Japanese encephalitis virus and rabies vaccines: how do we convince parents to give them to their traveling children? John C. Christenson, MD Ryan White Center for Pediatric Infectious Disease and Global Health Indiana University School of Medicine Riley Hospital for Children CISTM14, Quebec, Canada May 24, 2015 Disclosure information • I have NO financial relationships with the manufacturers of any commercial products and/or provider of commercial services discussed in this CME activity. • I do intend to discuss unapproved/investigative use of a commercial product/device in my presentation. • I acknowledge that today’s activity is certified for CME credit and thus cannot be promotional. I will give a balanced presentation using the best available evidence to support my conclusions and recommendations.

8/11/2015 3 Why do parents bring their children to travel clinic? • Required vaccine for entry into a country [yellow fever]. • Primary care physician told them to come. • Need for antimalarial prophylaxis. • Want to be completely prepared. • Need for “other” vaccines [hepatitis A, meningococcal, typhoid fever]. • While at visit [“by the way”]: how about rabies vaccine? How about Japanese encephalitis?

8/11/2015 4 Travel vaccines according to risk assessment • Give all available vaccines? • Prioritize recommended vaccines based on: severity, incidence among travelers, expected exposure? Give vaccine if: • High exposure rate [animal bites and rabies], and high mortality if disease develops. • Low exposure rate but with high mortality and sequelae if disease develops [JE].

8/11/2015 5 Animal bite with rabies risk

JEV

Rabies

Steffen R et al. J Travel Med 2015;22:1-12

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Steffen R, Connor BA. J Travel Med 2005;12:26-35 8/11/2015 7 Preventing “rare” infections in travelers: Japanese encephalitis, rabies • “Extremely” low risk of acquiring disease versus serious “untreatable” infections • Evolution of safer vaccines and immune globulins: Biken JE, equine rabies immune globulin • Lack of availability of rabies vaccine and immune globulin for postexposure prophylaxis. • Access to health care facility • Cost

8/11/2015 8 Missionary family to Thailand1

• 5 family members. Children: 7 & 5 years-old, and a 8 month-old. • Planning to stay in country for at least 30 years. Visit others countries in region. • Japanese encephalitis vaccine? • Rabies vaccine?

8/11/2015 9 Traveling to Vietnam to visit family1

• 15 month old boy is traveling with his parents to visit family near Ho Chi Minh City, small farming village near the Mekong River Delta. • Duration of stay: ~3 weeks • Offer Japanese encephalitis vaccine? • Offer rabies vaccines?

8/11/2015 10 Military family traveling to Cambodia for 2 years1 • Father is assigned to Joint POW/MIA Accounting Command. • Mother and 5 children are coming along. They will reside in embassy housing in Phnom Penh. • They anticipate shorts trips [≤7 days] to surrounding countries, including rural areas. • Offer Japanese encephalitis vaccine? • Offer rabies vaccine?

8/11/2015 11 Medical student is a doing an elective in Togo1

• Wants to bring family with him. • Duration of stay: ~2 months. • 11 month-old infant is coming with mother. She is breast feeding. • Rabies vaccine?

8/11/2015 12 High school students traveling in China1 • Visiting Beijing, Hong Kong, Shanghai, and Xian. • Staying in urban areas. • No visits planned to rural areas. • Large group. Traveling on tour buses. • Duration of trip: ~3 weeks • Offer Japanese encephalitis vaccine? • Offer rabies vaccine?

8/11/2015 13 Risk assessment rabies and JE • Rabies: frequent exposures, unknown number of cases prevented by postexposure prophylaxis. • ~1.1 per 100 travelers per month bitten by animals in Southeast Asia. 3.1 per 100 licked. • Japanese encephalitis: one-third of cases occurred in endemic areas with travel <1 month. ~60% in tourists. • Asymptomatic infection common. 1:200 develop clinical disease.

