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Immunogenicity of intradermal vaccination of Japanese rabies vaccine for preexposure immunization following WHO recommendation
J Infect Chemother (2012) 18:66–68 DOI 10.1007/s10156-011-0286-2
ORIGINAL ARTICLE
Immunogenicity of intradermal vaccination of Japanese rabies vaccine for preexposure immunization following WHO recommendation Naoki Yanagisawa • Naohide Takayama Kazuaki Mannen • Eiichi Nakayama • Akihiko Suganuma
•
Received: 28 April 2011 / Accepted: 12 July 2011 / Published online: 2 August 2011 Ó Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases 2011
Abstract In the present study, we evaluated the immunogenicity of intradermal vaccination of Japanese purified chick embryo cell rabies vaccine (PCEC-K) for preexposure immunization (PEI). A total of 39 healthy subjects were administered a single 0.1-ml dose of PCEC-K intradermally at the antebrachial region on days 0, 7, and 28. To assess immunogenicity, rabies neutralizing antibody (NA) titers were measured on days 7, 28, and 42 post vaccination. By day 42, all subjects developed NA titers C0.5 IU/ ml (geometric mean titer, 2.7 IU/ml), a level that is considered protective. The vaccine was well tolerated; vaccinated subjects displayed minimal redness and pruritus. Although a 1.0-ml dose of PCEC-K administered subcutaneously is considered the standard method, the intradermal regimen using a 0.1-ml dose of PCEC-K is immunogenic, safe, and highly recommended for situations of vaccine shortage. Keywords Japanese rabies vaccine Intradermal vaccination Immunogenicity Preexposure immunization
N. Yanagisawa (&) A. Suganuma Department of Infectious Diseases, Tokyo Metropolitan Komagome Hospital, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8677, Japan e-mail: [email protected] N. Takayama E. Nakayama Department of Pediatrics, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan K. Mannen Research Promotion Project, Oita University, Yufu, Japan
123
Introduction Rabies virus causes serious human mortality in many developing countries. The World Health Organization (WHO) estimates that between 30,000 and 70,000 people die worldwide of rabies each year [1]. With one clear exception [2], no patient has survived rabies virus exposure without subsequent vaccination [3], and postexposure prophylaxis is a primary component of rabies management. Preexposure immunization (PEI) greatly enhances the efficacy of postexposure prophylaxis. WHO recommends rabies immunoglobulin (RIG) administration after a severe exposure [4]; however, PEI completion would preclude the use of RIG in this situation. Considering the limited availability and difficult access to RIG worldwide, PEI should be offered to subjects at high risk of rabies virus exposure. For PEI, WHO recommends administering rabies vaccine on days 0, 7, and 21 or 28 [4]. When vaccine supplies are diminished, intradermal administration is an alternative option because this delivery method uses only 0.1 ml vaccine. Previous reports by Shiota et al. [5, 6] have shown that intradermal vaccination using Japanese purified chick embryo rabies vaccine (PCEC-K), following the WHO recommended schedule, induces protective titers safely and effectively. However, Shiota et al. administered the PCECK 0.1-ml dose at two sites, totaling 0.2 ml. If protective rabies-neutralizing antibody (NA) titers were inducible following a 0.1-ml dose vaccine, more vaccine would be available to immunize additional individuals. Moreover, a lower dose vaccine would reduce the physical stress experienced by vaccinees. Therefore, we studied the immunogenicity and safety of an intradermally administered 0.1-ml dose of PCEC-K, as recommended by WHO.
J Infect Chemother (2012) 18:66–68
67
Materials and methods
Table 1 Neutralizing antibody (NA) titers after vaccination on days 7, 28, and 42
Study population
Day
A total of 39 subjects (28 men, 11 women; mean age, 22.7 ± 1.9 years), who had self-reported an intent to receive the intradermal regimen of PCEC-K, were recruited in 2009 and 2010. Subjects were interviewed and examined by a physician and confirmed to have no previous animal bites, no previous rabies vaccines, no acute or chronic infectious diseases, and no concomitant use of corticosteroid therapy or antimalarial or immunosuppressive drugs. The study was conducted at Tokyo Metropolitan Komagome Hospital in Tokyo, Japan. The study was performed in accordance with the Declaration of Helsinki and was approved by the institutional review board (certificate number: 718). Informed consent was obtained from all participants.
