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Trend of human rabies prophylaxis in developing countries: Toward optimal rabies immunization
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Review
Trend of human rabies prophylaxis in developing countries: Toward optimal rabies immunization Nitipong Permpalung a , Supakanya Wongrakpanich b , Sira Korpaisarn c , Pansakorn Tanratana c,d , Jaruboot Angsanakul e,∗ a
Department of Medicine, Bassett Medical Center and Columbia University College of Physicians and Surgeons, Cooperstown, New York, USA Queen Savang Vadhana Memorial Hospital, Chonburi, Thailand c Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok, Thailand d Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, WI, USA e Queen Saovabha Memorial Institute, The Thai Red Cross Society (World Health Organization Collaborating Center for Research on Rabies Pathogenesis and Prevention), Bangkok, Thailand b
a r t i c l e
i n f o
Article history: Received 5 April 2013 Received in revised form 14 June 2013 Accepted 26 June 2013 Available online xxx Keywords: Rabies Prophylaxis Vaccine Developing countries
a b s t r a c t Rabies is a fatal infectious disease. Because prevention is the key management for rabies, many vaccination regimens have been developed and used worldwide. The aims for developing rabies vaccination regimens include decreasing the number and amount of dosages, decreasing the duration and the number of clinical visits, and reducing cost. Interestingly, some intradermal (ID) regimens have proved to be as effective as the standard intramuscular (IM) regimens, and have been increasingly used in developing countries because they are less expensive. In this article, we reviewed rabies vaccines based on results obtained from clinical trials and international treatment guidelines for post-exposure prophylaxis, pre-exposure prophylaxis for the high risk group, and booster vaccination. © 2013 Elsevier Ltd. All rights reserved.
Contents 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Post-exposure prophylaxis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Post-exposure prophylaxis in developing countries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pre-exposure prophylaxis (PrEP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Problems and future trend of PrEP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pre-exposure prophylaxis as expanded program on immunization (EPI) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Booster vaccination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Simplified booster vaccination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Post-exposure prophylaxis (PEP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pre-exposure prophylaxis (PrEP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Booster vaccination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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∗ Corresponding author at: Physician and Researcher at Queen Saovabha Memorial Institute, The Thai Red Cross Society (World Health Organization Collaborating Center for Research on Rabies Pathogenesis and Prevention), 14 Soi Preedepanomyong 26 Yak 15, Sukumvit 71 Road, Wattana District, Bangkok 10110, Thailand. Tel.: +66 80 610 9977; fax: +66 2 254 0212. E-mail addresses: [email protected], [email protected] (J. Angsanakul). 0264-410X/$ – see front matter © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.vaccine.2013.06.083
Please cite this article in press as: Permpalung N, et al. Trend of human rabies prophylaxis in developing countries: Toward optimal rabies immunization. Vaccine (2013), http://dx.doi.org/10.1016/j.vaccine.2013.06.083
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2
1. Introduction Rabies is a deadly zoonotic disease that causes the deaths of 55,000 people every year worldwide, predominately in Asia and Africa [1]. Almost all symptomatic rabies result in death even with an intensive treatment. Fortunately, human rabies can be prevented by post-exposure vaccination with or without immunoglobulin injection. The problems with post-exposure prophylaxis (PEP) are the cost of the vaccine and immunoglobulin as well as the availability of the immunoglobulin. Pre-exposure prophylaxis (PrEP) has played a role in decreasing the need for immunoglobulin injection especially in developing countries. Intradermal (ID) PEP and PrEP regimens were developed later. The World Health Organization (WHO) accepted and promoted certain intradermal regimens [2]. These strategies reduced the costs and increased the accessibility to adequate human rabies prophylaxis. However, the standard schedule is complicated, requires many visits and consumes a lot of time for the patients and doctors. Therefore, researchers have sought more convenient and cheaper regimens [3]. This review is based on the results from clinical studies and current standard treatment guidelines. The details are described below. 2. Post-exposure prophylaxis The standard post-exposure prophylaxis is composed of rabies immunization with or without rabies immunoglobulin injection, depending on the severity of the exposure. The most widely accepted intramuscular (IM) vaccine schedule is the Essen regimen (1-1-1-1-1) consisting of five doses in five visits on days 0, 3, 7, 14 and 28 [4]. Rupprecht et al., an Advisory Committee on Immunization Practices (ACIP) working group, reviewed many publications and found that 3 doses of IM rabies immunization ensured adequate antibody response (rabies neutralizing antibody titers more than 0.5 IU per ml measured by Rapid Fluorescent Focus Inhibition Test (RFFIT)) by day 14 and that the fifth dose did not significantly increase antibody levels compared to the fourth dose [5,6]. After receiving only 4 doses of IM rabies immunization, on days 0, 3, 7 and 14, some patients had adequate antibody levels for several years. In the US, there was no failure of post-exposure prophylaxis reported after incomplete post-exposure vaccination [6]. 3. Post-exposure prophylaxis in developing countries As cell culture and embryonated egg-based vaccines can be unaffordable in many developing countries, ID vaccination was developed to solve the problem. Many ID regimens were as effective as the Essen regimen in generating rabies neutralizing antibody levels either with or without rabies immunoglobulin injection [7–12]. There are two widely accepted ID regimens: first, the Thai Red Cross intradermal regimen (TRC-ID regimen), 2-site ID injections on days 0, 3, and 7 and 1-site ID injection on days 28 and 90 (2-2-2-0-1-1); second, the modified Thai Red Cross intradermal regimen (modified TRC-ID regimen), 2-site ID injections on days 0, 3, 7 and 28 (2-2-2-02). Both the TRC-ID and the modified TRC-ID have been widely used in many developing countries. However, the last dose of the TRC-ID was shown to be inconvenient as was demonstrated by a decrease in 11% of the patients for follow-up on day 90 [13]. Later, the day 90 dose of TRC-ID was removed from WHO recommendation and was replaced by the modified TRC-ID regimen [14]. Shantavasinkul et al. investigated a 4-site ID injection of 0.1 ml of purified Vero cell rabies vaccine (PVRV) on days 0, 3, and 7 (1-week PEP regimen or 4-4-4). The study revealed higher
rabies neutralizing antibody levels on days 14 and 28 in the 1-week PEP regimen compared with the conventional TRC-ID regimen (p < 0.001), but insignificant differences in the rabies neutralizing antibody levels on day 360 (geometric mean antibody titer [GMT] = 1.05, 95% confident interval [CI] = 0.30–5.34, versus GMT = 1.29, 95% CI = 0.97–1.72) [15]. Later, Sudarshan et al. compared PVRV with purified chick embryo cell vaccine (PCECV) when using this regimen. All participants had adequate rabies antibody levels from day 7 to day 365. There was no significant difference in rabies neutralizing antibody levels on days 7, 14, 28, 180 and 365. However, this study did not state the potency of either vaccines, and did not compare a 1-week PEP regimen with a standard regimen [16].
