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Travelers’ vaccines as solutions for travelers’ risks
Global standard in travel medicine: a risk management perspective
Robert Steffen
Vaccine relevant travel health risks
u Risk: situations — environment, host
u Vaccine preventable diseases: the 4 dimensions
– Incidence rate
– Impact
– Legal aspects
– Financial aspects
u Conclusions
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Cumulative exposure!
Traveler: death, sequelaePublic health: outbreaks
Environmental factors à risk profiles
Assess in detailu Destination
– Countries– Urban / rural
u Purpose of travel– Tourism / VFR– Work / business
u Travel style– Luxury– On budget
u Duration(s) of stay(Date of departure)
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Host factors – special risk groups
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u infants, children
u senior travellers
u pregnant women
u pre-existing disease / condition– immuno compromized– AllergicConsider also: pre-existing immunity
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Vaccine preventable diseases: first dimensionIncidence rate per month of infections among travelers in developing countries
100%
10%
1%
0.01%
0.001%
Malaria (overall West Africa)
Typhoid (South Asia, N/W/Central-Africa)
PPD conversion
Cholera
Influenza A or B
Typhoid (other areas)
Dengue infection (symptomatic)Animal bite with rabies risk
Tick borne encephalitis (rural Austria)
Legionella infection
Meningococcal disease
0.1%
Traveler’s diarrhea
0.0001%
Hepatitis A
Hepatitis B
HIV-infection
Japanese encephalitis
Fatal accident
Poliomyelitis
Malaria (overall Central America/Carib.)
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The first and second dimension:Incidence rate per month PLUS severity of infections among travelers
Steffen R & Connor BA. J Travel Med 2005;12:26-35
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Third dimension in travel vaccines: costs
u Relevance: Luxury vs. backpacker
u Vaccine cost categories (varies by country):u Low: EPI, e.g. diphtheria / tetanus, poliomyelitis
u Intermediate: hepatitis A, typhoid, rabies intradermal
u High: Japanese encephalitis, ‚new‘ vaccines
u Consider: Risk situations
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Fourth dimension: legal requirements
uRequired ++ Yellow fever± Meningococcal± Measles± Cholera
+++ WHO / EPI (+)+++ National vaccine plan
l Routine
l Recommended
Risk assessment —> priorities
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Yellow Fever (YF) endemic countries(reported cases, underreporting common!)
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University of Zurich, Travelers' vaccines, Robert Steffen
Destination Yellow fever infectionin unvaccinated persons
Yellow fever vaccine, serious adverse event (SAE)
Incidence per 100,000/wk
Death per 100,000/wk
YEL-AVD / -AND* per 100,000
1-99 y ≥60y
Fatal SAE* per 100,000
≥60yAge group
Subsah. Africa- endemic 23.8 12- epidemic 357 179 0.7 ≥5.3 ≥2South America (1.6**)- endemic 2.4 1.2- epidemic 35.7 17.9
Risk of yellow fever vs risk of vaccine(Khromava et al. 2005, Monath TP et al. 2005, Muñoz JM et al. JTM 2008;15:202-5)
YEL-AVD= yellow fever vaccine associated viscerotropic diseaseYEL-AND = yellow fever vaccine associated neurotropic disease* = all cases occurred in primary yellow fever vaccinees** = including other severe adverse reactions
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Yellow fever (YF) vaccination
Indicated ifRequired– direct: Tropical Africa, etc.– transit via infected areas– only by approved Centers, MDs
Recommended if considerable exposure in infected area
Info: - Travel Info Manual- WHO / ITH- US / CDC Yellow book- Embassies?
