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Bats are now the leading source of rabies postexposure prophylaxis.

The epidemiology of human rabies postexposure prophylaxis (PEP) in 4 upstate New York counties was described from data obtained from 2,216 incidences of PEP recorded by local health departments from 1995 to 2000. Overall annual incidence for the study period was 27 cases per 100,000 persons. Mean annual PEP incidence rates were highest in rural counties and during the summer months. PEP incidence was highest among patients 5–9 and 30–34 years of age. Bites accounted for most PEP (51%) and were primarily associated with cats and dogs. Bats accounted for 30% of exposures, more than any other group of animals; consequently, bats have replaced raccoons as the leading rabies exposure source to humans in this area.

SYNOPSIS

Objective

The aim of this study was to summarize the Alaska experience in centralizing distribution of rabies postexposure prophylaxis (PEP).

Methods

Data were collected from standard treatment sheets used to track doses and notes related to the exposure investigations.

Results

From 2002 to 2007, the annual PEP usage rate was 2.2 per 100,000. Dogs were involved in 79% (68/86) of exposures. More than 50% (49/87) of people were exposed to a confirmed rabid animal; 31 (63%) of those people experienced nonbite exposures. Conversely, of the remaining 38 people exposed to an animal for which rabies status could not be confirmed, 35 (92%) sustained a bite or puncture. Direct and indirect costs averaged more than $3,000 per person.

Conclusions

The Alaska PEP usage rate was lower and the proportion of people exposed to confirmed rabid animals was higher when compared with other states. Alaska public health personnel invested significant time to ensure that PEP was only given when indicated. Without this gatekeeper approach, PEP would likely be administered at a much higher rate because medical facility staff lacks the time or ability to investigate animal exposures to rule out rabies. In Alaska, centralizing rabies PEP not only serves the patient's best interest, but it also makes efficient use of a potentially scarce product and supports rabies surveillance efforts by guaranteeing animals for testing. Such a program might not be feasible for a more populous state or jurisdiction, or areas with different rabies epizootiology; however, that may change if the supply of rabies biologics changes in the future.

SYNOPSIS

Objectives

South Carolina mandates reporting of animal bites and manages distribution of biologics for rabies postexposure prophylaxis (PEP). Incidence and epidemiologic characteristics of potential human rabies exposures and preventive treatment in South Carolina from 1993 through 2002 were examined to help assess the burden of PEP in the state and determine if the incidence of rabies exposures has changed over time.

Methods

Data on animal exposure investigations and PEP administration at the state and county level were examined, and the annual incidences of potential rabies exposures and human PEP courses were calculated.

Results

The incidence of animal exposures for which investigations were initiated was 297.9 per 100,000 population per year, and the incidence of PEP was 10.6 per 100,000 population per year. At the county level, the incidence of PEP appeared inversely correlated with the population density. Most courses of PEP were administered following exposures to domestic species, although these animals accounted for only a small proportion of rabid animals in the state. The annual PEP incidence was similar throughout the study period, but it was markedly higher than estimates from 1981 (<5/100,000 population per year).

Conclusions

The incidence of PEP in South Carolina is higher than previously thought, and these findings suggest that incidence extrapolations for other states and at the national level may be underestimated. An accurate estimation of the incidence of PEP and an understanding of rabies epidemiology is important at the state level to allow for better public health planning.

Monoclonal antibodies are successful biologics in treating a variety of diseases, including the prevention or treatment of viral infections. CL184 is a 1:1 combination of two human monoclonal IgG1 antibodies (CR57 and CR4098) against rabies virus, produced in the PER.C6 human cell line. The two antibodies are developed as replacements of human rabies immune globulin (HRIG) and equine rabies immune globulin (ERIG) in postexposure prophylaxis (PEP). The rapid fluorescent focus inhibition test (RFFIT) is a cell-based virus neutralization assay which is usually performed to determine the biological potency of a vaccine and to measure the levels of protection against rabies in humans and animals. In order to confirm the suitability of this assay as a pharmacodynamic assay, we conducted a validation using both HRIG- and CL184-spiked serum samples and sera from vaccinated donors. The validation results met all analytical acceptance criteria and showed that HRIG and CL184 serum concentrations can be compared. Stability experiments showed that serum samples were stable in various suboptimal conditions but that rabies virus should be handled swiftly once thawed. We concluded that the assay is suitable for the measurement of polyclonal and monoclonal rabies neutralizing antibodies in clinical serum samples.

Background

Thousands of human deaths from rabies occur annually despite the availability of effective vaccines following exposure, and for disease control in the animal reservoir. Our aim was to assess risk factors associated with exposure and to determine why human deaths from endemic canine rabies still occur.