4. Pre-exposure prophylaxis (PrEP) Primary immunization provides accelerated secondary immune response after booster vaccination and eliminates the need of immunoglobulin injection which might not be available in some countries [4,17]. This strategy might also prevent infection from unrecognized exposure to the virus. WHO considered IM and ID regimens as standards (see Table 2). These regimens have been demonstrated to have long lasting immunity in normal hosts for 5–21 years [17]. However, ACIP recommended only intramuscularly injected vaccine using the same schedule [18]. Many studies demonstrated that ID PrEP was immunogenic [19–22]. In Thailand, ID PrEP was used as the primary method for many decades with good results, especially by veterinarians and veterinary students. PrEP is recommended for people at high risk of exposure to the virus including laboratory workers, veterinarians, animal handlers, and travelers going to endemic areas [14]. This is particularly true where WHO recommended that post exposure therapy may not be available or is unreliable. Although PrEP has been proven effective by immunogenicity studies, the clinical immunogenicity without post-exposure booster vaccination is still controversial. Many experts recommend rabies booster vaccination after every exposure [14]. The details of booster vaccination are described in the last section.
5. Problems and future trend of PrEP Currently recommended pre-exposure schedules need 3–4 weeks, but some travelers or at risk persons have limited time such that complete regimens might be ignored. Some people choose not to get PrEP if they do not have the time to complete it. There were 4 studies from the Thai Red Cross Society and Australia that showed the immunogenicity of abbreviated ID pre-exposure schedules at 1 week [23–26]. Khawplod et al., demonstrated that 0.1 ml 2-site ID and full dose IM on days 0, 3, 7 were comparable to 0.1 ml 2site ID days 0, 7, 28 for rabies neutralizing antibody levels on day 360 and that all volunteers had adequate antibody response (rabies neutralizing antibody titers more than 0.5 IU per ml) within 7 days after standard booster vaccination [25,26]. Even a single full dose IM or 0.1 ml 2-site ID could prime the immune response, and the standard booster injections could elicit adequate antibody response on day 7 post booster vaccination [23,25,26]. However, 10 out of 40 and 1 out of 33 test subjects did not seroconvert after primary vaccination with 0.1 ml 2-site ID and full dose IM, respectively [23]. A 2-site ID on days 0, 7 study from Australia was reported to elicit adequate antibody response (94.5%) during day 21–28 [24]. The author did not investigate the booster response after primary immunization. In addition, enzyme-linked immunosorbent assay (ELISA), which is not a WHO accepted method, was used to measure the neutralizing antibody levels.
Please cite this article in press as: Permpalung N, et al. Trend of human rabies prophylaxis in developing countries: Toward optimal rabies immunization. Vaccine (2013), http://dx.doi.org/10.1016/j.vaccine.2013.06.083
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6. Pre-exposure prophylaxis as expanded program on immunization (EPI)
Table 1 Post-exposure prophylaxis regimens. Regimens
The published data from Thailand reported at least one-third of Thai children at 15 years old had one or more dog-bite experiences which made them at risk for rabies infection [27,28]. An effective pre-exposure schedule that could be provided simultaneously with the routine immunization program might resolve this problem. Lang et al. found that infants who were simultaneously vaccinated with DTwP-IPV and purified Vero cell rabies vaccine (PVRV) at age 2, 3 and 4 months had an adequate rabies antibody response (anti-rabies antibodies ≥0.5 IU per ml as measured by RFFIT in BHK21 cells) by 1 month after vaccination. The PVRV IM group had significantly higher rabies antibody titers than the PVRV ID group (geometric mean titer (GMT) = 30.6 IU per ml, 95% complete inhibition (CI) = 27.9–33.7 versus GMT = 12.0 IU per ml, 95% CI = 10.5–13.6). One year later, a booster vaccination with PVRV IM resulted in adequate antibody response by day 14. The immunities against diphtheria, tetanus, pertussis and polio did not alter by the concomitant rabies vaccination [29,30]. Another clinical trial from Thailand found that giving Japanese encephalitis vaccination concomitantly with rabies vaccination as follows: PCECV 1.0 ml IM on day 0, 7 and 28; PCECV 0.5 ml IM on day 0, 7 and 28; PCECV 0.1 ml ID on day 0, 7 and 28; and PCECV 0.1 ml ID on day 0 and 28, provided adequate rabies antibody response by day 49. All groups sufficiently responded to a single booster dose by day 7 post vaccination. However, PCECV IM groups had significantly higher rabies antibody titers than PCECV ID groups [31]. In summary, we found two rabies vaccination schedules that could be added to the EPI: intradermal or intramuscular administration with DTP-IPV at 2, 3 and 4 months; and intradermal administration with JE vaccine at 12–18 months and 1 month later [29–31]. Some evidence showed that these strategies might be economical. Each year, 15 million people need PEP, and the data from Thailand showed that of the 73% of patients presented with WHO category III exposure, less than 3% were given immunoglobulin [14,28]. Focusing on cost comparison, Chulasugandha et al. demonstrated that using PrEP with PCECV ID was equivalent to PEP with PRVR or PCEC ID in combination with Equine Rabies Immunoglobulin (ERIG) at a dog bite prevalence of 7% [27]. The information supported the proposition that PrEP could be economically extended in EPI without additional visits and that this strategy could solve the short supply of rabies immunoglobulin. Other endemic countries may also apply this strategy to lessen overall cost of rabies prevention.
