Economical intradermal rabies vaccine application By F.X Meslin and M.Warrell at the occasion of the international seminar on "intradermal

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1 Economical intradermal rabies vaccine application By F.X Meslin and M.Warrell at the occasion of the international seminar on "intradermal immunization: an alternative route for vaccine administration" Les Pensières, France 7-9 April 2008.

2 Estimated Annual Human Rabies Deaths in Africa and Asia due to dog rabies: ,500 23,700 India: ~ 19,000 China: ~ 3,000 Rural 83% Knobel et al., Bulletin WHO, 2005 Urban 17%

3 Rabies exposures 98% of human rabies deaths come from bites of rabid dog Many children (40% average) who come face to face with them

Human Rabies Post-exposure Country Rate/million Prophylactic Vietnam 1.1 regimens, Number Thailand of PEP: Estimated at more than 0.4 12 Asia,2004million/year China in Asia alone 2.

4 Human Rabies Post-exposure Country Rate/million Prophylactic Vietnam 1.1 regimens, Number Thailand of PEP: Estimated at more than Asia,2004million/year China in Asia alone 2.4 Sri 8 Lanka million in China (600/ ) 4.0 India 2.5 million in India (250/ ) 20.0 Philippines 700, 000 in Vietnam(1000/ ) 3.3 Nepal , 000 in Thailand (550/ ) Cambodia , 000 in Sri Lanka (1000/ ) in Bangladesh (60/ ) Lao People s Democratic Republic , 000 in Iran (180/ ) Pakistan 17.0 Bangladesh Mostly provided by the intramuscular 12.0 Myanmar route 4.1 Rate/mil 8,105 5,500 5,400 4,200 2,568 1,338 1,085 1, Indonesia Mongolia TOTAL Average: 5.3 Approx. 2,000

Rabies in Africa and Asia One person dies every 10 minutes, 50% likely to be a child under 15 years - Vast majority of people dying of rabies had no PEP (no failure) - Limited access to

5 Rabies in Africa and Asia One person dies every 10 minutes, 50% likely to be a child under 15 years - Vast majority of people dying of rabies had no PEP (no failure) - Limited access to RV: reduced availability and total cost of San Lazaro Hospital, PHILIPPINES rabies PEP IM is US$40 in Africa and US$49 in Asia. (5.8% in Africa and 3.9 % in Asia of per capita GNIncome )

Intradermal RV application decreases costs of human rabies

20 5 ID regimens Vaccine requiring costs considerably less

appropriate where vaccine or money is in short supply.

6 Intradermal RV application decreases costs of human rabies post-exposure prophylaxis $ Mvaccine im 20 5 ID regimens Vaccine requiring costs considerably less vaccine than IM PEP regimens in are particularly SMBV VIETNAM appropriate where vaccine or money is in short supply. Modern vaccine id ID reduces modern vaccine volume and cost by 60% to 80%

(1997) o Sri Lanka (1995) o Thailand (1987 NTV: Bangladesh Myanmar Pakistan Economic PEP using the

7 Discontinuation of nervous tissue derived vaccines (NTV) in Asia N CCRVs: o Vietnam (2007) o Nepal (2006) o Bhutan o Cambodia (2005) o China (1990) o India (2004) Indonesia o o Lao PDR (2005) o Philippines (1997) o Sri Lanka (1995) o Thailand (1987 NTV: Bangladesh Myanmar Pakistan Economic PEP using the intradermal route: a viable alternative for change in vaccine type delivered by the public sector in these countries.

