Varicella Disease Incidence During the Introduction of a Routine Two Dose Varicella Vaccination Program, Antelope Valley, California, 2005-2008 Amanuel Hussien, MSc, MSW Research Analyst Varicella Active Surveillance Project Los Angeles County Department of Public Health Good Afternoon- Today I will report on varicella disease incidence during the introduction of a routine 2 dose varicella vaccination program in Antelope Valley, CA. The period of interest is from 2005-2008, which encompasses 2 years prior to 2 doses varicella vaccination and 2 years after the introduction. However, some of the slides will review surveillance data commencing in 2000.

Background: Varicella Vaccination Recommendations March 1995: Live attenuated varicella vaccine licensed in U.S. 1995: Recommendations by ACIP & AAP 1 dose recommended for children 12-18 months Vaccination of susceptible older children, adolescents and adults June 2006: Updated ACIP Recommendations Additional 2nd dose of varicella vaccination to vaccine schedule for children 4-6 years Adults and adolescents > 13 yrs- 2 doses Let’s review the history of varicella vaccination in the U.S. March 1995: Live attenuated varicella vaccine licensed in U.S. 1995: Recommendations by ACIP (American College of Immunization Practices) & AAP (American Academy of Pediatrics) 1 dose recommended for children 12-18 months Vaccination of susceptible older children, adolescents and adults Adults and adolescents > 13 yrs- 2 doses, 4-8 weeks apart Despite the overall decline in varicella incidence, there were increasing reports of varicella outbreaks among highly vaccinated population. As a result, in June 2006: Recommendation of additional 2nd dose of varicella vaccination to childhood vaccination schedule for children 4-6 years

Varicella Active Surveillance Project, Antelope Valley, CA Project funded by Centers for Disease Control and Prevention One of two national sites for carrying out varicella and herpes zoster (HZ) surveillance Varicella surveillance: January 1, 1995 - present VASP is a joint cooperative research project with the CDC. One of two national sites for carrying out varicella and herpes zoster (HZ) surveillance- our second site in in West Philadelphia, PA Varicella surveillance has been conducted since- January 1, 1995 - present

Study Site: Antelope Valley, California Geographically circumscribed Located in Northeastern corner of Los Angeles County (LAC) Assumption: Most people that live in the Antelope Valley (AV) get their medical care locally and children attend schools in AV ~ 2,200 square miles with total population ~ 366,000 Mean birth cohort: 5,800 infants 2005-08 The Antelope valley in California is located in the northern Los Angeles County and the southeastern portion of Kern County and western tip of the Majove Desert. It is high desert community covers 2,200 square miles with total population 366,000. It is assumed that most people that live in the Antelope Valley get their medical care locally and children attend school in Antelope Valley. From 2005-2008 the mean birth cohort was 5,800 infants. D11:\Slide Template_DPH #3 No. 4

*National Immunization Survey Data Varicella Vaccination Coverage among Children 19-35 months*, Los Angeles County, CA , 1996-2008 Now let’s look at varicella vaccination coverage in Los Angeles County collected annually by the National Immunization Survey. Since 1996 single dose varicella vaccination coverage for children between 19-35 months has increased from 13% to over 90%., Coverage has maintained at over 90% since 2002. *National Immunization Survey Data D11:\Slide Template_DPH #3 No. 5 5

Objectives (1) Describe age- specific varicella incidence rate (IR) trends from 2000-08 Describe varicella vaccine doses administered in surveillance area from 2000-08 Compare IR of varicella disease during end of single dose varicella vaccination era (2005-2006) compared to IR from initiation of two dose era (2007-2008) Calculate relative risk (RR) of 1 dose exposure IR versus 2 dose exposure IR for varicella disease The objectives of this presentation are : Describe age- specific varicella incidence rate (IR) trends from 2000-08. Describe varicella vaccine doses administered in surveillance area from 2000-08. Compare IR of varicella disease during end of single dose varicella vaccination era (2005-2006) compared to IR from initiation of two dose era (2007-2008). Compare the proportion of verified breakthrough (BT) varicella during the 2 time periods. Describe the clinical presentation of varicella disease during these 2 time periods.

