The Influence of Inaccurate Vaccine Brand Identification On the Analysis of Hib Vaccination Coverage Rates From Immunization Information System Data Karen E. White, MPH Epidemiologist/Business Analyst Minnesota Department of Health Presented by: Kris Ehresmann, MPH, RN Division Director, Infectious Disease Epidemiology, Prevention and Control April 21, 2010

Resurgence of rare disease leads to warning: Vaccinate Hib infection in children makes a deadly return In January 2009, the Minnesota Department of Health noted an increase in cases of invasive Haemophilus Influenzae type b, or Hib, in children. These are some headlines from the Minnesota Star-Tribune, USA-Today, and the Washington Post, describing an unusual increase, and urging parents to vaccinate their children. At this time, staff in Minnesota and at CDC wondered if “Minnesota was like a canary in a coal-mine”, was an indicator of what might occur throughout the U.S. During this seminar, I will tell you more about the public health response to possible outbreak. Infections May Indicate Deadly Bug's Comeback January 2009

Haemophilus influenzae Gram-negative rod Encapsulated strains express antigenically distinct capsular polysaccharides Serotypes a-f Encapsulated and nonencapsulated cause invasive and non-invasive disease Type b caused most invasive disease Haemophilus influenzae is a gram-negative rod. Encapsulated strains express antigenically distinct capsular polysaccharides, and are referred to as serotypes a through f. Both encapsulated and non-encapsulated strains can cause invasive and non-invasive disease. Prior to the availability of the vaccine, type b caused most invasive disease.

Haemophilus influenzae type b Major cause of morbidity and mortality in children < 5 years > 20,000 cases annually in the United States prior to vaccine introduction 5% case-fatality ratio Leading cause of bacterial meningitis in countries with no Hib vaccine In the US, Haemophilus influenzae type b was a major cause of morbidity and mortality in children under five years of age, with over 20,000 cases occurring annually prior to vaccine introduction and a case-fatality ratio of 5%. It remains a leading cause of bacterial meningitis in countries with no Hib vaccine.

Cases of Hib in Children < 72 Months of Age, Minnesota, 1983–2007 Year of Diagnosis Number of Cases Conjugate vaccine licensed for >2 months (1990) Conjugate vaccine licensed for >15 months (1989) Polysaccharide vaccine licensed >18 months (1985) 50 100 150 200 250 300 1983 1987 1991 1995 1999 2003 2007 This figure shows the numbers of invasive Hib cases in children <72 months of age reported from 1983 until 2007 in Minnesota. The first Hib vaccine, a polysaccharide vaccine, was licensed for children greater than 18 months of age in 1985 in the US. A conjugate vaccine became available for children greater than or equal to 15 months of age in 1989. Finally, a Hib conjugate vaccine for infants was licensed in 1990, and lead to the near-elimination of this major cause of invasive infections. After the conjugate vaccine was licensed, cases dropped from hundreds each year to no more than two per year in the past decade.

Invasive Hib Cases <5 Years of Age, Minnesota, 1992–2008 This graph shows the number of invasive Hib cases among children less than 5 years of age in Minnesota from 1992 through 2008. In 2008 the Minnesota Department of Health detected 5 cases of invasive Hib disease, the most since 1992. MMWR.1/23/09. 58:1-3.

Hib Cases, Minnesota, 2008 (n=5) St. Louis Fillmore Dakota Lyon Lac Qui Parle Anoka All different counties All in south-central part of state No known relationship All of the cases were from different counties but all were found in the south-central part of the state, highlighted in red. They had no known relationship to each other.

Hib-containing Vaccines 2008 Company Primary Series Booster Dose Merck 2 doses 2 and 4 mo 1 booster 12-15 months Sanofi-Pasteur 3 doses 2, 4, and 6 mo To give you a better perspective on what complete or incomplete vaccination against Hib means, this slide summarizes Hib-containing vaccines produced in 2008 Merck and Sanofi-Pasteur were the main vaccine manufacturers. The Merck product is given as a two dose series at ages 2 and 4 months. The Sanofi-Pasteur product is given as a three dose primary series at ages 2, 4, and 6 months. With either type of product, a booster dose was recommended at 12-15 months of age.

Merck PedvaxHib (Hib-OMP) Recall December 2007 FDA web site “These lots of PedvaxHIB and COMVAX are being recalled due to lack of assurance of product sterility.” ACIP recommended 4th dose booster be deferred Manufacture PedvaxHib suspended Sanofi Pasteur ActHib (Hib-PRP-TT) was still available Pentacel (DTaP/Polio/Hib) became available late 2008 CDC maintained stores of non-recalled lots of PedvaxHib for high-risk groups (AI/AN) where Hib-OMP is the vaccine of choice with higher antigenicity

All Hib Vaccination Brands Given During 2008 by Market Share, Minnesota Sentinel Site, N=7,664 60.0 PedvaxHib 50.0 Comvax 40.0 ActHib Percent 30.0 Pentacel 20.0 10.0 NOS 0.0 Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec Month