Methods and Findings

Contact tracing was used to gather data on rabies exposures, post-exposure prophylaxis (PEP) delivered and deaths in two rural districts in northwestern Tanzania from 2002 to 2006. Data on risk factors and the propensity to seek and complete courses of PEP was collected using questionnaires. Exposures varied from 6–141/100,000 per year. Risk of exposure to rabies was greater in an area with agropastoralist communities (and larger domestic dog populations) than an area with pastoralist communities. Children were at greater risk than adults of being exposed to rabies and of developing clinical signs. PEP dramatically reduced the risk of developing rabies (odds ratio [OR] 17.33, 95% confidence interval [CI] 6.39–60.83) and when PEP was not delivered the risks were higher in the pastoralist than the agro-pastoralist area (OR 6.12, 95% CI 2.60–14.58). Low socioeconomic class and distance to medical facilities lengthened delays before PEP delivery. Over 20% of rabies-exposed individuals did not seek medical treatment and were not documented in official records and <65% received PEP. Animal bite injury records were an accurate indicator of rabies exposure incidence.

Conclusions

Insufficient knowledge about rabies dangers and prevention, particularly prompt PEP, but also wound management, was the main cause of rabies deaths. Education, particularly in poor and marginalized communities, but also for medical and veterinary workers, would prevent future deaths.

Author Summary

Thousands of human deaths from rabies occur annually despite availability of effective vaccines for humans following exposure, and for disease control in domestic dog populations. We established a 5-year contact-tracing study in northwest Tanzania to investigate risk factors associated with rabies exposure and to determine why human deaths from canine rabies still occur. We found that children were at greater risk of being bitten and of developing rabies than adults and that incidence of bites by suspected rabid animals was higher in an area with larger domestic dog populations. A large proportion (>20%) of those bitten by rabid animals are not recorded in official records because they do not seek post-exposure prophylaxis (PEP), which is crucial for preventing the onset of rabies. Of those that seek medical attention, a significant proportion do not receive PEP because of the expense or because of hospital shortages; and victims who are poorer, and who live further from medical facilities, typically experience greater delays before obtaining PEP. Our work highlights the need to raise awareness about rabies dangers and prevention, particularly prompt PEP, but also wound management. We outline practical recommendations to prevent future deaths, stressing the importance of education, particularly in poor and marginalized communities, as well as for medical and veterinary workers.

Economic assessments and modeling studies suggest that these programs yield cost savings and public health benefits.

Progressive elimination of rabies in wildlife has been a general strategy in Canada and the United States; common campaign tactics are trap–vaccinate–release (TVR), point infection control (PIC), and oral rabies vaccination (ORV). TVR and PIC are labor intensive and the most expensive tactics per unit area (≈$616/km2 [in 2008 Can$, converted from the reported $450/km2 in 1991 Can$] and ≈$612/km2 [$500/km2 in 1999 Can$], respectively), but these tactics have proven crucial to elimination of raccoon rabies in Canada and to maintenance of ORV zones for preventing the spread of raccoon rabies in the United States. Economic assessments have shown that during rabies epizootics, costs of human postexposure prophylaxis, pet vaccination, public health, and animal control spike. Modeling studies, involving diverse assumptions, have shown that ORV programs can be cost-efficient and yield benefit:cost ratios >1.0.

We describe the epidemiology of human rabies postexposure prophylaxis (PEP) in four upstate New York counties during the 1st and 2nd year of a raccoon rabies epizootic. We obtained data from records of 1,173 persons whose rabies PEP was reported to local health departments in 1993 and 1994. Mean annual PEP incidence rates were highest in rural counties, in summer, and in patients 10 to 14 and 35 to 44 years of age. PEP given after bites was primarily associated with unvaccinated dogs and cats, but most (70%) was not attributable to bites. Although pet vaccination and stray animal control, which target direct exposure, remain the cornerstones of human rabies prevention, the risk for rabies by the nonbite route (e. g., raccoon saliva on pet dogs' and cats' fur) should also be considered.

Aims:

The aim of this study was to determine the incidence of humans being bitten by rabies-suspected animals, and the victims’ adherence to post-exposure prophylaxis (PEP) regimen.

Materials and Methods:

A retrospective analysis of data of victims treated at Bugando Medical Centre during the period 2002-2006 (n=5 years) was done.