8 Characteristics of economical multisite rabies ID PET Lower Cost decreased vaccine dose (by 60 to 80%) reduced number of visits to clinic (5 to 3) Equal or higher immunogenicity (than IM) Strong immune stimulus for low responders, HIV+ etc. Not suppressed by RIG Minimal side effects

9 ID regimens as immunogenic as IM: clinical trials Warrell MJ et al Lancet; ii: site ID HDCV+/- RIG Suntharasamai et al Epidem Infect 99; site ID PCECV +/- RIG Phanuphak-P et al Asian Pac J All Imm 5: site ID PVRV Briggs et al Bull WHO 78; site ID PVRV, PCEC (serology +/- RIG in a single group)

10 8-site ID rabies post-exposure vaccine regimen 1.0 ml 8 sites (804011) 0.4 ml ml ml 1 Day RIG with PCECV and HDCV Dose: 0.1 ml per id site

11 2-site ID rabies post-exposure vaccine regimen (22202) volume 0.2 sites ml ml 2 Day RIG With PVRV, PCECV, HDCV: id dose=0.1ml / site

12 8-site ID regimen: clinical trials Dose-finding immunogenicity studies in volunteers HDCV Warrell MJ et al. Lancet 1983; ii: Warrell MJ et al. Lancet 1984; i: PCECV Suntharasamai P et al. Epidem Inf 1987; 99: Post-exposure trials HDCV: Warrell MJ et al. Lancet 1985; i: RCT: 8-site regimen 78 pts v Semple vaccine bitten by proved rabid animal within 5 days. ERIG for severe exposure (50%). Serology on all: day 7-1 yr PCECV: Madhusudana SN et al. Int J Infect Dis 2002;6: pts proved rabid dog bites within 3 days, RIG in 22 Serology on all : day 7 to 3 yrs. Recommended in 1997 WHO doc.

13 2-site ID regimen: clinical trials Dose-finding immunogenicity study in volunteers PVRV Phanuphak-P et al 1987 Asian Pac J All Imm 5: 33-7 PCECV 0.2 ml/ site Tanterderm 1991 J MedAsTh 74; 498. Post-exposure trial PVRV Chutivongse S et al. Lancet 1990; 335: pts bitten by proved rabid animal within 48 hours All + RIG, Serology 10 people Comparison of 8-site and 2-site regimens: Madhusudana SN et al. Natl Med J India 2001;14:145-7 PCECV 2-site 0.2ml v 8-site; 39-43/gp Ab day 7 to 1yr all sig higher with 8-site.

14 2-site ID 0.1ml regimen: clinical trials Dose-finding immunogenicity study in volunteers PCECV Charanasri site regimen 0.1 ml PCECV 65 subjects v IM (0. 1ml low ab levels day 14) Suntharasamai site 0.1 ml PCECV +/- RIG Meets WHO criterion for PEP (No comparative group) Madhusudana site ID 0.1 ml PCECV 25 subjects Meets WHO criterion for PEP (No comparative group) Briggs site ID 0.1 ml with PVRV, PCEC ID or IM +/- RIG Meets WHO criterion for PEP (serology +/- RIG in a single group) PDEV Khawplod 1995 PDEV 0.1 ml and 0.2 ml doses 2-site v PVRV v HDCV (no stats ) Post-exposure trial (only applies to PCECV) Quiambao cat III pts proved rabid bite within 24 hrs (severe) or 48 hrs (mild). PCECV 0.1ml 2-site all + RIG, with serology. (Madhusudana 2006 exposure? within 48hrs, 5 proved rabid 2-site 0.1 ml PCECV 58 or PVRV 52 all + RIG, with serology)

15 PEP after a previous immunisation Regimen: 2 booster doses: days 0 and 3; IM or ID Immunogenicity studies PVRV Kositprapa 1997 CID 25; 614 Pre-exposure PVRV IM or ID; months later boosters same route days O and 3: day 14 all >0.5 Suwansrinon 2006 Vaccine 24; 3878 PEP 5-20 yrs previously, 0.1 ml ID, days O and 3: day 7 all~0.5 PDEV Naraporn 1999 J Travel med 6; 134 PEP > 5 yrs prev. PDEV 0.2 ml/ site days O and 3. Ab day 7 all >0.5 IU. PCECV Jaijaroensup et al J Travel med 6; 234. Pre-exp PCECV IM or ID 0.1 or 0.2ml, 28/gp. After 1 yr, boost days O, 3 IM / ID combinations. Day 5 : ID 0.1 ml lowest ab but no statistics Kamoltham et al. J Pediatr 2007; Pre-exp children PCECV ID, 1 yr later (GMT = 0.33IU/ml) boost ID 0.1 ml days 0,3; day 7 all>0.5