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Rabies risk

WHO Rabies: the facts • ~100% fatality. • ~50,000-55,000 people die from rabies worldwide each year. • 25,000-30,000 deaths in India alone. • >3 billion people live at risk. • 95% of reported rabies cases: Africa, Asia. • Mostly all bitten by rabid dog. • Preexposure prophylaxis: cost-effective? ~$275,000 per case prevented. • Over 10 years: 22 confirmed rabies in travelers. Africa, Asia, Central America, Haiti, Philippines [6/22 cases]. LeGuerrier P et al. Vaccine 1996;14:167-176. Animal-associated injuries, travelers • GeoSentinel Surveillance Network • 320 cases, 1998-2005 • Median duration of travel: 23 days. • Females > males. More likely to be <15 years. • More animal bites in SE Asia & rest of Asia. • 75% of bites occur in countries endemic for rabies. • Dogs: 51.3% [mostly males]. Monkeys: 21.2% [females] • 66.1% received postexposure prophylaxis.

Gautret P et al. Vaccine 2007;25:2656-2663. Rabies postexposure management, travelers, New Zealand • 459 post-travel, 1998-2006: two travel clinics. • 54 exposed to animals abroad. • Mean age: 30.4 years. Highest exposure risk: 16- 30 years of age [38.9%]. 0-15 years [16.7%]. Children 5-15 years: most affected by rabies. • South and SE Asia: 83.3% of exposures. • Most common animal: dogs [66.7%] • 90.7%: no preexposure prophylaxis.

Shaw MTM et al. J Travel Med 2009;16:13-17.

8/11/2015 19 Rabies post-exposure [PET], Australia, 2007-20112 780 persons exposed to mammals overseas: • Median age: ~33 years • Age 0-19 years: 32% • 456 [58.5%] received human rabies immune globulin [HRIG]. • 70 [9%] received HRIG abroad. • Mean delay injury-HRIG: 15 days. Kardamanidis K et al. Travel Med Infect Dis 2013;11:421-426. 8/11/2015 20 Rabies: an avoidable infection1 • Avoid exposures • Animal bites: 7th most common health problem, travelers. Children > adults [3-4X]. • Highest risk with longer trips. Median: 5 weeks [Menachem M et al. J Travel Med 2008;6:12-16.] • Dogs bites in 1.3% travelers, average stay, 32 days. • Backpackers, 54% of bites in first 10 days. • Tourists, expatriates, exposure to possible rabid animal: 0.19%-3.2%/year. Warrell MJ. Travel Med Infect Dis 2012;10:1-15.

8/11/2015 21 Rabies: an avoidable infection2

• Young children with lack of inhibitions, inability to protect themselves. • Asia: Playing with, feeding or patting monkeys at the “monkey forest” or “monkey temple”. • Travelers initiated contact with animal: 60%

Mills DJ et al. Med J Aust 2011;195:673-675.

8/11/2015 22 Rabies post-exposure [PET], Australia, 2007-20111 • Free rabies post-exposure treatment, New South Wales. • 1195 people received PET. 780 exposed abroad. 78.3% in SE Asia. 47.6% in Indonesia [Bali: 95.2%]. • Injuries abroad: 49.4% monkey bites, dogs 35.8%. • Vaccination, pre-exposure, international traveler: 4% Kardamanidis K et al. Travel Med Infect Dis

8/11/2015 2013;11:421-426. 23 Does your child need rabies vaccine? • Risk assessment: infant vs toddler vs adolescent • Recreational or occupational activities: example; mission work with vet vaccinating farm animals and pets • Length of stay in country • Nearest health care facility • Availability of rabies immunoglobulin and vaccines in-country • Financial

Global availability of rabies immune globulin: direct care providers to travelers

Jentes ES et al. J Travel Med 2013;20:148-158.

8/11/2015 25 Global availability of rabies vaccine: direct care providers to travelers

Jentes ES et al. J Travel Med 2013;20:148-158.

8/11/2015 26 Global availability of rabies immune globulin: direct care providers to travelers1 • Global survey to travel medicine providers and clinics, 2011. Never or Often or Region Sometimes seldom always Australia & 6% 0 94% Pacific Islands North America 19% 7% 74% Tropical South 80% 0 20% America South Asia 0 11% 89%

Jentes ES et al. J Travel Med 2013;20:148-158.