7. Booster vaccination Pre-exposure rabies vaccination does not eliminate the need for rabies vaccination after exposure. There was a reported case of rabies in a patient who received a full course of intradermal PrEP and was exposed to a dog bite within 8 months. The patient did not seek a booster vaccination [32]. This failure proved the necessity for post-exposure booster vaccination. Booster vaccination has been widely used as a post-exposure vaccination for previously vaccinated persons. The acceptable schedules must induce rabies neutralizing antibody levels to greater than 0.5 IU per ml, determined by RFFIT, on day 5 or 7 after the first booster injection, in order to prove immunogenic [33]. The standard post-exposure booster vaccination consists of 1 dose of cell culture or embryonated egg-based (CCEEVs) vaccine, ID or IM injection on days 0 and 3 [14]. The standard ID booster vaccination resulted in adequate antibody response by day 7 in all subjects, even 5 to 21 years after the pre- and post-exposure vaccination [17,34–40]. However, physicians should identify people who
3
Current recommendations (WHO) Essen Zagreb Modified TRC-ID Possible regimen ACIP, USAa [48] Investigational regimens Shantavasinkul et al. QSMI, Thailand [15]
Route (sites)
Days
IM (1-1-1-1-1) IM (2-1-1) ID (2-2-2-0-2)
0, 3, 7, 14, 28 0, 7, 21 0, 3, 7, 28
IM (1-1-1-1)
0, 3, 7, 14
ID (4-4-4)
0, 3, 7
QSMI, Queen Saovabha Memorial Institute; ACIP, The Advisory Committee on Immunization Practices; USA, United States of America. a WHO accepted this as an alternative regimen in immunocompetent patients. We would classify this regimen as a “possible” regimen because its immunocompetence is still undetermined.
were previously vaccinated with nervous tissue-derived vaccine, instead of cell culture or embryonated egg-based vaccine, because some individuals vaccinated with the nervous tissue-derived vaccines did not respond well to the booster vaccination [41]. Low potency of those vaccines might be the reason behind the failures [42]. Therefore, nervous tissue-derived vaccine treated persons should not receive post-exposure prophylaxis with the strategy described above. This issue has been commonly found in many developing countries since they have been using nervous tissuederived vaccine for a long period. 8. Simplified booster vaccination Briggs et al. showed that one dose of PCECV IM booster injection induced adequate antibody response after booster vaccination by day 7. The antibody levels were comparable to a standard twodose booster injection [43]. The 4-site ID regimen (0.1 ml 4-site ID injection, both deltoid and anterior thigh areas) was proven to be immunogenic. The regimen resulted in higher rabies neutralizing antibody levels than 1 dose IM injection on days 0 and 3 demonstrated by GMT on day 7 [44,45]. In addition, significantly higher antibody levels were observed at least one year after vaccination (GMT = 8.62 versus GMT = 1.86, p < 0.05) than with standard ID booster vaccination [45]. Moreover, the clinical immunogenicity of this regimen was shown [46,47]. 9. Discussion We found that many simplified regimens, especially intradermal regimens, can reduce cost, time and out-patient visits. Post-exposure prophylaxis, pre-exposure prophylaxis. booster vaccination and related strategies are summarized as follow: 10. Post-exposure prophylaxis (PEP) Two possible regimens are showed in Table 1. The four-dose IM vaccine schedule, which has been recommended by ACIP, was indirectly proven immunogenic by immunologic information of the Essen regimen [48]. This schedule decreases the regimen by one vial of rabies vaccine and shortens the time by 2 weeks. However, Uwanyiligira et al. found that 6.7% of the patients without a history of an immunocompromised condition had inadequate antibody response after this schedule [49]. Direct immunogenicity study of 4-dose IM compared with the Essen regimen is being investigated at Queen Saovabha Memorial Institute [50]. The ID regimen (4-4-4) induced adequate antibody response [15,16]. This regimen could prove to be a new standard regimen to be used as a post-exposure prophylaxis either with or without rabies immunoglobulin injection only in WHO category 2 exposures. Bleeding wounds require immunoglobulin injected into
Please cite this article in press as: Permpalung N, et al. Trend of human rabies prophylaxis in developing countries: Toward optimal rabies immunization. Vaccine (2013), http://dx.doi.org/10.1016/j.vaccine.2013.06.083
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4 Table 2 Pre-exposure prophylaxis regimens. Regimens Standard recommendations WHO ACIP, USA Investigational regimens Khawplod et al. QSMI, Thailand [26] Mills et al. Australia [24]
Route (sites)
Days
IM, ID IM
0, 7, 21 or 28 0, 7, 21 or 28
IM, ID ID (2)
0, 3, 7 0, 7
QSMI, Queen Saovabha Memorial Institute; ACIP, The Advisory Committee on Immunization Practices; USA, United States of America.
Table 3 Post-exposure booster vaccination regimens. Regimens Standard recommendations WHO WHOa ACIP, USA Investigational regimen Briggs et al. USA [43]
Route (sites)
Days
ID, IM ID (4) IM
0, 3 0 0, 3
IM
0
ACIP, The Advisory Committee on Immunization Practices; USA, United States of America. a WHO accepted this as an alternative regimen.
wounds for the most effective treatment. It decreases the regimen by two vials of rabies vaccine and shortens the time by one week. However, the number of participants in these studies was too small to provide conclusive evidence that this should become an accepted regimen. Currently, a larger trial is being considered in Asia [51]. In addition, the novel agent “a recombinant human IgG antirabies monoclonal antiboby (SII RMab)” has been evaluated in a randomized, open label, dose-escalation phase I trial in order to replace rabies immunoglobulin in India. [52] The study demonstrated that the vaccine plus SII RMAb and the vaccine plus HRIG had comparable anti-rabies antibody levels by RFFIT. 11. Pre-exposure prophylaxis (PrEP) We found three promising regimens as shown in Table 2. Khawplod et al. demonstrated that pre-exposure prophylaxis with 0.1 ml 2-site ID and full dose IM on days 0, 3, 7 induced sufficient immune response in all participants. In addition, the booster response in this study was satisfactory (neutralizing rabies antibodies >0.5 IU per ml. by RFFIT) [26]. These regimens decreased the time of vaccination by one week but increased vaccine dosage. Another study was conducted in Australia, Mill DJ et al. found that pre-exposure prophylaxis with 0.1 ml 2-site ID on days 0, 7 regimen could seroconvert all participants by day 21–28. This regimen abbreviates the time of the vaccination by one week and reduces the cost of pre-exposure vaccination. However, this study did not use RFFIT to measure antibody response and did not investigate the booster response after exposure to rabies and the length of acceptable immune response [24]. We discourage single full dose IM or 0.1 ml 2-site ID to be used as PrEP. Although these regimens primed the immune response and resulted in adequate immune response after booster vaccination, some participants did not seroconvert after the first vaccination [23]. 12. Booster vaccination We found two interesting regimens as shown in Table 3. The 4-site ID regimen is affordable (decrease in total cost was approximately 50% less than the IM regimen), convenient (only one visit needed) and alleviates the vaccine storage and management
