Influenza Disease Burden and Influenza Vaccine Options 1
Influenza Disease Burden and Influenza Vaccine Options 1
Influenza Affects Millions of People Each Year in the United States Deaths Hospitalizations >200, 0001* ≈36, 0001* Physician visits ≤ 25 million 2 Infections† ≈15 to 60 million 1, 3 *All-cause hospitalization and mortality associated with influenza virus infection. †Includes symptomatic and asymptomatic infections. 1. CDC. Influenza (flu) Fact Sheet. Available at: http: //www. cdc. gov/flu/keyfacts. htm. Accessed May 14, 2007. 2. Couch RB. Ann Intern Med. 2000; 133: 992 -998. 3. U. S. Census Bureau. Available at: http: //www. census. gov/main/www/popclock. html. Accessed May 24, 2007. 2
Children Are Primary Vectors Other children Family members and other close contacts Children Day care, preschool and school-age Community including high-risk populations 1. Glezen WP, et al. N Engl J Med. 1978; 298: 587 -592. 2. Weycker D, et al. Vaccine. 2005; 23: 1284 -1293. 5
P&I* Mortality Rate 14 70 All-cause Mortality Rate 12 60 10 50 8 40 6 30 4 20 10 0 19 98 19 94 1987: Parents allowed to refuse vaccination 19 86 19 82 19 78 19 74 19 70 19 62 19 58 19 54 19 50 0 19 66 1962: Program to vaccinate school children with inactivated influenza vaccine begins 19 90 2 Excess Deaths From All Causes (per 100, 000 Population) Excess Deaths From Pneumonia and Influenza (per 100, 000 Population) Japanese School Vaccination Program Reduced Mortality in the Community *P&I=pneumonia and influenza. Reichert TA, et al. N Engl J Med. 2001; 344: 889 -896. 6
2007 -2008 ACIP Recommendations • Routine vaccination is recommended for – All individuals, including school-age children, who want to reduce the risk of becoming ill with influenza or of transmitting influenza to others – Individuals at high risk for influenza-related complications and severe disease, including • • Children aged 6 to 59 months Pregnant women Individuals of any age with certain chronic medical conditions Adults aged ≥ 50 years – Household contacts (including children) and caregivers of • Children aged <5 years • Adults aged ≥ 50 years • Individuals at high risk – Healthcare personnel (HCP) Please refer to the specific prescribing information for each manufacturer’s influenza vaccine as not all influenza vaccines are indicated for each group within the ACIP recommendations. CDC. MMWR. 2007; 56(RR-6): 1 -54. 7
Estimated Pediatric Influenza Vaccination Rates in 2006 6 -23 Months Target Population Percent Vaccinated 24 -59 Months (High Risk) 24 -59 Months (Household Contacts) 24 -59 Months (Other) 5 -17 Years (High Risk) 5 -17 Years (Household Contacts) Population Estimate (Millions) Influenza target population: 218. 1 million (73. 1% of US population) Influenza target population aged 6 months to 17 years: 44. 6 million CDC. Influenza (flu). Available at: http: //www. cdc. gov/flu/professionals/vaccination/pdf/targetpopchart. pdf. Accessed April 8, 2006. 8
Compliance With Recommendations for 2 Doses of Influenza Vaccine in Vaccine-naïve Children* n=85, 631 In a study of children receiving inactivated influenza vaccine: • Less than 25% of children aged 2 -8 years who were vaccinated received a second dose • Highest compliance for 2 nd dose occurred when first vaccination was early (before mid-November) Influenza Season *Data from 85, 631 children aged 2 to 8 years who received their first inactivated influenza vaccine dose in the 2001 -2002, 2002 -2003, or 2003 -2004 influenza seasons (US). Adapted from Jackson LA, et al. Pediatrics. 2006; 118: 2032 -2037. 9
Structure of the Influenza Virus Hemagglutinin (HA) Neuraminidase (NA) M 2 Nucleoprotein (NP) M 1 Polymerase Proteins (PP) Adapted from: Hayden FG, Palese P. Clinical Virology. 6 th ed. 1997: 911 -942. 10
Antigenic Drift and Shift Drift Shift • Minor change, within subtype • Major change, new subtype • Point mutations • Exchange of gene segments • Occurs in A and B subtypes • Occurs in A subtypes only • Can cause an epidemic • Can cause a pandemic Occurs Continuously Cox NJ, et al. Lancet. 1999; 354: 1277 -1282. Occurs Infrequently 11
