Introducing intra-dermal rabies vaccination in India: Rationale and action plan

M.K.Sudarshan, B.J.Mahendra and D.H. Ashwath Narayana


Following the discontinuation of Semple (or sheep brain /nerve tissue) vaccine in December 2004 the government hospitals in the country are facing an acute shortage of modern rabies vaccines. This is due to limited budget and the modern rabies vaccines are expensive by intramuscular route. However, there is a dilemma to replace the Semple vaccine by intradermal rabies vaccination (IDRV). There are also opinions in certain quarters that IDRV is inferior / substandard and the technique of ID administration is difficult to practice. In this context, this paper elaborates on the scope of IDRV in India.

What is intradermal rabies vaccination ?

It is deposition of approved modern rabies vaccine (or antigen) in the layers of dermis of skin. Subsequently the antigen is carried by antigen presenting cells via the lymphatic drainage to the regional lymph nodes and later to the reticulo-endothelial system eliciting a prompt and highly protective antibody response. Immunity is believed to depend mainly upon the CD4 + T- cell dependent neutralizing antibody response to the G protein. In addition, cell-mediated immunity has long been reported as an important part of the defense against rabies. Cells presenting the fragments of G protein are the targets of cytotoxic T- cells and the N protein induced T helper cells. The immune response induced by IDRV is adequate and protective against rabies.

What are the current recommendations of World Health Organization ?

WHO Recommendations, 2005.

Considering the recommendations on intradermal application of rabies vaccines in the eighth report of the WHO Expert Committee on Rabies published in 1992, a number of WHO consultations have contributed over time to the further assessment and wider use of reduced dosage intradermal vaccination regimens for rabies pre- and post-exposure prophylaxis. These regimens consist of the intradermal administration of a fraction of the intramuscular dose of certain rabies vaccines at multiple sites. The use of this route leads to considerable savings in terms of the total amount of vaccine needed for a full pre- or post-exposure vaccination series, thereby reducing the cost of active immunization.

These intradermal regimens are of particular interest in areas where rabies vaccines are in short supply or available but inaccessible, in view of their price, to people at risk of contracting rabies. The intradermal route for rabies vaccine administration should advantageously replace post-exposure prophylaxis using brain-tissue vaccines in all countries where these vaccines are still produced and usually administered to the poorest segment of the population. The decision to implement economical intradermal post-exposure prophylaxis rests with government agencies that define rabies prevention and treatment policies in their own countries.

When the intradermal route is used, precautions include staff training, conditions and duration of vaccine storage after reconstitution, use of appropriate 1 ml syringe and short hypodermic needles. Vaccines to be applied by intradermal route of administration should meet WHO requirements for production and control related to vaccines for intramuscular use, including an NIH test potency of at least 2.5 IU per single (intramuscular) dose. In addition, immunogenicity and safety of the vaccine in question should be demonstrated in appropriate human trials using WHO post-exposure prophylaxis regimens.

In countries where relevant national authorities have approved the intradermal route for rabies pre- and/or post-exposure prophylaxis, and for vaccines that can be used by that route, the vaccine package leaflet should include a statement indicating that the potency as well as immunogenicity and safety allow safe use of the vaccine for intradermal pre- and post-exposure prophylaxis, in addition to other relevant information as described in the WHO requirements for vaccine production and control.

Intradermal regimens

A limited number of rabies vaccines have been recognized to date by WHO as safe and efficacious for post-exposure prophylaxis when administered by the intradermal route in two different regimens. Local manufacturers in rabies-endemic countries are beginning to produce rabies vaccines. The intradermal use of these vaccines should be based on adherence to WHO requirements for that route and approval by national health authorities. New vaccine manufacturers should provide clinical evidence that their products are immunogenic and safe when used intradermally. Clinical evidence should include clinical trials involving a vaccine of known immunogenicity and efficacy when used by this route as control, serological testing with rapid fluorescent focus inhibition test, and publication in internationally peer-reviewed journals.

Updated Thai Red Cross intradermal regimen (𙹔𣇺2 regimen)

Sufficient clinical evidence was presented indicating that a single dose of vaccine given on day 90 of the original Thai Red Cross regimen (𙹔𣇺𢴏 regimen) can be replaced if two doses of vaccine are given on day 28 (𙹔𣇺2 regimen). The Thai Red Cross regimen considerably lowers the cost of vaccination as the total volume of vaccine required is much less than that needed for intramuscular regimens.

