NEWS
Biting back:
Vaccine efforts redoubled as rabies deadline looms
npg
Scott Camazine / Alamy
© 2015 Nature America, Inc. All rights reserved.
By Shraddha Chakradhar
It was nearly 10 o’clock at night. Naseem Salahuddin, an infectious disease specialist at Indus Hospital in Karachi, Pakistan, rushed in to work: nearly 20 people had been brought to the hospital after being bitten by the same rabid dog. Salahuddin was used to seeing between 10 and 20 people with suspected rabies exposure a day, but never this many bitten by the same dog within a short amount of time. A man who had been walking in a nearby field witnessed the dog biting several of these people and stepped in to help. “He brought in a child who had been bitten badly,” says Salahuddin. It was lucky that the man immediately brought the child to the hospital; beginning treatment almost as soon as a bite occurs is essential to preventing the onset of rabies. “He dropped off the child with us in the hospital, went out and throttled the dog to death.” Stories like this are not hard to come by in Pakistan, where in 2010 alone health officials recorded 97,000 cases of dog bites, according to the World Health Organization (WHO). And these stories can involve unexpected situations. Once, when she was conducting a workshop on rabies treatment in the Pakistani city of Lahore, a doctor attending the workshop brought in a boy who had been bitten by a sheep that itself had been bitten by a stray dog, Salahuddin recalls: “Pakistani villages are full of such stories.” In the developed world, rabies cases in 8
humans are rare; when they do occur they are typically a result of exposure to infected bats, raccoons and other woodland creatures. But in developing regions of the world, rabies continues to impose a large burden. The WHO estimates that 84% of all rabies deaths occur in rural areas of developing countries, and that children account for about 40% of all deaths from the disease. Whereas the WHO puts the worldwide burden of rabies at roughly 55,000 deaths per year, experts at the New York–based Global Alliance for Rabies Control think the number is actually closer to 70,000. As part of its ongoing effort to eliminate rabies, in 2011 the WHO set elimination deadlines for several rabies-endemic regions of the world, the earliest of which is December 2015 for Latin American countries. Latin America seems to be on track to meet its 2015 elimination deadline, but parts of Asia have a 2020 goal that is unlikely to be met. Africa sees roughly 24,000 rabies deaths annually but has no WHO-set deadline. The lack of attention to rabies in Africa may be because other diseases that cause many more deaths in that region take a higher place on the list of priorities. Only Kenya has taken it upon itself to prioritize rabies and has a road map for a 2030 elimination goal. Reversing a death sentence Rabies researchers and public health experts have largely focused on preventive techniques— mostly vaccination campaigns against rabies
vectors such as dogs. Eliminating the disease at the source is a much more cost-effective way of tackling the disease because, for nearly everybody who does contract the disease, rabies is a death sentence. “Many doctors don’t attempt treatment because, to them, it’s just a matter of time before the patient dies,” says Madhusudana Shampur, a virologist at the National Institute of Mental Health and Neurosciences in India, a country that sees roughly 20,000 rabies deaths annually. “They recommend to the patients that they go home to be with their family” for the time they have left. Although it is rare, the ‘furious’ form of rabies, which is marked by hyperactivity coupled with an extreme fear of water, can be transmitted by infected people. In this form of the disease, comprising about 70% of all rabies cases, patients who are sent home often receive sedatives to counter their symptoms and only live for a few days. The other form of the disease, which accounts for about 30% of all rabies cases, is known as paralytic rabies. It causes a gradual paralysis in all muscles, eventually leading to coma and in some cases death. Only seven people have been known to survive either form of the disease, according to a 2013 WHO report, and nearly all of them were bitten by bats and had received the proper post-exposure treatment. For dogrelated rabies cases, which make up nearly all the cases in Asia and Africa, rabies is still
VOLUME 21 | NUMBER 1 | JANUARY 2015 NATURE MEDICINE