Results:

A total of 767 bite injuries inflicted by rabies-suspected animals were reported, giving a mean annual incidence of ~58 cases per 100,000 (52.5% males, 47.5% females). The proportion of children bitten was relatively higher than that of adults. All victims were treated by using inactivated diploid-cell rabies vaccine and were recommended to appear for the second and third doses. However, only 28% of the victims completed the vaccination regime. Domestic dogs were involved in 95.44% of the human bite cases, whereas cats (3.9%), spotted hyena (Crocuta crocuta) (0.03%), vervet monkey (Cercopithecur aethiops) (0.01%) and black-backed jackal (0.01%) played a minor role. The majority of rabies-suspected case reports were from Nyamagana district and occurred most frequently from June to October each year.

Conclusions:

In conclusion, this study revealed that incidences of humans being bitten by dogs suspected of rabies are common in Tanzania, involve mostly children, and victims do not comply with the prophylactic regimen. Rigorous surveillance to determine the status of rabies and the risk factors for human rabies, as well as formulation and institution of appropriate rabies-control policies, is required.

Although fatal if untreated, human rabies can be prevented through post-exposure prophylaxis (PEP), which involves a course of vaccination and immunoglobulin administered immediately after exposure. However, high costs and frequent lack of rabies vaccine and immunoglobulin lead to about 55,000 deaths per year worldwide. Using data from a detailed study of rabies in Tanzania, we calculate a cost-effectiveness ratio for PEP when the WHO-recommended Essen regimen, a 5-dose intramuscular vaccination schedule, is adopted. Our analyses indicate a cost-effectiveness ratio for PEP of $27/quality-adjusted life year (QALY) from a health care perspective and $32/QALY from a societal perspective in Tanzania. From both perspectives, it is “very cost-effective” to administer PEP to patients bitten by an animal suspected to be rabid. Moreover, PEP remains “very cost-effective” provided that at least 1% of doses are administered to people who were actually exposed to rabies.

As the demand for rabies post-exposure prophylaxis (PEP) treatments has increased exponentially in recent years, the limited supply of human and equine rabies immunoglobulin (HRIG and ERIG) has failed to provide the required passive immune component in PEP in countries where canine rabies is endemic. Replacement of HRIG and ERIG with a potentially cheaper and efficacious alternative biological for treatment of rabies in humans, therefore, remains a high priority. In this study, we set out to assess a mouse monoclonal antibody (MoMAb) cocktail with the ultimate goal to develop a product at the lowest possible cost that can be used in developing countries as a replacement for RIG in PEP. Five MoMAbs, E559.9.14, 1112-1, 62-71-3, M727-5-1, and M777-16-3, were selected from available panels based on stringent criteria, such as biological activity, neutralizing potency, binding specificity, spectrum of neutralization of lyssaviruses, and history of each hybridoma. Four of these MoMAbs recognize epitopes in antigenic site II and one recognizes an epitope in antigenic site III on the rabies virus (RABV) glycoprotein, as determined by nucleotide sequence analysis of the glycoprotein gene of unique MoMAb neutralization-escape mutants. The MoMAbs were produced under Good Laboratory Practice (GLP) conditions. Unique combinations (cocktails) were prepared, using different concentrations of the MoMAbs that were capable of targeting non-overlapping epitopes of antigenic sites II and III. Blind in vitro efficacy studies showed the MoMab cocktails neutralized a broad spectrum of lyssaviruses except for lyssaviruses belonging to phylogroups II and III. In vivo, MoMAb cocktails resulted in protection as a component of PEP that was comparable to HRIG. In conclusion, all three novel combinations of MoMAbs were shown to have equal efficacy to HRIG and therefore could be considered a potentially less expensive alternative biological agent for use in PEP and prevention of rabies in humans.

Author Summary

Human mortality from endemic canine rabies is estimated to be 55,000 deaths per year in Africa and Asia, yet rabies remains a neglected disease throughout most of these countries. More than 99% of human rabies cases are caused by infections resulting from a dog-bite injury. In the vast majority of human exposures to rabies, patients require post-exposure prophylaxis (PEP), which includes both passive (rabies immunoglobulin, RIG) and active immunization (rabies vaccine). The number of victims requiring PEP has increased exponentially in recent years, and human and equine RIG (HRIG and ERIG) were not sufficiently available in countries where canine rabies is endemic. Rabies virus-neutralizing monoclonal antibodies (MAbs) of mouse (Mo) origin have been identified as promising alternatives to HRIG and ERIG. We have developed and assessed both in vitro and in vivo unique mouse monoclonal antibody (MoMAb) cocktails, which are highly efficacious. Three novel combinations were shown to have an equal or superior efficacy to HRIG and therefore could be considered a potentially less expensive alternative for passive prophylactic use to prevent the development of rabies in humans, particularly where needed most in developing countries.

