The Anti - Rabies Vaccination Programme in India at the crossroads
Dr. Amlan Goswami
Consultant Physician, Kolkata. Founder Life Member APCRI.
The use of the Sheep Brain derived Nerve Tissue Vaccine (NTV) used for post-exposure anti-rabies prophylaxis in the numerous Anti – rabies clinics, in Government (Govt) Hospitals and Health centers in India will come to an end by the end of September 2005. This vaccine was invented by Sir David Semple in 19111, and was used for the treatment of animal bite victims at Central Research Institute, Kasauli (CRI Kasauli) from 1919 onwards. At that time Sir David Semple was its Director2. This vaccine is also known as the “Semple Vaccine”. The vaccine had undergone many modifications since its invention. The inactivating agent and process of manufacture changed from Phenol to Betapropiolactone, and the number and the volume of the doses also changed from 14 doses to 10 doses and the maximum volume that can be injected sub-cutaneously per dose from 10 ml to 5 ml. Patients getting ARS received 2 boosters in addition (in both). The changes did not decrease the incidence of its “Adverse reactions and Complications”. The most serious being the much feared neuroparalytic complications which can sometimes be life – threatening also. The most common being the pain, swelling, itching and redness at the site of the injection, around the umbilical zone of the anterior abdominal wall. Some patients also suffer from systemic reactions to the vaccine. The numerous visits to the vaccination center, often after traveling for hours and the long hours spent in waiting at the treatment centers, often negates the free supply of vaccine for which the ignorant people come.
The modern Tissue Culture Vaccines (TCV) are in use for both pre and post-exposure prophylaxis against rabies for more than two decades. The advantage of using TCVs are visible to both the physicians treating an animal bite victim and the patient receiving it. Without Govt support more than 50.1% of the patients receiving post exposure vaccination against rabies take TCVs as revealed by the APCRI WHO Survey 2004. All of these patients were taking TCVs in “ESSEN” schedule the only schedule approved by the Drug Controller General of India (DCGI). This schedule is very easy to administer, does not cause any problems for the recipient, it is highly immunogenic and has a good margin of safety4. At the time of getting this article for printing this is the only legally permitted schedule to be used for post-exposure vaccination against rabies.The cost of the five doses of TCV to be used for a full course is considered by many State Govts funding the programme in their respective states to be beyond their means.
The use of micro doses of TCVs by intra-dermal (ID) route in Thai Red Cross (TRC) schedule is being considered for replacing NTV in Govt Hospitals. As the situation stands on this day, very few vaccines are approved for use by WHO Expert consultation in Rabies5. They are PCECV (Chiron) and PVRV (Sanofi – Pasteur). Indian Council of Medical Research (ICMR) had carried out a multi – centric study on the TRC-ID vaccination using indigenously manufactured vaccines, compared against PVRV (Sanofi – Pasteur) used in the conventional “ESSEN” schedule of five IM injections in the deltoid on Day 0, 3, 7, 14 and 28. The ICMR study summarized results were that, not all indigenous TCVs being tested for use in TRC ID vaccination schedule gave satisfactory results. The control vaccine PVRV (Sanofi-Pasteur) used in “ESSEN” schedule as expected gave very satisfactory results. However further studies would be required to pass any remark on the suitability of the vaccines which did not come up to the WHO approved standard for ID usage. The ICMR trial sample was not big enough for passing any concrete opinion on the suitability of the vaccines for ID usage. The trial was carried out on a small number of volunteers. For regulatory approval, the trial should be conducted on actual patients seeking treatment after animal bites in those centers, after obtaining clearance from the DCGI and the appropriate ethics committees and should be done by following all the GCP norms. It would be better to have the trial carried out on confirmed rabid animal bite cases, to have any importance in the regulatory process. This procedure was followed in some countries. When a policy decision regarding the choice of vaccines for mass use, and the introduction of a new type of treatment is involved, then all the pros and cons have to be carefully considered and a legally and technically perfect procedure adopted for its proper implementation.
