Licensed Vaccines That Are Not Being Used Widely in LDCs

Transcription

1 Licensed Vaccines That Are Not Being Used Widely in LDCs Cholera: rbs-wc, WC Hepatitis A: Inactivated Hib: PRP-conjugates HPV: VLP JE: Inactivated, live-attenuated MMR: Live-attenuated Meningococcal: Conjugate Pneumococcal: Conjugate Pertussis: Acellular Rabies: Cell-culture based Rotavirus: Live-attenuated, reassortant Typhoid: Vi, Ty21a Varicella: Live-attenuated Yellow fever: Live-attenuated

2 Gaps in evidence about vaccine performance in developing country settings

3 Performance in the most relevant settings?

4 Results of Recent Randomized Placebo-Controlled Trials of 2 New Generation Rotavirus (RV) Vaccines (Vesikari, 2006; Ruiz Palacios, 2006) Vaccine Producer Regimen Sites PE vs. Hospitalized RV Diarrhea Human Monovalent (G1P [8]) GSK 2 oral doses beginning at 6-13 wks and given 1-2 mo interval Latin America Finland 85% (70-94%) Pentavalent Human-Bovine (WC3) Reassortant Merck 3 oral doses beginning at 6-12 wks and given at 4-10 wk intervals U.S Finland Belgium Jamaica 95% + (91-97%) Sweden + Also includes emergency room visits

5 Results of Placebo-Controlled, Randomized Field Trials of RIT 4237 Vaccine Against Rotavirus Diarrhea No. of Immunized PE vs. All PE vs.severe Site(yr) Doses Children RV Diarrhea RV Diarrhea Finland % 88% ** (1984) (-10%,75%) (63%,96%) Rwanda % NR (1986) (304%,67%) Gambia %* 7% (1987) (4%,53%) (-37%,37%) Peru 1 ca % 63% (1998) (-41%,48%) (-9%,88%) 2 ca % 28% (-47%,45%) (-76%,70%) 3 ca % 58% (-24%,55%) (-15%,85%) * P<.05; **P<.01

6 Cholera Outbreak in Zaire in 1994

7 Performance when given to the most relevant age groups?

8 Licensed Newer Generation Vaccines against Typhoid Fever 2 licensed vaccines available: * Live oral Ty21a * Parenteral Vi polysaccharide Indicated for persons > 2 yrs

9 Annual Incidence (per 1,000) of Blood Culture-Confirmed Typhoid Fever in the 5 DOMI Sites Age Group Karachi, Pakistan (N=41,845) Kolkata, India (N=56,946) N. Jakarta, Indonesia (N=160,261) Hue, Vietnam (N=84,488) Hechi, China (N=98,103) 0-1 years na na na 2-4 years na na 5-15 years years na * Surveillance was conducted between 01/AUG/02 and 31/Jul/03 in Hijrat Colony and Sultanabad, and between 01/Aug/03 and 31/Jul/04 in Bilal Colony ** Source : For Hue, Vietnam, the age is up to 18 years For Hechi, China, the age is up to 60 years na : not available

10 Protective Efficacy of 2 Doses of Vi-rEPA Conjugate Vaccine Given to 2-5 Year-Olds in Vietnam (Lin, 2001 ; Lanh, 2006) Interval Post- Vaccination Vaccinees (N=5,525) Cases of Typhoid in: Placebo Recipients (N=5,566) 0-27 mo mo 3 17 PE (95% CI) 92% (77%-97%) 82% (22%-99%)

11 Safety and effectiveness in persons with underlieing HIV infection?

12 Adverse Events after Ingestion of CVD 103-HgR Live Oral Cholera Vaccine or Placebo (Perry,1998) No. of cases with symptoms after administration HIV During first 4 days of follow-up Status Treatment Diarrhoea Fever Emesis During entire 12 days of follow-up Diarrhoea Fever Emesis Seronegative Vaccine 1/31 (3) 4/37 (11) 0/38 (0) 1/27 (4) 5/34 (15) 1/34 (3) Placebo 1/31 (3) 3/37 (8) 0/38 (0) 2/27 (7) 6/34 (18) 1/34 (3) Seropositive Vaccine 2/30 (7) 4/37 (11) 0/27 (0) 2/27 (7) 6/36 (17) 1/34 (3) Placebo 1/30 (3) 6/37 (16) 1/27 (3) 1/27 (4) 6/36 (17) 1/34 (3)

13 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.

14 Effectiveness when given in conjunction with non-vaccine cointerventions?

15 Electron micrographs of a single layer of sari cloth filters. Pore size is µm in old (laundered) sari 20cloth, but µm if folded four to eight times

16 Comparison of cholera cases among control, sari filtration, and nylon filtration groups of villages

17 1 0.8 Unvaccinated Vaccinated B * A * Probability of Disease D C Number of Ingested Vibrios A B : Improved water-sanitation A C : Vaccination A D : Improved water-sanitation +Vaccination

18 Effectiveness against the most relevant outcomes?

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20 Choosing Appropriate Outcomes in Evaluating Enteric Vaccine Protection Thinking vertically: beyond immediate outcomes

21 DALY Outcomes Requiring Evaluation in Trials of Enteric Vaccines in Children Growth Neurobehavioral development

22 Deaths Among Three-Dose Recipients of Killed Oral Cholera Vaccines, by Age at Vaccination (Clemens, 1988) Age Group BS-WC WC K yr 42 (-9%) 38 (3%) 39 > 15 yr 42 (45%, 20% to 62%) 50 (33%,5% to 53%) 76 Total 84 (26%) 88 (23%) 115

23 Choosing Appropriate Outcomes in Evaluating Enteric Vaccine Protection Thinking horizontally: vaccine herd protection as an outcome

24 Herd Protective Effects of Vaccines Occur when the protective impact of a vaccine in a population exceeds that expected on the basis of: 1. The proportion of the population vaccinated 2. The protective efficacy of the vaccine Can result from: 1. Transmission of a live vaccine from vaccinee to neighboring non-vaccinee 2. Reduction of transmission of the target pathogen after introduction of a vaccine into a population

25 Herd Protective Effects of Vaccines Can result in: 1. Protection of non-vaccinees 2. Enhanced protection of vaccinees Can dramatically improve the benefits that can be obtained from vaccination, including making the cost-effectiveness ratio more favorable

26 Cholera Risk by the Level of Cholera Vaccine Coverage, Matlab, Bangladesh (Ali, 2005) 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

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28 Critical importance of: * Equal partnerships in the research * Training and capacity building

29 Summary Classical vaccine development and modern biotechnology have yielded an abundance of vaccines and vaccine candidates of potential value for developing countries While biotechnology has moved forward rapidly, clinical evaluations of vaccines have lagged behind in addressing many questions of great importance to policy

30 Summary Greater attention will be needed in the future to designing studies that address the following questions: -- Do the vaccines work in the most impoverished environments? -- Do the vaccines work when deployed in epidemics? -- Do the vaccines work in the age groups of most relevance to programmatic implementation and disease epidemiology? -- Are the vaccines safe and effective in HIV-infected individuals? -- What is the combined preventive impact of vaccine and nonnon-vaccine interventions? -- What is the impact of the vaccines upon the clinical sequelae of infections that are important determinants of DALYs? -- What is the impact of the vaccines upon mortality? -- Do the vaccines confer herd protection?

31 Summary Providing answers to these important questions constitutes an important future research agenda for facilitating movement of new and improved vaccines into programs for the poor in developing countries