Recent WHO Data (2002)

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1 Recent WHO Data (2002) 142,311 cases and 4,564 deaths, from 52 countries 97% of cases reported from Africa These represent gross underestimates: -- More realistic estimates : 5.5 million cases; 100, ,000 deaths

2 Approaches to Oral Immunization Killed vaccines Live vaccines

3 BS-WC Vaccine Inactivated whole cells Heat-killed V. cholerae O1 Inaba classical 2.5 X10 10 Formalin-killed V. cholerae O1 Inaba El Tor 2.5 X10 10 Heat-killed V. cholerae O1 Ogawa classical 2.5 X10 10 Formalin-killed V. cholerae O1 Ogawa classical 2.5 X10 10 Cholera toxin B subunit

4 Bangladesh Trial of BS-WC and WC-only Killed Oral Cholera Vaccines Conducted in the mid-1980s among children aged 2-15 yrs and women >15 yrs in Matlab, Bangladesh Subjects were randomized to 3 doses of BS-WC, WC, or placebo Protective efficacy: Follow-up BS-WC WC 6 mos 85% 58% 3 yrs 50% 50% Protective efficacy of 2 doses= protective efficacy of 3 doses rbs-wc currently internationally licensed by SBL

5 Development of Vietnamese Killed Oral WC-Only Vaccine Began in 1980 s, led by Professor DD Trach, as part of Vietnam s policy of self-sufficiency in vaccines Technology transfer from Professor Jan Holmgren Focus on WC-only vaccine, rather than BS-WC or rbs-wc, due to IP considerations and cheaper production

6 Field Trial of Locally-Produced, Oral Killed WC Vaccine in Hue, Vietnam, 1993 (Trach, 1997) Occurrence of Ogawa El Tor Cholera : Group Vaccinees Controls PE 1-5 yrs olds 7/7,192 19/7,057 64%* (50%, 86%) >5yrs olds 30/58,943 73/58,802 59%*** (36%, 74%) Overall 37/67,395 92/67,058 60%*** (40%, 73%)

7 Limitations on the Use of Killed Oral Vaccines Neither vaccine is currently deployed as a routine tool for developing countries rbs-wc is internationally licensed by SBL, but used only by travellers, because of questions about feasibility and expense for endemic populations WC-only vaccine is licensed in Vietnam but not used outside of Vietnam, because the vaccine has never been evaluated for efficacy in a double-blind RCT, and is not being produced by a WHO-approved manufacturer

8 Vaccines to Prevent Diseases of the Most Impoverished The DOMI Program A program to accelerate the development and begin the introduction of new vaccines against cholera, shigellosis, and typhoid fever International Vaccine Institute Seoul, Korea

9 Key Questions about Killed WC-Based, Oral Cholera Vaccines Feasible to administer in real-life programs?

10 Hue, Vietnam

11 Breakdown of Costs of Programmatic Campaign of Vaccination using a Locally Produced, Killed Oral Whole Cell Cholera Vaccine in Hue City, Vietnam, 1998 Item US$ % of Total Vaccine delivery Personnel 13, Training 3, Review meeting Publicity Supplies 2, Transportation 1, Total cost Vaccine delivery 21, Vaccine production 83, Grand total 105, Cost per person fully 0.89 vaccinated

12 Mass Immunization Using a 2-dose Regimen of rbs-wc Killed Oral Cholera Vaccine in Mozambique Major epidemics of cholera documented since the mid-1990 s The Mozambique government is interested in introducing the oral cholera vaccine Mass immunization (Dec 2003 Jan 2004) in collaboration with: Ministry of Health (Ministério da Saúde, Moçambique) Médecins Sans Frontières / Epicentre World Health Organization International Vaccine Institute

13 Mass Immunization in Beira, Mozambique 1 st round - December 11 to 20, 2003 (10 outposts) Inter-dose interval - 15 days 2 nd round - January 5 to 12, 2004 (8 outposts)

14 Key Questions about Killed WC-Based, Oral Cholera Vaccines Potency and safety of the locally produced, Vietnamese vaccine?

15 Percent of Subjects Showing >4-Fold Rise in Anti-O1 or Anti-O139 Vibriocidal Antibody Titers in Paired Blood Specimens Adult Study Children Study Antibody response Biv- WC/H 2 O (N=35) Biv- WC/buffer (N=35) rbs-wc (N=35) Placebo (N=36) Biv- WC/H 2 O (N=27) rbs-wc (N=33) Placebo (N=31) Anti-O1 54%** 57%** 63%** 0% 93%** 88%** 3% Anti-O %* 40%* 3% 11% 68%** 19% 13% * P<0.01 (2-tailed) for contrast of cited group with the placebo group. ** P<0.001 (2-tailed) for contrast of cited group with the placebo group. + Response to either O139 test strain (4260B and M010-T4).