The schedule for the updated Thai Red Cross intradermal regimen is as follows: one dose of vaccine, in a volume of 0.1 ml is given intradermally at two different lymphatic drainage sites, usually the left and right upper arm, on days 0, 3, 7 and 28. Vaccine administered intradermally must raise a visible and palpable 揵leb in the skin. In the event that a dose of vaccine is inadvertently given subcutaneously or intramuscularly, a additional dose should be administered intradermally. Currently there are two vaccines that have been proven to be efficacious in the Thai Red Cross regimen: purified Vero cell rabies vaccine produced by Aventis Pasteur and purified chick embryo cell rabies vaccine produced by Chiron Vaccines.

Eight-site intradermal regimen (𛯚𣯒𢴏 regimen)

One dose of 0.1 ml is administered intradermally at eight different sites (upper arms, lateral thighs, suprascapular region, and lower quadrant of abdomen) on day 0. On day 7, four 0.1 ml injections are administered intradermally into each upper arm (deltoid region) and each lateral thigh. Following these injections, one additional 0.1 ml dose is administered on days 28 and 90. This regimen lowers the cost of vaccine administered by intramuscular regimens and generally produces a higher antibody response than the other recommended schedules by day 14. It does not result in a significantly earlier antibody response and in order to ensure optimal treatment, a passive immune product must be administered to patients presenting with severe exposures. Only two commercial products are today considered safe and efficacious when administered according to this regimen. They include a human diploid cell vaccine produced by Aventis Pasteur and a purified chick embryo cell rabies vaccine produced by Chiron Vaccines.

Staff trained in this technique must administer intradermal injections. Vaccine vials should be stored between 2 篊 and 8 篊 after reconstitution and the total content should be used as soon as possible, but at least within 8 hours. Rabies vaccines formulated with an adjuvant should not be administered intradermally.

The changing scenario of rabies in India : 2000 2005

The situation of rabies is quickly changing in the recent times and a few parameters are given below :

All these show that there is a decline in the incidence of disease following an improvement in the usage of rabies biologicals. This is due to the overall socio-economic development consequent to improvement in the education, employment and economic condition of the people.

Production of rabies biologicals in India

The production of rabies biologicals viz. both modern vaccines and immunoglobulins are vastly improving as given in tables 1 and 2. There is a quantum jump in the production (and capacity for future) of vaccines and sera in both government and private sectors. In fact following a Supreme Court order the sudden stoppage of production of Semple (NTV) vaccine in December 2004 without adequate contingency plans is leading to a difficult and crisis like situation in government hospitals in the country.

The human rabies immunoglobulins (HRIGs) being imported, are not only scarce but also expensive thus making them the privilege of the rich of the country. It is time that planned indigenous production of HRIGs is started in the country. There is enough scope for its consumption in the country and the prospective producers need not be worried about this. In the due course of time if HRIGs are made less expensive it will ensure a wider usage of RIGs in the country and further reduce the burden of human rabies incidence.

The current production and capacity for future vaccine production is fairly adequate provided they are not exported for better profits ignoring the local demands. In fact the vaccines produced in the government sector have been found good for intra-dermal administration and their production is also adequate to launch IDRV in the country by Government of India without depending on vaccines from the private outlet. On the contrary it is now important to promote the use of proper WHO approved rabies prophylaxis by professional educational programmes and public awareness campaigns.

Compulsions for IDRV

In 2001, the central government launched the animal birth control (ABC) programme for control of stray dog population in municipal areas of the country. In contravention to the previous municipal laws, which ensured removal of stray dogs from the streets the new ABC programme permits the presence of stray dogs on the streets. These continue to be menacing to the public especially the poor who are mostly their bite victims. These ABC dogs receive modern rabies vaccines from municipal funds while their bite victims paradoxically received the WHO banned Semple (NTV) vaccine till December 2004. Following the stoppage of NTV in December 2004 at least now the central government must ensure that these life saving modern rabies biologicals (viz. both vaccines and sera) are made available to the poor of the country at government expense. This must be viewed as an issue of social justice and human rights vis-a-vis lopsided animal rights misadventures in the country. Such gross neglect and contempt for the poor is possible only in a developing country like India where the mass majority are poor, illiterate, ignorant and not organized.