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YF vaccine requirement (transit rule): from the Victoria Falls to Johannesburg
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Immunization required by South African authorities
Meningococcal diseaseCaused by the bacterium Neisseria meningitidis
– Most epidemics caused by serogroups A, B, C, W-135 and X– Spread from person to person
u Incidence is highest in the “African Meningitis Belt” (AMB) of sub-Saharan Africa
u Outbreaks have occurred inHajj pilgrims (until 2003)
u Symptomatic disease is fatal in 5–10% of cases
u Up to 20% have permanent neurological sequelae
WHO: International Travel and Health 2011, pp. 105-8. Map: http://gamapserver.who.int/mapLibrary/Files/Maps/Global_MeningitisRisk_ITHRiskMap.png
Meningococcal meningitis, countries at high risk, 2009
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uRequired for pilgrims to Mecca (tetravalent vaccine to be used)
u ... should be considered for travellers to countries where outbreaks ... are known to occur, e.g.
u Sub-Saharan meningitis belt... (December - June)
u College students at risk
Meningococcal vaccine
Use tetravalent ACW135Y vaccine, monovalent C conjugate vaccine preferred only
in infants and college students**where tetravalent conjugate vaccine has not yet been licenced
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Anecdotal cases of meningococcal disease in travelers, from 1996 (selection)Type of traveler Origin Location OutcomeChildrenPHLS. CDR Weekly 1996;6:191
UK, Germany Majorca, Spain 2 died, 2 recovered(2 children died in same hotel)
Students (2)Zuscheid et al. Euro Surveill 2008, Nov 6; Rapp C et al J Travel Med 2010;17:1-7
Swiss / French Germany 1 died, 1 recovered
AthleteCummiskey J et al. J Sports Med
Phys Fitness 2008;48:125-8
unknown Jaca, Spain(1500 athletes from 43 countries)
recovered
TouristAnonymous. NZZ 1 November 2006
Swiss Tirol, Austria died(only in public media)
JournalistWilder-Smith A & Goh KT. J Travel Med 2003;10:59-60 (W135)
UK Morocco > Japan> Singapore
recovered
BusinessmanLapadula G et al. Emerg Infect 2009;15:52-54
Italy Delhi, Chennai recovered
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Vaccine Child Adolescent Adult SeniorDipht/Tetanus/Pertussis +++ ++§ ++§ ++§Hepatitis B most c/u c/u (risk)Haemophilus influenzae B + (≤5 yrs) Ø Ø ØHuman Papilloma Virus Ø + (female) c/u ØInfluenza §, risk §, risk §, risk ++MMR +++ c/u (2 doses) c/u ØPneumococcal disease § risk risk +§Rotavirus § Ø Ø ØTuberculosis § Ø / c/u Ø ØVaricella § c/u c/u Ø
+ to +++ = routine (EPI), Ø = not indicated, c/u = catch-up if previously missed,§ = see national recommendations
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Routine immunizations
Measles genotypes, SwitzerlandEpidemic with >5000 cases; 2006-11
N
EW
S0 50 100 150 Kilometers
D5B3A
Genotype
Courtesy: Prof. Ch. Aebi
Origin of the Swiss measles epidemic 2007-11 (mostly genotype D5) ?
Courtesy: Prof. Ch. Aebi
Swiss Exports: Measles 2006 / 10
courtesy Prof. Ch. Aebi29.02.2012
8 July 2010:• Passenger (23 mo/old) no-MMR• Flight Zurich - Boston• Diagnosis measles on arrival 8 July
Consequence 1:• 31 passengers exposed• 29/31 notified • Measles confirmed: 1 student
Consequence 2:• 270 students, teachers exposed• 2 non-immunes: Quarantine!
MMWR 2010;59:1073 (August 27)
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Measles in Japanese travelers
Measles outbreak associated with an international youth sporting event in the United States, 2007.„The index case occurred in a child from Japan aged 12 years.
Contact tracing among 1250 persons in 8 states identified 7 measles cases ... linking the outbreak to contemporaneous measles virus genotype D5 transmission in Japan.
Chen TH et al. Pediat Infect Dis 2010;29:794-800.See also: Takahashi H & Saito H. Measles exportation from Japan to the U.S. 1994-2006. J Travel Med 2008;15:82-6.
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Influenza — trivial?