8/11/2015 27 Global availability of rabies immune globulin: direct care providers to travelers2 Never or Often or Region Sometimes seldom always Western Europe 22% 0 78% Mexico, Central America & 100% 0 0 Caribbean

East & SE Asia 33% 0 67%

West, Central & East Africa 25% 25% 50%

Jentes ES et al. J Travel Med 2013;20:148-158.

8/11/2015 28 Type of rabies immune globulin: direct care providers to travelers3

Region HRIG ERIG Unknown

Western Europe 77% 0 13%

Mexico, Central 100% 0 0 America & Caribbean

East & SE Asia 60% 20% 0

West, Central & East 33% 33% 0 Africa South Africa 82% 0 18%

Jentes ES et al. J Travel Med 2013;20:148-158. 8/11/2015 29 Global availability of rabies IG and vaccine: US embassies survey Rabies immune globulin available: Never or Often or Sometimes seldom always 0-50% [12] 0-58% [25] 8-100% [63] Rabies vaccine available: Never or Often or Sometimes seldom always 0-33% [10] 0-47% [21] 42-100% [69]

Jentes ES et al. J Travel Med 2013;20:148-158.

8/11/2015 30 Rabies: CDC Public Image Library 8/11/2015 31 JEV epidemiology • The main JEV transmission cycle involves Culex tritaeniorhynchus mosquitoes. • <1% of human JEV infections result in encephalitis. Humans are dead-end hosts. • JE is primarily a disease of children. Most adults have natural immunity after childhood infection. • Most temperate areas, Asia, transmission mainly during the warm season [May-October]. • Tropics and subtropics: transmission occurs year-round. Intensifies during rainy season. Shlim DR, Solomon T. Clin Infect Dis 2002;35:183-188. 8/11/2015 32 Japanese encephalitis: epidemiology, risk in travelers1 • Japanese encephalitis virus (JEV): mosquito- borne flavivirus. • Important cause of severe encephalitis in Asia. • Case fatality rate: 20-30%. • Neurologic or psychiatric sequelae, survivors: 30-50%. • No antiviral therapy is available. Disease is vaccine-preventable. Campbell GL et al. Bull World Health Organ 2011;89:766-774. CDC Public Image Library: Western Cambodia’s, Battambang province, 2013 8/11/2015 34

Deshpande BR et al. Am J Trop Med Hyg 2014;91:694-698. 8/11/2015 35 Japanese encephalitis: epidemiology, risk in travelers

• Risk for most travelers: very low. • Risk varies based on destination, duration, season, and activities. • The overall estimated incidence, persons from nonendemic countries traveling to Asia: <1 case:1 million travelers. Campbell GL et al. Bull World Health Organ 2011;89:766-774. Japanese encephalitis: epidemiology, risk in travelers • Risk expatriates and travelers who stay for prolonged periods in rural areas with active JEV transmission: 5-50 cases per 100,000 children per year. • Increased risk: extensive outdoor or nighttime exposure in rural areas during periods of active transmission. • Travel restricted to major urban areas: minimal risk for JEV infection. Campbell GL et al. Bull World Health Organ 2011;89:766-774. 8/11/2015 37 Japanese encephalitis vaccines • SA 14-14-2 JE vaccine: Chengdu Institute of Biological Products. Live attenuated vaccine. • Ixiaro, inactivated vaccine: Biological E Ltd. Intercell SA & Jeev. Inactivation of SA 14-14-2 strain. • Mouse brain-derived vaccines: Vietnam, Thailand and Republic of Korea • Chimeric viral vaccine, IMOJEV: Sanofi Pasteur. Available in Australia, Malaysia, Brunei, Phillipines, and Myanmar WHO. Weekly epidemiological record. 19 July 2013