problems (one vial can be used to treat one to two patients). However, this schedule uses more vaccine than the conventional intradermal booster regimen. Another regimen, a single full dose IM injection, can also induce adequate antibody response [43]. Combining only 1 vial of rabies vaccine and one visit, this regimen is also promising as a booster vaccination. 13. Conclusion Briefly, there are possible simplified rabies vaccination regimens and strategies that may be used, especially intradermal regimens, to immunogenically and efficiently treat patients in high risk rabies endemic areas with less cost and less clinical visits. Application of these schedules could tremendously increase access to appropriate human rabies prophylaxis by decreasing costs and time commitments and increasing overall availability. However, some of these regimens require further study before becoming standard care procedures. Acknowledgements The authors would like to thank Dr. Pakamatz Khawplod, PhD. for her personal communications and advice and Professor Dr. Terapong Tantawichien, MD. for his advice about rabies vaccination standards. Conflict of interest statement: All authors do not have conflict of interest to declare. Funding: None. References [1] Knobel DL, Cleaveland S, Coleman PG, Fevre EM, Meltzer MI, Miranda ME, et al. Re-evaluating the burden of rabies in Africa and Asia. Bull World Health Organ 2005;83(5):360–8. [2] WHO Expert Committee on Rabies. World health organ technical report series, vol. 824; 1992. p. 1–84. [3] Shantavasinkul P, Wilde H. Postexposure prophylaxis for rabies in resourcelimited/poor countries. Adv Virus Res 2011;79:291–307. [4] WHO. Rabies vaccines: WHO position paper-recommendations. Vaccine 2010;28(44):7140–2. [5] WHO Expert Committee on rabies: seven report, vol. 709. World Health Organ Tech Rep Ser; 1984. [6] Rupprecht CE, Briggs D, Brown CM, Franka R, Katz SL, Kerr HD, et al. Evidence for a 4-dose vaccine schedule for human rabies post-exposure prophylaxis in previously non-vaccinated individuals. Vaccine 2009;27(51):7141–8. [7] Khawplod P, Glueck R, Wilde H, Tantawichien T, Chomchey P, Thipkong P, et al. Immunogenicity of purified duck embryo rabies vaccine (Lyssavac-N) with use of the WHO-approved intradermal postexposure regimen. Clin Infect Dis 1995;20(3):646–51. [8] Suntharasamai P, Chaiprasithikul P, Wasi C, Supanaranond W, Auewarakul P, Chanthavanich P, et al. A simplified and economical intradermal regimen of purified chick embryo cell rabies vaccine for postexposure prophylaxis. Vaccine 1994;12(6):508–12. [9] Chutivongse S, Wilde H, Supich C, Baer GM, Fishbein DB. Postexposure prophylaxis for rabies with antiserum and intradermal vaccination. Lancet 1990;335(8694):896–8. [10] Suntharasamai P, Warrell MJ, Viravan C, Chanthavanich P, Looareesuwan S, Supapochana A, et al. Purified chick embryo cell rabies vaccine: economical multisite intradermal regimen for post-exposure prophylaxis. Epidemiol Infect 1987;99(3):755–65. [11] Ubol S, Phanuphak P. An effective economical intradermal regimen of human diploid cell rabies vaccination for post-exposure treatment. Clin Exp Immunol 1986;63(3):491–7. [12] Warrell MJ, Warrell DA, Suntharasamai P, Viravan C, Sinhaseni A, Udomsakdi D, et al. An economical regimen of human diploid cell strain anti-rabies vaccine for post-exposure prophylaxis. Lancet 1983;2(8345):301–4. [13] Khawplod P, Wilde H, Sirikwin S, Benjawongkulchai M, Limusanno S, Jaijaroensab W, et al. Revision of the Thai Red Cross intradermal rabies post-exposure regimen by eliminating the 90-day booster injection. Vaccine 2006;24(16):3084–6. [14] World Health Organization. Rabies vaccines. WHO position paper. Wkly Epidemiol Rec 2010;85:309–20. [15] Shantavasinkul P, Tantawichien T, Wilde H, Sawangvaree A, Kumchat A, Ruksaket N, et al. Postexposure rabies prophylaxis completed in 1 week: preliminary study. Clin Infect Dis 2010;50(1):56–60.
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[35] Kositprapa C, Limsuwun K, Wilde H, Jaijaroensup W, Saikasem A, Khawplod P, et al. Immune response to simulated postexposure rabies booster vaccinations in volunteers who received preexposure vaccinations. Clin Infect Dis 1997;25(3):614–6. [36] Kamoltham T, Thinyounyong W, Khawplod P, Phraisuwan P, Phongchamnaphai P, Anders G, et al. Immunogenicity of simulated pcecv postexposure booster doses 1, 3, and 5 years after 2-dose and 3-dose primary rabies vaccination in school children. Adv Prev Med 2011;2011:403201. [37] Roukens AH, Vossen AC, van Dissel JT, Visser LG. Reduced dose pre-exposure primary and booster intradermal rabies vaccination with a purified chick embryo cell vaccine (PCECV) is immunogenic and safe in adults. Vaccine 2008;26(27-28):3438–42. [38] Kamoltham T, Thinyounyong W, Phongchamnaphai P, Phraisuwan P, Khawplod P, Banzhoff A, et al. Pre-exposure rabies vaccination using purified chick embryo cell rabies vaccine intradermally is immunogenic and safe. J Pediatr 2007;151(2):173–7. [39] Fishbein DB, Dreesen DW, Holmes DF, Pacer RE, Ley AB, Yager PA, et al. Human diploid cell rabies vaccine purified by zonal centrifugation: a controlled study of antibody response and side effects following primary and booster pre-exposure immunizations. Vaccine 1989;7(5):437–42. [40] Burridge MJ, Sumner JW, Baer GM. Intradermal immunization with human diploid cell rabies vaccine: serological and clinical responses of immunized persons to intradermal booster vaccination. Am J Public Health 1984;74(5):503–5. [41] Khawplod P, Wilde H, Yenmuang W, Benjavongkulchai M, Chomchey P. Immune response to tissue culture rabies vaccine in subjects who had previous postexposure treatment with semple or suckling mouse brain vaccine. Vaccine 1996;14(16):1549–52. [42] Parviz S, Chotani R, McCormick J, Fisher-Hoch