Economics of Intradermal rabies vaccination

Based on the available studies and prevailing cost factors a comparative study of IDRV, Semple vaccination and modern vaccines by intramuscular route show that IDRV would cost nearly one third of the intramuscular Essen regimen (Table-3). A comparison with the recently discontinued Semple vaccine shows that the cost of CCV for IDRV is lower than the cost of NTV. This should enable the Government to favour IDRV to replace Semple vaccine. Besides, the Semple vaccine was inferior, less efficacious, highly reactogenic and was disapproved by WHO. On the contrary, IDRV is safe, highly efficacious and approved by WHO.

Global Experiences of IDRV

The WHO approved IDRV in 1992, about thirteen years ago. It is considered as an ethical and cost-effective replacement of NTV. Besides IDRV is generally considered as a pro-poor 拻 vaccination. Following the launch of IDRV in Thailand in 1986, the annual incidence of human rabies reduced from 300 to 19; in Philippines in 1993, the annual incidence of human rabies dropped from 600 to 200; in Sri Lanka in 1997, the annual incidence of human rabies decreased from 200 to 76. All these denote the success stories of IDRV.

Pre-requisites for India

In August 2002 foreseeing this situation APCRI submitted a memorandum to Sri. Shatrughan Sinha, then Union Health Minister to introduce IDRV in the country.

Table-1
Production of rabies biologicals in India, 2004-06

Modern Vaccines

Quantity (in doses)

2004    
(Production)    

2006
(Capacity)

Private
       (a) Imported Verorab (PVRV)
            (Sanofi - Pasteur)

1.1 million

 

       (b) Indigenous
           4Rabipur (PCEC) (Chiron Vaccines / Sanofi Aventis)
           4Vaxirab (PDEV) (Zydus Cadila)
           4Rabivax (HDCV Adsorbed) (Serum Institute of India)             


5.0 million
1.0 million
5.69 lakhs


6.0 million
2.5 million
2.0 million

Subtotal (a)

7.7 million

10.5 million

Government
           4Abhayrab (PVRV) (Human Biologicals Institute)
           4PVRV (Pasteur Institute of India, Coonoor)


1.1 million
0.1 million


4.0 million
1.0 million

Subtotal (b)

1.2 million

5.0 million

Grand Total [(a)+(b)]

8.9 million

15.5 million

Sera (ERIGs)

Quantity (in ml)

2004
(Production)

2006
(Capacity)

Private
           4Equirab (Bharat Serums and Vaccines)
           4CARIG (Cadila Pharma)


500 liters
40 liters


3000 liters
 75 liters

Subtotal (c)

540 liters

3075 liters

Government
           4ARS (CRI, Kasauli)
           4Abhay Rig (Human Biologicals Institute)


120 litres
750 liters (in 2005)


300 liters
1500 liters

Subtotal (d)

870 liters

1800 liters

Grand Total [(c)+(d)]

1410 liters

40875 liters

Note: HRIGs are scarce, expensive and only imported.

 

Table-2
Indigenous Production of rabies biologicals in India, 2004-06

Rabies Biologicals 2004 (Production) 2006 (Capacity)

Private
           4Modern Vaccines (PCEC/PDEV/HDCV)
           4Sera / ERIG


6.6 million (85%)
540 liters (38%)


10.5 million
3075 liters

Government
           4Modern Vaccines (PVRV)
           4Sera / ERIG


1.1 million (15%)
870 liters (62%)


5.0 million
1800 liters

Subsequently at the behest of DCGI, Indian Council of Medical Research (ICMR) initiated a multi-centric feasibility study on IDRV in India. The result of this study is favourable for its implementation and it is before DCGI for his approval. Now it is very crucial that DCGI approves the use of IDRV in India. This will make the manufacturers of the ID approved vaccines to incorporate ID guidelines in the product insert and thus permit their usage by the physicians of the country. The progressive state governments must come forward boldly to implement IDRV in select anti-rabies clinics (ARCs). An ideal IDRV clinic shall be

As and when IDRV is launched in India, on the lines of pulse polio campaign mass media viz. television, newspaper and radio publicity be given for IDRV utilizing the services of popular and famous film and public personalities of the country.

Proposed action plan

Following the approval of IDRV by DCGI, its phasing in may be done as follows:

1st month: Launch IDRV in select hospitals in Delhi.