16 Key Questions about Killed WC-Based, Oral Cholera Vaccines Protection in a population with a high seroprevalence of HIV?

17 Effectiveness of Mass Oral Cholera Vaccination in Beira, Mozambique Marcelino E.S. Lucas, M.Sc., Jacqueline L. Deen, M.D., M.Sc., Lorenz von Seidlein, M.D., Ph.D., Xuan-Yi Wang, M.D., Ph.D., Julia Ampuero, M.D., M.Sc., Mahesh Puri, M.S., Mohammad Ali, Ph.D., M. Ansaruzzaman, M.Sc., Juvenaldo Amos, M.D., M.P.H., Arminda Macuamule, M.S., Philippe Cavailler, M.D., M.Sc., Philippe J. Guerin, M.D., M.P.H., Claude Mahoudeau, Pierre Kahozi-Sangwa, M.D., M.P.H., Claire-Lise Chaignat, M.D., M.P.H., Avertino Barreto, M.D., M.P.H., Francisco F. Songane, M.D., M.P.H., M.Sc., and John D. Clemens, M.D.

18 Key Questions about Killed WC-Based, Oral Cholera Vaccines Capable of inducing herd protection?

19 Re-analysis of the Phase 3 Trial to Assess Herd Protection Bangladesh trial of BS-WC and WC vaccines was individually randomized However, vaccine coverage varied considerably in the 6,423 residential clusters ( baris ) Possible to analyze the risk of cholera in different baris according to level of vaccine coverage Indirect ( herd ) protection: risk of cholera in placebo recipients should be inversely related to level of vaccine coverage Enhanced total protection (direct + indirect): risk of cholera in vaccinees should be inversely related to level of vaccine coverage

20 Levels of Vaccine Coverage, Matlab, 1985

21 Cholera Risk by the Level of Cholera Vaccine Coverage, Matlab, Bangladesh Target population Vaccinated group Placebo group Level of vaccine coverage N % N Cases Risk/ 1000 persons* N Cases Risk/1000 persons** <28% 24, , , % 25, , , % 24, , , % 24, , , %+ 22, , , Total 121, , , * P=.05 for trend ** P<.0001 for trend

22 Key Questions about Killed WC-Based, Oral Cholera Vaccines Licensure of the Vietnamese vaccine by a WHO-approved regulatory authority?

23 Technology Transfer of the Oral Killed Bivalent WC Cholera Vaccine VABIOTECH oral cholera vaccine Tech. transfer Bulk Sale/ Tech. transfer X DCGI requirements Double-blind Randomised efficacy trial (Kolkata) Fill & Finish Shantha Biotechnics, India BioFarma, Indonesia Bridging study Complete NRA requirements Local licensure

24 Urban Slums in Kolkata

25 NICED-IVI Team

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29 Summary Oral, killed whole cell-based cholera vaccines, either with or without cholera toxin B subunit, have proven safe and protective, but are currently used only in travellers from industrialized countries and in one country Vietnam-- with endemic cholera IVI s Diseases of the Most Impoverished (DOMI) Program has conducted research on these vaccines to augment the base of evidence available to decisionmakers considering the use of these vaccines These studies have demonstrated that the rbs-wc vaccine produced in Sweden can be feasibly delivered even in a densely populated, impoverished, Sub-Saharan setting, and can confer a high level of protection to a population with a high prevalence of HIV infectionss

30 Summary The studies have also shown that serum vibriocidal immune responses to the WC-only vaccine manufactured in Vietnam were equivalent to those to the rbs-wc vaccine made in Sweden Finally, the studies have demonstrated major levels of herd protection of non-vaccinees when populations are immunized by oral, killed whole cell-based vaccines

31 Summary Work is now ongoing to transfer the Vietnamese oral killed whole cell cholera vaccine to producers in India and Indonesia, and to conduct studies needed for licensure in these countries, including a placebocontrolled, randomized efficacy trial now underway in 70,000 participants in Kolkata In aggregate, this research has yielded considerable evidence in support of the use of these vaccines for the control of endemic cholera, and the transfer of production technology for killed oral cholera vaccines to WHO-approved producers in India and Indonesia will ensure international access to these vaccines at affordable prices

32 THANK YOU