Vaccine Mismatch Occurred in 5 of the Last 11 Years* Season Vaccine Strain Drifted Strain/ All Strains (All Isolates) 1997 -1998 A/Wuhan/(H 3 N 2) A/Sydney/(H 3 N 2) 77% 2000 -2001 B/Beijing B/Sichuan 40% 2003 -2004 A/Panama/(H 3 N 2) A/Fujian/(H 3 N 2) 82% 2004 -2005 A/Wyoming/(H 3 N 2) A/California/(H 3 N 2) 51% 2005 -2006 B/Shanghai B/Victoria 26% *CDC. MMWR. 1998: 47: 280 -284. Available at: http: //www. cdc. gov/mmwr/PDF/wk/mm 4714. pdf. Accessed July 7, 2006. CDC. Flu activity. Available at: http: //www. cdc. gov/flu/weekly/fluactivity. htm. Accessed June 20, 2006. 12
Influenza Vaccines Available in the United States Flu. Mist® (Influenza Virus Vaccine Live, Intranasal)* Trivalent Inactivated Influenza Vaccine (Intramuscular) • Attenuated vaccine with multiple antigens 1, 2 • HA is the only standardized component; other antigens may be present 3, 4 *Image adapted from: Clinical Virology. 6 th ed. 1997: 911 -942. 1. Flu. Mist [prescribing information]. Gaithersburg, MD: Med. Immune Vaccines, Inc. ; 2007. 2. Hayden FG, et al. Clinical Virology. 6 th ed. 1997; 911 -942. 3. Fluzone® [prescribing information]. Swiftwater, PA: Sanofi-Pasteur, Inc. ; 2006. 4. Fluvirin® [prescribing information]. Emeryville, CA: Novartis Vaccines and Diagnostics, Inc. ; 2006. 13
What Is Flu. Mist (Influenza Virus Vaccine Live, Intranasal)? • Flu. Mist is a live, attenuated, cold-adapted (1), Ig. A 1 (Ig. G) Ig. A temperature-sensitive (2), trivalent intranasalmist influenza virus vaccine 1 • Contains attenuated live vaccine strains that are engineered not to cause disease 1 • Designed to stimulate an immune response that more closely resembles the body’s response to natural infection 2* 2 Ig. G *Immune mechanisms conferring protection against influenza following receipt of Flu. Mist vaccine are not fully understood. 1 1. Flu. Mist [prescribing information]. Gaithersburg, MD: Med. Immune Vaccines, Inc. ; 2007. 2. Cox RJ, et al. Scand J Immunol. 2004; 59: 1 -15. 14
Flu. Mist Versus Inactivated Influenza Vaccine: Comparative Pivotal Study Design • Randomized, double-blind, double-dummy, multinational study, 2004 -2005 influenza season (enrollment October 2004)1 • 8475 children aged 6 to 59 months were enrolled 1 • Principal exclusion criteria 1, 2 – Children with wheezing, steroid use (systemic or inhaled), or – – – bronchodilator use within 42 days of enrollment Children with a history of severe asthma Children with a known immunosuppressive condition Children with a history of hypersensitivity to any component of the live attenuated vaccine or the inactivated vaccine Children with body temperature higher than 37. 8°C (100°F) measured orally or the equivalent within 3 days of enrollment Use of aspirin or salicylate-containing products within 30 days of enrollment 1. Belshe RB, et al. N Engl J Med. 2007; 356: 685 -696. 2. Data on file. Med. Immune, Inc. 15
Flu. Mist Versus Inactivated Influenza Vaccine: Comparative Pivotal Study Design (Cont’d) • Randomization was stratified by the following baseline characteristics 1, 2: – Age on receipt of first dose • 6 -23 months or 24 -35 months or 36 -59 months – Presence or absence of previous influenza vaccination – Presence or absence of history of recurrent wheezing • ≥ 3 wheezing episodes, each requiring medical follow-up or hospitalization – Country of residence 1. Belshe RB, et al. N Engl J Med. 2007; 356: 685 -696. 2. Data on file. Med. Immune, Inc. 16
Flu. Mist Versus Inactivated Influenza Vaccine: Comparative Pivotal Study Design (Cont’d) Efficacy • Primary endpoint – Culture-confirmed modified CDC-ILI against antigenically matched influenza virus strains • Secondary endpoint – Culture-confirmed modified CDC-ILI against antigenically mismatched influenza virus strains Safety • Medically significant wheezing (MSW) – Prospectively defined safety endpoint of primary interest – Defined as the presence of wheezing on a physical examination conducted by a healthcare provider, with a prescription for a daily bronchodilator; respiratory distress; or hypoxemia ILI=influenza-like illness. Belshe RB, et al. N Engl J Med. 2007; 356: 685 -696. 17