S, Luby S. Rabies deaths in Pakistan: results of ineffective post-exposure treatment. Int J Infect Dis 2004;8(6):346–52. [43] Briggs DJ, Dreesen DW, Nicolay U, Chin JE, Davis R, Gordon C, et al. Purified chick embryo cell culture rabies vaccine: interchangeability with human diploid cell culture rabies vaccine and comparison of one versus two-dose post-exposure booster regimen for previously immunized persons. Vaccine 2000;19(9–10):1055–60. [44] Khawplod P, Benjavongkulchai M, Limusanno S, Chareonwai S, Kaewchompoo W, Tantawichien T, et al. Four-site intradermal postexposure boosters in previously rabies vaccinated subjects. J Travel Med 2002;9(3):153–5. [45] Tantawichien T, Benjavongkulchai M, Limsuwan K, Khawplod P, Kaewchompoo W, Chomchey P, et al. Antibody response after a four-site intradermal booster vaccination with cell-culture rabies vaccine. Clin Infect Dis 1999;28(5):1100–3. [46] Tantawichien T, Supit C, Khawplod P, Sitprija V. Three-year experience with 4-site intradermal booster vaccination with rabies vaccine for postexposure prophylaxis. Clin Infect Dis 2001;33(12):2085–7. [47] Shantavasinkul P, Tantawichien T, Jaijaroensup W, Lertjarutorn S, Banjongkasaena A, Wilde H, et al. A 4-site, single-visit intradermal postexposure prophylaxis regimen for previously vaccinated patients: experiences with >5000 patients. Clin Infect Dis 2010;51(9):1070–2. [48] Rupprecht CE, Briggs D, Brown CM, Franka R, Katz SL, Kerr HD, et al. Use of a reduced (4-dose) vaccine schedule for postexposure prophylaxis to prevent human rabies: recommendations of the advisory committee on immunization practices. MMWR Recomm Rep 2010;59(RR-2):1–9. [49] Uwanyiligira M, Landry P, Genton B, de Valliere S. Rabies post-exposure prophylaxis in routine practice in view of the new CDC and WHO recommendations. Clin Infect Dis 2012;55(2):201–5. [50] Clinical trials: immunogenicity study of a reduced (4-dose) vaccine schedule and rabies immunoglobulins [database on the internet]. Queen Saovabha Memorial Institute; 2012. http://www.clinicaltrials.gov/ct2/show/ NCT01641315?term=4+dose+AND+rabies&rank=1 [cited 02.12.12]. [51] Clinical trials: immunogenicity and safety of verorab® in a “one-week” intradermal post-exposure prophylaxis regimen [database on the internet]. Sanofi Pasteur; 2012. http://www.clinicaltrials.gov/ct2/show/ NCT01622062?term=4-4-4&rank=1 [cited 02.12.12]. [52] Gogtay N, Thatte U, Kshirsagar N, Leav B, Molrine D, Cheslock P, et al. Safety and pharmacokinetics of a human monoclonal antibody to rabies virus: a randomized, dose-escalation phase 1 study in adults. Vaccine 2012;30(50):7315–20.
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Contents lists available at SciVerse ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Review
Trend of human rabies prophylaxis in developing countries: Toward optimal rabies immunization Nitipong Permpalung a , Supakanya Wongrakpanich b , Sira Korpaisarn c , Pansakorn Tanratana c,d , Jaruboot Angsanakul e,∗ a
Department of Medicine, Bassett Medical Center and Columbia University College of Physicians and Surgeons, Cooperstown, New York, USA Queen Savang Vadhana Memorial Hospital, Chonburi, Thailand c Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok, Thailand d Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, WI, USA e Queen Saovabha Memorial Institute, The Thai Red Cross Society (World Health Organization Collaborating Center for Research on Rabies Pathogenesis and Prevention), Bangkok, Thailand b
a r t i c l e
i n f o
Article history: Received 5 April 2013 Received in revised form 14 June 2013 Accepted 26 June 2013 Available online xxx Keywords: Rabies Prophylaxis Vaccine Developing countries
a b s t r a c t Rabies is a fatal infectious disease. Because prevention is the key management for rabies, many vaccination regimens have been developed and used worldwide. The aims for developing rabies vaccination regimens include decreasing the number and amount of dosages, decreasing the duration and the number of clinical visits, and reducing cost. Interestingly, some intradermal (ID) regimens have proved to be as effective as the standard intramuscular (IM) regimens, and have been increasingly used in developing countries because they are less expensive. In this article, we reviewed rabies vaccines based on results obtained from clinical trials and international treatment guidelines for post-exposure prophylaxis, pre-exposure prophylaxis for the high risk group, and booster vaccination. © 2013 Elsevier Ltd. All rights reserved.
Contents 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Post-exposure prophylaxis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Post-exposure prophylaxis in developing countries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pre-exposure prophylaxis (PrEP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Problems and future trend of PrEP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pre-exposure prophylaxis as expanded program on immunization (EPI) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Booster vaccination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Simplified booster vaccination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Post-exposure prophylaxis (PEP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pre-exposure prophylaxis (PrEP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Booster vaccination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
00 00 00 00 00 00 00 00 00 00 00 00 00 00 00
∗ Corresponding author at: Physician and Researcher at Queen Saovabha Memorial Institute, The Thai Red Cross Society (World Health Organization Collaborating Center for Research on Rabies Pathogenesis and Prevention), 14 Soi Preedepanomyong 26 Yak 15, Sukumvit 71 Road, Wattana District, Bangkok 10110, Thailand. Tel.: +66 80 610 9977; fax: +66 2 254 0212. E-mail addresses: [email protected], [email protected] (J. Angsanakul). 0264-410X/$ – see front matter © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.vaccine.2013.06.083
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2