Influenza in travelersFollow-up study:Population: 1450 travelers to developing countries (1/1998 -3/ 2000)
Febrile illness: 289 (19.9%)
Two serum samples: 211 (73.0%) + 321 matched controls
Seroconversion for influenza virus infection (WHO CC London)
40 (67% with fever, 33% asymptomatic, 18 w/≥4x ab)
Incidence rate / 100 person-months: 1.0
Most frequent vaccine preventable infection!Mütsch M et al Clin Infect Dis 2005;40:1282-87
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Large summertime outbreak of respiratory illnessu Cruise to Alaska, 1998u Doctor visits for ARI per 1000 tourists: 11.6u 5361 cases of ARI, 53% of ILIu 171 (3.2%) pneumoniau 4 deaths (all elderly)u Influenza A in 71%
Uyeki TM et al. Clin Infect Dis 2003;36:1095-1102Courtesy: Prof. Annelies Wilder-Smith, Singapore
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Seasonal Influenza Vaccines
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Year A/H3N2 A/H1N1 B2001/2N Moscow/10/99 New Caledonia/20/99 Sichuan/379/992002/3N same same Hongkong 330/012003/4N same same same2004/5N Fujian 411/02 same Shanghai 361/022005/6N California 7/04 same same2006/7N Wisconsin 67/05 same Malaysia 2506/042007/8N dito Solomon IsI/3/06 same2008 S Brisbane 10/07 same Florida 4/062008/9N same Brisbane 59/07 same2009/10N same same Brisbane 60/082010S Perth 16/09 California 7/09 same2010/11N
2011S
2011/12N
same
same
same
same
same
same
same
same
same
University of Zurich, Travelers' vaccines, Robert Steffen
WHO Map of HBV Risk Areas
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Risk of hepatitis B transmission
10 - 15% in high-risk situation
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University of Zurich, Travelers' vaccines, Robert Steffen
Hepatitis B vaccinationVaccine to be considered for virtually all non-immunes… travelling to areas with moderate to high transmission:- Africa- Asia (excl. Japan, Singapore)- Latin America (excl. Argentina, Chile) - Eastern Europe, remote countries
Consider ’special risk groups’ but NOTE: >10% ’at risk’!
Contraindication:- Immunity by previous infection
WHO: International Travel and Health, Geneva 2011
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Hepatitis B vaccine does NOT prevent HIV / Aids!
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WHO Map of HAV Risk Areas
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Hepatitis A — impact
ON PUBLIC HEALTH� Epidemic: 352 Tourists (Germans) diagnosed 2004 after a stay in the Siva Grand Beach Hotel, Hurghada, Egypt
� Outbreaks in kindergardens, day-nurseries
� Outbreaks associated with food-handlers
� Clusters around adopted children, refugees
ON INDIVIDUAL PATIENT• Incapacitation 4-10 weeks• Case fatality rate
- over 40 years old 2.1%- over 60 years old 4.0%
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University of Zurich, Travelers' vaccines, Robert Steffen
„all non-immune travellers to endemic areas“
„those at high risk strongly encouraged to accept vaccination“
„all travellers to, and all expatriates living in, moderately / highly endemic areas“
„travellers visiting areas of hepatitis A risk, particularly those visiting friends and relatives, long-term travellers and those visiting areas of poor sanitation“
„All susceptible persons traveling to or working in countries that have high or intermediate hepatitis A endemicity should be vaccinated“
Hepatitis A vaccination recommended for...
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Australian Immunisation Handbook, 9th Edition 2008
Immunisation against Infectious Diseases, The Green Book 2007
CDC Health Information for International Travel, The Yellow Book 2010
International travel and health, WHO 2010
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Typhoid risk in travellersHigh risk-Destinations:
>0.2 pro 1000
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High risk-Travelers:l VFRl ‚Backpackers‘l Stay > 1 month
TF in Japanese travelers:Thapa R et al. (Nepal) J Travel Med 2010;17:199-200.
Typhoid fever vaccinationRecommended for:- Destination: High risk countries or areas - Duration of stay: > 1 month - Exposure: food or beverages away from
the usual tourist routes in developing countries
Particularly appropriate where antibiotic-resistance strains of S. typhi are prevalent
WHO: International Travel and Health, Geneva 2011, 126-8.See also: Takayama N. Kansenshogaku Zasshi 2005;79:254-9.
