1. Varicella Outbreak Involving Two Dose Vaccine Recipients — Arkansas, 2006
Philip L. Gould, MD MPH
Division of Viral Diseases
National Center for Immunization and Respiratory Diseases (proposed)
Centers For Disease Control and Prevention
National Immunization Conference
March 8, 2007
CHANGE IN TITLE

2. New ACIP Recommendations for Varicella Immunization
June 2005
2nd dose for children to control outbreaks, resources permitting
June 2006
Routine 2-dose vaccination for all children

3. Arkansas Outbreak: September 2006
31 cases (as of 10/2)
8 were 2-dose vaccine recipients
Elementary school complex
Prior outbreak in same complex January 2006
Vaccination Clinic (per ACIP): ~ 400 students
Many received 2nd dose
All reported to have mild or atypical disease

4. Elementary School Complex
Student Population:
School A (Pre-K): 100
School B (K-3): 429
School C (4-6): 351
School B
Computer labs
Library
School C
Gym
Feb 2006 vaccine clinic
targeted schools B and C
Add some of the community notes to this slide
PG for
School A
School A

5. Objectives of Investigation
Confirm varicella as cause of outbreak
Confirm varicella in 2-dose vaccine recipients
Characterize vaccine effectiveness among 1- and 2-dose vaccine recipients.

6. Methods

7. Outbreak Case Definition
CSTE Case definition (acute maculopapulovesicular rash without other apparent cause)
In vaccinated persons:
Mild with
Fewer than 50 skin lesions
Shorter duration of illness
May be atypical in appearance (maculopapular with few or no vesicles)
Operationally used 3 lesions as lower cut-off

8. Case Finding Students in school complex Cases identified from:
Health Unit
School nurse
Parental survey
Rash onset from Sept 1 – Nov 22

9. Survey and Case Investigation
School wide survey:
“Rashes, insect bites, bumps, spots, or blisters since start of school year”
Vaccination status & varicella history
Medical conditions
Case investigation
Clinical information
Medications

10. Vaccination Records Arkansas Immunization Registry Vaccination status
Limited disease history (on unvaccinated cases)
Alternate sources
Local paper records
Parental survey
Vaccinations ≤ 42 days prior to rash onset
1st dose = Unvaccinated
2nd dose = Indeterminate

11. *All 2-dose cases, otherwise 1-2 cases per week
Specimen Collection
Lesion
IgM
Saliva
Case after Sep 15 +
Active Case (Oct 9 to 20)
Active Case after Oct 20*
*All 2-dose cases, otherwise 1-2 cases per week

12. Environmental Sampling
Swabs of school locations, school buses, patient houses, etc were taken
2 sets of PJs
1 one dose
1 case vaccinated 30 days prior to rash)
1 pillowcase (from 1 dose case)

13. Results

14. School Wide Survey School Total # Surveys Returned % Surveys Returned
School A (Pre-K)
100 81
81%
School B
(K-3)
429
362
84%
School C*
(4-6)
351
253
72%
880
696
79%
* p < 0.001

15. Responders vs Non Responders
Race/Ethnicity: African-American children less likely to be responders (65% vs. 86% for white/Hispanic, p < 0.001)
Gender: No difference
Vaccination Status: No difference

16. 2 cases with unknown rash onset dates excluded
Add the data from the cases overview
2 cases with unknown rash onset dates excluded

17. Clinical Comparison
No differences between 1 and 2 dose vaccine recipients in:
Number of lesions (All had < 250 lesions)
Rash characteristics
Duration
Percent having fever

18. Case Example Highlighting Challenges to Case Ascertainment
Clinical characteristics of a 2 dose vaccine recipient
No disease history
Only 4 papules at any one time
1 to 2 vesicles
Itchy
Lasted 3 – 4 days
Specimens obtained on day of rash onset
Lesion: Positive
Saliva: Negative

19. Vaccination and Disease History of Cases (N=78)
Vaccination Status
Cases
% Cases
2 doses
- w/prior disease - w/unknown disease hx 25
2 1
32%
1 dose
- w/prior disease 48 6
62%
0 doses 5 6%

20. Vaccination Coverage VACCINATION STATUS SCHOOL TOTAL N = 758* PRE-K
4 – 6
N = 265
Unvaccinated 1% 2% 4% 3%
1 Dose
84%
54%
48%
56%
2 Doses**
15%
44%
41%
Total Vaccinated
98%
97%
96%
*Excluded:
106 students with history of disease
9 students with no vaccination data
** Includes 22 cases with 2nd dose within 42 days

21. Clinical Lab Results 27 cases tested: 6 positive 5 PCR (lesion)
1 two dose recipient
3 one dose recipients
1 unvaccinated with history of disease
1 IgM serum spot (one dose recipient)
All saliva PCR of cases negative
1 junior high student saliva positive