Background

Australia uses a protocol combining human rabies immunoglobulin (HRIG) and rabies vaccine for post-exposure prophylaxis (PEP) of rabies and Australian bat lyssavirus (ABLV), with the aim of achieving an antibody titre of ≥0.5 IU/ml, as per World Health Organization (WHO) guidelines, as soon as possible.

Methodology/Principal Findings

We present the course of PEP administration and serological testing for four men with complex requirements. Following dog bites in Thailand, two men (62 years old, 25 years old) received no HRIG and had delayed vaccine courses: 23 days between dose two and three, and 18 days between dose one and two, respectively. Both seroconverted following dose four. Another 62-year-old male, who was HIV-positive (normal CD4 count), also suffered a dog bite and had delayed care receiving IM rabies vaccine on days six and nine in Thailand. Back in Australia, he received three single and one double dose IM vaccines followed by another double dose of vaccine, delivered intradermally and subcutaneously, before seroconverting. A 23-year-old male with a history of allergies received simultaneous HRIG and vaccine following potential ABLV exposure, and developed rash, facial oedema and throat tingling, which was treated with a parenteral antihistamine and tapering dose of steroids. Serology showed he seroconverted following dose four.

Conclusions/Significance

These cases show that PEP can be complicated by exposures in tourist settings where reliable prophylaxis may not be available, where treatment is delayed or deviates from World Health Organization recommendations. Due to the potentially short incubation time of rabies/ABLV, timely prophylaxis after a potential exposure is needed to ensure a prompt and adequate immune response, particularly in patients who are immune-suppressed or who have not received HRIG. Serology should be used to confirm an adequate response to PEP when treatment is delayed or where a concurrent immunosuppressing medical condition or therapy exists.

Author Summary

In Australia, the administration of rabies post-exposure prophylaxis (PEP) occurs for potentially exposed returned travellers from endemic regions or for potential local exposure to Australian Bat Lyssavirus. For Australian tourists, delays in commencing PEP or not receiving HRIG or all recommended doses of vaccine are common. We report a case series where serology provided information in four patients with delayed, incomplete, or complicated PEP treatment. Three of these patients reported a dog bite in Thailand and the fourth was scratched by a bat and had bat urine enter his eye in Australia. Management was complicated by lack of HRIG administration, delays in the recommended timeframe for receipt of vaccine doses, and immunosuppression caused by co-administration of steroids and by HIV infection with a normal CD4 count. All patients seroconverted but this was delayed in some cases, and in the HIV-positive subject required a double dose of vaccine delivered intradermally and subcutaneously. In complex or non-standard PEP delivery, including delayed treatment and immunosuppression due to steroid treatment, HIV or another immunosuppressing medical condition, serology can be used to guide further treatment and should be used to confirm seroconversion.

Over two-thirds of the world's population lives in regions where rabies is endemic, resulting in over 15 million people receiving multi-dose post-exposure prophylaxis (PEP) and over 55,000 deaths per year globally. A major goal in rabies virus (RABV) research is to develop a single-dose PEP that would simplify vaccination protocols, reduce costs associated with RABV prevention, and save lives. Protection against RABV infections requires virus neutralizing antibodies; however, factors influencing the development of protective RABV-specific B cell responses remain to be elucidated. Here we used a mouse model of IL-21 receptor-deficiency (IL-21R−/−) to characterize the role for IL-21 in RABV vaccine-induced immunity. IL-21R−/− mice immunized with a low dose of a live recombinant RABV-based vaccine (rRABV) produced only low levels of primary or secondary anti-RABV antibody response while wild-type mice developed potent anti-RABV antibodies. Furthermore, IL-21R−/− mice immunized with low-dose rRABV were only minimally protected against pathogenic RABV challenge, while all wild-type mice survived challenge, indicating that IL-21R signaling is required for antibody production in response to low-dose RABV-based vaccination. IL-21R−/− mice immunized with a higher dose of vaccine produced suboptimal anti-RABV primary antibody responses, but showed potent secondary antibodies and protection similar to wild-type mice upon challenge with pathogenic RABV, indicating that IL-21 is dispensable for secondary antibody responses to live RABV-based vaccines when a primary response develops. Furthermore, we show that IL-21 is dispensable for the generation of Tfh cells and memory B cells in the draining lymph nodes of immunized mice but is required for the detection of optimal GC B cells or plasma cells in the lymph node or bone marrow, respectively, in a vaccine dose-dependent manner. Collectively, our preliminary data show that IL-21 is critical for the development of optimal vaccine-induced primary but not secondary antibody responses against RABV infections.

