Dr. Amlan Goswami, Consultant Physician, Kolkata. Founder Life Member APCRI.

Annually 1.7% of the population of India on an average gets bitten by an animal, or suffers from a confirmed or suspected Rabies Exposure.l  Some of these exposures are repeat exposures. Some of these repeat exposures occur in persons who are Pre-exposure immunized against Rabies in a planned manner or have received the full course of TCVs against Rabies or RIG and TCVs against Rabies in WHO recommended schedule for a previous exposure.

WHO expert committee on Rabies following its latest consultation in October 2004 has given a general guideline which is not at all a categorical advice. It begins by saying that the recommendations given are intended as a general guideline. Modifications may be warranted in certain situations but not limited to them (The situations mentioned in the guideline) only. A careful risk assessment should be conducted by a qualified medical professional on every patient exposed to a potentially rabid animal. ²

From my Personal Experience in treating cases of animal bites for about 2 (two) decades, I have seen many changes in the guidelines given in package insert of various TCV s against Rabies by their manufacturers, and the guidelines are not same for all vaccines though WHO says it should be.  

A clinician treating a case of severe degree animal bite by a clinically suspected rabid animal will always be in a Dilemma of following which advice. Every one has protected themselves by mentioning about a potent TCV being used in the primary course of immunization.

We know that even WHO approved TCVs can have a low potency if there is a cold chain break. The users, doctors and patients have no way to know about the potency of a vaccine, other than from what is printed in the carton, which may not be true always.

From my clinical experience in treating animal bite cases, I can mention about 15 cases in the past two years where the Rabies Virus Neutralizing Antibody Titers were found to be <0.3 i.u./ m.l. of serum or not detectable at all even after taking full course of anti-rabies vaccination with modem TCVs in ESSEN schedule, or taking boosters after a course of at least 5 doses with modem TCVs in ESSEN schedulr has been completed and some time interval of time has elapsed after the last course.

It is always the concern of the clinician of not losing any patient he/she has treated. In Rabies post-­exposure management it is either success of total failure and nothing in between.

I am reporting only two cases here for illustrating my concern.

Case No: 1.

A male patient aged 32 years was bitten by a stray dog on 08.12.2004. The said dog was suspected to be Rabid on clinical grounds. The dog had bitten 17 persons since early morning of that day, and all were without provocation. My patient was 5th in the line of attack. The said dog was subsequently killed by the local people with bamboo sticks. When the dog was being attacked with sticks, it caught hold of one stick by clenching it with its teeth, and was not leaving it in spite of being bitten by persons with other sticks. The clinical features suggested it to be suffering of Rabies.

My patient was bitten over his Left Hand and there were multiple trans-dermal injuries. He had a history of receiving 6 doses of PCEC vaccine by IM route in ESSEN schedule about two years ago. The records were not available and he could not mention the dates.

Rabies virus neutralizing antibody titres were checked at the only commercially available facility. Elisa method was used by them and not RIFFIT. The titre on 08.12.2004 was < 0.3 i.u. / m.l. of serum. The report was available on 12.12.2004.

The Patient started to take PCEC vaccine on 09.12.2004. On 12.12.2004 he received ERIG by local infiltration. He subsequently completed his vaccination against Rabies in the ESSEN schedule.

Rabies virus neutralizing antibody titre was again checked on 09.02.2005 in the same laboratory by the same method. It was found to be > 10 i.u. / m.l. of serum.

Case No : 2.

A male patient aged 45 years was bitten by a stray dog on 02.12.2004. The said dog was not available for observation. This patient gave a history of receiving 6 doses of PCEC vaccine in ESSEN schedule from 20.09.2002 to 19.12.2002.

He also gave a history of receiving boosters for re-exposure. He received 2 boosters, one each on DO and D3 on 10.03.2004 and 13.03.2004.

For another case of exposure in  July 2004, he again received 2 boosters, one each on 14.07.2004 and on 17.07.2004.

Following the Dog bite on 02.12.2004, the patient got the Rabies virus neutralizing antibody titre checked at the only commercial facility. Again, his sera was tested, by using the ELISA technique. It was found to be < 0.3 Lu. Im.l. of serum, and below the minimum protective level prescribed by WHO.