Objectives (2) Compare the proportion of verified breakthrough (BT) varicella during the 2 time periods Describe the clinical presentation of varicella disease during these 2 time periods The objectives of this presentation are : Describe age- specific varicella incidence rate (IR) trends from 2000-08. Describe varicella vaccine doses administered in surveillance area from 2000-08. Compare IR of varicella disease during end of single dose varicella vaccination era (2005-2006) compared to IR from initiation of two dose era (2007-2008). Compare the proportion of verified breakthrough (BT) varicella during the 2 time periods. Describe the clinical presentation of varicella disease during these 2 time periods. D11:\Slide Template_DPH #3 No. 7 7

Methods: Data Collection Cases ascertained through active surveillance Surveillance sites report every 2 weeks, even if no cases identified Reporting sites (n=310) include schools, day cares, healthcare providers, large employers Each case interviewed by telephone to collect detailed demographic and clinical data Surveillance sites report vaccine doses by age quarterly Merck also reports to the project annual vaccine doses supplied to Antelope Valley The VASP conducts varicella case surveillance through active surveillance- All surveillance sites report every 2 weeks, even if no cases identified Reporting sites (>300) include schools, day cares, healthcare providers, large employers, etc. Each case interviewed by telephone to collect detailed demographic and clinical data Clinical data- rash description, # lesions, accompanying symptoms (i.e. fever, sore throat), complications, antiviral treatment Vaccine providers reported varicella vaccine doses administered by age group on a monthly basis. In addition, Mark also reports to the project annual vaccine doses supplied to Antelope Valley.

Case Definitions Verified varicella case Acute onset diffuse papulovesicular rash without other known cause (diagnosed by parent, school, medical provider) Case report completed validating the clinical diagnosis Resident of Antelope Valley Breakthrough varicella case Illness >42 days after varicella vaccination Let’s review our case definitions: Verified varicella case Acute onset diffuse papulovesicular rash without other known cause (diagnosed by parent, school, medical provider) Completion of case report validating the clinical diagnosis Resident of Antelope Valley Breakthrough varicella disease Meets criteria of verified varicella case Varicella disease > 42 days after vaccination (confirmed by immunization record or provider office)

Methods: Data Analysis Incidence Rate (IR) calculation Numerator- all verified varicella cases for the specified year Denominator- age-specific US census data for Antelope Valley by specified year Compare 2 year IR: 2005-06 versus 2007-08 Mantel Haenzel RR: to compare incidence rates 2005-06 and 2007-08 Chi square test All data was entered via Microsoft Access and data analysis was performed with SAS 9.2. Only verified cases were included in the analysis. Varicella incidence rate were calculated using 2005-08 US AV census data as denominators. The relative risk of acquiring varicella in the one dose era compared to the 2-dose vaccine era was calculated comparing the incidence of varicella from 2005-6 to the incidence of varicella during 2007-8. The Chi-square test was used to assess statistical significance among variables.

Results: Total Annual Varicella Vaccine Doses Administered, Antelope Valley, CA, 2000 - 2008 Now let’s look at the total vaccination doses administered by vaccine providers since 2000 Total vaccination doses in AV VASP increased from 5,721 doses to over 18,000 doses. Increases notable by 2007 with 2nd dose requirement. From 2006 to 2008- the vaccine doses increased from 14,858 in 2005-2006 to 37,107 doses in 2007-2008.

Results: Annual Varicella Vaccine Doses by Age-Group, Antelope Valley, CA, 2000 - 2008 This slide presents the annual vaccine doses ADMINSTERED by specific age group IN ANTELOPE VALLEY DURING 2000-2008. The violet represents the 1-2 year age group, the group where the 1st dose of varicella vaccine has been consistently recommended, this is the group where the greatest proportion of vaccine has been administered. YOU CAN see the vaccine doses increased IN THIS AGE GROUP from 2000 through 2006. For unclear reason, the total number of vaccine doses in this age group declined slightly in 2007-08. After the 1-2 year old group, the 5-9 year old group had the 2nd to the largest amount of delivered doses. This is most likely due to the school entry requirement, starting in 1999 in CA. With the 2nd dose recommendation, vaccination doses ADMINISTERED increased significantly in the 5-9 year, 10-12, and 13-19 AGE GROUPS in 2007. THERE WERE 37,107 doses ADMINISTERED in 2007 and 2008 compared to 14,983 in 2005 and 2006.

