CONTROVERSIES IN RABIES VACCINATION
Dr. Tapan Kr. Ghosh*
N.A.*
Rabies is an acute viral encephalitis, which is invariably 100% fatal in humans. It is primarily a disease of animal and affects human beings when they are exposed. By exposure we mean bite, scratches or licks by any rabid animal. Due to acceleration of urbanization in most of the endemic countries, the urban cycle, which is predominantly dependent on stray dog population, is becoming more prominent in maintaining and disseminating rabies in human.

Some countries of the world are free of rabies which are mainly island countries, some countries become free of rabies due to implication of effective preventive measures, namely control of stay dog population, licensing of pet dogs and their vaccination, proper vaccination strategies of human being and baiting of jungle animals, etc. Some countries for rabies have reduced the number of human rabies deaths drastically by adopting various vaccination polices e.g., switching to modern tissue culture vaccine (MTCV) replacing nerve tissue vaccine (NTV) and even accepting effective multi-dose intradermal regimen in many places.

India is the highly endemic country for rabies and tops the list regarding contribution of human deaths due to rabies in world. More than 80% of human deaths resulting from rabies in the world are reported from India though some recent statistical data from major institutions of our country seem to indicate that there is a sharp decline in the number of human deaths related to rabies during last 5-6 years in India. There lies many controversies in the field of strategies of rabies vaccination. If some of these can be solved the problem of rabies will also have some answer to a large extent.

Use of NTV is to be abandoned and replaced by MTCV?
Most important controversy of rabies vaccine policy in India is whether till today we shall continue use of nerve tissue vaccine (NTV) in the government antirabies clinics (ARCs) or the time has come to replace this preventive therapy by modern tissue culture vaccine (MTCV). How much economic burden will come out of this replacement procedure? Whether our country can afford at all the huge cost of MTCV in the innumerable ARCs ran by Department of Health of State and Central Government?

Definitely, the time has come to replace NTV by MTCV as a whole. Even in the 7th Report of WHO Expert Committee on Rabies more than 15 years back it was recommended to abandon the use of NTV even in developing countries along with developed countries and replace it by MTCV. Due to presence of high content of myelin of the adult brain tissue in Semple vaccine (NTV), there is a high incidence (1 in 5,500 to 1 in 11,000) of neuroparalysis after usage of the NTVo. But the use of NTV is continued even today even after the availability of safe and effective MTCV and purified avian tissue vaccine. After the Supreme Court order to phase out NTV and considering the fact that 3 manufacturing units are only presently producing NTV, it is now the best time to close this controversial chapter of continuing NTV treatment in animal bite cases and to switch on to MTCV.

Moreover, after the availability of MTCV for rabies prevention, it is possible to start administering pre-exposure vaccine to protect individuals at risk for rabies even before exposure namely, to the veterinary personnel, municipal workers, postmen, taxidermists, laboratory and research workers in the field of rabies, etc. This is not possible with NTVo. NTV is not only paralytico genic, it is less convenient, less immunogenic, more reactogenic, less tolerable and less acceptable with more number of doses needed and administration of which comprise comparatively a painful procedure whereas MTCV is more antigenic, acceptable, well tolerated, convenient with less reactogenicity.

On the contrary, cost effectivity is a problem in massive usage of MTCV in a vast country like India and possibly financially out of reach for the Government to replace NTV by MTCV with immediate effect. Here lies the main constrain.

This is a controversy persisting for long time whether we should immediately take decision of abandoning NTV in a phase out manner or wait for a longer time. Possibly consensus in now for the former one. And the steps have been already taken but implementation will definitely take sometime. Government of Kerala is the 1st State in India who is giving the pioneering effort in this direction.