GMT (IU/ml) Range n = C0.5 IU/ml Seroconversion (%)
7
28
42
–
1.2
2.7
All \0.5
\0.5–4.6
0.5–13.7
0/39
37/39
39/39
0
94.9
100
Seroconverted subject antibody titers were C0.5 IU/ml NA neutralizing antibody, GMT geometric mean titer range, lowest– highest value
frequency, duration, and intensity of adverse events after vaccination.
Results Immunogenicity
Vaccine In this study, we used PCEC-K manufactured by the Chemo-Sero-Therapeutic Research Institute (Kumamoto, Japan), the only human rabies vaccine available in Japan. Patients were vaccinated with PCEC-K lot numbers RB06, RB08, and RB11, which were inspected by the National Institute of Infectious Diseases, Japan. Subjects were vaccinated with a 0.1-ml dose intradermally at the antebrachial region on days 0, 7, and 28, according to the schedule recommended by WHO. Laboratory assays Postvaccination blood samples were collected from all subjects on days 7, 28, and 42. Rabies antibody (Ab) titers were determined by NA assay. All NA titers were analyzed at Oita University by using the fluorescent antibody virus neutralization test (FAVN), following the international standard procedure [7]. NA titers C0.5 IU/ml were considered positive. Safety assessments For safety assessments, every vaccinee was followed for 15 min after vaccination for immediate local reactions. In addition, subjects were requested to report any adverse effects after the vaccine injection on their next visit. Endpoints The immunogenicity endpoints were the proportion of the subjects with NA titers C0.5 IU/ml, which is considered the level of protection. Safety endpoints were the
Table 1 summarizes the NA titers measured on days 7, 28, and 42. NA titers were undetectable in all subjects on day 7; however, on day 28, 94.9% (37/39) seroconverted, with geometric mean titer (GMT) of 1.2 IU/ml (range, \0.5–4.6 IU/ml) among the seroconverted subjects. On day 42, 2 weeks after the third dose, all subjects had seroconverted, with GMT of 2.7 IU/ml (range, 0.5–13.7 IU/ml). Safety Overall, the vaccine was well tolerated by all subjects. After the first, second, and third doses, redness was observed in 9, 8, and 27 subjects, and pruritus was observed in 0, 3, and 2 subjects, respectively. No immediate anaphylactic adverse effect or systemic adverse effects were observed.
Discussion We evaluated the immunogenicity and safety of PCEC-K intradermal vaccination, according to WHO recommendation for PEI. We found subjects receiving 0.1 ml PCEC-K had protective NA titers after completion of three doses and that the vaccine was well tolerated. Previous reports by Shiota et al. [5] have demonstrated the efficacy of PCEC-K administered intradermally following the recommendation by WHO. In their initial report, 20 subjects were vaccinated with 0.1 ml PCEC-K at two sites (total, 0.2 ml), and all developed protective NA titers by day 42 (GMT, 4.46 IU/ml). Shiota et al. reported similar observations when the sample size increased to 50 subjects (GMT, 3.21 IU/ml) [6]. Our results are
123
68
comparable to both reports (GMT, 2.7 IU/ml), suggesting that a reduced dose of 0.1 ml is sufficient to induce protective NA levels. In contrast, a 1.0-ml dose of PCEC-K produces higher GMT titers (GMT, 5.7 IU/ml) when administered subcutaneously following the WHO regimen [8]; however, direct comparison to the 0.1-ml dose studies is difficult because of age, gender proportion, and sample size differences. A major outcome of our study is the small amount of PCEC-K required to develop protective titers. The protocol provided by the manufacturer indicates that a single dose of PCEC-K is 1.0 ml when administered subcutaneously. According to our data, ten subjects could be vaccinated intradermally with the dose required for