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Rabies on Bali
124 human cases since 2008
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Risk of rabies exposure in travelersu ANIMAL BITES with potential risk
- U.S. Peace Corps: 4.4% per year
- Swiss expatriates: 1.8% per yearBernard K & Fishbein DB. Vaccine 1991;9:833-6Hatz CF et al. Vaccine 1995;13:811-5 Pandey P et al. J Travel Med 2002;9:127-31
u Postexposure prophylaxis (PEP)- STRESS! Rabies-IG difficult to find outside big centers- Number unknown!
u Fatal rabies in travelers: 42 (1990-2010)Malerczyk C et al. J Travel Med 2011;18:402-7.Yamamoto S et al. J Travel Med 2008;15:372-4.
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Particular risk for rabies
Destination:India (15’000-20’000�)
Particularly, travel related:- Children*- Bicycle*/motorbike riders- Trekkers, hikers* (e.g. Nepal)- Prolonged stay*- Professionals with exposure*- Spelunkers*
* WHO: International Travel and Health, Geneva 2011
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„Pre-exposure prophylaxis for those planning a visit to rabies endemic country, especially if the visited area is farfrom urban centres, where...“
„Rabies pre-exposure vaccine should generally be given to adults and children who are at risk of rabies including thoseu travelling to remote areas where medical care is not readily availableu undertaking higher risk activities (e.g. cycling, running)u travelling for long periods through rabies endemic countriesu at occupational risk e.g. vets, animal handlers, and laboratory...“
„... rabies vaccine may be recommended based on u local incidence, u ... availability of appropriate anti-rabies biologicals,u intended activity and u duration of stay / repeat travel...“
Rabies immunization recommendations
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JE vaccine recommendations, travelersTraditional:- Stays in endemic zones ≥ 2-4 weeks- With RURAL overnight staysExample: Agronomics student preparing Ph. D. thesis, living
close to rice fields
NEW (2010): no more minimal stay- WHO: Extensive outdoor exposure: Camping, hiking, bicycle, outdoor occupational activities in rural areas
- CDC: Duration of stay > 1 month or short-term (< 1 month) if travel
- outside urban area- Area with outbreak- Uncertain specific destination, activities, duration
WHO: International Travel and Health, Geneva 2011CDC: ‘Yellow book’ 2012,wwwnc.cdc.gov/travel/yellowbook/2012/chapter-2/japanese-encephalitis.aspx
Do we protect all at risk? Consider:- Cumulative exposure
- Request for maximum protection
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Cholera
90% of episodes are mild or moderateand difficult to distinguish from other types of travellers diarrhea — usually not diagnosed
Ref. WHO Fact sheet No 107; Sack, Lancet, 2004; CDC - Center for Disease Control and Prevention
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www.gamapserver.who.int/mapLibrary/Files/Maps/World_CholeraCFR(WER)_CUM2007_colour.png
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Recommended immunizations in non-immune travelers for a stay in a developing countryExpert group WHO CATMAT CDC NaTHNaC NHMRC JAPAN
World Canada USA UK Australia Available
REQUIRED- Yellow fever ** ** ** ** ** +ROUTINE- Diphtheria/tetanus/MMR *** *** *** *** *** +- Poliomyelitis ** ** ** ** ** +- Hepatitis B *** *** *** * *** +RECOMMENDED- Hepatitis A *** *** *** ***/* ***/* +- Typhoid fever * * * * * ±- Rabies * * * * * +- Meningococcal disease * * * * * ±- Japanese encephalitis * * * * * +- Tick borne encephalitis * * * * * —- Tuberculosis * -/* - * * +- Cholera * * -/* * * ±- Influenza * * *** * ? +*** = all, ** = all when visit in endemic country, * = risk group only, - = none
Condition RestrictionAge- Infants- Elderly
Some vaccines not approvedConsider weak immune responseYF vaccine only if clearly at risk
Pregnancy- Live vaccines
- Inactivated vaccines
BCG, MMR, Varicella contraindicatedYF vaccine only if high riskYes, if no risk (safety often not determined)
Chronic medical problems- impaired immunity, incl.- steroids, methotrexate,TNFa, interferon
Caution with live vaccines if low CD4Consider weak immune response
Many contraindications
Finally: risks of travel vaccines —Caution and Contraindications
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Conclusions: what priorities?