The availability of adequate amount of TCVs for use in Govt Hospitals and Health centers will be a problem at present, and in the immediate future. If only “ESSEN” schedule is used then the crisis will be more acute. If, “TRC ID” schedule (2-2-2-0-1-1), is used then the total requirement of vaccine vials will be less than that for “ESSEN” schedule. Not All vaccines produced in INDIA are at present fit for ID usage as per facts revealed in some studies and the “WHO Expert Consultation on Rabies”, Technical Report Series 931 . ICMR study has not solved the ID usage problems of the country as it does not solve the problem of the suitability of the indigenous TCVs in TRC ID schedule. If the WHO Technical Report Series 931 is considered, then the only two eligible vaccines are PCECV (Chiron) and PVRV (Sanofi – Pasteur). The total number of available doses of these two vaccines combined in 2004 was 6 million doses6. The maximum number of doses of these two vaccines combined to be available in 2006 is expected to be 7.5 million doses. Both the manufacturers are multi-nationals and both are having interests in the retail trade as well as the global market. The entire amount of vaccine will not be available for Govt supply. As per APCRI WHO survey report 2004, 1.7 % of the population of India gets bitten by animals each year. The figure works out to be 17 million persons yearly. Only 47.9 % of the 17 million animal bite victims took anti-rabies vaccines. The NTV usage was 46.9 % of the persons taking anti-rabies vaccination3. This means that vaccination has to be arranged for about 4 million persons immediately. With the passage of time, the load of the patients coming for treatment following animal bites will increase . Along with the availability of TCVs free in Govt Hospitals and clinics, a proportion of patients taking TCVs on a self financing basis at present, will come to the Govt Hospitals and Clinics to obtain free treatment available there. This will further increase the load in the Govt sector.
The shift from NTV to TCV ID is very much desired by all. However, the change involves overcoming many challenges. They are (1) Public Health Challenges; (2) Socio Economic Challenges; (3) Clinicians Challenges; (4) Medical Challenges; and (5) Practical Challenges.
Public health challenge involves attending a large number of patients in a very short span of time . Almost half the number of patients are children below 14 years of age.
Socio economic challenges are the great possibility of drop-outs at the Day 90 dose, due to the occupational and personal problems. The loss of daily wages and earnings due to the loss of time in coming to the distant specialized centers offering free ID anti-rabies vaccination.
Clinician’s challenges are :- IM vaccination is easy to administer and trouble free. When a child or an adult does not want to take the vaccine shots due to the fear of the injections, but the vaccine shot has to be given forcibly as a life saving measure, then ID vaccination shots will be very difficult to administer. Moreover the ID shots are more painful than the IM shots and they leave tell tale marks at the site of administration. So the patient compliance is expected to be low.
Medical challenge involves administering ID correctly. If ID dose is given sub-cutaneously (SC) then there is a possibility of poor immune response due to low antigen load. This may be life threatening.
Practical challenges are the training of staff for ID anti-rabies vaccination. The vaccine vials which are reconstituted have to be used within 8 hours if kept in a fridge, otherwise in the same hour.There will be wastage of vials if the number of patients attending each day is less . ID is more time consuming than IM, so there will be problems if there is a large attendance of patients.
TRC ID schedule has been implemented in Thailand in many hospitals (not all), in Philippines, in most major centers and in Sri Lanka in some major hospitals9. These are small countries but India is a huge country. Here ID usage has to be started, but in a phased manner. The difficulties encountered in each step can be rectified in the next .Unfortunately the usage of NTV has been stopped abruptly without making the necessary arrangement for filling up the void.The policy makers do not face the patients and so they cannot think of the practical issues involved in the process.
Everyone, including myself will be very happy if this changeover goes on smoothly. However it will pain everyone a lot if we come to know that poor people died of Rabies due to the fact that they could not buy adequate doses of TCVs, and adequate doses of TCVs were not available in the Govt Hospitals and Clinics where they used to get free treatment in the past.
Semple, D. The preparation of safe and efficient antirabic vaccine. Sci. Men. Med. Sanit. Dept. Govt. of India, Bull. Inst. Pasteur, Paris , 1911: 9 : 1.
Singh, H. and Bhatia, R. Vaccines prospects and perspectives, volume 1, Forward Publishing, 1993, page 282 to 309.
Sudarshan, M. K. et all, Assessing the Burden of Rabies in India, Report of the APCRI WHO multi-centric rabies survey, May 2004.
WHO, Expert committee on Rabies, Eight Report, WHO Technical Report Series 824.
WHO Expert Consultation on Rabies, First Report, WHO Technical Report Series 931.
KIMS and NIMHANS, International Symposium on Prevention and Control of Rabies; Abstracts book, 2005, 18th & 19th March, Bangalore.
Goswami, Amlan. Intradermal Regimen in India : A Clinician’s Perspective. Proceedings of the National Seminar on Intradermal Rabies Vaccination, 25th February, 2003, KIMS, Bangalore, page 12.
Goswami, Amlan. Intradermal Anti-Rabies Vaccination in India- A Problem in Implementation, Souveneir of APCRICON 2003, Bhubaneshwar, July 5th & 6th, 2003, page 54.
Dodet, Betty. Meslin. Francois-Xavier. Symposium Proceedings, Rabies Control in Asia, Fourth International Symposium on Rabies Control in Asia, John Libbey, Eurotext. 2001.