subcutaneous administration. A lower dose of PCEC-K vaccine is an important strategy for times when vaccine supply is limited. In 2006, two cases of imported rabies were reported in Japan [9], resulting in rabies vaccine shortages for everyone, including veterinarians, rabies researchers, and laboratory personnel who are highly recommended for vaccination [10]. Because PCEC-K is the only rabies vaccine available for human use in Japan, our results suggest that more subjects who require PEI can be vaccinated when vaccine supplies are limited. Fortunately, Japan is one of the few rabies-free countries, where the last reported domestic rabies case occurred in 1957 [9]. Considering the regularity of international travel, importation of rabies from highly endemic areas is a concern for which Japan must be prepared. The major limitation of our study is that Ab titers were not addressed beyond day 42. In addition, we did not analyze the effect of a 0.1-ml dose vaccine on booster immunization. Previous studies utilizing the PCEC-K intradermal regimen reported that, 6 months after immunization, approximately half the subjects had reduced NA titers below 0.5 IU/ml and responded well to booster vaccination [5]. Khawplod et al. [11] have also shown that an intradermal booster dose achieved significant NA titers. It is strongly suggested by our data that a 0.1-ml booster inoculation of PCEC-K will produce protective titers, making the intradermal protocol a putative candidate for booster vaccination. However, further evaluation is needed
123
J Infect Chemother (2012) 18:66–68
to confirm this speculation. In addition, future studies should increase the sample size to validate the PCEC-K 0.1-ml dose intradermal regimen. In conclusion, the intradermal regimen using a 0.1-ml dose of PCEC-K is immunogenic and safe. Susceptible subjects can be immunized using the WHO intradermal protocol in situations of vaccine shortage. Acknowledgments This work was supported in part by grants from the Japanese Ministry of Health, Labour, and Welfare. Conflicts of interest
None declared.
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 WHO. 2005;83:360–8. 2. Willoughby RE Jr, Tieves KS, Hoffman GM, Ghanayem NS, Amlie-Lefond CM, Schwabe MJ, et al. Survival after treatment of rabies with induction of coma. N Engl J Med. 2005;352:2508–14. 3. Jackson AC, Warrell MJ, Rupprecht CE, Ertl HC, Dietzschold B, O’Reilly M, et al. Management of rabies in humans. Clin Infect Dis. 2003;36:60–3. 4. WHO (2005) WHO Expert Consultation on Rabies: first report. WHO technical report series 931. WHO, Geneva, Switzerland 5. Shiota S, Khawplod P, Ahmed K, Mifune K, Nishizono A. A pilot study on intradermal vaccination of Japanese rabies vaccine for pre-exposure immunization. Vaccine. 2008;26:6441–4. 6. Shiota S, Ahmed K, Mifune K, Nishizono A (2010) Efficacy of intradermal regimen using Japanese rabies vaccine for pre-exposure prophylaxis. Kansenshogaku Zasshi 84:9–13 (in Japanese) 7. Office International des Epizooties. Rabies, OIE manual of standards for diagnostic tests and vaccines. 3rd ed. Paris: OIE; 1996. p. 207–217. 8. Yanagisawa N, Takayama N, Nakayama E, Mannen K, Suganuma A. Pre-exposure immunization against rabies using Japanese rabies vaccine following the WHO recommended schedule. J Infect Chemother. 2010;16:38–41. 9. Takayama N. Rabies: a preventable but incurable disease. J Infect Chemother. 2008;14:8–14. 10. Tamashiro H, Matibag GC, Ditangco RA, Kanda K, Ohbayashi Y. Revisiting rabies in Japan: is there cause for alarm? Travel Med Infect Dis. 2007;5:263–75. 11. Khawplod P, Wilde H, Benjavongkulchai M, Sriaroon C, Chomchey P, et al. Immunogenicity study of abbreviated rabies preexposure vaccination schedules. J Travel Med. 2007;14:173–6.
