Vaccines for Enterically Transmitted Diseases in travelers Prof. Eli Schwartz MD,DTMH The Center of Geographic Medicine & Tropical Diseases Sheba Medical Center, Tel-Hashomer Sackler Faculty of Medicine, Tel-Aviv univ. ISRAEL

Typhoid: Global Epidemiology

Typhoid: Global Epidemiology 33 Million cases annually 600,000 deaths Incidence rates low: <1/105 population in developed countries high: >800/105 population in endemic areas

Typhoid: Global Epidemiology Greatest burden of disease in ASIA 13 million cases per year 400,000 deaths annually incidence rates as high as 900-1200/105 rise in cases since 1990s

Annual incidence of Typhoid Fever worldwide Conor BA, Schwartz E.Typhoid and paratyphoid fever in travelers. Lancet Infect Dis. 2005;5:623-8

Typhoid Epidemiology in Developed Countries

in Developed Countries Typhoid Epidemiology in Developed Countries Now a travel associated disease in industrialized countries

Incidence of Typhoid Fever (Lt) and % of travelers (Rt)-USA 8 100 90 7 80 6 70 5 60 4 50 % travelers USA: incidence/100,000 40 3 30 2 20 1 10 1940 1945 1950 1955 1960 1965 1970 1975 1980 1985 1990 1995 2000 USA: incidence/100,000 % travelers Connor BA, Schwartz E. Typhoid and paratyphoid fever in travelers.Lancet Infect Dis. 2005;5:623-8.

Risk Factors Travel to rural areas with poor sanitation Not following food and water precautions Not receiving pre-travel consultation Length of stay VFR’s

The pathogens Enteric fever, the more inclusive term, is caused by Salmonella enterica serotypes S. typhi and S. paratyphi. S. Typhi S. paratyphi A S. paratyphi B S. paratyphi C

Enteric Fever pathogens Geographic distribution & Geographic distribution The bacteria Geographic distribution S. typhi Developing countries, manily the Indian subcontinent and South-East Asia S. paratyphi A Indian subcontinent S. paratyphi B Indonesia, Malaysia, the Mediterranean region and South America S. paratyphi C Africa

Local population (Nepal) Rate of infection : S.Typhi vs S.paratyphi S.typhi S.paratyphi Local population (Nepal) 80% 20% Unvaccinated 67% 33% Vaccinated 32% 68% Schwarts E. et al, Arch Intern Med 150; 349-351, 1990

Annual cases of S. typhi and S.paratyphi in the UK http://www.hpa.org.uk/infections/topics_az/salmonella/data_typh.htm

Enteric Fever episodes in Asian Countries China India Pakistan Indonesia Country Hechi city Calcutta Karachi Jakarta Site 2001-2 2003-4 2002-3 Period 5-60 All ages 2-16 Age group (Y) 64% 24% 15% 14% % S.para A

“Boil it, Cook it, Peel it or Forget it “ Typhoid Prevention “Boil it, Cook it, Peel it or Forget it “ Easy to remember, impossible to do!

Typhoid vaccine

Typhoid vaccines Parenteral vaccines (anti Vi): circulating antibody response Live attenuated oral vaccines(Ty21a): vigorous secretory IgA response cell mediated response

Ty21a Vi -vaccine Mucosal Humoral Mode of action Live atenuated Killed Type Avirulent (lack Vi) Anti Vi (S.typhi) Target 3-4 doses 1 dose N. of doses Contraindication Ab, antimalaria Hep A Combination 3-4 y 2-3 Y. Booster .> 6 y. >2 y Age

Meta-analysis of typhoid vaccine efficacy Year 5 4 3 2 1 Efficay: % (95% CI) No data 50(-11-78) 52(4-76) 67 (44-81) Vi (1 dose) 47(-24-78) 78 (35-93) 60(35-76) 60 (44-71) 50 (18-69) Ty21a (3 doses) 67(43-80) 73 (42-87) 74(50-87) 72 (56-82) 74 (62-82) Whole cell (2 doses) Engels EA, et al. Typhoid fever vaccines: a meta-analysis of studies on efficacy and toxicity. BMJ 1998; 316: 110–16