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100% fatal. Without enough initiative and investment from governments to stop the spread of the disease, frustrated researchers are turning their attention away from preventive methods and focusing instead on reducing the number of rabies deaths by making significant improvements to the current post-exposure treatment. Although a preventive rabies vaccine made with inactivated virus is available, only those individuals who are considered at high risk of contracting the disease—health workers and veterinarians—are given this vaccine. However, post-exposure prophylaxis (PEP) has been available for more than 100 years, made available most famously by Louis Pasteur. This PEP vaccine was originally manufactured using animal nerve cell tissue, and was relatively cheap to produce and cost $4–$6 for the course of the treatment. But it carried a host of side effects and was quite painful. The WHO now recommends the use of cell culture–derived vaccines, which are made with inactivated forms of the virus but are more expensive (treatment costs $40–$50). The mechanism of the vaccine, however, remains largely unchanged: the vaccine contains inactivated rabies virus, which, on introduction to the body, results in the production of neutralizing antibodies that work against the virus. Unfortunately, the incubation period for rabies is highly variable; symptoms can appear as early as two weeks after a bite. But in some cases, symptoms have set in several years after a bite. In one instance, a girl who had lived in Hong Kong as a child lived in Australia for five years before she developed the disease. In this instance, a postmortem analysis concluded that the incubation period was anywhere from fourand-a-half to six years1. However, “if the PEP is correctly given, [the] chance of developing rabies is almost none,” says Salahuddin. “Failure to prevent rabies occurs only if PEP is not done correctly after a rabid [animal] bite.” Faster PEP Historically, PEP was administered over the course of three months. But even though the treatment regimen has been shortened to a one-month protocol, it remains a challenge in remote places without easy access to health infrastructure. Researchers have been working on reducing the treatment time even further. In Thailand, one of the countries in which rabies has traditionally been a problem, a group of researchers at the Queen Saovabha Memorial Institute and Chulalongkorn University in Bangkok, led by Prapimporn Shantavasinkul, demonstrated the efficacy of a treatment that
Madhusudana Shampur
© 2015 Nature America, Inc. All rights reserved.
N E W S F E AT U R E
Researching rabies: Madhusudana Shampur (far left) visits with a rabies patient.
used an increased dosage regimen for a oneweek protocol. Ninety volunteers were given three doses of purified vero cell vaccine (PVCV), manufactured by the French vaccine maker Sanofi Pasteur, spaced over a week’s time. About half of the study participants were given a slightly increased dosage—0.4 milliliters more— than the control group. When compared with the control group, the volunteers in the group who received the increased dosage for just the first week were found to have more rabiesneutralizing antibodies at days 14 and 28 (ref. 2). That early boost is important because “it’s really the first few days after [rabies] exposure that are crucial,” says Henry Wilde, an immunologist at Chulalongkorn University in Thailand and one of the authors of the study. “It’s not necessary to have a [prolonged] schedule and our method proved that.” However, because the rabies virus has a variable incubation period, physicians have relied on a longer PEP treatment period to ensure a persistent presence of rabies antibodies. An abbreviated schedule would help patients finish the course, but some physicians worry that a shortened regimen won’t provide the long-lasting protection that a one-month treatment period has historically provided. The one-week, increased-dose regimen was also tested by a group of rabies researchers in India, who also tested the schedule’s efficacy in two different vaccines. In a study of 80 people, half received the PVRV vaccine, called Imovax, used in the Thailand study, whereas the other half received a purified chick embryo cell vaccine called Rabipur and manufactured by Novartis. Both groups underwent the one-week
NATURE MEDICINE VOLUME 21 | NUMBER 1 | JANUARY 2015
schedule laid out in the earlier Thailand study, and, the volunteers in both groups had rabies neutralizing-antibody values of >0.5 IU/ml, the threshold needed for protection3. Given the success of the one-week, increaseddosage regimen, the WHO is currently considering approving the one-week protocol, according to Wilde, but approval will probably “entail a lengthy administrative process,” owing to a complete reorganization of the rabies committee within the WHO. Going for globulin While a lengthy vaccination schedule poses a significant hurdle, an equally difficult component is the administration of rabies immunoglobulin (RIG). RIG remains difficult to produce; it requires the recruitment of hyperimmunized volunteers, who have recently received the rabies vaccine and therefore produce antibodies against the virus, to donate blood from which plasma is isolated and then purified. Some countries, like Pakistan, use an equine form of RIG because the cost of equine RIG is about one-tenth the cost of its human counterpart. Equine RIG, however, carries a higher risk of side effects like anaphylaxis, causing doctors, when possible, to opt for the human form. To help overcome the production and administration problems that RIG has traditionally presented, many researchers are working on developing alternatives, mainly monoclonal antibodies (MAbs). Boston-based MassBiologics, for instance, has teamed up with the Serum Institute of India to develop an anti-rabies human monoclonal antibody (RMAb). Initial results from a phase 1 trial 9
npg
© 2015 Nature America, Inc. All rights reserved.