1. Introduction Rabies is a deadly zoonotic disease that causes the deaths of 55,000 people every year worldwide, predominately in Asia and Africa [1]. Almost all symptomatic rabies result in death even with an intensive treatment. Fortunately, human rabies can be prevented by post-exposure vaccination with or without immunoglobulin injection. The problems with post-exposure prophylaxis (PEP) are the cost of the vaccine and immunoglobulin as well as the availability of the immunoglobulin. Pre-exposure prophylaxis (PrEP) has played a role in decreasing the need for immunoglobulin injection especially in developing countries. Intradermal (ID) PEP and PrEP regimens were developed later. The World Health Organization (WHO) accepted and promoted certain intradermal regimens [2]. These strategies reduced the costs and increased the accessibility to adequate human rabies prophylaxis. However, the standard schedule is complicated, requires many visits and consumes a lot of time for the patients and doctors. Therefore, researchers have sought more convenient and cheaper regimens [3]. This review is based on the results from clinical studies and current standard treatment guidelines. The details are described below. 2. Post-exposure prophylaxis The standard post-exposure prophylaxis is composed of rabies immunization with or without rabies immunoglobulin injection, depending on the severity of the exposure. The most widely accepted intramuscular (IM) vaccine schedule is the Essen regimen (1-1-1-1-1) consisting of five doses in five visits on days 0, 3, 7, 14 and 28 [4]. Rupprecht et al., an Advisory Committee on Immunization Practices (ACIP) working group, reviewed many publications and found that 3 doses of IM rabies immunization ensured adequate antibody response (rabies neutralizing antibody titers more than 0.5 IU per ml measured by Rapid Fluorescent Focus Inhibition Test (RFFIT)) by day 14 and that the fifth dose did not significantly increase antibody levels compared to the fourth dose [5,6]. After receiving only 4 doses of IM rabies immunization, on days 0, 3, 7 and 14, some patients had adequate antibody levels for several years. In the US, there was no failure of post-exposure prophylaxis reported after incomplete post-exposure vaccination [6]. 3. Post-exposure prophylaxis in developing countries As cell culture and embryonated egg-based vaccines can be unaffordable in many developing countries, ID vaccination was developed to solve the problem. Many ID regimens were as effective as the Essen regimen in generating rabies neutralizing antibody levels either with or without rabies immunoglobulin injection [7–12]. There are two widely accepted ID regimens: first, the Thai Red Cross intradermal regimen (TRC-ID regimen), 2-site ID injections on days 0, 3, and 7 and 1-site ID injection on days 28 and 90 (2-2-2-0-1-1); second, the modified Thai Red Cross intradermal regimen (modified TRC-ID regimen), 2-site ID injections on days 0, 3, 7 and 28 (2-2-2-02). Both the TRC-ID and the modified TRC-ID have been widely used in many developing countries. However, the last dose of the TRC-ID was shown to be inconvenient as was demonstrated by a decrease in 11% of the patients for follow-up on day 90 [13]. Later, the day 90 dose of TRC-ID was removed from WHO recommendation and was replaced by the modified TRC-ID regimen [14]. Shantavasinkul et al. investigated a 4-site ID injection of 0.1 ml of purified Vero cell rabies vaccine (PVRV) on days 0, 3, and 7 (1-week PEP regimen or 4-4-4). The study revealed higher
rabies neutralizing antibody levels on days 14 and 28 in the 1-week PEP regimen compared with the conventional TRC-ID regimen (p < 0.001), but insignificant differences in the rabies neutralizing antibody levels on day 360 (geometric mean antibody titer [GMT] = 1.05, 95% confident interval [CI] = 0.30–5.34, versus GMT = 1.29, 95% CI = 0.97–1.72) [15]. Later, Sudarshan et al. compared PVRV with purified chick embryo cell vaccine (PCECV) when using this regimen. All participants had adequate rabies antibody levels from day 7 to day 365. There was no significant difference in rabies neutralizing antibody levels on days 7, 14, 28, 180 and 365. However, this study did not state the potency of either vaccines, and did not compare a 1-week PEP regimen with a standard regimen [16].
4. Pre-exposure prophylaxis (PrEP) Primary immunization provides accelerated secondary immune response after booster vaccination and eliminates the need of immunoglobulin injection which might not be available in some countries [4,17]. This strategy might also prevent infection from unrecognized exposure to the virus. WHO considered IM and ID regimens as standards (see Table 2). These regimens have been demonstrated to have long lasting immunity in normal hosts for 5–21 years [17]. However, ACIP recommended only intramuscularly injected vaccine using the same schedule [18]. Many studies demonstrated that ID PrEP was immunogenic [19–22]. In Thailand, ID PrEP was used as the primary method for many decades with good results, especially by veterinarians and veterinary students. PrEP is recommended for people at high risk of exposure to the virus including laboratory workers, veterinarians, animal handlers, and travelers going to endemic areas [14]. This is particularly true where WHO recommended that post exposure therapy may not be available or is unreliable. Although PrEP has been proven effective by immunogenicity studies, the clinical immunogenicity without post-exposure booster vaccination is still controversial. Many experts recommend rabies booster vaccination after every exposure [14]. The details of booster vaccination are described in the last section.
5. Problems and future trend of PrEP Currently recommended pre-exposure schedules need 3–4 weeks, but some travelers or at risk persons have limited time such that complete regimens might be ignored. Some people choose not to get PrEP if they do not have the time to complete it. There were 4 studies from the Thai Red Cross Society and Australia that showed the immunogenicity of abbreviated ID pre-exposure schedules at 1 week [23–26]. Khawplod et al., demonstrated that 0.1 ml 2-site ID and full dose IM on days 0, 3, 7 were comparable to 0.1 ml 2site ID days 0, 7, 28 for rabies neutralizing antibody levels on day 360 and that all volunteers had adequate antibody response (rabies neutralizing antibody titers more than 0.5 IU per ml) within 7 days after standard booster vaccination [25,26]. Even a single full dose IM or 0.1 ml 2-site ID could prime the immune response, and the standard booster injections could elicit adequate antibody response on day 7 post booster vaccination [23,25,26]. However, 10 out of 40 and 1 out of 33 test subjects did not seroconvert after primary vaccination with 0.1 ml 2-site ID and full dose IM, respectively [23]. A 2-site ID on days 0, 7 study from Australia was reported to elicit adequate antibody response (94.5%) during day 21–28 [24]. The author did not investigate the booster response after primary immunization. In addition, enzyme-linked immunosorbent assay (ELISA), which is not a WHO accepted method, was used to measure the neutralizing antibody levels.