MN Children Under-Vaccinated? Initial estimates of Hib coverage rates Cohort examined contained children who would be vaccinated after recall 11/01/2007-3/31/2008 Compared to other vaccines received at 2, 4 and 6 months of age: DTaP and PCV7 Rates appeared up to 10% lower at 12 months of age than other vaccines given on the same schedule

Happening in other states? Sentinel Site Area Cohort 11/2007-3/2008 Hib DTaP PCV7 % Difference N UTD % p-value Arizona 4,642 56.4 55.7 NS 54.0 +1.6 Colorado 843 52.6 62.3 <0.01 60.0 -8.6 Michigan 34,405 64.0 72.9 70.6 -7.8 Minnesota 7,664 53.4 62.6 62.0 -8.9 NY City 58,919 44.4 56.3 50.7 -9.1 N. Dakota 3,778 61.8 72.4 71.4 -10.1 Oregon 7,216 56.9 67.6 65.2 -9.5 Wisconsin 6,094 66.6 78.1 75.7 -10.3

Problems with the data… Reporting of discontinued brands Hib-PRP-D Hib-HbOC Merck lot numbers on Sanofi vaccinations 9999A Sanofi lot numbers on Merck vaccinations AA999AA Non-brand-specific vaccination data Historical shots Incomplete data submitted for administered shots

Data cleanup included Recoding based on lot number Calling provider organizations to see what they really gave instead of discontinued brands – always turned out to be ActHib Estimation of unknown brands Proportion Merck vs Sanofi distributed through Vaccines for Children program

Minnesota – Sentinel Site Data, n=7664 UTD Hib vaccine at 9 months, 07-08 cohort UTD with 2 doses of Merck or 3 doses of other brands Hib vaccine doses* 9 months 2 Merck doses1 337 3 Sanofi doses2 1471 1 Merck + 1 Sanofi or 1 NOS + 1 Merck (in that order) 40 1 Merck only + 2 Sanofi 283 1 Merck only + 2 Hib NOS3 223 1 Merck only + 1 Sanofi only + 1 Hib NOS 70 1 Sanofi only + 2 Hib NOS 293 2 Sanofi only + 1 Hib NOS 299 3 Hib NOS 1013 Total 4029 (53%) Not UTD with only 2 Hib vaccine doses Hib vaccine doses 9 months 2 Sanofi doses only 560 1 Merck only + 1 Sanofi only 111 1 Merck only + 1 NOS only 246 1 Sanofi only + 1 NOS only 241 2 NOS only 459 Total 1617 Vaccines for Children 2008 Merck 9.2% Sanofi 90.8% 23 + 42 UTD +4029 4094/7664 = 53.4%

Minnesota – Sentinel Site Data, n=7664 UTD Hib, PCV and DTaP at 9 months, 07-08 cohort Vaccine UTD at 9 months Hib 4094/7664 (53.4%) PCV7 4749/7664 (62.0%) DTaP 4797/7664 (62.6%) - 8.9% Hib percent is 8.9% lower than the average of PCV7 and DTaP

Minnesota – Sentinel Site Data, n=7059 UTD Hib vaccine at 9 months, 06-07 cohort UTD with 2 doses of Merck or 3 doses of other brands Hib vaccine doses* 9 months 2 Merck doses 3425 3 Sanofi doses2 284 1 Merck + 1 Sanofi or 1 NOS + 1 Merck (in that order) 45 1 Merck only + 2 Sanofi 11 1 Merck only + 2 Hib NOS3 32 1 Merck only + 1 Sanofi only + 1 Hib NOS 6 1 Sanofi only + 2 Hib NOS 17 2 Sanofi only + 1 Hib NOS 7 3 Hib NOS 164 Total 3991 (56.5%) Not UTD with only 2 Hib vaccine doses Hib vaccine doses 9 months 2 Sanofi doses only 125 1 Merck only + 1 Sanofi only 52 1 Merck only + 1 NOS only 131 1 Sanofi only + 1 NOS only 24 2 NOS only 972 Total 1304 Vaccines for Children 2007 Merck 89.9% Sanofi 10.1% 118 + 874 UTD +3991 4983/7059 = 70.6%

Minnesota – Sentinel Site Data, n=7059 UTD Hib, PCV and DTaP at 9 months, 06-07 cohort Vaccine UTD at 9 months Hib 4983/7059 (70.6%) PCV7 4648/7059 (65.8%) DTaP 4718/7059 (66.8%) Hib percent is 4.3 percent higher than the average of PCV7 and DTaP + 4.3%

Why was the rate lower in 2008? Not enough vaccine available to cover the primary series? CDC had evidence that there was enough Confusion regarding schedules in vaccinators? Force of habit – used to giving 2-dose Merck product

Schedule Differences by Brand for the Same Vaccine Type Rotavirus Rotarix – 2 doses at 2 and 4 months Rotateq = 3 doses at 2, 4, and 6 months

Proactive Measures to Prevent Vaccine Type Confusion in IIS Data Continuous update of codes available on-line at MIIC technical web page Notification of IT specialists via “GovDelivery” when changes occur Prompt follow-up with provider organizations who continue to use deleted codes