were announced in 2013: The volunteers were randomly divided up and received either human RIG or RMAb. Those who received RMAb did not show any side effects, nor did they have lower levels of rabies antibodies as compared with the group that received RIG4. Netherlands-based Crucell is also testing various MAb candidates, several of which have completed phase 2 trials. Similarly to the results with RMAb, Crucell has also seen largely positive results, with MAb performing just as well as human RIG when it came to providing immunity against the rabies virus5. However, although the WHO is firmly supportive of the idea of MAbs to replace RIG or even to be used in conjunction with RIG, others are skeptical. “MAb will only be useful if the cost is significantly lower than RIG,” Shampur says. Given that it’s still in the development phase, he added that it’s difficult to know how the product will be disbursed. Positively negative Improvements to the current treatment methods are not the only efforts that are being undertaken by rabies researchers. Researchers are also working on better understanding the neuropathology of the disease to identify novel drug targets. At the Pasteur Institute in Paris, Noël Tordo and his group are looking at the replication and transcription pathways of negative-strand RNA viruses (NSRV), such as the rabies virus, to determine if there is anything that might inform the development of new antivirals. Because most NSRVs behave similarly, Tordo believes that looking at the entire group will result in wide-spectrum antivirals that could be applied to a host of diseases. For instance, one of the targets the group is focused on is the rabies nucleoprotein, which is one of five proteins encoded by the rabies genome. During the transcription process of the rabies virus, nucleoproteins, along with two other proteins, form the basis of a protein core that is known as RNP. Blocking the formation of this protein core also halts the transcription and replication process of the virus. By searching for molecules with a high affinity for the rabies nucleoprotein, Tordo and his colleagues have identified five promising peptides that could serve as antiviral molecules. “It’s difficult to target the virus once it enters the nervous system,” Tordo says. “So blocking its replication process before that happens will help curb infection.” Another avenue of research in Tordo’s lab is research on inhibiting the entry of the rabies virus into the bloodstream. They are focusing on dermaseptins, which are peptides found on the skin of frogs and which are known for their 10
Naseem Salahuddin
N E W S F E AT U R E
Public service: Naseem Salahuddin works to spread awareness about rabies in Pakistan.