Summary of Toxicity study on Typhoid Vaccines Whole cell (TAB) Ty21a Vi % A.E 15.7 (11.5-21.2) 2 (0.7-5.3) 1.1 (0.1-12.3) Fever 20.0 (12.9-29.7) - 3.7 (1.3-9.6) Swelling 2.1 (0.6-7.8) Vomiting 5.1 (1.7-14.5) Diarrhea 10.0 (6-16.2) Missed work/school

Typhoid Vaccine Efficacy 60-70%

Vi-Conjucated Vaccine (rEPA) [nontoxic recombinant Pseudomonas aeruginosa exotoxin A] Highly immunogenic Cumulative efficacy ~ 90% Long term immunity Probably immungenic in Infants <2 y. Lanh, M. N. et al ; N. Engl. J. Med. 349:1390-1391

Typhoid Vaccine Efficacy 60-70% All studies done in endemic areas among local population What it does mean for Travelers ?

Typhoid Vaccine Immunity : relative and can be overcome immunity can be overcome if large infecting dose is ingested protective effect of prior clinical infection only 28%

Differences between traveler and indigenous population no pre-existing immunity Try to avoid contaminated food and water More rapid and available access to medical care Indigenous population: Constant boosting Live in the same condition more severe clinical course

Typhoid: risk to the traveler CIWEC Clinic, Kathmandu Risk of acquiring enteric fever: vaccinated : 12/105 unvaccinated: 217/105 Schwartz E. et al, Arch Intern Med 150; 349-351, 1990

Meltzer E. , Sadik C, Schwartz E Meltzer E., Sadik C, Schwartz E. Enteric Fever in Israeli Travelers: a Nation-Wide study. J. of Travel Medicine 2005;12:275-81

Typhoid Vaccine: conclusions Vi vaccine- better protection for S.typhi Ty21a vaccine-better protection for S.paratyphi A Their mode of action is different, mucosal vs. humoral immunity Should we recommend a sequential immunization: Vi vaccines and Ty21a?!

Conclusions Typhoid vaccine is an important tool to protect travelers A more effective Typhoid vaccine is needed It should includes a Paratyphi A coverage as well.

Typhoid Vaccine: conclusions Typhoid fever remains a major health problem for travelers. All travelers to endemic areas are at potential risk. Increasing antimicrobial resistance has made preventive strategies even more essential. Typhoid fever vaccination may be offered to travelers to destinations where the risk of typhoid fever is high, and/or in locations where antibiotic-resistant strains of S. Typhi are prevalent. Vi and the Ty21a vaccines provide appreciable levels of protection and have a good record of safety.

One of the World’s Most Common Infectious Diseases Hepatitis A One of the World’s Most Common Infectious Diseases

Geographic Distribution of Hepatitis A Ref: Centers for Disease Control and Prevention MMWR 48(RR-12), 1999

Prevalence Changes with Improvement in Hygiene

Age-Specific Prevalence (%) of Anti-HAV in the Athens Area

HAV Seroprevalence in Israel 100 94 80 80 60 Prevalence % 55 46 40 20 1977 1987 1989 1995 2000 Year

Prevalence of HAV IgG in Israeli Travelers 82 76 68 HAV-IgG Positive 33 24 Age Group (years) Schwartz E. & Raveh D. ; Int J Epidem 27:118-120, 1998

Hepatitis A: Clinical Characteristics of Patients by Age Group 40+ yrs 15-39 yrs <1-14 yrs Clinical Characteristics 70.3% 86.8% 81.7% Jaundice 41.6% 23.2% 17.1% Hospitalized for Hepatitis 2.1% 0.3% 0.1% Death as a result of Hepatitis

Passive Immunization Short-term protection – requires frequent renewal No stimulation of antibody production in recipient Serum–derived product Large injection volumes

Active Vaccination Long-term protection from single course of vaccination Stimulates antibody production in the recipient Non serum-derived product Small injection volumes

HAV Antibody Titres in Persons with Active & Passive Immunization & After HAV Infection Natural infection Vaccinated persons Anti-HAV GMT mIU/ml Passive immunization

Havrix Hepatitis A Vaccine Seroconversion Rates Injections given at months 0 & 1 with a booster at 6 months Blood Sample Taken Month 7 6 2 1 100 99.9 95.6 % Seroconversion

Hepatitis A –combined vaccines Hepatitis A+ Typhoid Fever -Hepatirix – GlaxoSmithKline, Viatim-Sanofi Pasteur Hepatitis A +B - Twinrix – GlaxoSmithKline

Be careful! Thank you !