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The ‘Pooling Strategy’ in Himachal Pradesh, India: An Innovation for Rabies Post-exposure Prophylaxis During Crisis of Shortage of Life-saving Biologicals
Abstract
Resource-limited clinics and countries often face ethical dilemmas when treating patients exposed to rabies during rabies vaccine and rabies immunoglobulin (RIG) shortages. This chapter discusses an innovative ‘pooling strategy’ that was developed during shortage crises of life-saving biologicals in Himachal Pradesh, India. Patients received a fraction of a rabies vaccine vial administered via the intradermal route. RIG was prioritized and only given to high-risk patients with severe exposures. RIG was only infiltrated into wounds to provide immediate virus neutralization, and the dosage was determined by the size and number of wounds (as opposed to systemic administration of RIG intramuscularly using a dosage calculated by patient body weight). Residual drops of vaccine and RIG were consolidated, or ‘pooled’, to the next vial for the next patient – preventing even a single drop of waste. To date, this protocol has been > 99.9% effective and has saved considerable costs, rabies biologicals and human lives.
... In the Philippines, animal bite control centers utilize the One Health approach by serving multiple functions, including raising public awareness on zoonotic aspects of DMHR, promoting vaccination, and record keeping to enhance efficiency of their units [13]. Similarly, in Himachal Pradesh-India, the interdisciplinary collaboration enabled doctors to launch the pooling strategy for rabies prophylaxis, which has optimized vaccine use and addressed shortages [14]. China's approach to managing rabies in wild animals and Pakistan's emphasis on political will and civil society involvement illustrate the importance of context-specific strategies and thorough One Health interventions [7], [15]. ...
Rabies is a 100% fatal zoonotic disease and is preventable through timely and adequate Post-Exposure Prophylaxis (PEP). World Organization for Animal Health (WOAH) haven’t issued any guidelines for PEP for rabies in animals, still in certain Indian states like Himachal Pradesh (HP) PEP regimen with active immunization on 0,3,7,14 and 28 days mostly by Intramuscular Rabies Vaccine (IMRV) is being followed. Recently in
Rampur Bushahar, a suspected rabid dog later laboratory confirmed had bitten 21 dogs, 2 cows, and 2 men. We employed PEP in animals using Raksharab vaccine intra-dermally (IDRV) (0.2 ml, pre-scapular region) on days 0, 3, 7, 14, and 28 along with only local wound infiltration of eRIG in 8 out of 11 bitten dogs with Category III exposure. Furthermore 3 noncooperative dogs with Category III exposure were given IMRV (1ml) on day 0,3,7,14,28 with only wound infiltration of eRIG. 2 Cows were administered 0.2 ml IDRV in the skin at the middle of the neck with only wound infiltration of eRIG. Human bite victims also received 0.1 ml IDRV at 2 sites in the deltoid region on days 0,3, and 7 along with wound infiltration of eRIG at the nearby health center. Serum samples
were collected for Rapid Fluorescent Focus Inhibition Test (RFFIT) for estimation of Rabies Vaccine Neutralizing Antibody (RVNA) titer after day 14 for 8 dogs, 2 cows, and human bite victims, and all had RVNA titer >0.5 IU/ml on day 14 except one in IMRV group. None of the bitten victims had clinical manifestations of rabies even after 1 year of follow-up. This indicates wound infiltration with eRIG along with the vaccine could be a life-saving protocol.
Also using expired eRIG in emergencies was safe and life
saving in animals. Expired eRIG used was later tested and
was found to be potent.