antimicrobial properties. In unpublished work, Tordo’s group found that when dermaseptin S4 is added to hamster kidney cell clones known as BSR cells, the compound inhibits more than 95% of rabies infection in vitro, and it continues to offer this level of protection when it is added to cells an hour after the cells are exposed to rabies virus. This suggests that dermaseptins, like monoclonal antibodies, could potentially serve as a viable replacement for RIG. Tordo is also a part of the Asklepios Consortium, a European working group of academic researchers whose goal is to identify novel drug targets for the rabies virus. These neurobiologists, from various institutions around the continent, are currently working on putting together their individual findings and will meet in mid-2015 to pick one molecular target, which they hope to begin testing in animal models at the end of the year. Surveillance solutions Even if vaccine schedules are improved and novel drug targets are identified, one of the major hurdles that many rabies-endemic countries struggle with is the lack of proper surveillance systems to gauge the burden of the disease. Simple equipment, such as field microscopes, is needed to be able to trace disease back to its culprit animal or even back to those who succumb to the disease. To help, Shampur is developing direct Rapid Immunohistochemical Test (dRIT) kits for the detection of rabies in the field. These diagnostic kits, which were originally developed by the US Centers for Disease Control and Prevention, will cost around $2 and allow a brain smear from a deceased animal or person to be examined for rabies antibodies under a compound light microscope. The current
gold-standard diagnostic kit costs around $10, so having a cheaper, simpler test will allow for easier detection of rabies cases. Neither kit’s cost includes the cost of reagents, however. “It’s hard to say exactly how much this new kit will cost,” says Shampur, “but it will definitely be a vast reduction in cost compared to the current option.” Ultimately, all of these efforts to reduce the number of rabies deaths, although progressive, come from a place of frustration. “We talk about the same damn thing and nothing is done,” Wilde says. “It’s almost virtually a dead end when it comes to rabies.” What continues to frustrate researchers working with the disease is the fact that rabies is completely preventable. “It’s low-hanging fruit,” says Felix Lankester, a rabies researcher from Washington State University who works in Tanzania. “We have the tools to eliminate it quite effectively.” But elimination may not be immediately possible given the lack of funding for research, vaccination campaigns or improved drugs. Moreover, the prevalence of other higher-profile fatal diseases tends to put rabies on the back burner, but the current efforts to improve the vaccine schedule and identify novel targets might at least help reduce the mortality rate of the disease. Shraddha Chakradhar is an Assistant News Editor for Nature Medicine based in Cambridge, Massachusetts. 1. Johnson, N. et al. Emerg. Infect. Dis. 14, 1950–1951 (2008). 2. Shantavasinkul, P. et al. Clin. Infect. Dis. 50, 56–60 (2010). 3. Sudarshan, M.K. et al. Hum Vaccin. Immunother. 8, 1077–1081 (2012). 4. Gogtay, N. et al. Vaccine 30, 7315–7320 (2012). 5. Bakker, A.B. et al. Vaccine 26, 5922–5927 (2008).
VOLUME 21 | NUMBER 1 | JANUARY 2015 NATURE MEDICINE
Biting back:
Vaccine efforts redoubled as rabies deadline looms
npg
Scott Camazine / Alamy
© 2015 Nature America, Inc. All rights reserved.
By Shraddha Chakradhar
It was nearly 10 o’clock at night. Naseem Salahuddin, an infectious disease specialist at Indus Hospital in Karachi, Pakistan, rushed in to work: nearly 20 people had been brought to the hospital after being bitten by the same rabid dog. Salahuddin was used to seeing between 10 and 20 people with suspected rabies exposure a day, but never this many bitten by the same dog within a short amount of time. A man who had been walking in a nearby field witnessed the dog biting several of these people and stepped in to help. “He brought in a child who had been bitten badly,” says Salahuddin. It was lucky that the man immediately brought the child to the hospital; beginning treatment almost as soon as a bite occurs is essential to preventing the onset of rabies. “He dropped off the child with us in the hospital, went out and throttled the dog to death.” Stories like this are not hard to come by in Pakistan, where in 2010 alone health officials recorded 97,000 cases of dog bites, according to the World Health Organization (WHO). And these stories can involve unexpected situations. Once, when she was conducting a workshop on rabies treatment in the Pakistani city of Lahore, a doctor attending the workshop brought in a boy who had been bitten by a sheep that itself had been bitten by a stray dog, Salahuddin recalls: “Pakistani villages are full of such stories.” In the developed world, rabies cases in 8