Can not we adopt other methods of administration of MTCV to cut down the cost?
More effectivity of uses of MTCV can be improved by adopting some alternative regimen. It has been estimated that in private sector already 60 per cent usage of NTV has been replaced by MTCV without Government initiative and those uses are always in intramuscular regimen of Essen Protocol where minimum 5 doses are required on days 0, 3, 7, 14 and 28 or 30 in post-exposure cases 6. Nowadays the dose of day 90 is not routinely used and that is used only as an optional dose in some selective cases of immunodeficiency states, in indicated cases with history of death of animal in unsafe period. Apart from the Essen protocol, there is other protocol of intramuscular use, which is not practiced in India considering its high endemicity. Zagreb Protocol 6 recommend less number doses in a short period (4 doses in 2-1-1 schedule on day 0-7-21 i.e., 2 full doses on day 1 in different sites, 1 dose on day 7 and 1 dose on day 21). The gold standard for India is definitely the Essen protocol but the Zagreb protocol (Reduced dose IM Regimen) is an alternative regimen, can be used selectively in low risk cases and this protocol is claimed as equally effective as Essen Protocol.

But truly cost effective regimen for our country is intradermal schedule. There are 2 main types of multidose ID schedule.

  1. 8 site ID regimen or Oxford ID regimen (8-0-4-0-1-1)

    Days d0 d3 d7 d14 d28 d90
     

    8 doses* in 8 separate places

    No dose

    4 dose

    No dose

    1 dose

    1 dose

    No. of doses

    8

    0

    4

    0

    1

    1

  2. 2 site ID regimen or Thai Red Cross ID Regimen (TRC-ID) (2-2-2-0-1-1)

    Days d0 d3 d7 d14 d28 d90
     

    2 doses*

    2 dose

    2 dose

    No dose

    1 dose

    1 dose

    No. of doses

    2

    2

    2

    0

    1

    1


This TRC-ID regimen has been practiced by some Asian countries like Thailand, Sri Lanka and Philippines with success for a long time. And by adopting this schedule these countries8 have brought down the incidence of human deaths due to rabies. Though this schedule is only possible in clinics where there are good number of cases e.g., the government of municipal ARCs. In 19928, WHO conveyed several meetings with experts from different countries and finally approved 2 ID regimen to be followed with PVRV and PCEC. Subsequently WHO consultant in the year 1996 and 2001 have only further corroborated and strengthened the WHO's previous recommendations. Thailand and Sri Lanka are in no way economically superior to India but they have stopped the use of Semple vaccine (NTV) a decade ago and replaced with MTCV like PVRV and PCEC8. The intradermal regimens are WHO approved. But there are some challenges:

  • Public health challenges:



    • Crowded ARV clinic - Attending to a large number of patients in ARCs in a short time - Multiple ID injections need time.

    • Pediatric age group - Sixty percent patients of animal bites and scratches are children below 14 years - Acceptability of ID schedule by the children i.e., pricks in different places are definite question mark (IM vs. ID schedule).

    • Late reporting after bite/scratches - These cases are majority and need early response (IM vs. ID).

    • Category III exposure - More than 70% victims present with transdermal or mucosal injury, which also need early response (IM vs. ID).




  • Socioeconomic challenges:


    • Drop out cases - Thirty days are needed in IM course whereas 90 days in ID course, so chances of drop out will be more in ID regime.

    • IM Zagreb versus ID regimen - Three visits of Zagreb protocol versus 5 visits of TRC-ID protocol.

    • Indirect cost factors - These are to be added viz, that of man hour loss, travel time, etc.



  • Medical challenges:

    1. Safety, convenience, compliance, valid efficacy data are to be studied.
    2. Technique - ID injections may turn to subcutaneous injection, different dose amount in different days in ID course e.g., 2 doses on day 0, 3, 7 and 1 dose each on day 30 and 90, proper training of nurses and health workers of ARCs are needed.

All the above challenges will give rise to controversy in selection of ID regimen. We must have all country data regarding ID regimen ultimately and a decision shall be taken about its acceptability after that.