ORIGINAL ARTICLE
Immunogenicity of intradermal vaccination of Japanese rabies vaccine for preexposure immunization following WHO recommendation Naoki Yanagisawa • Naohide Takayama Kazuaki Mannen • Eiichi Nakayama • Akihiko Suganuma
•
Received: 28 April 2011 / Accepted: 12 July 2011 / Published online: 2 August 2011 Ó Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases 2011
Abstract In the present study, we evaluated the immunogenicity of intradermal vaccination of Japanese purified chick embryo cell rabies vaccine (PCEC-K) for preexposure immunization (PEI). A total of 39 healthy subjects were administered a single 0.1-ml dose of PCEC-K intradermally at the antebrachial region on days 0, 7, and 28. To assess immunogenicity, rabies neutralizing antibody (NA) titers were measured on days 7, 28, and 42 post vaccination. By day 42, all subjects developed NA titers C0.5 IU/ ml (geometric mean titer, 2.7 IU/ml), a level that is considered protective. The vaccine was well tolerated; vaccinated subjects displayed minimal redness and pruritus. Although a 1.0-ml dose of PCEC-K administered subcutaneously is considered the standard method, the intradermal regimen using a 0.1-ml dose of PCEC-K is immunogenic, safe, and highly recommended for situations of vaccine shortage. Keywords Japanese rabies vaccine Intradermal vaccination Immunogenicity Preexposure immunization
N. Yanagisawa (&) A. Suganuma Department of Infectious Diseases, Tokyo Metropolitan Komagome Hospital, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8677, Japan e-mail: [email protected] N. Takayama E. Nakayama Department of Pediatrics, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan K. Mannen Research Promotion Project, Oita University, Yufu, Japan
123
Introduction Rabies virus causes serious human mortality in many developing countries. The World Health Organization (WHO) estimates that between 30,000 and 70,000 people die worldwide of rabies each year [1]. With one clear exception [2], no patient has survived rabies virus exposure without subsequent vaccination [3], and postexposure prophylaxis is a primary component of rabies management. Preexposure immunization (PEI) greatly enhances the efficacy of postexposure prophylaxis. WHO recommends rabies immunoglobulin (RIG) administration after a severe exposure [4]; however, PEI completion would preclude the use of RIG in this situation. Considering the limited availability and difficult access to RIG worldwide, PEI should be offered to subjects at high risk of rabies virus exposure. For PEI, WHO recommends administering rabies vaccine on days 0, 7, and 21 or 28 [4]. When vaccine supplies are diminished, intradermal administration is an alternative option because this delivery method uses only 0.1 ml vaccine. Previous reports by Shiota et al. [5, 6] have shown that intradermal vaccination using Japanese purified chick embryo rabies vaccine (PCEC-K), following the WHO recommended schedule, induces protective titers safely and effectively. However, Shiota et al. administered the PCECK 0.1-ml dose at two sites, totaling 0.2 ml. If protective rabies-neutralizing antibody (NA) titers were inducible following a 0.1-ml dose vaccine, more vaccine would be available to immunize additional individuals. Moreover, a lower dose vaccine would reduce the physical stress experienced by vaccinees. Therefore, we studied the immunogenicity and safety of an intradermally administered 0.1-ml dose of PCEC-K, as recommended by WHO.
J Infect Chemother (2012) 18:66–68
67
Materials and methods
Table 1 Neutralizing antibody (NA) titers after vaccination on days 7, 28, and 42
Study population
Day
A total of 39 subjects (28 men, 11 women; mean age, 22.7 ± 1.9 years), who had self-reported an intent to receive the intradermal regimen of PCEC-K, were recruited in 2009 and 2010. Subjects were interviewed and examined by a physician and confirmed to have no previous animal bites, no previous rabies vaccines, no acute or chronic infectious diseases, and no concomitant use of corticosteroid therapy or antimalarial or immunosuppressive drugs. The study was conducted at Tokyo Metropolitan Komagome Hospital in Tokyo, Japan. The study was performed in accordance with the Declaration of Helsinki and was approved by the institutional review board (certificate number: 718). Informed consent was obtained from all participants.