Author Summary

Over two-thirds of the world's population lives in regions where rabies is endemic, resulting in over 15 million people receiving post-exposure treatment. A person, disproportionately a child, dies of rabies every 20 minutes and the cost of rabies prevention exceeds $1 billion US dollars per year. The development of a single-dose human rabies vaccine would greatly reduce the burden of rabies globally by lowering the cost associated with rabies vaccination and saving lives. Understanding how B cells develop to produce protective virus neutralizing antibodies would greatly help to achieve the goal of developing a single-dose vaccine. In this report, we show that IL-21 is critical for the induction of primary vaccine-induced anti-RABV G antibody titers and that the effects of IL-21 are highly dependent on the dose of vaccine administered. In our model of rabies immunogenicity and protection, the lack of IL-21 receptor influenced the detection of B cells in germinal centers in lymph nodes or of plasma cells in bone marrow after immunization with low or high doses of vaccine, respectively. Overall, these preliminary results indicate that IL-21 has the potential to influence B cell development and functions in the context of rabies vaccine-induced immunity and protection.

Background

The epidemic of rabies showed a rising trend in China in recent years. To identify the potential factors involved in the emergence, we investigated and analyzed the status and characteristics of human rabies between 1996 and 2008. Moreover, the status of rabies infection and vaccination in dogs, and prophylaxis of humans after rabies exposure were analyzed.

Methods

Human rabies data in China between 1996 and 2008 collected from the annual reports of Chinese Center for Disease Control and Prevention (China CDC) were analyzed. To investigate the status of dogs and postexposure prophylaxis (PEP) of humans, brain specimens of domestic dogs were collected and detected, and the demographic details, exposure status and PEP of rabies patients were obtained in 2005 and 2006 in Guangxi, Hunan and Guizhou provinces.

Results

The results showed 19,806 human rabies cases were reported in China from 1996 to 2008, with an average of 1,524 cases each year, and the incidence almost was rising rapidly, with the peak in 2007 (3,300 cases). It was notable that nearly 50% of the total rabies cases nationwide were reported in Guangxi, Hunan and Guizhou provinces. In these three provinces, the rabies infection rate in dogs was 2.3%, and 60% investigated cities had a dog vaccination rate of below 70%; among the 315 recorded human cases, 66.3% did not receive any PEP at all, 27.6% received inadequate PEP, and only 6.0% received a full regime of PEP.

Conclusions

In recent years, rabies is reemerging and becoming a major public-health problem in China. Our analysis showed that unsuccessful control of dog rabies and inadequate PEP of patients were the main factors leading to the high incidence of human rabies in China, then there are following suggestions: (1) Strict control of free-ranging dogs and mandatory rabies vaccination should be enforced. (2)Establishing national animal rabies surveillance network is imperative. (3) PEP should be decided to initiate or withhold according to postmortem diagnosis of the biting animal. (4) The cost of PEP should be decreased or free, especially in rural areas. (5)Education of the public and health care staff should be enhanced.

Background

The cost-benefit of raccoon rabies control strategies such as oral rabies vaccination (ORV) are under evaluation. As an initial quantification of the potential cost savings for a control program, the collection of selected rabies cost data was pilot tested for five counties in New York State (NYS) in a three-year period.

Methods

Rabies costs reported to NYS from the study counties were computerized and linked to a human rabies exposure database. Consolidated costs by county and year were averaged and compared.

Results

Reported rabies-associated costs for all rabies variants totalled $2.1 million, for human rabies postexposure prophylaxes (PEP) (90.9%), animal specimen preparation/shipment to laboratory (4.7%), and pet vaccination clinics (4.4%). The proportion that may be attributed to raccoon rabies control was 37% ($784,529). Average costs associated with the raccoon variant varied across counties from $440 to $1,885 per PEP, $14 to $44 per specimen, and $0.33 to $15 per pet vaccinated.

Conclusion

Rabies costs vary widely by county in New York State, and were associated with human population size and methods used by counties to estimate costs. Rabies cost variability must be considered in developing estimates of possible ORV-related cost savings. Costs of PEPs and specimen preparation/shipments, as well as the costs of pet vaccination provided by this study may be valuable for development of more realistic scenarios in economic modelling of ORV costs versus benefits.

To investigate rabies in Massachusetts, we analyzed bat rabies test results before and after introduction of raccoon variant rabies and after release of revised 1999 US Advisory Committee on Immunization Practices recommendations for rabies postexposure prophylaxis. Bat submissions were associated with level of rabies awareness and specific postexposure recommendations.

Objectives

To estimate the incidence of first-responder visits to emergency departments (EDs) for blood or body fluid exposures, elucidate any temporal patterns of these visits, and quantify human immunodeficiency virus (HIV) postexposure prophylaxis (PEP) utilization for these exposures.