Influenza Cases Reported During the Study Period Children Aged 24 -59 Months Treatment for Safety Population (Actual Received) Percentage Vaccine No. of Cases Attack Rate Inactivated Influenza Vaccine 205 9. 8% Flu. Mist 94 4. 5% RR, 54. 4% (95% CI: 41. 8, 64. 5) Inactivated Influenza Vaccine Flu. Mist November 2004 December 2004 January 2005 February 2005 March 2005 April 2005 May 2005 June 2005 Surveillance Period Surveillance was on the first day of each month. Data on file. Med. Immune, Inc. 18
Comparative Efficacy of Flu. Mist and Inactivated Influenza Vaccine: Primary Endpoint Children Aged 24 to 59 Months During the 2004 -2005 Influenza Season* Rate (%) Matched Efficacy Against Influenza Illness 52. 5% REDUCTION in flu cases (95% CI: 26. 7, 69. 7) (n=2082) (n=2084) 30 cases 61 cases *Data are representative of the indicated population; full study population is represented in the Prescribing Information and in the New England Journal of Medicine. 2007. The rates for Flu. Mist vs the inactivated influenza vaccine for all matched strains circulating during the 2004 -2005 flu season were as follows: A/New Caledonia (H 1 N 1) (0. 0% vs 1. 0%), A/Wyoming (H 3 N 2) (0% vs 0%), and matched B/Yamagata lineage (1. 4% vs 1. 9%, NS), respectively. 1. Flu. Mist [prescribing information]. Gaithersburg, MD: Med. Immune Vaccines, Inc. ; 2007. 2. Belshe RB, et al. N Engl J Med. 2007; 356: 685 -696. 3. Data on file. Med. Immune, Inc. 19
Comparative Efficacy of Flu. Mist and Inactivated Influenza Vaccine: Secondary Endpoints Children Aged 24 to 59 Months During the 2004 -2005 Influenza Season* Mismatched Efficacy Against Influenza Illness Rate (%) 54. 2% REDUCTION in flu cases (95% CI: 38. 8, 66. 0) (n=2082) (n=2084) 67 cases 147 cases *Data are representative of the indicated population; full study population is represented in the Prescribing Information and in the New England Journal of Medicine. 2007. The rates for Flu. Mist vs the inactivated influenza vaccine for all mismatched strains circulating during the 2004 -2005 flu season were as follows: A/California-like (H 3 N 2) (1. 2% vs 4. 9%) and mismatched B/Yamagata lineage and B/Victoria (2. 1% vs 2. 3%, NS), respectively. 1. Flu. Mist [prescribing information]. Gaithersburg, MD: Med. Immune Vaccines, Inc. ; 2007. 2. Belshe RB, et al. N Engl J Med. 2007; 356: 685 -696. 3. Data on file. Med. Immune, Inc. 20
Comparative Efficacy of Flu. Mist and Inactivated Influenza Vaccine: Secondary Endpoints (Cont’d) Children Aged 24 to 59 Months During the 2004 -2005 Influenza Season* Overall Efficacy Against Influenza Illness Rate (%) 54. 4% REDUCTION in flu cases (95% CI: 41. 8, 64. 5) (n=2082) (n=2084) 94 cases 205 cases *Data are representative of the indicated population; full study population is represented in the Prescribing Information and in the New England Journal of Medicine. 2007. The rates for Flu. Mist vs the inactivated influenza vaccine for all strains circulating during the 2004 -2005 flu season were as follows: A/New Caledonia (H 1 N 1) (0. 0% vs 1. 0%), A/Wyoming (H 3 N 2) (0% vs 0%), A/California-like (H 3 N 2) (1. 2% vs 4. 9%), matched B/Yamagata lineage (1. 4% vs 1. 9%, NS), and mismatched B/Yamagata lineage and B/Victoria (2. 1% vs 2. 3%, NS), respectively. 1. Flu. Mist [prescribing information]. Gaithersburg, MD: Med. Immune Vaccines, Inc. ; 2007. 2. Belshe RB, et al. N Engl J Med. 2007; 356: 685 -696. 3. Data on file. Med. Immune, Inc. 21
Maximize Early Vaccination Opportunities • Flu. Mist is expected to be available prior to the start of the influenza vaccination season, so you can vaccinate at regularly scheduled visits ― Well-child visits ― Back-to-school ― Sports physicals August September October November December January February • Starting vaccinations earlier can help protect more children at well-child visits through December 1, 2* *An analysis of well-child visits in the Medical Expenditure Panel Survey, U. S. Department of Health and Human Services (HHS). 1. United States Department of Health and Human Services. MEPS HC-089: 2004. Available at: http: //www. meps. ahrq. gov/mepsweb/data_stats/download_data_files_detail. jsp? cbo. Puf. Number=HC-089. Accessed March 21, 2007. 2. United States Department of Health and Human Services. MEPS HC-085 G: 2004. Available at: http: //www. meps. ahrq. gov/mepsweb/data_stats/download_data_files_detail. jsp? cbo. Puf. Number=HC-085 G. Accessed March 21, 2007. 22