GMT (IU/ml) Range n = C0.5 IU/ml Seroconversion (%)
7
28
42
–
1.2
2.7
All \0.5
\0.5–4.6
0.5–13.7
0/39
37/39
39/39
0
94.9
100
Seroconverted subject antibody titers were C0.5 IU/ml NA neutralizing antibody, GMT geometric mean titer range, lowest– highest value
frequency, duration, and intensity of adverse events after vaccination.
Results Immunogenicity
Vaccine In this study, we used PCEC-K manufactured by the Chemo-Sero-Therapeutic Research Institute (Kumamoto, Japan), the only human rabies vaccine available in Japan. Patients were vaccinated with PCEC-K lot numbers RB06, RB08, and RB11, which were inspected by the National Institute of Infectious Diseases, Japan. Subjects were vaccinated with a 0.1-ml dose intradermally at the antebrachial region on days 0, 7, and 28, according to the schedule recommended by WHO. Laboratory assays Postvaccination blood samples were collected from all subjects on days 7, 28, and 42. Rabies antibody (Ab) titers were determined by NA assay. All NA titers were analyzed at Oita University by using the fluorescent antibody virus neutralization test (FAVN), following the international standard procedure [7]. NA titers C0.5 IU/ml were considered positive. Safety assessments For safety assessments, every vaccinee was followed for 15 min after vaccination for immediate local reactions. In addition, subjects were requested to report any adverse effects after the vaccine injection on their next visit. Endpoints The immunogenicity endpoints were the proportion of the subjects with NA titers C0.5 IU/ml, which is considered the level of protection. Safety endpoints were the
Table 1 summarizes the NA titers measured on days 7, 28, and 42. NA titers were undetectable in all subjects on day 7; however, on day 28, 94.9% (37/39) seroconverted, with geometric mean titer (GMT) of 1.2 IU/ml (range, \0.5–4.6 IU/ml) among the seroconverted subjects. On day 42, 2 weeks after the third dose, all subjects had seroconverted, with GMT of 2.7 IU/ml (range, 0.5–13.7 IU/ml). Safety Overall, the vaccine was well tolerated by all subjects. After the first, second, and third doses, redness was observed in 9, 8, and 27 subjects, and pruritus was observed in 0, 3, and 2 subjects, respectively. No immediate anaphylactic adverse effect or systemic adverse effects were observed.
Discussion We evaluated the immunogenicity and safety of PCEC-K intradermal vaccination, according to WHO recommendation for PEI. We found subjects receiving 0.1 ml PCEC-K had protective NA titers after completion of three doses and that the vaccine was well tolerated. Previous reports by Shiota et al. [5] have demonstrated the efficacy of PCEC-K administered intradermally following the recommendation by WHO. In their initial report, 20 subjects were vaccinated with 0.1 ml PCEC-K at two sites (total, 0.2 ml), and all developed protective NA titers by day 42 (GMT, 4.46 IU/ml). Shiota et al. reported similar observations when the sample size increased to 50 subjects (GMT, 3.21 IU/ml) [6]. Our results are
123
68
comparable to both reports (GMT, 2.7 IU/ml), suggesting that a reduced dose of 0.1 ml is sufficient to induce protective NA levels. In contrast, a 1.0-ml dose of PCEC-K produces higher GMT titers (GMT, 5.7 IU/ml) when administered subcutaneously following the WHO regimen [8]; however, direct comparison to the 0.1-ml dose studies is difficult because of age, gender proportion, and sample size differences. A major outcome of our study is the small amount of PCEC-K required to develop protective titers. The protocol provided by the manufacturer indicates that a single dose of PCEC-K is 1.0 ml when administered subcutaneously. According to our data, ten subjects could be vaccinated intradermally with the dose required for