Human Rabies Prevention (Comment From a Canine‐Rabies‐Endemic Region)

Henry Wilde MD, FACP, Supaporn Wacharapluesadee PhD, Abhinbhen Saraya MD, Boonlert Lumlertdacha DVM, Thiravat Hemachudha MD, FACP
DOI: http://dx.doi.org/10.1111/jtm.12022 139-142 First published online: 1 May 2013

The article by Jentes and colleagues1 is a summary of current human rabies exposure management from the perspective of the developed world where biologicals are available, public health staff handle most rabies‐exposed subjects and mostly for free to the patients. The situation is different in rabies‐endemic regions where rabies vaccines and immunoglobulins are often not available or affordable to the average citizen. The fear of rabies, the adverse side effects from old brain‐tissue‐derived vaccines, the lengthy postexposure treatment schedules, and the dreadful death are still remembered. They discourage some patients from seeking professional help. This is particularly true in countries where World Health Organization (WHO)‐level treatment is only available at private hospitals, which most victims cannot afford. The article by Sibunruang and colleagues2 points out serious deficiencies in postexposure rabies management. It emphasizes the advisability for more travelers to rabies‐endemic countries to obtain preexposure prophylaxis. Furthermore, the article discusses a new WHO‐approved development in postexposure booster schedules for previously vaccinated persons with a new rabies exposure. It is an abbreviation of injections to four intradermal sites and one clinic visit, which produces higher antibody levels and saves much inconvenience for travelers replacing the former two clinic visits. One major reason for postexposure management deficiencies is the disregard for use of rabies immunoglobulins as recommended by WHO and others. Immunoglobulins are truly effective only when injected into and around bite wounds. It takes at least 1 week for the circulating antibody levels from the vaccine injections to reach sufficient levels to have virus‐killing effects at the inoculation sites. Travelers often reject this painful procedure, declaring that they will wait to “have this done later at home.” Vaccine is then administered alone with delay before seeking further medical care. This may be too late as injected immunoglobulin will then interfere with the native immune response generated by vaccine administered more than 7 days earlier. This increases the risk of treatment failure.3 A recent study from Switzerland brought this issue to our attention.4

Original WHO guidelines stressed the production of long‐lasting antibody levels at the expense of reaching the highest possible early immune response capable of killing the virus at the inoculation sites. This, before it attaches itself to nerve endings and starts to ascend centrally. Once the virus enters the nerves, it is in a partly immune‐protected environment. In the early 1970s, there were at least four postexposure prophylaxis vaccination schedules in use worldwide. These treatment methods continued the tradition of lengthy injection schedules dating back to days of poorly immunogenic brain‐tissue‐derived Semple vaccines. Initially, these 3‐month treatments also required six clinic visits to be completed.5 Lack of better understanding of the pathophysiology and immunology of rabies were the reasons for continuing these lengthy regimens. This, even though Dean and Baer had already shown, in animal studies in 1963, that neutralizing the virus at the inoculation sites is possible and can save additional lives.6 At the turn of the century, it became apparent that modern tissue and avian culture rabies vaccines are potent and result in long‐lasting immune memory.7 Bitten subjects, even when administered potent vaccines in a timely manner, may still require additional passive immunity (rabies immunoglobulin) to cover the “window period” before vaccine‐generated virus‐killing antibody appears in circulation. This is not before at least 7 days after start of a vaccine series.3 Treatment failures, in patients who received vaccine alone or were given immunoglobulin that was not injected into all bite wounds, are still being reported.8 Vaccination alone is effective in most rabies‐exposed subjects. This is due to the fact that only some bites result in early virus invasion into nerves. Virus excretion in saliva varies in rabid dogs and cats and the viral inoculum may range from none to very high levels. We cannot predict which patient will succumb without wound injection and which one might survive with vaccination alone. Many less advanced rabies‐endemic countries, being aware of this, have not provided costly immunoglobulins for the public sector. This was documented in the recent Bali rabies epidemic.9 Risk factors for rabies postexposure treatment failures are high viral load, bite site near peripheral nerve endings, immunocompromised host, and more virulent virus strain.5 Attempts to shorten the time for an effective antibody titer appearance were made by increasing initial antigen dose and administration using multi‐site intradermal injections, which stimulate different antigen receptor sites.10,11 These studies showed that it is possible to obtain higher but not earlier antibody titers by day 14. The intradermal vaccination schedule resulted in lower vaccine cost and was a major advance which is being increasingly recognized and studied using other costly vaccines. These studies were, nevertheless, disappointing as they did not result in earlier increased circulating antibody levels that could neutralize virus at bite sites and replace scarce and costly immunoglobulin injections.