Methods

This was a retrospective study of first responders presenting to Rhode Island EDs for blood or body fluid exposures from 1995 to 2001. Incidence rates for exposures with 95% confidence intervals (CIs) were estimated. Temporal trends for visits were modeled. Factors associated with HIV PEP utilization were identified using logistic regression. Odds ratios (ORs) with 95% CIs were estimated.

Results

The average incidence rate of ED visits for blood or body fluid exposures was 23.29 (20.07--26.52) ED visits per 100,000 ambulance runs. The incidence rose between 1995 and 1999 and then decreased. First-responder ED visits were lowest in October and highest in April and were lowest at 7 AM and highest at 7 PM. First responders presenting with a percutaneous or blood-to-mucous membrane exposure had a 4.13 (1.82--8.89) greater odds and those exposed to a known HIV-infected source had a 9.03 (1.59--51.26) greater odds of being offered HIV PEP. First responders presenting to a teaching hospital had a 2.21 (1.02--4.77) greater odds of being offered prophylaxis and a 4.20 (1.08--16.32) greater odds of accepting prophylaxis when it was offered.

Conclusions

First responders face a risk of blood or body fluid exposure that varies over the course of the day and the year. HIV PEP is more likely to be used if the exposures are percutaneous, or blood-to-mucous membrane, or if the source is known to be HIV-infected. Standardization of protocols across EDs for administering HIV prophylaxis appears to be needed.

Background

Prompt post-exposure prophylaxis (PEP) is essential in preventing the fatal onset of disease in persons exposed to rabies. Unfortunately, life-saving rabies vaccines and biologicals are often neither accessible nor affordable, particularly to the poorest sectors of society who are most at risk and upon whom the largest burden of rabies falls. Increasing accessibility, reducing costs and preventing delays in delivery of PEP should therefore be prioritized.

Methodology/Principal Findings

We analyzed different PEP vaccination regimens and evaluated their relative costs and benefits to bite victims and healthcare providers. We found PEP vaccination to be an extremely cost-effective intervention (from $200 to less than $60/death averted). Switching from intramuscular (IM) administration of PEP to equally efficacious intradermal (ID) regimens was shown to result in significant savings in the volume of vaccine required to treat the same number of patients, which could mitigate vaccine shortages, and would dramatically reduce the costs of implementing PEP. We present financing mechanisms that would make PEP more affordable and accessible, could help subsidize the cost for those most in need, and could even support new and existing rabies control and prevention programs.

Conclusions/Significance

We conclude that a universal switch to ID delivery would improve the affordability and accessibility of PEP for bite victims, leading to a likely reduction in human rabies deaths, as well as being economical for healthcare providers.

Background

In the United States, the risk of rabies transmission to humans in most situations of possible exposure is unknown. Controlled studies on rabies are clearly not possible. Thus, the limited data on risk has led to the frequent administration of rabies post-exposure prophylaxis (PEP), often in inappropriate circumstances.

Methods

We used the Delphi method to obtain an expert group consensus estimate of the risk of rabies transmission to humans in seven scenarios of potential rabies exposure. We also surveyed and discussed the merits of recommending rabies PEP for each scenario.

Results

The median risk of rabies transmission without rabies PEP for a bite exposure by a skunk, bat, cat, and dog was estimated to be 0.05, 0.001, 0.001, and 0.00001, respectively. Rabies PEP was unanimously recommended in these scenarios. However, rabies PEP was overwhelmingly not recommended for non-bite exposures (e.g. dog licking hand but unavailable for subsequent testing), estimated to have less than 1 in 1,000,000 (0.000001) risk of transmission.

Conclusions

Our results suggest that there are many common situations in which the risk of rabies transmission is so low that rabies PEP should not be recommended. These risk estimates also provide a key parameter for cost-effective models of human rabies prevention and can be used to educate health professionals about situation-specific administration of rabies PEP.

OBJECTIVE: Although records of animal bites and scratches are kept at most local health departments, little is known about the epidemiology and characteristics of these potential rabies exposures on a local level. Bite and scratch records for a four-and-a-half-year period from Montgomery County, Virginia, were examined in order to identify preventable trends. METHODS: The author retrospectively reviewed animal bite and scratch records from the Montgomery County Health Department dating from January 1992 through July 1996. RESULTS: Cat bites or scratches involved stray or feral animals more than eight times as often as dog bites or scratches. Cats were involved in the majority of incidents in which rabies postexposure prophylaxis (PEP) was recommended. Overall, PEP was recommended following 5.9% of reported incidents. The records also indicated that 65% of owned cats were unvaccinated at the time of the incident, while only 28% of owned dogs were unvaccinated. Children under the age of 18 were significantly more likely to be involved in a potential exposure than adults. CONCLUSIONS: Potential exposures should be analyzed periodically by local health departments. Suggestions for minimizing the number of potential rabies exposures in Montgomery County based on the results of the study reported here include: reducing the stray and feral cat population, targeting educational programs to children, and encouraging owners to vaccinate their pets.