2007 -2008 ACIP Recommendations: Early Vaccination • Healthcare providers should begin offering vaccination soon after vaccine becomes available and, if possible, by October, and should continue throughout the influenza season • “To avoid missed opportunities for vaccination, providers should offer vaccination during routine health-care visits or during hospitalizations whenever vaccine is available. ” CDC. MMWR. 2007; 56(RR-6): 1 -54. 23
CDC/ACIP Recommends Flu. Mist As an Option in Healthy Children As Young as 24 Months • On October 24, 2007, the CDC/ACIP expanded its recommendation for Flu. Mist (LAIV) in the Vaccines for Children (VFC) program to include all healthy children (those who do not have underlying medical condition that predispose them to influenza complications) 2 years through 18 years – This means that VFC Flu. Mist doses for the 2007 -2008 influenza season can now be administered to eligible children as young as 2 years of age CDC. Vaccines for Children (VFC) Resolutions, Influenza. http: //www. cdc. gov/vaccines/programs/vfc/downloads/resolutions/1007 influenza. pdf. Accessed November 6, 2007. 24
Indications and Usage • Flu. Mist is a live attenuated influenza virus vaccine indicated for the active immunization of individuals aged 2 to 49 years against influenza disease caused by influenza virus subtypes A and type B contained in the vaccine Flu. Mist [prescribing information]. Gaithersburg, MD: Med. Immune Vaccines, Inc. ; 2007. 25
Contraindications • Flu. Mist is contraindicated in individuals with a history of hypersensitivity, especially anaphylactic reactions, to eggs, egg proteins, gentamicin, gelatin, or arginine or with life-threatening reactions to previous influenza vaccinations • Flu. Mist is contraindicated in children and adolescents (2 -17 years of age) receiving aspirin therapy or aspirincontaining therapy, because of the association of Reye’s syndrome with aspirin and wild-type influenza infection See Warnings and Precautions for other limitations. Flu. Mist [prescribing information]. Gaithersburg, MD: Med. Immune Vaccines, Inc. ; 2007. 27
Warnings and Precautions • Do not administer Flu. Mist to children <24 months of age. In clinical trials, an increased risk of wheezing post-vaccination was observed in Flu. Mist recipients <24 months of age. An increase in hospitalizations was observed in children <24 months of age after vaccination with Flu. Mist • Flu. Mist should not be administered to any individuals with asthma and children <5 years of age with recurrent wheezing because of the potential for increased risk of wheezing post vaccination unless the potential benefit outweighs the potential risk • Do not administer Flu. Mist to individuals with severe asthma or active wheezing because these individuals have not been studied in clinical trials Please see PI for complete information, including all Warnings and Precautions. Flu. Mist [prescribing information]. Gaithersburg, MD: Med. Immune Vaccines, Inc. ; 2007. 28
Warnings and Precautions (Cont’d) • If Guillain-Barré syndrome has occurred within 6 weeks of any prior influenza vaccination, the decision to give Flu. Mist should be based on careful consideration of the potential benefits and potential risks • Administration of Flu. Mist, a live virus vaccine, to immunocompromised persons should be based on careful consideration of potential benefits and risks. Although Flu. Mist was studied in 57 asymptomatic or mildly symptomatic adults with HIV infection, data supporting the safety and effectiveness of Flu. Mist administration in immunocompromised individuals are limited • Safety has not been established in individuals with underlying medical conditions that may predispose them to complications following wild-type influenza infection. Flu. Mist should not be administered unless the potential benefit outweighs the potential risk Flu. Mist [prescribing information]. Gaithersburg, MD: Med. Immune Vaccines, Inc. ; 2007. 29