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6. Pre-exposure prophylaxis as expanded program on immunization (EPI)
Table 1 Post-exposure prophylaxis regimens. Regimens
The published data from Thailand reported at least one-third of Thai children at 15 years old had one or more dog-bite experiences which made them at risk for rabies infection [27,28]. An effective pre-exposure schedule that could be provided simultaneously with the routine immunization program might resolve this problem. Lang et al. found that infants who were simultaneously vaccinated with DTwP-IPV and purified Vero cell rabies vaccine (PVRV) at age 2, 3 and 4 months had an adequate rabies antibody response (anti-rabies antibodies ≥0.5 IU per ml as measured by RFFIT in BHK21 cells) by 1 month after vaccination. The PVRV IM group had significantly higher rabies antibody titers than the PVRV ID group (geometric mean titer (GMT) = 30.6 IU per ml, 95% complete inhibition (CI) = 27.9–33.7 versus GMT = 12.0 IU per ml, 95% CI = 10.5–13.6). One year later, a booster vaccination with PVRV IM resulted in adequate antibody response by day 14. The immunities against diphtheria, tetanus, pertussis and polio did not alter by the concomitant rabies vaccination [29,30]. Another clinical trial from Thailand found that giving Japanese encephalitis vaccination concomitantly with rabies vaccination as follows: PCECV 1.0 ml IM on day 0, 7 and 28; PCECV 0.5 ml IM on day 0, 7 and 28; PCECV 0.1 ml ID on day 0, 7 and 28; and PCECV 0.1 ml ID on day 0 and 28, provided adequate rabies antibody response by day 49. All groups sufficiently responded to a single booster dose by day 7 post vaccination. However, PCECV IM groups had significantly higher rabies antibody titers than PCECV ID groups [31]. In summary, we found two rabies vaccination schedules that could be added to the EPI: intradermal or intramuscular administration with DTP-IPV at 2, 3 and 4 months; and intradermal administration with JE vaccine at 12–18 months and 1 month later [29–31]. Some evidence showed that these strategies might be economical. Each year, 15 million people need PEP, and the data from Thailand showed that of the 73% of patients presented with WHO category III exposure, less than 3% were given immunoglobulin [14,28]. Focusing on cost comparison, Chulasugandha et al. demonstrated that using PrEP with PCECV ID was equivalent to PEP with PRVR or PCEC ID in combination with Equine Rabies Immunoglobulin (ERIG) at a dog bite prevalence of 7% [27]. The information supported the proposition that PrEP could be economically extended in EPI without additional visits and that this strategy could solve the short supply of rabies immunoglobulin. Other endemic countries may also apply this strategy to lessen overall cost of rabies prevention.
7. Booster vaccination Pre-exposure rabies vaccination does not eliminate the need for rabies vaccination after exposure. There was a reported case of rabies in a patient who received a full course of intradermal PrEP and was exposed to a dog bite within 8 months. The patient did not seek a booster vaccination [32]. This failure proved the necessity for post-exposure booster vaccination. Booster vaccination has been widely used as a post-exposure vaccination for previously vaccinated persons. The acceptable schedules must induce rabies neutralizing antibody levels to greater than 0.5 IU per ml, determined by RFFIT, on day 5 or 7 after the first booster injection, in order to prove immunogenic [33]. The standard post-exposure booster vaccination consists of 1 dose of cell culture or embryonated egg-based (CCEEVs) vaccine, ID or IM injection on days 0 and 3 [14]. The standard ID booster vaccination resulted in adequate antibody response by day 7 in all subjects, even 5 to 21 years after the pre- and post-exposure vaccination [17,34–40]. However, physicians should identify people who
3
Current recommendations (WHO) Essen Zagreb Modified TRC-ID Possible regimen ACIP, USAa [48] Investigational regimens Shantavasinkul et al. QSMI, Thailand [15]
Route (sites)
Days
IM (1-1-1-1-1) IM (2-1-1) ID (2-2-2-0-2)
0, 3, 7, 14, 28 0, 7, 21 0, 3, 7, 28
IM (1-1-1-1)
0, 3, 7, 14
ID (4-4-4)
0, 3, 7
QSMI, Queen Saovabha Memorial Institute; ACIP, The Advisory Committee on Immunization Practices; USA, United States of America. a WHO accepted this as an alternative regimen in immunocompetent patients. We would classify this regimen as a “possible” regimen because its immunocompetence is still undetermined.
were previously vaccinated with nervous tissue-derived vaccine, instead of cell culture or embryonated egg-based vaccine, because some individuals vaccinated with the nervous tissue-derived vaccines did not respond well to the booster vaccination [41]. Low potency of those vaccines might be the reason behind the failures [42]. Therefore, nervous tissue-derived vaccine treated persons should not receive post-exposure prophylaxis with the strategy described above. This issue has been commonly found in many developing countries since they have been using nervous tissuederived vaccine for a long period. 8. Simplified booster vaccination Briggs et al. showed that one dose of PCECV IM booster injection induced adequate antibody response after booster vaccination by day 7. The antibody levels were comparable to a standard twodose booster injection [43]. The 4-site ID regimen (0.1 ml 4-site ID injection, both deltoid and anterior thigh areas) was proven to be immunogenic. The regimen resulted in higher rabies neutralizing antibody levels than 1 dose IM injection on days 0 and 3 demonstrated by GMT on day 7 [44,45]. In addition, significantly higher antibody levels were observed at least one year after vaccination (GMT = 8.62 versus GMT = 1.86, p < 0.05) than with standard ID booster vaccination [45]. Moreover, the clinical immunogenicity of this regimen was shown [46,47]. 9. Discussion We found that many simplified regimens, especially intradermal regimens, can reduce cost, time and out-patient visits. Post-exposure prophylaxis, pre-exposure prophylaxis. booster vaccination and related strategies are summarized as follow: 10. Post-exposure prophylaxis (PEP) Two possible regimens are showed in Table 1. The four-dose IM vaccine schedule, which has been recommended by ACIP, was indirectly proven immunogenic by immunologic information of the Essen regimen [48]. This schedule decreases the regimen by one vial of rabies vaccine and shortens the time by 2 weeks. However, Uwanyiligira et al. found that 6.7% of the patients without a history of an immunocompromised condition had inadequate antibody response after this schedule [49]. Direct immunogenicity study of 4-dose IM compared with the Essen regimen is being investigated at Queen Saovabha Memorial Institute [50]. The ID regimen (4-4-4) induced adequate antibody response [15,16]. This regimen could prove to be a new standard regimen to be used as a post-exposure prophylaxis either with or without rabies immunoglobulin injection only in WHO category 2 exposures. Bleeding wounds require immunoglobulin injected into
Please cite this article in press as: Permpalung N, et al. Trend of human rabies prophylaxis in developing countries: Toward optimal rabies immunization. Vaccine (2013), http://dx.doi.org/10.1016/j.vaccine.2013.06.083
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4 Table 2 Pre-exposure prophylaxis regimens. Regimens Standard recommendations WHO ACIP, USA Investigational regimens Khawplod et al. QSMI, Thailand [26] Mills et al. Australia [24]
Route (sites)
Days
IM, ID IM
0, 7, 21 or 28 0, 7, 21 or 28
IM, ID ID (2)
0, 3, 7 0, 7
QSMI, Queen Saovabha Memorial Institute; ACIP, The Advisory Committee on Immunization Practices; USA, United States of America.