humans are rare; when they do occur they are typically a result of exposure to infected bats, raccoons and other woodland creatures. But in developing regions of the world, rabies continues to impose a large burden. The WHO estimates that 84% of all rabies deaths occur in rural areas of developing countries, and that children account for about 40% of all deaths from the disease. Whereas the WHO puts the worldwide burden of rabies at roughly 55,000 deaths per year, experts at the New York–based Global Alliance for Rabies Control think the number is actually closer to 70,000. As part of its ongoing effort to eliminate rabies, in 2011 the WHO set elimination deadlines for several rabies-endemic regions of the world, the earliest of which is December 2015 for Latin American countries. Latin America seems to be on track to meet its 2015 elimination deadline, but parts of Asia have a 2020 goal that is unlikely to be met. Africa sees roughly 24,000 rabies deaths annually but has no WHO-set deadline. The lack of attention to rabies in Africa may be because other diseases that cause many more deaths in that region take a higher place on the list of priorities. Only Kenya has taken it upon itself to prioritize rabies and has a road map for a 2030 elimination goal. Reversing a death sentence Rabies researchers and public health experts have largely focused on preventive techniques— mostly vaccination campaigns against rabies
vectors such as dogs. Eliminating the disease at the source is a much more cost-effective way of tackling the disease because, for nearly everybody who does contract the disease, rabies is a death sentence. “Many doctors don’t attempt treatment because, to them, it’s just a matter of time before the patient dies,” says Madhusudana Shampur, a virologist at the National Institute of Mental Health and Neurosciences in India, a country that sees roughly 20,000 rabies deaths annually. “They recommend to the patients that they go home to be with their family” for the time they have left. Although it is rare, the ‘furious’ form of rabies, which is marked by hyperactivity coupled with an extreme fear of water, can be transmitted by infected people. In this form of the disease, comprising about 70% of all rabies cases, patients who are sent home often receive sedatives to counter their symptoms and only live for a few days. The other form of the disease, which accounts for about 30% of all rabies cases, is known as paralytic rabies. It causes a gradual paralysis in all muscles, eventually leading to coma and in some cases death. Only seven people have been known to survive either form of the disease, according to a 2013 WHO report, and nearly all of them were bitten by bats and had received the proper post-exposure treatment. For dogrelated rabies cases, which make up nearly all the cases in Asia and Africa, rabies is still
VOLUME 21 | NUMBER 1 | JANUARY 2015 NATURE MEDICINE
npg
100% fatal. Without enough initiative and investment from governments to stop the spread of the disease, frustrated researchers are turning their attention away from preventive methods and focusing instead on reducing the number of rabies deaths by making significant improvements to the current post-exposure treatment. Although a preventive rabies vaccine made with inactivated virus is available, only those individuals who are considered at high risk of contracting the disease—health workers and veterinarians—are given this vaccine. However, post-exposure prophylaxis (PEP) has been available for more than 100 years, made available most famously by Louis Pasteur. This PEP vaccine was originally manufactured using animal nerve cell tissue, and was relatively cheap to produce and cost $4–$6 for the course of the treatment. But it carried a host of side effects and was quite painful. The WHO now recommends the use of cell culture–derived vaccines, which are made with inactivated forms of the virus but are more expensive (treatment costs $40–$50). The mechanism of the vaccine, however, remains largely unchanged: the vaccine contains inactivated rabies virus, which, on introduction to the body, results in the production of neutralizing antibodies that work against the virus. Unfortunately, the incubation period for rabies is highly variable; symptoms can appear as early as two weeks after a bite. But in some cases, symptoms have set in several years after a bite. In one instance, a girl who had lived in Hong Kong as a child lived in Australia for five years before she developed the disease. In this instance, a postmortem analysis concluded that the incubation period was anywhere from fourand-a-half to six years1. However, “if the PEP is correctly given, [the] chance of developing rabies is almost none,” says Salahuddin. “Failure to prevent rabies occurs only if PEP is not done correctly after a rabid [animal] bite.” Faster PEP Historically, PEP was administered over the course of three months. But even though the treatment regimen has been shortened to a one-month protocol, it remains a challenge in remote places without easy access to health infrastructure. Researchers have been working on reducing the treatment time even further. In Thailand, one of the countries in which rabies has traditionally been a problem, a group of researchers at the Queen Saovabha Memorial Institute and Chulalongkorn University in Bangkok, led by Prapimporn Shantavasinkul, demonstrated the efficacy of a treatment that
Madhusudana Shampur
© 2015 Nature America, Inc. All rights reserved.