For a change, he was advised to take a fresh course of post-exposure vaccination against Rabies, this time with PVRV in ESSEN schedule, from 09.12.2004 onwards because he reported to me, for the first time after that exposure with his serum analysis reports on 09.12.2004.

The Rabies virus neutralizing antibody titres were again checked on 10.02.2005. This time it was > 10 i.u. / m.l. and very satisfactory.

Some of the patients( of the 15 mentioned previously) have received 6 doses of PCEC vaccine and some 5 doses of PCEC vaccine in ESSEN schedule. The antibody titer was not checked 14 days after the primary course of vaccination. So their immunization status was not known at the time of the Repeat Exposure. They came to me for management of the Repeat Exposure, which was very serious in nature and caused by a clinically suspected rabid animal. The Antibody titer in those cases was checked for safety reasons. The patients had received the primary course of vaccination only 2 to 1 year ago. Those patients were then treated as a fresh case with RIG and 5 doses of PCEC vaccine and again the antibody titer was checked 14 days after the day 28 dose. It was found to be > 10 i.u. / m.l. of serum in all the cases.

A review of the Medical Literature on the topic of Boosters for re-exposure reveals that there are a lot of grey areas. There is a possibility of poor immune responders in about 25% of the population. Patients do not come with labels attached to them. There is every possibility of poor immune responders succumbing to Rabies in a re-exposure case. Fortunately most dogs are not Rabid. Even if a rabid dog bites there is only 56% possibility of the victim succumbing toi Rabies. 3 People are surviving because of this factor in many cases.

Some interesting literature in this topic of re-exposure is being mentioned here:

1. C. Strady et al. in their paper "Predictive factors for the neutralizing antibody response following pre-exposure rabies immunization: validation of a new booster dose strategy" which was published in Vaccine, states that :- A prospective cohort of 312 subjects who received pre-exposure rabies immunization and who were monitored serologically with a 10-year follow-up was assessed using multivariate analysis. The aim was to propose a new booster dose strategy by identifying predictive factors for the durability of the neutralizing antibody response. Evaluation bore on several factors relating to: (1) demographic characteristics: age, gender; (2) vaccines: type of vaccine (HDCV or PVRV), injection regimen (DO;D28;D365 or DO;D7;D28;D365) and vaccine lots' antigenic potency; and (3) resulting antibody titers. Logistic regression analysis enabled the authors to establish a predictive model for immunized subjects' serological status at ten years' follow-up expressed as a P probability for sero-reversion (antibody titer <0.5 IU/ml). Highly significant factors were the immunization regimen, the type of vaccine used and the antibody titer at D379. A P value <0.4 identified subjects as "good" responders who were sure to be have satisfactory antibody titers at 10 years and who -required a single booster dose every 10 years. A P value>O.4 identified subjects as "poor" responders in whom a specific follow-up and booster dose strategy is proposed. This new immunization strategy could at least be applied to subjects with a frequent risk of exposure, as defined by institutional guidelines.
   
   This new strategy is based essentially on the evaluation of the immunological response profile to immunization. Unlike institutional recommendations, this strategy does not take into account the level of exposure to the virus. In absence of possibility of serological testing for immunization at D379 and/or Y3, this strategy proposes that a booster dose may be injected every 5 years. However, it must be borne in mind that it would leave "poor responders" vulnerable. Therefore, this strategy should not be used in place of institutional recommendations without caution and discussion. In the present instance, this strategy should not be applied to subjects with continuous risk of exposure but it would be tested in case of frequent risk of exposure. 4
    

2. Alain Strady,et all, in their paper titled "Antibody Persistence Following Pre-exposure Regimens of Cell-Culture Rabies Vaccines: 10-Year Follow-Up and Proposal for a New Booster Policy", which was published in the Journal of Infectious Diseases mentions about an important study involving 312 Subjects who received either the human diploid cell rabies vaccine (HDCV) or the purified

   Vero cell rabies vaccine (PVRV) according to either two-injection (days 0 and 28) or three-injection (days 0, 7, and 28) primary regimens. They received a booster injection at 1 year. Rabies antibody levels were measured after the primary series and the booster and then each year for the next 10 years. The results confirm the superior long-term immunogenicity of the three-injection over the two-injection protocol. HDCV and PVRV in three doses were equally immunogenic. A booster injection at 1 year provides long-term sero-conversion (titer >0.5 lU/mL). Antibody titers 2 weeks after the I-year booster allowed prediction of long-term immunity. Good responders, with titers of 30 lU/mL or more, were protected for at least 10 years. An algorithm for differentiation between good responders and poor responders with respect to vaccine booster strategies is proposed. A pre-­exposure rabies immunization regimen of only four doses on days 0, 7, 28, and 365,will seroconvert >75% of the population at non-continuous risk of rabies for at least 10 years.

