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

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

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

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

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.

Methods

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

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

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

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

*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

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)

Results

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

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

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

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

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

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%

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

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

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

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%

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 – .7845 = .2155 or 21.5% 95% CI: - 27.5 to 51.7%

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

Summary and Conclusions

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

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

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

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

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.

Backup

All Cases

2 cases with unknown rash onset dates excluded

Attack Rates School A (Pre-K): 15.0% (15 / 100) School B (K-3): 10.3% (44 / 429) School C (4-6): 8.0% (28 / 351) All 3 schools: 9.9% (87 / 880)

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%

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 – 0.7176 = .2824 or 28.2% 95%CI : - 14.3 to 54.9%

All Community Patients

11 cases with unknown rash onset dates excluded

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

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%

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

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

Attack Rates Overall: No Disease History: School A (Pre-K): 15.0% (15 / 100) School B (K-3): 9.8% (42 / 429) School C (4-6): 6.0% (21 / 351) Total: 8.9% (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): 6.0% (10 / 167) Total: 11.4% (64 / 562)

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 = 1 - .7259 = .2740 or 27.4% 95% CI: - 15.3% to 54.3%

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 = 1 - .7488 = .2422 or 24.2% 95% CI: - 20.7% to 52.3%

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 = 1 - .7577 = .2423 or 24.2% 95% CI: - 17.9% to 51.3%

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 = 1 - .3075 = .6925 or 69% 95% CI: 48% to 82%

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%)

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

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) 250 - 499 > = 500 Unknown 7% (3) 9% (2) 31% (4) *p = .3230

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=.64 **p=.37 ***p = .17

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

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

Specimens Positive by Rash Onset — Lesion 0 1 2 3 4 5 6 7 22 Rash Onset Positive Negative

Specimens Positive by Rash Onset — IgM 0 1 2 3 4 5 6 7 21 Rash Onset Positive Negative

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

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 1 / 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. 2004 Aug 11;292(6):704-8.

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 50-249 lesions 5 with 450-499 lesions Fever 5 with fever 3 cases from Jan outbreak are cases in this outbreak

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

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

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%)

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%