N E W S F E AT U R E
Researching rabies: Madhusudana Shampur (far left) visits with a rabies patient.
used an increased dosage regimen for a oneweek protocol. Ninety volunteers were given three doses of purified vero cell vaccine (PVCV), manufactured by the French vaccine maker Sanofi Pasteur, spaced over a week’s time. About half of the study participants were given a slightly increased dosage—0.4 milliliters more— than the control group. When compared with the control group, the volunteers in the group who received the increased dosage for just the first week were found to have more rabiesneutralizing antibodies at days 14 and 28 (ref. 2). That early boost is important because “it’s really the first few days after [rabies] exposure that are crucial,” says Henry Wilde, an immunologist at Chulalongkorn University in Thailand and one of the authors of the study. “It’s not necessary to have a [prolonged] schedule and our method proved that.” However, because the rabies virus has a variable incubation period, physicians have relied on a longer PEP treatment period to ensure a persistent presence of rabies antibodies. An abbreviated schedule would help patients finish the course, but some physicians worry that a shortened regimen won’t provide the long-lasting protection that a one-month treatment period has historically provided. The one-week, increased-dose regimen was also tested by a group of rabies researchers in India, who also tested the schedule’s efficacy in two different vaccines. In a study of 80 people, half received the PVRV vaccine, called Imovax, used in the Thailand study, whereas the other half received a purified chick embryo cell vaccine called Rabipur and manufactured by Novartis. Both groups underwent the one-week
NATURE MEDICINE VOLUME 21 | NUMBER 1 | JANUARY 2015
schedule laid out in the earlier Thailand study, and, the volunteers in both groups had rabies neutralizing-antibody values of >0.5 IU/ml, the threshold needed for protection3. Given the success of the one-week, increaseddosage regimen, the WHO is currently considering approving the one-week protocol, according to Wilde, but approval will probably “entail a lengthy administrative process,” owing to a complete reorganization of the rabies committee within the WHO. Going for globulin While a lengthy vaccination schedule poses a significant hurdle, an equally difficult component is the administration of rabies immunoglobulin (RIG). RIG remains difficult to produce; it requires the recruitment of hyperimmunized volunteers, who have recently received the rabies vaccine and therefore produce antibodies against the virus, to donate blood from which plasma is isolated and then purified. Some countries, like Pakistan, use an equine form of RIG because the cost of equine RIG is about one-tenth the cost of its human counterpart. Equine RIG, however, carries a higher risk of side effects like anaphylaxis, causing doctors, when possible, to opt for the human form. To help overcome the production and administration problems that RIG has traditionally presented, many researchers are working on developing alternatives, mainly monoclonal antibodies (MAbs). Boston-based MassBiologics, for instance, has teamed up with the Serum Institute of India to develop an anti-rabies human monoclonal antibody (RMAb). Initial results from a phase 1 trial 9
npg
© 2015 Nature America, Inc. All rights reserved.
were announced in 2013: The volunteers were randomly divided up and received either human RIG or RMAb. Those who received RMAb did not show any side effects, nor did they have lower levels of rabies antibodies as compared with the group that received RIG4. Netherlands-based Crucell is also testing various MAb candidates, several of which have completed phase 2 trials. Similarly to the results with RMAb, Crucell has also seen largely positive results, with MAb performing just as well as human RIG when it came to providing immunity against the rabies virus5. However, although the WHO is firmly supportive of the idea of MAbs to replace RIG or even to be used in conjunction with RIG, others are skeptical. “MAb will only be useful if the cost is significantly lower than RIG,” Shampur says. Given that it’s still in the development phase, he added that it’s difficult to know how the product will be disbursed. Positively negative Improvements to the current treatment methods are not the only efforts that are being undertaken by rabies researchers. Researchers are also working on better understanding the neuropathology of the disease to identify novel drug targets. At the Pasteur Institute in Paris, Noël Tordo and his group are looking at the replication and transcription pathways of negative-strand RNA viruses (NSRV), such as the rabies virus, to determine if there is anything that might inform the development of new antivirals. Because most NSRVs behave similarly, Tordo believes that looking at the entire group will result in wide-spectrum antivirals that could be applied to a host of diseases. For instance, one of the targets the group is focused on is the rabies nucleoprotein, which is one of five proteins encoded by the rabies genome. During the transcription process of the rabies virus, nucleoproteins, along with two other proteins, form the basis of a protein core that is known as RNP. Blocking the formation of this protein core also halts the transcription and replication process of the virus. By searching for molecules with a high affinity for the rabies nucleoprotein, Tordo and his colleagues have identified five promising peptides that could serve as antiviral molecules. “It’s difficult to target the virus once it enters the nervous system,” Tordo says. “So blocking its replication process before that happens will help curb infection.” Another avenue of research in Tordo’s lab is research on inhibiting the entry of the rabies virus into the bloodstream. They are focusing on dermaseptins, which are peptides found on the skin of frogs and which are known for their 10
Naseem Salahuddin
N E W S F E AT U R E
Public service: Naseem Salahuddin works to spread awareness about rabies in Pakistan.