Contact With Immunocompromised Individuals • Current PI (Patient Counseling Information) – Vaccine recipients or their parents/guardians should be informed by the healthcare provider that Flu. Mist is an attenuated live virus vaccine and has the potential for transmission to immunocompromised household contacts 1 • Previous PI (Information for Vaccine Recipients or Parents/Guardians) – Due to the possible transmission of vaccine virus, vaccine recipients or their parents/guardians should be advised that vaccine recipients should avoid close contact (eg, within the same household) with immunocompromised individuals for at least 21 days 2 1. Flu. Mist [prescribing information]. Gaithersburg, MD: Med. Immune Vaccines, Inc. ; 2007. 2. Flu. Mist [prescribing information]. Gaithersburg, MD: Med. Immune Vaccines, Inc. ; May 2006. 30
Finnish Day Care Study: Transmission of Live, Attenuated Influenza Virus Strains • Randomized (1: 1), double-blind, placebo-controlled 1 • N=197 children aged 9 to 36 months attending day care 1 • Nasal cultures on the first 2 days after dosing and at least 3 times per week for 3 weeks 1 Transmission in Finnish Day Care Children 2 1 confirmed Type B 4 unconfirmed A strains plus 1 confirmed B Probability (95% CI)* 0. 58% (0%-1. 7%) 2. 4% (0. 13%-4. 6%) Comments 1 of 11 swabs positive (Day 15) Retained ts, ca, att phenotypes of the vaccine strain Samples not available for further characterization *Reed-Frost Model. • Low probability of Flu. Mist viral strain transmission 1 Do not administer Flu. Mist to children aged <24 months due to an increased risk of hospitalization and wheezing that was observed in clinical trials. Flu. Mist should not be administered to any individual with asthma and children aged <5 years with recurrent wheezing unless the potential benefit outweighs the potential risk. 1. Vesikari T, et al. Pediatr Infect Dis J. 2006; 25: 590 -595. 2. Flu. Mist [prescribing information]. Gaithersburg, MD: Med. Immune Vaccines, Inc. ; 2007. 31
Can Shedding or Transmission of Flu. Mist Lead to Illness? • “In rare instances, shed vaccine viruses can be transmitted from vaccine recipients to nonvaccinated persons. However, serious illnesses have not been reported among unvaccinated persons who have been infected inadvertently with vaccine viruses. ” 1 • A study of 197 children aged 9 to 36 months in close contact in a day care setting demonstrated a vaccine virus transmission rate of only 0. 58% to 2. 4%. In the single confirmed case: 2, 3 – The transmitted virus did not revert to wild-type 2, 3 – The child exhibited a mild cough and runny nose, but showed no other reactogenicity events or safety concerns 2 • Patient Counseling Information 3 – Vaccine recipients or their parents/guardians should be informed by the healthcare provider that Flu. Mist is an attenuated live virus vaccine and has the potential for transmission to immunocompromised household contacts § Note: there is no longer a specific recommendation in the Prescribing Information to avoid close contact with immunocompromised persons for 21 days Do not administer Flu. Mist to children aged <24 months due to an increased risk of hospitalization and wheezing that was observed in clinical trials. Flu. Mist should not be administered to any individual with asthma and children aged <5 years with recurrent wheezing unless the potential benefit outweighs the potential risk. 1. CDC. MMWR. 2007; 56(RR-6): 1 -54. 2. Vesikari T, et al. Pediatr Infect Dis J. 2006; 25: 590 -595. 3. Flu. Mist [prescribing information]. Gaithersburg, MD: Med. Immune Vaccines, Inc. ; 2007. 32
Use in Specific Populations: Pregnancy Category C • Animal reproduction studies have not been conducted with Flu. Mist. It is not known whether Flu. Mist can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Flu. Mist should be given to a pregnant woman only if clearly needed Flu. Mist [prescribing information]. Gaithersburg, MD: Med. Immune Vaccines, Inc. ; 2007. 33
