Total

Hospital Day care Family School Overseas travel

Community

61 2 13 14 4 13 107

(57.0%)

Transmission routes of measles cases in 2014 as of Jul 18

Total Hospital Day care Family School Overseas

travel Community

157 3 12 124 14 19 419

(37.5%)

2ndary Transmission in Children’s Hospital

7% of neonates have no measles Ab, 90% of infants have no measles Ab at 6 months of age in USA

J Infect Dis 2004;190:83, J Infect Dis 2007;196:1459

Measles Sero-positive Rates under 2 years olds in Korea

Measles Sero-positive Rates

In infants under 1 year old

Kim KH, 2009

Kim SS et al. Vaccine23(2004)290–297

Decrease of Passive Immunity in infants

Atypical rash of a recent measles case

*Atypical mild measles clinical features & low measles incidence Difficulty in diagnosis

홍역 발생 상황 평가 : 청소년/성인 백신 접종자 중심 집단적인 홍역발생

Typical measles rash

* Unvaccinated cases were more likely to present classic manifestations of measles [OR=3.656 (p <0.000)](among 330 measles cases with available data).

Classic measles (F+R+3C)

Non-classic measles

Vaccinated 87 82 169

Unvaccinated 128 33 161

215 115 330

Atypical Measles Manifestations in Pts with Vaccination history

Index case

Early detection and notification from clinics are important for control

Delayed Notice Lead Wide Transmission

Index case

Early detection and notification from clinics are important for control

Delayed Notice Lead Wide Transmission

38%

9% 31%

22% Never

1 dose

2 doses

Unknown

* A study in USA (2014.1.1-5.23)(n: 288)

: unvaccinated : 200(69%), unknown : 58(20%), vaccinated : 30(10%)

* A study in Japan (2014.1.1-3.13)(n: 183)

: unknown or unvaccinated : 146(80%), vaccinated : 37(20%)

Reported measles cases, Jan-July 2014, KCDC

Vaccine Failure : Primary vs 2ndary

P.O.Viana et al. J C linImmunol 2010

Vaccination Natural infection

Davidkin I et al. JID 2008:197

Waning Immunity after Vaccination

• Measles Outbreak in a Vaccinated School Population: Epidemiology, Chains of Transmission and the Role of Vaccine Failures Nkowane et al. Am J Public Health 1987

• Outbreak of measles among persons with prior evidence of immunity, New York

Rosen et al. CID 2014

• A Limited Measles Outbreak in a Highly Vaccinated US Boarding School

Yeung et al. Pediatrics, 2005

• In case the level of neutralizing Ab is not enough, measles infection is possible. The present neutralizing Ab can’t prevent atypical measles. (continuum of clinical illness) Chen RT et al.

JID 1990

• Based on the large cohort study(n=763) in U.S., 8.9% of vaccinees at 7.4 years after 2-dose MMR have Ab level < 210mIU/mL (protective threshold). There was no difference between ethnic groups Haralambieva IH et al. Vaccine 2011

• Genetic factors(HLA class I, II genotype, SNP polymorphism) may determine the response to Measles containing vaccine…

Haralambieva IH et al Expert Rev. Vaccines 2013

Secondary Vaccine Failure

Classification Clinical IgM IgG PCR

Vaccine reaction Fever/Rash P P or N Positive and

Sequence indicates vaccine strain

Measles Meets CCD* P P or N Positive PCR can confirm IgM

Secondary vaccine Failure

CCD or Modified# P or N P Positive PCR can confirm case

*=clinical case definition (CCD)

#=modified or mild presentation does not meet CCD

Presented by Paul Rota, Meeting at Korea CDC, March 17 2014

In patients with vaccination history,

Mild symptoms

– IgM may be negative in acute serum

– Characterized by rapid and robust IgG response

– If a second serum sample collected 5-10 days later remains IgM negative, then the paired serum samples can be tested in a PRN assay or quantitative or semi-quantitative IgG EIA

CDC VPD Surveillance Manual, 6th Edition, 2013 Measles: Chapter 7-9

Utility of PCR for Measles Case Confirmation

Vaccine effectiveness (2014)

No. of Hospitalized No. of infected Incidence

Total 105 2 1.9%

With vaccination hx 92 0 0.0%

No vaccination hx 13 2 15.4%

No. of Hospitalized No. of infected Incidence

Total 39 1 2.6%

With vaccination hx 35 0 0

No vaccination hx 4 2 50%

No. of hospitalized : All the hospitalized patients during the infective period of the index case of a hospital in Kyeonggi province

No. of hospitalized : All the hospitalized patients during the infective period of the index case at the same ward of a hospital in Daejeon city

Vaccination is the most important Protective Measure

* Measles vaccine efficacy: Proportion of Vaccinee with measles specific Ab level (protective threshold) 15 years later after vaccination : 91.1% (Vaccine, 2011) * Measles vaccine effectiveness: 1st dose measles vaccine: 9-11mo: 77.0% (IQR, 62%-91%) ≥ 12mo: 92.5% (IQR, 84.8%-97.0%) 2nd dose measles vaccine: 94.1% (IQR, 88.3%-98.3%) (JID, 2013)

Latest Data of Measles Vaccine Efficacy/Effectiveness

Acknowledgements