Since 2008, we in Himachal Pradesh have used a "pooling strategy" to help patients save money by pooling vials of antirabies vaccine at a centralized hospital and sharing them using the intradermal technique. In 2014, there was an acute shortage of rabies immunoglobulins (RIG) and two patients died after four injections of rabies vaccine were administered without RIG, which was not commercially available. After an extensive literature review and technical and ethical committee clearances, in June 2014 we started to infiltrate equine RIG (eRIG) into wound/s only without the recommended systemic intramuscular (IM) injection. WHO recommended this technique in 2018. During the four-year period June 2014 to June 2018, 7506 of 10,830 patients exposed to suspected rabid animals were injected with eRIG in and around the wounds in a single clinic at DDU Hospital Shimla without any adverse outcomes. The average volume of eRIG used per patient was 0.75 mL and cost US$ 0.75. Of the 80% of patients who were followed up, all were healthy at the end of a year, including 26 patients bitten by laboratory-confirmed rabid dogs. The reaction rate after PEP administration also declined significantly. Since February 2018, Himachal has started following the new WHO recommendations on PEP regimens of three intradermal antirabies vaccines instead of four, thereby saving hundreds of vaccine vials that became useful during shortages of rabies vaccine in India. To date, more than 700 vaccine vials have been saved in a single clinic at DDU hospital during the past 6 months alone. Not giving PEP to patients who have consumed raw milk from a suspected rabid cow has also saved 62 vials. Currently, 90 "pooling centers" have been established for sharing of vaccine and eRIG vials in Himachal State, generating huge savings that have enabled the government to provide PEP free of charge to all. The new WHO guidelines are a positive step towards a rabies-free world by 2030.
Rabies is a dreaded disease of zoonotic origin, responsible for an
estimated 55,000 deaths annually, of which 20,000 deaths are in
India. Some animal bite patients need rabies immunoglobulin
(RIG) for post exposure prophylaxis, in addition to the vaccine
against rabies. The major reason for the high death rate in India is
the high cost of RIG. Until 2017, the WHO-recommended protocol
required a large amount of RIG. I describe how a cost-saving
protocol for RIG was implemented in Himachal Pradesh. The
published results contributed to the modification of the WHO’s
global recommendations on RIG use.
Rabies is fatal in all unvaccinated patients bitten by dogs, and so post-exposure vaccine regimens must be robust enough to ensure their survival under all conditions. Treatment tends to be excessive for most people, but there is justified anxiety about reducing vaccine dosage and shortening regimens. Recently, World Health Organisation (WHO) recommended one week primary post-exposure intradermal regimens requiring 3 clinic visits, but these are unlikely to prove economical where rabies vaccination is most needed, in deprived rural areas of Africa and Asia. A highly immunogenic regimen involving two doses of intradermal vaccine given one week apart has advantages over other regimens. Anyone exposed to a possibly rabid animal would be given intradermal (ID) injections at 4 sites using a whole vial of vaccine. Those who had not been previously vaccinated would be given 2-site ID injections using half a vial one week later. Those who might be immunosuppressed could be given an optional single ID dose on day 28. The rationale for this regimen is discussed in the context of the recently revised WHO recommendations for rabies prophylaxis.
Pre- as well as post-exposure prophylaxis plays an important role in controlling the number of deaths associated with human rabies. Rabies vaccines, classically injected intramuscularly, are now also administered by intradermal (ID) route. Vaccines to be administered by the ID route should meet the same quality, safety and efficacy specifications as vaccines for intramuscular (IM) use. The aim of this paper is to provide information based on publicly available data regarding the ID use of rabies vaccines and to identify potential needs for further analysis of the potency, immunogenicity and effectiveness of rabies vaccines administered by this route. A first literature search, focused on the immunogenicity of rabies vaccines given by ID route, identified 338 publications in the period 1997–2018, 40 of which were included in our analyses. A second search investigating the effectiveness of ID vaccination resulted in 371 hits for the period 2007–2018, of which 13 suitable publications were retained. The immunogenicity of current rabies vaccines was analyzed in 3 ways: proportion of subjects reaching the antibody threshold of 0.5 IU/ml after ID vaccination, relationship between potency and immunogenicity of the vaccine given intradermally, and comparison of antibody responses after IM or ID vaccination. Overall, vaccines administered intradermally were found immunogenic. Post-exposure prophylaxis by ID route appeared at least as immunogenic as by IM regimens. By contrast, ID pre-exposure prophylaxis trended towards lower antibody titers than IM vaccination, but the observation was not associated with any clinical relevance. Vaccine effectiveness was assessed by investigating survival after exposure. Data from more than 30,000 patients who sought rabies post-exposure prophylaxis did not indicate that current vaccines administered by ID route lack efficacy. These results support current recommendations for ID vaccination against rabies. However, published data on ID performance were associated with significant weaknesses that future research should better address.