Sureau and colleagues first shortened the lengthy 3‐month “Essen” postexposure schedule. Their 3‐week, “Zagreb” or “2‐1‐1” intramuscular schedule was the first abbreviated method and was approved in 1992 by WHO. It is being used successfully worldwide but not in North America12 and can be completed in three visits within 3 weeks. It is a forerunner to the modified Essen 2‐week method that was approved in 2011.13 Others also started to shorten postexposure schedules, making them more rational and less costly. Aims were to reduce the burden of multiple doctor visits that required expensive and inconvenient travel as well as loss of wages. The original Thai Red Cross intradermal schedule, which cut vaccine costs by as much as 75%, was reduced from the initial 3 months to 1 month and from five to four doctor visits.13 This revised intradermal schedule is used at animal bite clinics in Thailand, Philippines, Cambodia, India, Nepal, and Pakistan. The eight‐site (Oxford) intradermal schedule was eliminated by WHO in 2011.13 The original “Gold Standard” intramuscular “Essen” regimen went from six injections, administered over 3 months, to five over 1 month and now to four over 2 weeks and was approved by WHO in 2009.12 A promising 1‐week intradermal modification of the Thai Red Cross schedule is now undergoing additional WHO sponsored trials. It will eliminate travel costs, which can be a major burden, particularly in rural societies and for international travelers. It results in higher but not earlier antibody titers than the 1‐month Thai version.14,15

Rabies immunoglobulin injections into bite wounds can be life saving.5 They are available as imported or locally produced medications in most countries but are unfortunately not widely distributed outside major population centers. Equine rabies immunoglobulins are manufactured as purified, safe, and effective products in Europe, Thailand, India, China, Russia, and South America. They cause occasional serum sickness reaction (about 1%) and, like many agents, extremely rare cases of anaphylaxis (1–2 in 15,000 cases). Human immunoglobulin is costly to produce and virtually unavailable in many canine‐rabies‐endemic counties. Furthermore, equine immunoglobulin, even when locally available, is not being used except in a minority of those where it is indicated. This is a major ongoing cause of preventable rabies deaths. Patients are vaccinated but high‐risk wounds are often not cleansed and, if injected with immunoglobulin at all, it is not infiltrated carefully into all wounds. A recent study of physicians' attitudes in Thailand, India, and Pakistan showed that it is the doctor's reluctance to inject immunoglobulins into wounds that is at least partly responsible for worldwide treatment failures (I. Nuchprayoon and colleagues, unpublished data). International tourists often refuse to have their bite wounds injected with immunoglobulin at an animal bite clinic. All these make it evident that more education and better motivation of health care providers and travelers are urgently needed. Human and equine immunoglobulins have some limitations leading to a search for replacements. Specific monoclonal antibodies provide a promising future approach. They can kill rabies virus as effectively as human rabies immunoglobulin (HRIG).16 Studies are now conducted to evaluate the efficacy of rabies monoclonal antibody cocktails in comparison with HRIG. Results showed equivalence, and it is very likely that these products will become eventually available. They may replace HRIG but whether they will be more affordable in a developing country remains to be seen.

We are far from controlling the canine vector in most endemic countries. In South and Southeast Asia, it is the stray dog but, surprisingly, in China it is owned pet dogs that are the major cause of over 2,000 annual human rabies deaths. It is not yet generally recognized or accepted that rabies can be controlled only by sustainable dog vaccination, responsible pet ownership, and serious population control of stray dogs. Dog control and regular vaccination are expensive and may even conflict with some cultural and even religious beliefs. Rather than confront this issue, it is easy for the public health official to cite other “more urgent” demands on funding. Effective dog control and rabies elimination also require legislation and enforcement. Rabies control was accomplished in this manner in Europe, North America, Australia, Japan, Taiwan, Malaysia, and Singapore. Sadly, not one additional country in Asia has been declared rabies free by WHO during the past three decades, although we have the tools to do so. Worse, several previously rabies‐free Asian regions have new ongoing canine rabies epidemics. Flores and Bali islands now report over 200 human rabies deaths in the last 4 years.7

Survival of an American teenager with rabies raised hopes that rabies is treatable using a complex aggressive protocol with induced deep anesthesia and several unproven drugs. This treatment has since become known as the “Milwaukee Protocol.”17 Many efforts to duplicate it have failed.18 No evidence of viral RNA in saliva, skin biopsies, or body fluids could be detected in the few survivors with rabies, irrespective of whether they had been subjected to the Milwaukee Protocol or had only received supportive care. All had serum rabies antibodies on admission without having received any rabies vaccine previously. It has been long known that there have been natural rabies recoveries in many animals and among rare humans.18–21 Abortive human cases, subjects who did not recall any neurological illness yet carry neutralizing rabies antibodies, have also been reported.22,23,24 It is almost certain that the Milwaukee Protocol was not responsible for the survival, but that recovery had been due to an early vigorous native defense response and/or a lower virulent bat virus strain as well as good supportive care. Important is that the Milwaukee Protocol may add severe adverse reaction risks to patients who are already dreadfully ill and may have recovered with good intensive care alone. It needs to be abandoned.

Dedication

This commentary is dedicated to Dr Francois X. Meslin, of the Zoonosis and Rabies Divisions of WHO and to Dr Charles E. Rupprecht of the Zoonosis Division of the US‐CDC who, sadly, both retired this year. They will be missed by the international rabies community and will be difficult to replace. Most of their contributions will be a permanent part of the rabies literature.

Declaration of Interests

The authors state they have no conflicts of interest to declare.

Acknowledgments

The WHO Collaborating Center receives financial and technical support from the Thai Government, the Thai Red Cross Society, and from the US Navy Health Research Center grant BAA‐10‐93 under W911NF‐11‐2‐004. All authors have participated in vaccine manufacturers' supported scientific conferences and have received support for travel and accommodations but have accepted no stipends or salaries.

References

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