22. Environmental Samples
36 swabs:
30 from school, school buses
6 from patient bedding
All swabs negative
Bedclothes positive for wild- type virus
PJs in 2 dose (indeterminate)
Pillowcase in 1 dose

23. Vaccine Effectiveness Using Historic Attack Rates
If we compare attack rates with historic rates for any varicella disease in unvaccinated:
ARunvacc of 80%
2 doses to unvaccinated:
VE2 = 1 – (10.4% / 80%) = 87%
1 dose to unvaccinated:
VE1 = 1 – (13.3% / 80%) = 83%

24. Marginal Vaccine Effectiveness (No Known History of Disease)
Attack
Rate
Case
Non-Case 22
189 42
274
2 doses
211
10.4%
1 dose
316
13.3%
VEM = 1 – RR = 1 – = or 21.5%
95% CI: to 51.7%

25. Limitations May not have had sufficient power to detect differences
Misclassification of case status
Broad clinical definition  False positives
Mild disease  False negatives
Lesion-based laboratory diagnostics only helpful while transient rash still present
Misclassification of disease history
Based on parental report

26. Summary and Conclusions

27. Summary
Varicella confirmed as cause of outbreak on both epidemiologic and laboratory criteria
Lab confirmation included two-dose recipient
78 cases identified
25 (32%) two-dose recipients
Similar clinical picture in 1 vs. 2 dose recipients
97% school vaccination coverage
41% two doses*
Marginal vaccine effectiveness was 22% with broad confidence limits including zero
*Includes persons with 2nd dose < 42 days

28. Conclusions
One of the largest varicella outbreaks investigated in recent years
First U.S. outbreak reported with significant number of second dose vaccine recipients
Case ascertainment is challenging and may preclude evaluation of 2 vs. 1 risk reduction assessments in outbreak settings
Moderate 2-dose coverage was insufficient to prevent this outbreak

29. Recommendations
Fully implement routine 2-dose childhood varicella vaccination policy in order to achieve better herd immunity and reduce number of varicella outbreaks
Will need to monitor the number and size of outbreaks as a key outcome to assess effects of the routine 2 dose policy
Reassess the case definition & classification for varicella in the maturing vaccination era
Develop newer laboratory techniques to confirm varicella after lesions resolve

30. Acknowledgements Ashley County Health Unit- Hamburg Connie Scott
Nan Erwin
Southeast Public Health Region Office
Donetta McGriff
Carolyn (Sue) Hutton
AR State Health Department
Linda Gladden
Karen Fowler
Haytham Safi
Sandra Snow
Helen Dang
AR State Lab
Schools
CDC Atlanta
Jessica Leung
Meredith Reynolds
Adriana Lopez
Sandra Chaves
Rafael Harpaz
Tureka Watson
John Zhang
Scott Schmid
National VZV Lab

31. Thank you
The findings and conclusions in this presentation have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy
Thank you.

32. Backup

33. All Cases

34. 2 cases with unknown rash onset dates excluded

35. Attack Rates School A (Pre-K): 15.0% (15 / 100)
School B (K-3): 10.3% (44 / 429)
School C (4-6): % (28 / 351)
All 3 schools: % (87 / 880)

36. Vaccination and Disease History of Cases (N=87)
Vaccination Status
Cases
% Cases
2 doses
- w/prior disease - w/unknown disease hx 26
2 1
30%
1 dose
- w/prior disease 54 6
62%
0 doses 7 8%

37. Incremental Risk Reduction (No Known History of Disease)
Attack
Rate
Case
Non-Case 23
188 48
268
2 doses
211
10.9%
1 dose
316
15.2%
Incremental Risk Reduction
= 1- RR = 1 – = or 28.2% 95%CI : to 54.9%

38. All Community Patients

39. 11 cases with unknown rash onset dates excluded

40. Community Cases 173 patients in outside community including
59 Junior High school students
40 High school students
74 in community, mostly in daycare facilities

41. Vaccination and Disease History of Entire Community of Cases (N = 260)
Vaccination Status
Cases
% Cases
2 doses
- w/prior disease - w/unknown disease hx 29
3 1
11.1%
1 dose
w/prior disease - w/unknown disease hx
116
8 5
44.6%
0 doses
- w/prior disease
114 96
43.8%
Unknown Vaccination Status
-w/prior disease 1
0.4%

42. Outbreak Definitions
Pediatric setting: 5 or more confirmed cases epidemiologically linked
School
Daycare
Other common setting
Adult setting: 3 or more confirmed cases