Cattle are the backbone of household economy in rural areas of India and many of them die after bites by potentially rabid dogs, despite being given currently recommended five shots of intramuscular (IM) rabies vaccination as Post Exposure Prophylaxis (PEP). In 2016, seven of 21 bovine bitten by rabid dogs given IM rabies vaccination died due to rabies in Shimla Municipality. This scenario prompted the authors to look for a suitable protocol, based on human studies, to save animals. We tested various schedules of IDRV in bovine and found that a schedule of 0.2 ml given in middle 1/3rd of neck on day
0, 3, 7, 14 and 28 along with local wound infiltration of eRIG is sufficiently immunogenic and life saving in all of them, even if bitten by lab confirmed rabid dogs/mongoose as tested by CRI. Rabivac Vet, a Cell Culture Rabies Vaccine, available as 1 ml per vial was used off level for IDRV. While injecting the vaccine, a raised papule of ≥1 cm will appear slowly causing a peaud’ orange appearance. All 60 bovine serum samples tested by RFFIT after IDRV, had titres more than 0.5 IU/ml on day 14. Thereafter, a total of 150 animals were given five doses of IDRV as PEP, with or without RIG, after their exposure to clinically or lab confirmed rabid dogs/mongoose and all survived for more than a year. Serum samples from 15 animals bitten by lab confirmed rabid dogs/mongoose were collected on day 14 and tested for RVNA by RFFIT from NIMHANS Bangalore and all had desired antibody titers above 0.5 IU/ml, without any immunosuppression. The RFFIT titers in 55% bovine in all groups were more than adequate after one year and 100% of them had anamnestic response to a single 0.2 ml booster given at one year. Few of the bovine and even one equine (Horse. Figure 4) brought for PEP at some of nearby vet hospitals were given IM rabies vaccine with local eRIG infiltration also survived. Local eRIG infiltration appeared to have covered the lacuna of longer window period required for indigenous antibodies production
through IM route in bovine that are not sufficiently produced by day 14. While five times less vaccine was used in this low cost protocol and the survival was 100% compared to traditional IM protocol where survival was 66%. Pre-exposure prophylaxis was found to be effective as 0.2 ml dose of IDRV on day 0, 3, 7 and all bovine had titers higher than the desired by day seven after single 0.2 ml vaccine booster at one year. Our study points towards a possibility of having short schedules of three shots IDRV vaccination in bovine with or without local RIG (depending on presence or absence of wound/s) as PEP
and single shot IDRV as PrEP, but further studies are required on a large number of animals. Our study also points out for allowing intra-dermal use in animals as well and labelling vaccines for the same as this is low cost more immunogenic and less painful compare to IM administration.
An increasing number of dog bite victims were being presented to public hospitals in Himachal Pradesh in 2014 amidst virtual non availability of any rabies immunoglobulin (RIG). Only a small quantity of equine rabies immunoglobulin (eRIG) was available from the government owned Central Research Institute (CRI) Kasauli. This available eRIG was used in 269 patients as an emergency response and only for local infiltration of severe bite wounds by suspected rabid dogs. This was followed by rabies vaccination, using the WHO approved intra-dermal Thai Red Cross Society vaccination schedule. A subgroup of 26 patients were later identified who had been severely bitten by laboratory confirmed rabid dogs. They were followed for more than one year and all were found to be alive.
To determine the role of systemic injection of rabies immunoglobulin (RIG) in rabies vaccination, we analyzed the level of antibody against rabies virus in the serum of mice that received various doses of RIG combined with rabies vaccine. Our results indicate that systemic injection of RIG does not contribute detectably to passive or adaptive immunization, suggesting that the main function of RIG in individuals with category III exposure is to neutralize rabies virus via immediate local infiltration of the wound.
There are a number of errors in Table 3. The table legend should read: Breakdown of economic costs of rabies by cluster in millions of USD. The headings for columns six, seven, and eight are incorrect. They should be in the following order: Dog vaccination, Dog population management, Livestock losses. Please see the correct Table 3 below.
Table 3
Breakdown of economic costs of rabies by cluster in millions of USD.