A three steps strategies have been practical to accept this TRC-ID schedule:

  • Step 1: Get rid of NTV

  • Step 2: Introduction of modern tissue culture vaccine of rabies

  • Step 3: Selection of regimen from 4 WHO approved regimen - 2 IM regimen
(Essen protocol and Zagreb protocol) and 2 ID regimen (Oxford-ID and TRC-ID)

Ultimately ID regimen may be accepted for its cost effectiveness and this is no doubt a good option for India if all the controversies can be sorted out and proper training programme of public health medical staff including the doctors and nurses can be undertaken.

In this respect, the Sri Lankan experience 9 says that "To overcome this financial burden, WHO recommended intradermal administration of a reduced volume of rabies cell culture vaccine and this was introduced in 1997. At present, all major hospitals in the country are practicing this new schedule, we have been able to overcome the shortage of vaccine and reduce the cost of post-exposure therapy".

Lastly a few things to be kept in mind in relation to ID schedule:
  1. Cannot be recommended in private practice.
  2. Does not make economical sense for just one post-exposure case at a time.
  3. Reconstituted vials must be discarded in 6-8 hours.
  4. Should be administered by trained staff only.
  5. The antigenic content of reconstituted vaccine should be 0.25 IU per 0.1 ml.
  6. The volume per intradermal site is usually one-fifth of IM dose:
    • 0.1 ml of PVRC (Purified vero cell vaccine 0.5 ml vial).
    • 0.2 ml of PCECV (Purified chick embryo cell vaccine - 1 ml vial).
    • 0.1 ml of PCECV may also be considered for use by national health authorities only.

Routine Pre-exposure vaccination to children:
Many vaccines have been accepted by IAP Committee on Immunization (IAPCOI) for routine use in children including vaccine like Hepatitis A, Varicella, and Typhoid vaccine as additional vaccines. In India the number of animal bite consultations is approximately 1 million and 60% victims are children. Considering rabies as a cent percent killer disease, we can estimate easily the burden of this situation of the children.

The routine use of an IM pre-exposure regime of total 3 doses, one dose each on day 0, day 7 and day 21 or day 28 may be an option to reduce the incidence of rabies in children. The children are vulnerable to animal bite for their curiosity to animals especially to pets, their short height, their ignorance to the fate of this sequence and underreporting to the parents after the exposure.

When so many vaccines have been accepted as additional vaccines in the immunization schedule of the children, inclusion of pre-exposure doses of MTCV will definitely improve the situation of rabies control 6.

Is it possible to include rabies vaccines in EPI schedule? - Another controversy in this connection.
Rabies vaccine had been administered along with DPT-IPV in Vietnamese infants at 6, 14 weeks of age recently and has been found to be safe and efficacious. This could lead to future integration of pre-exposure rabies vaccination into EPI of countries where rabies is enzootic 10.

Schedule in Re-exposure and repeated booster with MTCV:
When there is a re-exposure i.e. animal bite or scratch for the 2nd or 3rd time, there must be a unanimous consensus about the uses of vaccine when a complete course of vaccines (MTCV) has been completed during the 1st exposure. If a 5 dose IM post-exposure schedule of MTCV was taken during 1st exposure only 2 IM doses of MTCV one on day 0 and another on day 3 are the best choice irrespective of time interval between the 1st and the subsequent exposure and between the 1st vaccination (Post-exposure) and the next vaccination. In this type of cases rabies immunoglobulin (RIG) will not be necessary for the 2nd time.

Even if a pre-exposure IM schedule of 3 doses on day 0, 7 and 21 is taken, for an exposure later on, 2 IM doses, one on day 0 and one on day 3 will be sufficient.
Routine yearly or 3 yearly booster for life long is not to be recommended for all. Only in cases the person is involved in someway where there is chance of repeated exposure to animal or virus like veterinarians, laboratory workers in rabies research, postmen, municipal workers, workers in vaccine production units, taxidermists will only need regular booster doses. Nowadays a yearly boostering with only 0.1 ml PCECV is practiced replacing full IM dose in some centers like NIMHANS, Bangalore.