Standardized protocols and diagnostic-based surveillance are imperative for detection and elimination.

Rabies is a reemerging disease in China. The high incidence of rabies leads to numerous concerns: a potential carrier-dog phenomenon, undocumented transmission of rabies virus from wildlife to dogs, counterfeit vaccines, vaccine mismatching, and seroconversion testing in patients after their completion of postexposure prophylaxis (PEP). These concerns are all scientifically arguable given a modern understanding of rabies. Rabies reemerges periodically in China because of high dog population density and low vaccination coverage in dogs. Mass vaccination campaigns rather than depopulation of dogs should be a long-term goal for rabies control. Seroconversion testing after vaccination is not necessary in either humans or animals. Human PEP should be initiated on the basis of diagnosis of biting animals. Reliable national systemic surveillance of rabies-related human deaths and of animal rabies prevalence is urgently needed. A laboratory diagnosis–based epidemiologic surveillance system can provide substantial information about disease transmission and effective prevention strategies.

Postexposure prophylaxis may avert Q fever illness and death when the probability of exposure is above the population-specific threshold point.

Coxiella burnetii is a category B bioterrorism agent. We numerically evaluated the risks and benefits from postexposure prophylaxis (PEP) after an intentional release of C. burnetii to the general population, pregnant women, and other high-risk populations. For each group, we constructed a decision tree to estimate illness and deaths averted by use of PEP/100,000 population. We calculated the threshold points at which the number of PEP-related adverse events was equal to the cases averted. PEP was defined as doxycycline (100 mg 2×/day for 5 days), except for pregnant women, where we assumed a PEP of trimethoprim-sulfamethoxazole (160 mg/800 mg 2×/day) for the duration of the pregnancy. PEP would begin 8–12 days postexposure. On the basis of upper-bound probability estimates of PEP-related adverse events for doxycycline, we concluded that the risk for Q fever illness outweighs the risk for antimicrobial drug–related adverse events when the probability of C. burnetii exposure is >7% (pregnant women using trimethoprim-sulfamethoxazole = 16%).

Background

The need for economical rabies post-exposure prophylaxis (PEP) is increasing in developing countries. Implementation of the two currently approved economical intradermal (ID) vaccine regimens is restricted due to confusion over different vaccines, regimens and dosages, lack of confidence in intradermal technique, and pharmaceutical regulations. We therefore compared a simplified 4-site economical PEP regimen with standard methods.

Methods

Two hundred and fifty-four volunteers were randomly allocated to a single blind controlled trial. Each received purified vero cell rabies vaccine by one of four PEP regimens: the currently accepted 2-site ID; the 8-site regimen using 0.05 ml per ID site; a new 4-site ID regimen (on day 0, approximately 0.1 ml at 4 ID sites, using the whole 0.5 ml ampoule of vaccine; on day 7, 0.1 ml ID at 2 sites and at one site on days 28 and 90); or the standard 5-dose intramuscular regimen. All ID regimens required the same total amount of vaccine, 60% less than the intramuscular method. Neutralising antibody responses were measured five times over a year in 229 people, for whom complete data were available.

Findings

All ID regimens showed similar immunogenicity. The intramuscular regimen gave the lowest geometric mean antibody titres. Using the rapid fluorescent focus inhibition test, some sera had unexpectedly high antibody levels that were not attributable to previous vaccination. The results were confirmed using the fluorescent antibody virus neutralisation method.

Conclusions

This 4-site PEP regimen proved as immunogenic as current regimens, and has the advantages of requiring fewer clinic visits, being more practicable, and having a wider margin of safety, especially in inexperienced hands, than the 2-site regimen. It is more convenient than the 8-site method, and can be used economically with vaccines formulated in 1.0 or 0.5 ml ampoules. The 4-site regimen now meets all requirements of immunogenicity for PEP and can be introduced without further studies.