antimicrobial properties. In unpublished work, Tordo’s group found that when dermaseptin S4 is added to hamster kidney cell clones known as BSR cells, the compound inhibits more than 95% of rabies infection in vitro, and it continues to offer this level of protection when it is added to cells an hour after the cells are exposed to rabies virus. This suggests that dermaseptins, like monoclonal antibodies, could potentially serve as a viable replacement for RIG. Tordo is also a part of the Asklepios Consortium, a European working group of academic researchers whose goal is to identify novel drug targets for the rabies virus. These neurobiologists, from various institutions around the continent, are currently working on putting together their individual findings and will meet in mid-2015 to pick one molecular target, which they hope to begin testing in animal models at the end of the year. Surveillance solutions Even if vaccine schedules are improved and novel drug targets are identified, one of the major hurdles that many rabies-endemic countries struggle with is the lack of proper surveillance systems to gauge the burden of the disease. Simple equipment, such as field microscopes, is needed to be able to trace disease back to its culprit animal or even back to those who succumb to the disease. To help, Shampur is developing direct Rapid Immunohistochemical Test (dRIT) kits for the detection of rabies in the field. These diagnostic kits, which were originally developed by the US Centers for Disease Control and Prevention, will cost around $2 and allow a brain smear from a deceased animal or person to be examined for rabies antibodies under a compound light microscope. The current
gold-standard diagnostic kit costs around $10, so having a cheaper, simpler test will allow for easier detection of rabies cases. Neither kit’s cost includes the cost of reagents, however. “It’s hard to say exactly how much this new kit will cost,” says Shampur, “but it will definitely be a vast reduction in cost compared to the current option.” Ultimately, all of these efforts to reduce the number of rabies deaths, although progressive, come from a place of frustration. “We talk about the same damn thing and nothing is done,” Wilde says. “It’s almost virtually a dead end when it comes to rabies.” What continues to frustrate researchers working with the disease is the fact that rabies is completely preventable. “It’s low-hanging fruit,” says Felix Lankester, a rabies researcher from Washington State University who works in Tanzania. “We have the tools to eliminate it quite effectively.” But elimination may not be immediately possible given the lack of funding for research, vaccination campaigns or improved drugs. Moreover, the prevalence of other higher-profile fatal diseases tends to put rabies on the back burner, but the current efforts to improve the vaccine schedule and identify novel targets might at least help reduce the mortality rate of the disease. Shraddha Chakradhar is an Assistant News Editor for Nature Medicine based in Cambridge, Massachusetts. 1. Johnson, N. et al. Emerg. Infect. Dis. 14, 1950–1951 (2008). 2. Shantavasinkul, P. et al. Clin. Infect. Dis. 50, 56–60 (2010). 3. Sudarshan, M.K. et al. Hum Vaccin. Immunother. 8, 1077–1081 (2012). 4. Gogtay, N. et al. Vaccine 30, 7315–7320 (2012). 5. Bakker, A.B. et al. Vaccine 26, 5922–5927 (2008).
VOLUME 21 | NUMBER 1 | JANUARY 2015 NATURE MEDICINE