Rabies is a zoonotic disease and an estimated 55 000 people die because of rabies worldwide every year, mostly in Asia and Africa. The recent review on clinical management of monkey bites in travellers1 and subsequent report of deaths in patients bitten by monkeys2 (Macaca mulatta) points towards monkeys carrying the rabies virus in rabies endemic countries such as India. We have recently demonstrated rabies virus in a monkey (M. mulatta), reported dead in Shimla municipality. The monkey was rabies virus negative with fluorescent antibody technique (FAT) but biological test (BT) positive for rabies virus as done by the Central Research Institute (CRI) Laboratory, Kasauli, Himachal Pradesh. There appears to be frequent transmission of rabies virus from rabies–carrying stray dogs3,4 to even wildlife of all types, especially monkeys that were till date thought to be free of rabies virus. The monkeys are frequently interacting with stray dogs (Figure 1) and probably monkeys and other wildlife animals get infected due to increased interaction with rabies–carrying stray dogs. Surprisingly, brain samples of some of the other wild animals such as Langoor (Semnopithecus entellus) and Himalayan Palm Civet (Paguma larvata) were found positive for rabies virus (FAT& BT). Some of the stray dogs that were found recently dead in Shimla municipality were tested for rabies virus with FAT and all were found positive. Even garbage collectors of Shimla municipality who used to carry dead bodies of stray dogs/monkeys for burial were found to have high titters of rabies antibodies in their blood5 without any history of rabies prophylaxis. Travelers need to be cautious when bitten by monkeys in rabies endemic countries such as India and need full rabies post-exposure prophylaxis for protection and better option is, if they had pre-exposure vaccination before travel to rabies endemic countries. https://academic.oup.com/jtm/article-lookup/doi/10.1093/jtm/taw028
Presently the dose of rabies immunoglobulin (RIG) which is an integral part of rabies post exposure prophylaxis (PEP) is calculated based on body weight though the recommendation is to infiltrate the wound(s). This practice demands large quantities of RIG which may be un- affordable to many patients. In this background, we conducted this study to know if the quantity and cost of RIG can be reduced by restricting passive immunization to local infiltration alone and avoiding systemic intramuscular administration based on the available scientific evidence. Two hundred and sixty nine category III patients bitten by suspect or confirmed rabid dogs/ animals were infiltrated with equine rabies immunoglobulin (ERIGs) in and around the wound, the quantity of ERIG used was proportionate to the size and number of wounds irrespective of their body weight. They were followed with a regular course of rabies vaccination by intra-dermal route. As against 363 vials of RIGs required for all these cases as per current recommendation based on body weight, they required only 42 vials of 5ml RIG. Minimum dose of RIGs given was 0.25ml and maximum dose given was 8 ml. On an average 1.26 ml of RIGs was required per patient that costs Rs. 150 ($3). All the patients were followed for 9 months and they were healthy and normal at the end of observation period. With local infiltration, that required small quantities of RIG, the RIGs could be made available to all patients in times of short supply in the market. A total of 30 (11%) serum samples of patients were tested for rabies virus neutralizing antibodies by the rapid fluorescent focus inhibition test (RFFIT) and all showed antibody titers >0.5 IU/mL by day 14. In no case the dose was higher than that required based on body weight and no immunosuppression resulted. To conclude, this pilot study shows that local infiltration of RIG need to be considered in times of non availability in the market or un-affordability by poor patients. This preliminary study needs to be done on larger scale in other centers with long term follow up to substantiate the results of our study.