Trial Registration

Controlled-Trials.com ISRCTN 30087513

Author Summary

All human deaths from rabies result from failure to give adequate prophylaxis. After a rabid animal bite, immediate wound cleaning, rabies vaccine and immunoglobulin injections effectively prevent fatal infection. Immunoglobulin is very rarely available in developing countries, where prevention relies on efficacious vaccine. WHO approved vaccines are prohibitively expensive, but 2 economical regimens (injecting small amounts of vaccine intradermally, into the skin, at 2 or 8 sites on the first day of the course) have been used for many years in a few places. Practical or perceived difficulties have restricted widespread uptake of economical methods. These could largely be overcome by introducing a new, simpler regimen, involving 4 site injections on the first day. We vaccinated volunteers to compare the antibody levels induced by the 4-site intradermal regimen with those induced by the current 2-site and 8-site regimens and the “gold standard” intramuscular regimen favoured internationally. All the economical intradermal regimens were at least as immunogenic as the intramuscular method. The results provide sufficient evidence that the 4-site regimen meets the criteria necessary for its recommendation for use wherever the cost of vaccine is prohibitive and especially where 2 or more patients are treated on the same day.

We previously reported that A/WySnJ mice vaccinated via a tail scratch with a recombinant raccoon poxvirus (RCN) expressing the rabies virus internal structural nucleoprotein (N) (RCN-N) were protected against a street rabies virus (D. L. Lodmell, J. W. Sumner, J.J. Esposito, W.J. Bellini, and L. C. Ewalt, J. Virol. 65:3400-3405, 1991). To improve our understanding of the mechanism(s) of this protection, we investigated whether sera of A/WySnJ mice that had been vaccinated with RCN-N but not challenged with street rabies virus had anti-rabies virus activity. In vivo studies illustrated that mice inoculated in the footpad with preincubated mixtures of anti-N sera and virus were protected. In addition, anti-N sera inoculated into the site of virus challenge protected mice. The antiviral activity of anti-N sera was also demonstrated in vitro. Infectious virus was not detected in cultures 24 h following infection with virus that had been preincubated with anti-N sera. At later time points, infectious virus was detected, but inhibition of viral production was consistently > or = 99% compared with control cultures. The protective and antiviral inhibitory activity of the anti-N sera was identified as anti-N antibody by several methods. First, absorption of anti-N sera with goat anti-mouse immunoglobulin serum, but not normal goat serum, removed the activity. Second, radioimmuno-precipitation and sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis of sucrose density gradient-fractionated anti-N sera showed that antiviral activity was present only in the fraction containing anti-N antibody. Finally, absorption of anti-N sera with insect cells infected with a baculovirus expressing the N protein removed the protective activity. These data indicate that anti-N antibody is a component of the resistance to rabies virus infections.

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This report summarizes the spread of a raccoon rabies epizootic into New York in the 1990s, the species of animals affected, and human postexposure treatments (PET). A total of 57,008 specimens were submitted to the state laboratory from 1993 to 1998; 8,858 (16%) animals were confirmed rabid, with raccoons the most common species (75%). After exposure to 11,769 animals, 18,238 (45%) persons received PET, mostly because of contact with saliva or nervous tissue. We analyzed expenditure reports to estimate the cost of rabies prevention activities. An estimated $13.9 million was spent in New York State to prevent rabies from 1993 to 1998. Traditional prevention methods such as vaccinating pets, avoiding wildlife, and verifying an animal’s rabies status must be continued to reduce costly PET. To reduce rabid animals, exposures, and costs, oral vaccination of wildlife should also be considered.

Rabies, the most fatal of all infectious diseases, remains a major public health problem in developing countries, claiming the lives of an estimated 55,000 people each year. Most fatal rabies cases, with more than half of them in children, result from dog bites and occur among low-income families in Southeast Asia and Africa. Safe and efficacious vaccines are available to prevent rabies. However, they have to be given repeatedly, three times for pre-exposure vaccination and four to five times for post-exposure prophylaxis (PEP). In cases of severe exposure, a regimen of vaccine combined with a rabies immunoglobulin (RIG) preparation is required. The high incidence of fatal rabies is linked to a lack of knowledge on the appropriate treatment of bite wounds, lack of access to costly PEP, and failure to follow up with repeat immunizations. New, more immunogenic but less costly rabies virus vaccines are needed to reduce the toll of rabies on human lives. A preventative vaccine used for the immunization of children, especially those in high incidence countries, would be expected to lower fatality rates. Such a vaccine would have to be inexpensive, safe, and provide sustained protection, preferably after a single dose. Novel regimens are also needed for PEP to reduce the need for the already scarce and costly RIG and to reduce the number of vaccine doses to one or two. In this review, the pipeline of new rabies vaccines that are in pre-clinical testing is provided and an opinion on those that might be best suited as potential replacements for the currently used vaccines is offered.