43. Attack Rates by Vaccination Status All Cases (N = 87)*
2 doses
Hx of disease 14.3% ( 2 / 14 )
No hx 11.0% (23 / 211)
Unknown 1.5% ( 1 / 67 )
1 dose
Hx of disease 14.0% ( 6 / 43 )
No hx 15.3% (48 / 313)
Unknown: 0.0% ( 0 / 112)
Unvacc
Hx of disease: 14.3% ( 7 / 49 )
No hx / Unk 0.0% ( 0 / 33 )
*Excludes 22 indeterminate & 16 records without vaccination status

44. Attack Rates Overall: No Disease History:
School A (Pre-K): 15.0% (15 / 100)
School B (K-3): % (42 / 429)
School C (4-6): % (21 / 351)
Total: % (78 / 880)
No Disease History:
School A (Pre-K): 19.2% (15 / 78)
School B (K-3): 12.3% (39 / 318)
School C (4-6): % (10 / 167)
Total: % (64 / 562)

45. Incremental Risk Reduction No Disease Hx & Indeterminate = 1 dose
Attack
Rate
Case
Non-Case 23
188 50
283
2 doses
211
10.9%
1 dose
333
15.0%
Incremental Risk Reduction
= 1 – RR = = or 27.4%
95% CI: % to 54.3%

46. Incremental Risk Reduction Both No Disease & Unknown Disease
Attack
Rate
Case
Non-Case 24
255 49
383
2 doses
278
8.6%
1 dose
425
11.5%
Incremental Risk Reduction
= 1 – RR = = or 24.2%
95% CI: % to 52.3%

47. Incremental Risk Reduction All vaccine recipients
Attack
Rate
Case
Non-Case 26
266 55
413
2 doses
292
8.9%
1 dose
468
11.7%
Incremental Risk Reduction
= 1 – RR = = or 24.2%
95% CI: % to 51.3%

48. Incremental Risk Reduction from Kuter et al 2004
Attack
Rate
Case
Non-Case 17
1000 60
1044
2 doses
1017
1.67%
1 dose
1104
5.43%
Incremental Risk Reduction
= 1 – RR = = or 69%
95% CI: 48% to 82%

49. Vaccination Records 880 students N In State DB? Y 622 records
In Ashley Co paper recs? Y
168 records N
90 records
Recheck AR DB Y
46 records N
28 records Y
44 records
In parental survey?
= 864 records (98%) N
16 records (3%)

50. Integrity of Prior Vaccine: February 2006 Vaccine Clinic
Vaccine was kept refrigerated throughout the clinic
Only 10 doses were prepared before administration at a time
No elevations in temperature were noted
Colorimetric temperature indicators on vaccine
Thermometers
Same personnel involved in preparation and administration at all times

51. Disease Severity *p = .3230 No Prior Disease 1 dose N = 42
Prior Disease N = 13
Number of Lesions*
< 50
81% (34)
91% (21)
62% (8)
50-249
12% (5)
0% (0)
8% (1)
> = 500
Unknown
7% (3)
9% (2)
31% (4)
*p = .3230

52. Disease Characteristics
No Prior Disease
1 dose N = 42
2 dose N = 23
Prior Disease N = 13
Rash Description*
Maculopapular
86% (36)
78% (18)
62% (8)
Vesicular
43% (18)
43% (10)
23% (3)
Itchy
87% (20)
100% (13)
Med Rash Duration**
(range)
6 days
(1-13 days)
4 days
(1-16 days)
(1-7 days)
Fever***
29% (12)
17% (4)
15% (2)
*p= **p= ***p = .17

53. Comparison—Responder vs Non Responder
Survey Completed
Race/
Ethnicity *
Total
Yes No B
194
127 (18%)
67 (36%) H 99
86 (12%)
13 (7%) W
587
483 (69%)
104 (57%)
Sex ** M
424
342 (49%)
82 (45%) F
456
354 (51%)
102 (55%)
880
696
184
* p < 0.001
** p = 0.189

54. Comparison—Responder vs Non Responder
Vaccination Status
Total
SURVEY COMPLETED
YES NO
Unvaccinated 82
65 (9%)
17 (10%)
1 Dose
468
372 (54%)
96 (57%)
2 Doses
292
239 (34%)
53 (32%)
Indeterminate 22
20 (3%)
2 (1%)
864
696
168
16 students with no vaccination records or surveys
p = 0.444
Indeterminate = Vaccinated with 2nd dose after July 21

55. Specimens Positive by Rash Onset — Lesion
Rash Onset
Positive
Negative

56. Specimens Positive by Rash Onset — IgM
Rash Onset
Positive
Negative

57. National Statistics on Varicella Vaccination
2004 National Immunization Survey:
87.5% of children 19 to 35 months of age vaccinated with one dose
46 states with mandatory requirements for documentation of appropriate immunity for daycare or school entry
21 states with mandatory requirements for documentation of appropriate immunity for middle or high school

58. Household transmission
Secondary attack rates in household members without evidence of immunity between 30 and 72%
72% in age 1 to 9 years
30% in persons >= 15 years
Vaccinated cases with >= 50 lesions as infectious as unvaccinated cases with >= 50 lesions
Vaccinated cases with fewer than 50 lesions only / 3 as contagious as unvaccinated cases with >= 50 lesions
From Seward JF, Zhang JX, et al, “Contagiousness of varicella in vaccinated cases: a household contact study.” JAMA Aug 11;292(6):704-8.