Use of RIG in Category III (WHO) cases In all category III (WHO) exposure rabies immunoglobulin (RIG) is indicated11. By category III exposure of moist surface i.e. cut in these areas, even licking by suspected animal in mouth cavity or anus, drinking of unboiled milk of rabid animal. But in cases of category III exposure with wounds RIG is indicated.

Two types of RIG are available: (i) Human RIG (HRIG) and (ii) Equine RIG. Both are in short and irregular supply. Nowadays HRIG is available in open market but ERIG is not available in private shops. When availability of HRIG is there, affordability is always not possible due to its huge cost. The ARS produced by CRI, Kasauli is always insufficient for a vast country like India, and moreover this is not available for private cases.

But where there is a category III injury in skin or mucous membrane RIG is to be given (20 units/kg of HRIG or 40 units/kg of ERIG) preferably in the same day of 1st vaccination in a separate place away from IM sites. But it can be given even along with 3 doses of vaccine by latest. The seriousness of medical professional is demanded in this respect. Controversy is why it is not advised routinely? Another question is how to give the RIG. This shall not be given intramuscularly but to be given intralesionally in and around the wound including the deep bases of wound where virus can settle for a few days before multiplication. Idea of RIG administration is to neutralize those virus by trapping with immunoglobulin immediately as MTCV needs sometime (7 to 14 days) to develop antibodies and in a number of cases the disease sets early even before 10 days. HRIG is gold standard but ERIG is also effective though there is chance of serum sickness like reaction in a few number cases and anaphylaxis in a very rare percentage of cases.

RIG is commonly avoided by medical practitioners leading to treatment failure in the fear of reactogenicity. There should not be any controversy in using RIG, when available and affordable. Serovaccination therapy with proper cleaning of wound immediately after exposure is the key to success of prevention of rabies in category III cases. There should not be any controversy of using RIG in this category with wounds and liberal use of RIG will definitely keep the risk of rabies away.
References :
  1. Gongol GN, Rai JN. The rabies situation in Nepal. J Assoc Prev Control Rabies India (JAPCRI) 200;1:39-42.
  2. Sudarshan MK. Prevention of human rabies. J Assoc Prev Control Rabies India (JAPCRI) 1999;1:2.
  3. APCRI. Background Document of Orientation Workshop for APCRI Trainers in Modern WHO Approved Rabies Prophylaxis. Held on March 31st, 2001 NIMHANS, Bangalore, p6.
  4. WHO Expert Committee on Rabies, Seventh Report, WHO Techn Rep Series 709. Geneva: WHO, 1994:68-70.
  5. Singh H, Bhatia R. Vaccines : Prospects and Perspectives. Vol. 1, 1st ed. Delhi : Forward Publishing Company, 1993:282-309.
  6. Ghosh TK. Rabies vaccine. In; Shendurnikar N, Agarwal M, eds. Immunization in Children, 1st ed. Hyderabad, Bangalore : Paras Publishing, 2002:171-82.
  7. Vakil HB, Parikh S. Rabies vaccines : current perspective and further direction. Indian J Intern Med 2002;11:25-30.
  8. Madhusudana SN. Intradermal immunization with cell culture vaccines : a cost effective strategy to replace nerve tissue vaccine [Editorial]. APCRI J 2001;2:4.
  9. Omala W. Rabies Control in Asia. Abstract. WHO Workshop. Hanoi, Vietnam, March 5-9, 2001.
  10. Lang J, Duong Q Hoa, Nguyen VG. Randomized feasibility trial of Pre-exposure rabies vaccination with dPT-IPV infants. Lancet 1997;349:1663-5.
  11. Bompart F, Dutta AK, Wood SC. Rabies immunoglobulins in WHO category III exposures. J Assoc Prev Control Rabies India 2000;1:7-9.
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