Results: Overall Varicella Incidence Rates by Year, Antelope Valley, CA, 2000-2008 With corresponding increasing in vaccine doses delivered to the surveillance sites, there was an overall varicella IR declined from 2000-2008. Overall varicella IR from 2000 has declined from 2.7 per 1000 population to -0.6 per 1000. The numbers of cases were also declined by 286% from 2000 to 2008. This decline steadily continued from 2006-2008.

Results: Age-Specific Varicella Incidence Rates, Antelope Valley, CA, 2000-2008 Age specific incidence rates across all age groups from 2000-2003 showed a steady decline. There is a noticeable increase in 2004 DUE TO a resurgence of breakthrough varicella outbreaks. We see in all age groups, especially 5-9 years. Varicella IR declined 2004-2008 with consistent stead decline across all groups 2006-2008 with the exception of 15-19 year old group.

Results: Age-specific Varicella Incidence Rate, Antelope Valley, CA, 2005-2008 Age-group 2005-2006 2007-2008 RR (95% CI) P-Value n (%) IR < 1* 36 (4.8) 3.3 24 (4.7) 2.0 1.7 (1.27-2.13) 0.0422* 1 – 4* 92 (12.1) 2.2 72 (14.0) 1.5 1.5 (1.28-1.72) 0.0246* 5 – 9** 286 (37.8) 5.4 179 (34.9) 3.5 1.5 (1.36-1.64) 0.0001** 10 – 14** 249 (32.9) 3.8 168 (32.7) 2.7 1.4 (1.26-1.54) 0.0008** 15 – 19 38 (5.0) 0.6 37 (7.2) 0.5 1.2 (0.93-1.47) 0.8084 > 19** 56 (7.4) 0.12 33 (6.4) 0.07 1.7 (1.45-1.95) 0.0059** Total 757 (100) 1.1 513 (100) 0.7 1.6 (1.52-1.68) Now, I would like to present a comparison of incidence rates by 2 year intervals- 2005-06 (THE END OF THE 1 DOSE ERA) and 2007-08 (THE INITIATION OF THE 2 DOSE ERA). All age groups, with the exception of 15-19 years, there was a greater IR DURING THE END OF THE one dose ERA compared to THE INITIATION OF THE 2 dose era. BASED ON our Relative Risk Calculations, THE RISK OF VARICELLA WAS GREATER DURING THE END OF THE ONE DOSE ERA COMPARED TO THE INITIATION OF THE 2 DOSE ERA. THE CHI-SQUARE TEST ALSO SHOWED SIGNIFICANT DECLINE IN IR during the initiation of the 2-dose era AMONG ALL AGE-GROUPS, ECXEPT 15-19 YEARS OLD. Significant decline in IR from 2005-2006 to 2007-2008, P<0.05* & P<0.01**

Results: Varicella Breakthrough (BT) Cases by Age-Group, Antelope Valley, CA, 2005-2008 Verified BT cases also declined in 2007-2008 compared to the number reported in 2005-2006. Of 1270 verified cases documented from 2005-08, 727 cases were breakthrough (BT). The highest breakthrough varicella cases documented among 5-9 age-groups during these 2 periods. The overall proportion of breakthrough (BT) cases declined among all age groups by 32.3% from 414 in 2005-2006 to 313 in 2007-2008. Although the largest proportion of BT cases were among 5-9 age-group during these two periods, it also showed a declined by 55% from 242 to 156, respectively. The median age of BT cases also increased from 8 years in 2005-2006 to 9 years in 2007-08.