Background: Rabies is a dreaded disease and an estimated 55,000 people die of rabies every year. Himachal Pradesh is in the North bordering China and is predominantly rural and hilly. Villages are near forests, where wild reservoirs of rabies exist. Since health facilities are not accessible easily, we need to innovate on existing schedules of rabies vaccination keeping in view the compliance of the patients and affordability so as to give them the best possible option of treatment. In the year 2006 and 2007, we, at DDU Hospital Shimla, experienced a severe shortage of rabies vaccine and patients were running from pillar to post to fetch rabies vaccine. At the same time, we 130 learnt that some of the patients died because either they were not able to purchase the vaccine, mostly because of its high cost, $35, or they ignored the animal bites and did not seek the treatment. Since last year, we have been experiencing non-availability of rabies immunoglobulins (RIGs) in the market and have to innovate new schedules and techniques to save lives of the patients. Methods: During shortage of rabies vaccine in 2008, we contemplated to start a low cost in-tra-dermal (ID) clinic so as to make rabies vaccine affordable as intramuscular (IM) vaccination cost five times more than ID vaccination. But, there were three main hurdles. One hurdle was the non-availability of rabies vaccine vials having written on them " For IM/ID use " and another hurdle was only fewer animal bite patients attending the DDU Hospital, sometimes only one or two per day, which was insufficient to open a vaccine vial and distribute among them. The third problem being faced was reluctance of the hospital doctors to prescribe ID vaccine as this was not the practice at higher teaching institutions, including medical colleges. We contacted a vaccine company and few vials labeled as " For IM/ID use " were sourced from Mumbai (1200 km away from here). We asked the Chief Medical Officer, Shimla district to write a letter to all health facilities around our Hospital to give first aid to animal bite patients and then refer them to DDU Hospital for vaccination. Now we were able to pool the patients and divide a single 1 ml vaccine vial among four patients. After continuous advocacy, our stress that WHO has given its approval for ID use of rabies vaccine and that subsequent approval has been granted by Government of India was enough for doctors to prescribe the vaccine as ID. Last Year, we got ethical approval to inject rabies Im-munoglobulins (RIGs) only locally in and around the wound at times of scarcity of RIGs in the market. The subsequent follow up of patients proved life saving in crisis of shortage of RIGs. Due to shortage of RIGs we innovatively vaccinated people bitten by rabid dogs or people who had consumed rabid cow's milk and followed them for outcome, apart from having Rabies Fluorescent Focus Inhibition Test (RFFIT) was done for few of the patiens for verification of protective titers. We innovated a technique of extraction of last drop of vaccine from the vial and also saved a drop of RIGs being used for test dose before giving RIGs to the patients. Results: The first low cost an-ti-rabies clinic was started on August 2, 2008 after long advocacy sessions with the authorities and the doctors. Since then, we have done many innovations based on local requirements and patients' feedback and accessibility to treatment. We have given pre and post-exposure prophylaxis to more than 12,000 animal bite victims over more than five years period in this single clinic, saving lives as well as money without any failure even in difficult rabid animal bite cases. Our innovation helped us save the vaccine and immunoglobulins till the last drop. Conclusions: Innovative ways by health providers backed by extensive literature review and scientific evidence can help patients get low cost health deliverables that increase their compliance as medicines/vaccines become affordable to them. Third world countries need to innovate their own ways to solve their problems of scanty resources and find innovative solutions to conquer them, rather than looking elsewhere for solutions.
Background: Rabies is a zoonotic disease and many vulnerable sections like rag pickers and municipality workers neglect animal bites due to ignorance of their potential deadly outcomes. Stray
dogs abound in garbage pits and this population is exposed to their attacks. It should be a mandate for municipalities to help protect their sanitary workforce, especially rag pickers, from deadly infectious diseases such as Rabies, Hepatitis-B, HIV, Tetanus etc. Objectives: Objective of this study was to study methods to provide pre-exposure Rabies vaccination for such highly exposed populations by engaging them and understanding their perception of this disease through a constant dialogue with them. Methods: We started by engaging with the rag pickers to know how best to entice them to get themselves immunized. We then attempted to search literature for the most practical methods likely to succeed in reducing risk of rabies deaths in this population. Results: WHO approved 3 injections of 0.1 ml tissue culture vaccine on days 0, 7 and 21 were tried but were
shown to result in many dropouts among rag pickers for repeat injections. We then followed a method where 0.1 ml of rabies vaccine was injected at 4 different anatomical sited in one setting.
This proved acceptable and relatively inexpensive. A small number of subjects were studied by determination of neutralizing antibody by RFFIT, which proved immunogenic having anamnestic response on boosters given single IM or at 4 sites ID subsequently, implying that short schedule rabies pre-exposure vaccination can be done in high risk groups and may save lives if applied to the poorest that are highly exposed.