8/11/2015 38 Japanese encephalitis virus vaccines, US • JE-mouse brain derived [JE-VAX, Biken]: children aged ≥1 year and adults. No longer available. • JE-Vero cell culture-derived [Ixiaro]: only JE vaccine available in US. • 2009, JE-VC was licensed and recommended for use in persons aged ≥17 years. • May 2013, US FDA licensed JE-VC: children aged 2 months-16 years. MMWR 2013;62:898-902 Japanese encephalitis virus vaccine (Ixiaro®) in young children • Adult vaccination: two injections of 6 μg in a 28-day interval, intramuscular. • Immunogenicity, reduced dose in children: 3 μg (95.7%) Kaltenböck A et al. Vaccine • Well tolerated. 2010;28:834-839

Approved in May 2013: 3 μg (0.25 mL): ≥ 2 months to < 3 years 6 μg (0.5 mL): ≥ 3 years

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8/11/2015 41 Traveling to Vietnam to visit family2 • 15 month old boy is traveling with his parents to visit family near Ho Chi Minh City; in a small farming village near the Mekong Delta. • Duration of stay: ~3 weeks • Offer Japanese encephalitis vaccine? YES • Offer rabies vaccines? YES

8/11/2015 42 Traveling to Vietnam to visit family3 • 15 month old boy is traveling with his parents to visit family near Ho Chi Minh. • You inform parents that JE and rabies vaccines are not covered by insurance. • Parents are expected to pay for the vaccine. Price per dose. JE: ~$300-1000 Rabies: ~$400-1300

8/11/2015 43 Traveling to Vietnam to visit family4

• 15 month old boy is traveling with his parents to visit family near Ho Chi Minh. • You inform parents that JE and rabies vaccines are not covered by insurance. • Parents are expected to pay. • Parents decide not to give the JE and rabies vaccines.

8/11/2015 44 Military family traveling to Cambodia for 2 years2 • Father is assigned to Joint POW/MIA Accounting Command. • Mother and 5 children are coming along. They will reside in embassy housing in Phnom Penh. • They anticipate shorts trips [≤7 days] to surrounding countries, including rural areas. • Offer Japanese encephalitis vaccine? YES • Offer rabies vaccine? YES

8/11/2015 45 Missionary family to Thailand2 • 5 family members. Children: 7 & 5 years-old, and 8 month-old. • Planning to stay in country for at least 30 years. • Japanese encephalitis vaccine? YES • Rabies vaccine? YES • “Travel” vaccines covered by medical insurance. Children got vaccines.

8/11/2015 46 Medical student is a doing an elective in Togo2

• 11 month-old infant is coming with mother. She is breast feeding. • Rabies vaccine? YES • Their medical insurance does not cover travel vaccines. • Parents elect to pay for the vaccine.

8/11/2015 47 High school students traveling in China2 • Visiting Beijing, Hong Kong, Shanghai, and Xian. • Staying in urban areas. • No visits planned to rural areas. • Large group. Traveling on tour buses. • Duration of trip: ~3 weeks • Offer Japanese encephalitis vaccine? NO • Offer rabies vaccine? NO

8/11/2015 48 “Selling” Japanese encephalitis, rabies • “Extremely” low risk of acquiring disease versus serious “untreatable” infections • Evolution of safer vaccines and immune globulins: Biken JE, equine rabies immune globulin • Lack of availability of rabies vaccine and immune globulin for postexposure prophylaxis. • Access to health care facility • Cost

8/11/2015 49 Effective messages in vaccine promotion? • Study of effectiveness of messages designed to reduce vaccine misperceptions and increase vaccination rates, MMR. US parents. 1. Lack of evidence MMR-autism, by CDC. 2. Textual information, dangers of diseases, VIS 3. Images of children with diseases prevented by MMR. 4. Dramatic narrative, infant died of measles, CDC. • Interventions did not increase parent intent to vaccinate. Nyhan B et al. Pediatrics 2014;133:e835-e842.

8/11/2015 50 Pre-clinic visit “counseling” phone call • Countries and regions to be visited. Planned activities. • Preparation of country-specific education and handouts. • Brief discussion about vaccines needed for the trip. • Notify parents that travel clinic services are “fee-for-service”. Payment at end of visit.

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