1. Incidence: Influenza
2. Impact: Neurotropic IDs
3. Legal:Yellow fever
4. Costs vs. risk analysisRabies
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Tuberculosis vaccination (BCG)(EPI in many national recommendations)
Indicated for:
To be considered* for:
(*US/CDC: no BCG!)
Not for travel
u infants <6 months traveling to (remote) high-risk areas
u health workers
WHO: International Travel and Health, Geneva 2011Rieder H. Clin Infect Dis 2001;33:1393-96
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Global Neisseria meningitidisSerogroup Distribution
References upon request.
CANADA1
USA2
EUROPE4
BRAZIL3
AFRICAN MENINGITIS
BELT6
JAPAN9
TAIWAN8
AUSTRALIA10 NEWZEALAND11
Represents serogroups not defined for each individual country
YW-135B CA X
23% 59%
35%
31%
25%
25%
68%
ARGENTINA3
52%37%
69%14%
17%
78%
SOUTH AFRICA7
47%10%
11%
50%35%
57%21%
84%11%
82%
14%
TURKEY5
35%
18%
COLOMBIA3
29%29%
33%
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Worldwide WC-rCTB (Dukoral®) marketing
Hill DR et al. Lancet Infect Dis 2006;6:361-73
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Efficacy of WC/rBS vaccine against choleraIn >6y/o in first 12 months: PE 76% (95% CI 60-85)
AND additional herd immunity in BangladeshAli M et al. Lancet 2005;366:7-9
In >2y/o in first >6 months: PE 78% (95% CI 39-92)
in Beira, MozambiqueLucas ME et al. N Engl J Med 2005;352:757-67
NOTE: No longer available worldwide
uCVD103HgR (Orochol®, Mutachol® / BernaBiotech)u ‘Traditional’ injectable vaccine
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Structural, functional and immunological similarities of:
LTB (ETEC) vs. CTB (Cholera)
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Efficacy of WC/rCTB oral CHOLERA vaccine againstheat labile enterotoxigenic E. coli (LT-ETEC)Basing on similarities some evidence on efficacy against LT-ETEC from:
uBangladesh: PE 67% (95% CI 16-87, p=0.02)
uFinns in Morocco: PE 60%PE against ETEC+Salmonella 82%(!)
uUS in Mexico: PE50% (7d after dose 2, given in Mexico!)
Clemens JD et al. J Infect Dis 1988;158:372-7Peltola H et al. Lancet 1991;338:1285-9Scerpella E.G. et al. J Travel Med 1995;2:22-7
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Estimated benefit of WC-rCTB vaccine (Dukoral®) in travelers
Travelers with
TD
!
1 2 3 4 5 65%
Steffen R et al. In Travelers’ diarrhea, Ericsson et al. Eds. BC Decker, Hamilton, London 2003University of Zurich, Travelers' vaccines, Robert Steffen29.02.2012 Page 51
Routine schedule for travel vaccines
1st CONSULTATION 2nd CONSULTATION- Yellow fever *2nd / 3rd dose- Diphtheria / Tetanus if necessary to- Hepatitis A complete primary- Typhoid (Ty 21a / Vi) vaccination- Poliomyelitis- Hepatitis B*, A+B*- Rabies*- Meningococcal meningitis- Japanese encephalitis*- MMR, etc.
ideally
DepartureWeeks priorto departure
6 5 4 3 2 1 0
REQUIREDROUTINE
RISKGROUPS
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Application of vaccines in travelersGENERAL RULESu store as recommended by manufactureru shake well before useu administer as recommended IM, SC, IDu select deltoid in adults and children >1 y/o,
anterolateral thigh in infantsu cleanse skin with antiseptic, ideally wait 5 minutes
NOTEu travel industry NOT reliable for vaccine selectionu vaccine manufacturers NOT reliable for indication
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