Concomitant Use With Live Vaccines • Concurrent administration of Flu. Mist with the measles, mumps and rubella vaccine and the varicella vaccine was studied in 1245 children 12 -15 months of age • Adverse events were similar to those seen in other clinical trials with Flu. Mist • No evidence of interference with immune responses to measles, mumps, rubella, varicella and Flu. Mist vaccines was observed • The safety and immunogenicity in children >15 months of age have not been studied Flu. Mist [prescribing information]. Gaithersburg, MD: Med. Immune Vaccines, Inc. ; 2007. 34
Storage and Handling • Flu. Mist should be stored in a refrigerator between 2 -8°C (35 -46°F) upon receipt and until use before the expiration date on the sprayer label • Do not freeze • Cold chain (2 to 8°C) must be maintained when transporting Flu. Mist [prescribing information]. Gaithersburg, MD: Med. Immune Vaccines, Inc. ; 2007. 35
For Medical Information About Flu. Mist, Call: 1 -877 -FLUMIST (1 -877 -358 -6478) www. flumist. com 36
Healthcare Personnel and Influenza • ACIP recommendations: 2007 to 2008 – All healthcare personnel (HCP) should be vaccinated against influenza annually • Applies to physicians, nurses, other workers in hospital and outpatient care settings, and medical emergency response workers, as well as those in training to be healthcare providers – Facilities should provide vaccine to workers using approaches that are effective in increasing vaccination levels • HCP influenza vaccination rate in 2005 was 33. 5% – “Studies have demonstrated that organized campaigns can attain higher rates of vaccination among HCP with moderate effort and using strategies that increase vaccine acceptance. ” Please refer to the specific prescribing information for each manufacturer’s influenza vaccine as not all influenza vaccines are indicated for each group within the ACIP recommendations. CDC. MMWR. 2007; 56(RR-6): 1 -54. 37
Flu. Mist Is Engineered Not to Cause Disease • Each of the 3 vaccine strains in Flu. Mist is 1 – Attenuated • Weakened so as not to cause influenza-like illness – Cold adapted • Replicates efficiently in the cooler temperatures of the nasopharynx – Temperature sensitive • Does not replicate efficiently in the warmer temperatures of the lower respiratory tract • Odds of reversion to wild-type are 1 in 1020 replication cycles 2, 3 1. Flu. Mist [prescribing information]. Gaithersburg, MD: Med. Immune Vaccines, Inc. ; 2007. 2. Smith DB et, al. J Gen Virol. 1987; 68: 2729 -2740. 3. Data on file. Med. Immune, Inc. 38
Individuals in Close Contact With High-risk Populations • Patient Counseling Information 1 – Vaccine recipients or their parents/guardians should be informed by the healthcare provider that Flu. Mist is an attenuated live virus vaccine and has the potential for transmission to immunocompromised household contacts § Note: there is no longer a specific recommendation in the prescribing information to avoid close contact with immunocompromised persons for 21 days • The CDC/ACIP states that individuals such as healthcare personnel (HCP) who are in contact with persons with less than severe immunodeficiency, including those with diabetes, asthma taking corticosteroids, or HIV, may receive Flu. Mist 2 – All individuals are included except those who have close contact with severely immunocompromised persons (eg, hematopoietic stem cell transplants) during those periods when the immunocompromised persons are in a protective environment 2 § “Neonates in an NICU are not considered severely immunocompromised. NICU personnel may receive LAIV [Flu. Mist] if otherwise eligible. . . ” 3 1. Flu. Mist [prescribing information]. Gaithersburg, MD: Med. Immune Vaccines, Inc. ; 2007. 2. CDC. MMWR. 2007; 56(RR-6): 1 -54. 3. Atkinson WL, et al. Needle Tips and Hepatitis B Coalition News. Volume 15: October 15, 2005. 39
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