   In addition, only a single blood sample on day 379 is required to confirm this 10-year sero­conversion on condition that the antibody titer determined by a standardized RFFIT assay is least 30 IU/mL. ⁵
    

3. Dr. Anil Dutta, in his presentation on "Rabies Re-exposure Schedule-What do we know?" at APCRICON 2005, at Shimla on 08.07.2005 concluded with the following conclusions.

   (i) While accepting the theory of Anamnestic response there is a need to have enough Immunological data to support the Hypothesis that we will be confident enough to change our practice of advising full ' course after 5 yrs (best solution can be the study like pre-exposure booster study)

   (ii) If we could trace back previously immunized subjects (5 or 10 yrs back) and study their Titers at Day 0 and 14 days after a Day 3 dose to observe Sero-protection status then it would be a sound basis for such a recommendation

   (iii)A prospective follow up study on patients receiving full course PET is needed. 6

The conclusions derived after scanning all the available product inserts of TCV s against Rabies and the WHO expert committee on Rabies guidelines and from my personal studies and experience are:

1.   Only after determining the Rabies virus neutralizing antibody tire, 14 days after the day 28 dose

in both pre and post exposure vaccination against rabies with TCV s can we say that the person is immunized against Rabies, if the titer >0.5 i.u./ m.l. of serum.

2.   In repeat exposure cases, the schedule of only 2 doses of TCV s, one on day 0 and one on day 3 holds good, only if after the primary course of vaccination the Rabies virus neutralizing antibody titer has been checked and found to be >0.5 i.u. / m.l. of serum. Otherwise the repeat exposure should be treated as a fresh case with RIG and 5 doses of TCVs in ESSEN schedule.

3.   Even in those cases where the rabies virus neutralizing titer was >0.5 i.u. / m.l. of serum after the primary course of vaccination, it cannot be said with legal certainty, that only 2 doses, one on day 0 and one on day 3 will suffice, whatever be the time interval after the primary course of vaccination. Where are the research papers on the basis of which these statements are being made for products which are in use for a period of less than two decades to a couple of years only? Hypothesis and reality are two different things. Authorities should act in a more responsible manner in formulating guidelines meant to be followed by masses. A single wrong step might result in loss of a human life.

References:

(1) M.K.Sudarshan et all, "ASSESSING BURDEN OF RABIES IN INDIA" WHO Sponsored and APCRI Conducted, NATIONAL MULTI-CENTRIC RABIES SURVEY, 2003. 

(2)WHO Technical Report Series 931,WHO EXPERT CONSULTATION ON RABIES, First Report. 

(3) N. Veera Raghavan, (1969) Ann. Rep. of the Director, Pasteur Institute of South India, Coonoor. 

(4) C. Strady, et al. / Predictive factors for the neutralizing antibody response following pre-exposure rabies immunization: validation of a new booster dose strategy, Vaccine 18 (2000) 266H:2667 

(5) Alain Strady, et all, Antibody Persistence Following Pre-exposure Regimens of Cell-Culture Rabies Vaccines: 10- Year Follow-Up and Proposal for a New Booster Policy The Journal of Infectious Diseases 1998;177:1290-5

(6)Dr.Anil Dutta, Rabies Re-exposure Schedule-What do we know? Paper presented at APCRlCON 2005, at Shimla on 08.07.2005. 

Address for correspondence with the author: Dr. Amlan Goswami,
                                                                 28-A, Gariahat Road,
                                                                 2nd Floor, Flat 2A,
                                                                 Kolkata - 700029. India.
                                                                 E-Mail:  amlan__kolkata29@rediffmail.com