Background: In India every year an estimated 20,000 patients die of Rabies. Major reason for poor compliance to anti-rabies prophylaxis is the high cost of anti-rabies vaccine being prescribed intramuscularly (IM) as a routine i.e. 44.5 USD per course of five injections. In 1992 WHO recommended low cost intra-dermal rabies vaccination (IDRV), which costs only 7.5 USD or less per animal bite course. Methods: Interviews with doctors revealed that they were not prescribing intra-dermal anti rabies vaccination as they were either not aware or were not confident of this route of rabies vaccination. Also the vaccine vial did not have the label for “intra-dermal use”. These barriers were removed by advocacy efforts with policy makers & drug companies, credit sharing & team building, which led to starting of first intra dermal anti-rabies clinic of North India on 2nd August 2008. Results: Within a month of start of intra-dermal rabies vaccination clinic, i.e. by 2nd September, 2008, there was an increase in the hospital patient load by 2.8 times, and poor patients load by 3.2 times. In just less than two-year time, 200,000 USD of poor patients were saved and 5769 patients vaccinated. Each patient was asked to bring one vial on first visit & rest of doses were given “free” by pooling strategy. Pooling strategy involved distribution of one vial of vaccine among four persons and keep the three vials for use one by one by all the four patients on subsequent three visits. Another offshoot of the strategy was to prevent wasting of even few drops of vaccine that used to remain in each vial of 1 ml after distribution among four patients (0.2 mL or less). Out of more than 5000 vials utilised, every time we would transfer the left out drops of vaccine to the next new vial and use it immediately on a new pool of patients waiting for vaccination. We would, however, discard the unused vaccine after eight hours of reconstitution at the end of the day. The vaccine so saved turned to be a stock of more than 100 vials in less than two years that we were able to give free to more than 225 rag pickers, garbage collectors and newspaper hawkers on World Rabies Day, Sep 28, 2010. Conclusions: With intra-dermal clinic, we were able to successfully introduce the new cost effective intra-dermal method of rabies vaccination despite all odds & vested interests of companies & old mindset of doctors that had blocked this technique till now. This will go a long way in reducing the burden of disease & death due to rabies from India.
Rabies is a life-threatening neglected tropical disease: tens of thousands of cases are reported annually in endemic countries (mainly in Africa and Asia), although the actual numbers are most likely underestimated. Rabies is a zoonotic disease that is caused by infection with viruses of the Lyssavirus genus, which are transmitted via the saliva of an infected animal. Dogs are the most important reservoir for rabies viruses, and dog bites account for >99% of human cases. The virus first infects peripheral motor neurons, and symptoms occur after the virus reaches the central nervous system. Once clinical disease develops, it is almost certainly fatal. Primary prevention involves dog vaccination campaigns to reduce the virus reservoir. If exposure occurs, timely post-exposure prophylaxis can prevent the progression to clinical disease and involves appropriate wound care, the administration of rabies immunoglobulin and vaccination. A multifaceted approach for human rabies eradication that involves government support, disease awareness, vaccination of at-risk human populations and, most importantly, dog rabies control is necessary to achieve the WHO goal of reducing the number of cases of dog-mediated human rabies to zero by 2030.
Passive immunization is a crucial parameter for prevention of human rabies. Presently as World Health Organization (WHO) strongly advocates local infiltration of rabies immunoglobulin in and around the bite wound, we feel that there is no basis for calculating the dose of immunoglobulin based on body weight. Keeping this in view we conducted both in vitro and in vivo studies to know whether the dose of immunoglobulin can be reduced and still obtain complete neutralization of the virus. In vitro neutralization studies were conducted using CVS strain of virus and BHK 21 cells. In vivo experiments were conducted in 4 weeks old Swiss albino mice by initial challenge with CVS followed by infiltration with increasing dilutions of either human rabies immunoglobulin( HRIG) and equine rabies immunoglobulin (ERIG). In vitro studies showed that a dose of 100 FFD 50 of CVS was neutralized by increasing dilution of both HRIG and ERIG and 100% neutralization was observed with HRIG and ERIG in as low quantities as 0.025 IU. In mice studies there was 100% survival of mice infiltrated with 0.025 IU of both HRIG and ERIG compared to 100% mortality in mice infiltrated with normal saline. These results suggest that it is possible to reduce the dose of rabies immunoglobulins by at least 16 times the presently advocated dose. These findings needs to be further evaluated using larger animal models and street viruses prevalent in nature but cannot serve as recommendations for use of RIG for passive immunization in humans.
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