59. January Outbreak Cases
21 total cases
1 School A (Pre-K) Case
12 School B (K-3) Cases
3 School C (4-6) Cases
1 Jr High Case
1 High School Case
3 Adult Cases (Aged 21, 34, and 71)
Vaccination and Disease History
15 one- dose vaccinated cases with no disease history
2 unvaccinated with prior disease history
4 unvaccinated with no disease history
Rash Description
9 with < 50 lesions
7 with lesions
5 with lesions
Fever
5 with fever
3 cases from Jan outbreak are cases in this outbreak

60. Household Cases Household Links
8 household links with at least 1 case part of school population
HH4: 2 dose vaccine recipient student (onset 9/17/06) and 1 dose vaccine recipient student (onset 9/18/06)
HH9: both 1 dose vaccine recipient students (onset date 9/8/06)
HH10: 1 dose vaccine recipient student (onset 9/6/06) and case with unknown vax status and no history (onset 9/25/06)
HH15: 2 dose vaccine recipient student (onset 9/8/06) and 1 dose vaccine recipient student (onset 9/28/06)
HH27: 2 dose vaccine recipient student (onset 9/28/06) and parent* case with unknown vax and disease history (onset 9/28/06); *parent heavily involved in school activities
HH30: 2 dose vaccine recipient student (onset 9/17/06) and 2 dose jr high case (onset 9/28/06)
HH43: 1 dose vaccine recipient student (onset 9/24/06) and 1 dose vaccine recipient student (onset 9/30/06)
HH47: 1 dose vaccine recipient student (onset 10/13/06), two 1 dose vaccine recipient non-student cases (onset 10/13/06), and one unvaccinated non-student case (onset 10/13/06)
3 additional pairs household cases with none of the cases part of pre-K or elementary school population

61. Post-licensure Varicella Vaccine Effectiveness
Study
Vaccine Effectiveness
Study method
Setting/Design
All disease
Mod/severe dz
Outbreaks N=23
71%-90%
93-100%
Outbreak investigations
Child care centers, schools
Galil, NEJM, 2002
44% (7, 66%)
86% (39, 97%)
Child care center
Outbreak MD
59% (-1, 84%)
75% (-4, 95%)
School
Lee, JID, 2004
56%
90%
Clements, PIDJ, 1999
83% (69-91%)
100%
CCC prospective cohort
Vazquez, NEJM, 2001
85% (78-90%)
97% (93, 99%)
Case control, clinical practice
Seward, JAMA, 2004
79% (70-85%)
92-100%
Household contact study

62. Varicella Outbreak Investigations: Vaccine Effectiveness 71-100%
Study
State
All disease
Mod/severe dz
Setting
Izurieta, JAMA, 1997 GA
86% (73-92%)
100%
Child Care Center
Tabony, IDSA, 1998 TX
84% (60-94%)
Buchholz, Peds, 1999 CA
71%, 100%
93%, 100%
McCarthy, NIC, 2000 CT
76% (29-92%)
Galil, JID, 2002 PA
79% (66-88%)
95%
Laitin/Lett, NIC, 2001 MA
84% (69-92%)
96% (85-91%)
School
Dworkin, CID, 2002 IL
88% NA
Maine, 2002 ME
90% (70-95%)
98% (88-100%)
Watson, 2002
Phil
81% (60-91%)
NH, 2002 NH
73% (48-86%)
90% (66-97%)

63. Varicella Outbreak Investigations: Vaccine Effectiveness 71-100%
Study
State
All disease
Mod/severe dz
Setting
Los Angeles, 2002 CA
86% (79, 91%) NA
School
Utah, 2003 (2) UT
87%, 89%
Over 98%
Maine, 2003 ME
89% (79-94%)
96% (88-99%)
Lopez, Peds, 2006 AR
83% (77-87%)
NH, 2003 NH
84% (72-94%)
Michigan, 2003 MI
85% (77-90%)
98% (95-99%)
Tug well, Peds, 2004 OR
72% (3-87%)
California, 2004
79% (52-91%)
Nebraska, 2004 NE
81% (66-89%)
93% (82-97%)
Maine, 2006
87% (82-90%)
100%