Table 3 Post-exposure booster vaccination regimens. Regimens Standard recommendations WHO WHOa ACIP, USA Investigational regimen Briggs et al. USA [43]
Route (sites)
Days
ID, IM ID (4) IM
0, 3 0 0, 3
IM
0
ACIP, The Advisory Committee on Immunization Practices; USA, United States of America. a WHO accepted this as an alternative regimen.
wounds for the most effective treatment. It decreases the regimen by two vials of rabies vaccine and shortens the time by one week. However, the number of participants in these studies was too small to provide conclusive evidence that this should become an accepted regimen. Currently, a larger trial is being considered in Asia [51]. In addition, the novel agent “a recombinant human IgG antirabies monoclonal antiboby (SII RMab)” has been evaluated in a randomized, open label, dose-escalation phase I trial in order to replace rabies immunoglobulin in India. [52] The study demonstrated that the vaccine plus SII RMAb and the vaccine plus HRIG had comparable anti-rabies antibody levels by RFFIT. 11. Pre-exposure prophylaxis (PrEP) We found three promising regimens as shown in Table 2. Khawplod et al. demonstrated that pre-exposure prophylaxis with 0.1 ml 2-site ID and full dose IM on days 0, 3, 7 induced sufficient immune response in all participants. In addition, the booster response in this study was satisfactory (neutralizing rabies antibodies >0.5 IU per ml. by RFFIT) [26]. These regimens decreased the time of vaccination by one week but increased vaccine dosage. Another study was conducted in Australia, Mill DJ et al. found that pre-exposure prophylaxis with 0.1 ml 2-site ID on days 0, 7 regimen could seroconvert all participants by day 21–28. This regimen abbreviates the time of the vaccination by one week and reduces the cost of pre-exposure vaccination. However, this study did not use RFFIT to measure antibody response and did not investigate the booster response after exposure to rabies and the length of acceptable immune response [24]. We discourage single full dose IM or 0.1 ml 2-site ID to be used as PrEP. Although these regimens primed the immune response and resulted in adequate immune response after booster vaccination, some participants did not seroconvert after the first vaccination [23]. 12. Booster vaccination We found two interesting regimens as shown in Table 3. The 4-site ID regimen is affordable (decrease in total cost was approximately 50% less than the IM regimen), convenient (only one visit needed) and alleviates the vaccine storage and management
problems (one vial can be used to treat one to two patients). However, this schedule uses more vaccine than the conventional intradermal booster regimen. Another regimen, a single full dose IM injection, can also induce adequate antibody response [43]. Combining only 1 vial of rabies vaccine and one visit, this regimen is also promising as a booster vaccination. 13. Conclusion Briefly, there are possible simplified rabies vaccination regimens and strategies that may be used, especially intradermal regimens, to immunogenically and efficiently treat patients in high risk rabies endemic areas with less cost and less clinical visits. Application of these schedules could tremendously increase access to appropriate human rabies prophylaxis by decreasing costs and time commitments and increasing overall availability. However, some of these regimens require further study before becoming standard care procedures. Acknowledgements The authors would like to thank Dr. Pakamatz Khawplod, PhD. for her personal communications and advice and Professor Dr. Terapong Tantawichien, MD. for his advice about rabies vaccination standards. Conflict of interest statement: All authors do not have conflict of interest to declare. Funding: None. References [1] Knobel DL, Cleaveland S, Coleman PG, Fevre EM, Meltzer MI, Miranda ME, et al. Re-evaluating the burden of rabies in Africa and Asia. Bull World Health Organ 2005;83(5):360–8. [2] WHO Expert Committee on Rabies. World health organ technical report series, vol. 824; 1992. p. 1–84. [3] Shantavasinkul P, Wilde H. Postexposure prophylaxis for rabies in resourcelimited/poor countries. Adv Virus Res 2011;79:291–307. [4] WHO. Rabies vaccines: WHO position paper-recommendations. Vaccine 2010;28(44):7140–2. [5] WHO Expert Committee on rabies: seven report, vol. 709. World Health Organ Tech Rep Ser; 1984. [6] Rupprecht CE, Briggs D, Brown CM, Franka R, Katz SL, Kerr HD, et al. Evidence for a 4-dose vaccine schedule for human rabies post-exposure prophylaxis in previously non-vaccinated individuals. Vaccine 2009;27(51):7141–8. [7] Khawplod P, Glueck R, Wilde H, Tantawichien T, Chomchey P, Thipkong P, et al. Immunogenicity of purified duck embryo rabies vaccine (Lyssavac-N) with use of the WHO-approved intradermal postexposure regimen. Clin Infect Dis 1995;20(3):646–51. [8] Suntharasamai P, Chaiprasithikul P, Wasi C, Supanaranond W, Auewarakul P, Chanthavanich P, et al. A simplified and economical intradermal regimen of purified chick embryo cell rabies vaccine for postexposure prophylaxis. Vaccine 1994;12(6):508–12. [9] Chutivongse S, Wilde H, Supich C, Baer GM, Fishbein DB. Postexposure prophylaxis for rabies with antiserum and intradermal vaccination. Lancet 1990;335(8694):896–8. [10] Suntharasamai P, Warrell MJ, Viravan C, Chanthavanich P, Looareesuwan S, Supapochana A, et al. Purified chick embryo cell rabies vaccine: economical multisite intradermal regimen for post-exposure prophylaxis. Epidemiol Infect 1987;99(3):755–65. [11] Ubol S, Phanuphak P. An effective economical intradermal regimen of human diploid cell rabies vaccination for post-exposure treatment. Clin Exp Immunol 1986;63(3):491–7. [12] Warrell MJ, Warrell DA, Suntharasamai P, Viravan C, Sinhaseni A, Udomsakdi D, et al. An economical regimen of human diploid cell strain anti-rabies vaccine for post-exposure prophylaxis. Lancet 1983;2(8345):301–4. [13] Khawplod P, Wilde H, Sirikwin S, Benjawongkulchai M, Limusanno S, Jaijaroensab W, et al. Revision of the Thai Red Cross intradermal rabies post-exposure regimen by eliminating the 90-day booster injection. Vaccine 2006;24(16):3084–6. [14] World Health Organization. Rabies vaccines. WHO position paper. Wkly Epidemiol Rec 2010;85:309–20. [15] Shantavasinkul P, Tantawichien T, Wilde H, Sawangvaree A, Kumchat A, Ruksaket N, et al. Postexposure rabies prophylaxis completed in 1 week: preliminary study. Clin Infect Dis 2010;50(1):56–60.
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