16 Antibody persistence after pre-exposure vaccine Intramuscular Intradermal Ab present No. Subjects Ab present No. subjects 1 year % % years 100 % % ½ yrs 2½- 5 yrs - 81 % % 90 % Rapid Fluorescent Focus Inhibition (RFFIT) Test >0.5 IU/ml ( 1:25) titre >1:5 Refs: Dreesen 1983 Bernard 1985 Horman 1987 Morrison 1987 Dreesen 1989 Briggs 1992 Strady 1998 Sabchareon 1998 Jaijaroensup 1999 Briggs 2001 Kamoltham 2007

17 WHO validation and promotion of economical multisite low dose ID PEP regimens For PEP WHO recommends use of the id route for those rabies vaccines that have 1992 WHO Expert Committee on rabies. WHO TRS 824 Eighth Report 1997 WHO Recommendations on rabies post-exposure treatment WHO/EMC/ZOO Report of a WHO consultation on id PEP, Bangkok. WHO/CDS/CSR/APH/ WHO Expert Consultation on rabies. WHO TRS 931 First Report 2005 WHO Recommendations for inactivated rabies vaccine for human use produced in cell substrates and embryonated eggs. Annex 2, 56th meeting of the Expert Committee on Biological Standardization 2007 WHO position paper on rabies vaccines Weekly epidemiological record, No. 49/ Meeting of the Immunization Strategic Advisory Group of Experts (SAGE), November 2007,Conclusions and recommendations, WER, N 1,208,83,1-16 1/ a potency of at least 2.5 IU per single immunizing dose (IM) 2/ have been shown to be immunogenic and efficacious in 0.1 ml injection per id site against a known reference vaccine using one of the WHO recommended regimens. Current (short) list includes: PVRV (Verorab, Imovax), HDCV ( Rabivac) and PCECV (Rabipur)

18 Rabies Deaths in Sri Lanka clinically diagnosed laboratory confirmed

19 2steps: step 1: Progressive introduction of TCV - Elimination of NTV 1986 HDCV introduced only in Teaching & General Hospitals. NTV used in all other hospitals PVRV & PCEC vaccines introduced. Category II 2 : 1 : 1 (Zagreb) Category III RIG + 5 dose (Essen) 1995 Production of NTV stopped. All hospitals used TCV. Training of staff country wide. RIG introduced up to base Hospital level.

20 Step 2: Introduction of ID PEP Intradermal administration of TCV introduced in 2 Teaching Hospitals in Colombo (several studies conducted) / 1999 Expanded to other Teaching & General Hospitals / 2002 Base & District Hospitals (> 6pts per day) Introduced in Teaching & Base Hospitals in North & East / 2005 All hospitals in the country except a few District Hospitals & Peripheral Units.

21 Hospitals using ID Rabies PEP 2001 Hospitals using ID Rabies PEP 2006

22 ID immunisation getting more widely used in developing countries Thailand ( to PEP/year) Sri Lanka ( PEP/year) Philippines ( PEP/year preventive immunizations) Vietnam India Expansion not as fast as expected: perceptions Lack of confidence in low dose regimens Confusing regimens and dosages Need for specific training Sharing of ampoules: Vaccines not in multidose vials ( off- label use ) Technique to be used only in large clinics

World Health Organization Communicable Disease Surveillance and Control

WHO/CDS/CSR/APH/2000.5 Intradermal application of rabies vaccines Report of a WHO consultation Bangkok, Thailand 5-6 June 2000 World Health Organization Communicable Disease Surveillance and Control This