Results: Clinical Presentation of Varicella Disease, Antelope Valley, CA, 2005-2008 2005-2006 n (%) 2007-2008 Rash Description Maculo-papular* 472 (62.2%) 256 (69.5%) Vesicular* 287 (36.7%) 117 (22.9%) Max. # Lesions <50 lesions* 403 (55.2%) 288 (62.1%) 50-250 252 (34.5%) 140 (30.1%) >250 59 (9.2%) 30 (6.5%) With increasing varicella doses in 2007-2008, the clinical presentation had a greater proportion with maculo papular presentation and fewer that reporter vesicular presentation. With THE increasing NUMBER OF varicella vaccine doses ADMINISTERED in 07-08, a significantly greater proportion of cases had fewer THAN 50 lesion (<50 lesion). * P <0.05

Conclusions (1) Coincident with implementation of the 2 dose vaccination recommendations, varicella cases and disease incidence declined across most age groups The most substantial IR declines were among the 5-9 and the 10-14 year age group There was a significant decline in the proportion of BT cases reported in the 2 dose versus 1 dose era To summarize our findings- Coincident with implementation of the 2 dose vaccination recommendations, varicella cases and disease incidence declined across most age groups. There was a 47.6 % overall decline in overall incidence from 2005-2006 compared to 2007-2008. The most substantial IR declines were among 5-9 and the 10-14 year age group. There was also a significant decline in the proportion of BT cases reported in the 2 dose versus 1 dose era. A greater proportion of reported varicella cases were described to have milder clinical presentations (cases with <50 lesions) with the introduction of the second dose recommendation. Continued surveillance and epidemiologic studies are needed to further assess the impact of routine 2-dose varicella vaccination in children.

Conclusions (2) A greater proportion of reported varicella cases were described to have milder clinical presentations (cases with <50 lesions) with the introduction of the second dose recommendation Continued surveillance and epidemiologic studies are needed to further assess the impact of routine 2-dose varicella vaccination in children To summarize our findings- Coincident with implementation of the 2 dose vaccination recommendations, varicella cases and disease incidence declined across all age groups. There was a 47.6 % overall decline in overall incidence from 2005-2006 compared to 2007-2008. The most substantial IR declines were among 5-9 and the 10-14 year age group. There was also a significant decline in the proportion of BT cases reported in the 2 dose versus 1 dose era. A greater proportion of reported varicella cases were described to have milder clinical presentations (cases with <50 lesions) with the introduction of the second dose recommendation. Continued surveillance and epidemiologic studies are needed to further assess the impact of routine 2-dose varicella vaccination in children. D11:\Slide Template_DPH #3 No. 19 19

Study Limitations (1) Only two years of data analyzed post- 2nd dose recommendation Longer term data needed to establish clear incidence trends Varicella clinical presentation is evolving and becoming increasingly mild Could lead to missed varicella disease reports and underestimating true incidence There are some important study limitations to consider: 1. We examined only two years of data post- 2nd dose recommendation, Longer term data needed to establish clear incidence trends 2. Varicella disease clinical presentation is evolving and becoming increasingly milder Mild clinical presentations could lead to missed varicella disease reports and underestimating true incidence

Study Limitations (2) Varicella case definition based on clinical presentation and not laboratory confirmation “Reporting Fatigue” among surveillance sites may result in missed disease reports Lack of 2 dose varicella vaccination coverage data in surveillance area We used vaccine doses administered as a proxy for 2 dose varicella vaccination coverage Additional study limitations include: 3. Varicella case definition based on clinical presentation and not laboratory confirmation 4. “Reporting Fatigue” among surveillance sites may result in missed disease reports We used vaccine doses administered as a proxy for 2 dose varicella vaccination coverage.

Acknowledgements Laurene Mascola, MD, MPH, VASP Principal Investigator Rachel Civen, MD, MPH, VASP Co-Principal Investigator VASP Research Staff Christina Jackson, MPH Karen Kuguru, MS Michael Borquez Michelle Armijo Division of Viral Diseases, NCIRD, Centers for Disease Control and Prevention, Stephanie Bialek, MD, MPH Adrianna Lopez, MPH

QUESTIONS AND ANSWERS ? ? ? ? ? ? ?

Breakthrough Varicella Cases, Antelope Valley, CA, 2000-2008