subcutaneous administration. A lower dose of PCEC-K vaccine is an important strategy for times when vaccine supply is limited. In 2006, two cases of imported rabies were reported in Japan [9], resulting in rabies vaccine shortages for everyone, including veterinarians, rabies researchers, and laboratory personnel who are highly recommended for vaccination [10]. Because PCEC-K is the only rabies vaccine available for human use in Japan, our results suggest that more subjects who require PEI can be vaccinated when vaccine supplies are limited. Fortunately, Japan is one of the few rabies-free countries, where the last reported domestic rabies case occurred in 1957 [9]. Considering the regularity of international travel, importation of rabies from highly endemic areas is a concern for which Japan must be prepared. The major limitation of our study is that Ab titers were not addressed beyond day 42. In addition, we did not analyze the effect of a 0.1-ml dose vaccine on booster immunization. Previous studies utilizing the PCEC-K intradermal regimen reported that, 6 months after immunization, approximately half the subjects had reduced NA titers below 0.5 IU/ml and responded well to booster vaccination [5]. Khawplod et al. [11] have also shown that an intradermal booster dose achieved significant NA titers. It is strongly suggested by our data that a 0.1-ml booster inoculation of PCEC-K will produce protective titers, making the intradermal protocol a putative candidate for booster vaccination. However, further evaluation is needed
123
J Infect Chemother (2012) 18:66–68
to confirm this speculation. In addition, future studies should increase the sample size to validate the PCEC-K 0.1-ml dose intradermal regimen. In conclusion, the intradermal regimen using a 0.1-ml dose of PCEC-K is immunogenic and safe. Susceptible subjects can be immunized using the WHO intradermal protocol in situations of vaccine shortage. Acknowledgments This work was supported in part by grants from the Japanese Ministry of Health, Labour, and Welfare. Conflicts of interest
None declared.
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 WHO. 2005;83:360–8. 2. Willoughby RE Jr, Tieves KS, Hoffman GM, Ghanayem NS, Amlie-Lefond CM, Schwabe MJ, et al. Survival after treatment of rabies with induction of coma. N Engl J Med. 2005;352:2508–14. 3. Jackson AC, Warrell MJ, Rupprecht CE, Ertl HC, Dietzschold B, O’Reilly M, et al. Management of rabies in humans. Clin Infect Dis. 2003;36:60–3. 4. WHO (2005) WHO Expert Consultation on Rabies: first report. WHO technical report series 931. WHO, Geneva, Switzerland 5. Shiota S, Khawplod P, Ahmed K, Mifune K, Nishizono A. A pilot study on intradermal vaccination of Japanese rabies vaccine for pre-exposure immunization. Vaccine. 2008;26:6441–4. 6. Shiota S, Ahmed K, Mifune K, Nishizono A (2010) Efficacy of intradermal regimen using Japanese rabies vaccine for pre-exposure prophylaxis. Kansenshogaku Zasshi 84:9–13 (in Japanese) 7. Office International des Epizooties. Rabies, OIE manual of standards for diagnostic tests and vaccines. 3rd ed. Paris: OIE; 1996. p. 207–217. 8. Yanagisawa N, Takayama N, Nakayama E, Mannen K, Suganuma A. Pre-exposure immunization against rabies using Japanese rabies vaccine following the WHO recommended schedule. J Infect Chemother. 2010;16:38–41. 9. Takayama N. Rabies: a preventable but incurable disease. J Infect Chemother. 2008;14:8–14. 10. Tamashiro H, Matibag GC, Ditangco RA, Kanda K, Ohbayashi Y. Revisiting rabies in Japan: is there cause for alarm? Travel Med Infect Dis. 2007;5:263–75. 11. Khawplod P, Wilde H, Benjavongkulchai M, Sriaroon C, Chomchey P, et al. Immunogenicity study of abbreviated rabies preexposure vaccination schedules. J Travel Med. 2007;14:173–6.