3rd month: Launch IDRV in select hospitals in other capital cities of volunteering state governments.

6th month: Launch IDRV in district hospitals of these implementing states.

12th month: Launch IDRV in Taluka/ Tehsil hospitals of these implementing states.

Likewise over the next five years, by 2010, the entire country can be covered. This ethical and cost-effective anti-rabies vaccination is expected to further reduce the burden of human rabies in India. If simultaneously, suitable supportive canine population and rabies control activities are started, then the prospects of 揜abies Free India by 2020 appear distinctly plausible.

 

Table-2
Cost-estimate of Anti-Rabies Vaccination (per case) in Government Hospitals

Sl. No. Estimate Essen
Regimen
Semple
Vaccine
TRC
Regimen
Updated
TRC Regimen
Type Cost (Intramescular)
(5 visits)
(Subcutaneous)
(10 visits)
(Intradermal)
(5 visits)
(Intradermal)
(5 visits)
1 Vaccine Rs. 5 per mL (NTV)+ NA Rs. 150=00 NA NA
Rs. 150 per mL (CCV)+

Rs. 750=00

NA Rs. 120=00 Rs. 120=00
2 Other medicines Rs. 65 per case Rs. 65=00 Rs. 65=00 Rs. 65=00 Rs. 65=00
3 ARC overheads Rs. 7.65 per case per day Rs. 38=00 Rs. 76=00 Rs. 38=00 Rs. 30=00
4 Transport Rs. 11.50 per day Rs. 57=00 Rs. 115=00 Rs. 57=00 Rs. 46=00
5 Loss of wages Rs. 30.30 per day Rs. 151=00 Rs. 303=00 Rs. 151=00 Rs. 121=00

Total

Rs. 1061=00 Rs. 709=00 Rs. 431=00 Rs. 382=00

Note:

  1. Five intramuscular injections of CCV on days 0, 3, 7, 14 & 28.

  2. One subcutaneous injection daily for ten days (Average of 30 mL).

  3. ID regimen of 2-2-2-0-1-1(0.1 mL per site at two sites on days 0, 3, 7 and at one site on days 28 & 90).

  4. ID regimen of 2-2-2-0-2 (0.1 mL per site at two sites on days 0, 3,7 & 28)

  5. NA = Not Applicable.

+ Based on the study by Dr M K Sudarshan, et al (2002)
++
This is an estimated value for supply of CCV (of 1 mL IM dose) to Government Institutions.

References and suggested further readings:

  1. World Health Organization. WHO expert committee on rabies. Eighth report, 1992, Geneva, Switzerland.

  2. World Health Organization. WHO recommendations on rabies post-exposure treatment and the correct technique of intradermal immunization against rabies, WHO/EMC/ZOO.96.6, 1997, Geneva, Switzerland.

  3. World Health Organization. Intradermal application of rabies vaccines, Report of a WHO consultation, WHO/CDS/CSR/APH/2000.5, 2000, Bangkok, Thailand.

  4. Association for Prevention and Control of Rabies in India. National Seminar on intradermal rabies vaccination, 2003, KIMS, Bangalore.

  5. Association for Prevention and Control of Rabies in India. Assessing burden of rabies in India, WHO sponsored national multi-centric rabies survey, 2004, KIMS, Bangalore.

  6. World Health Organization. WHO expert consultation on rabies. Ninth report, 2005, Geneva, Switzerland.

  7. KIMS and NIMHANS. International Symposium on Prevention and Control of Rabies; Abstracts book 2005 Bangalore.

  8. M K Sudarshan, B J Mahendra, D H Ashwath Narayana, Cost- accounting analysis of production of Semple vaccine in India-J of APCRI, Vol. iv, Issue 1 & 2, Jan-July 2002, 40-41.

  9. D M Satapathy et al., Cost- factor analysis: Thai Red Cross vs. Oxford regime with PCEC vaccine, Souvenir, 5th APCRICON, July, 2003, Bhubaneshwar.

  10. Amlan Goswami et al., Actual cost of rabies Post exposure treatment Souvenir, 6th APCRICON, July 2004, Kolkata.

  11. Subrato Pradhan et al., Pharmaco economics of anti-rabies treatment- the case for Intra dermal administration of Cell Culture Vaccines - Indian J of Internal Medicine. 2002, Vol. 11, No. 6, 5-12.