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One clinic visit for pre-exposure rabies vaccination (a preliminary one year study)
Vaccine 30 (2012) 2918–2920
Contents lists available at SciVerse ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Short communication
One clinic visit for pre-exposure rabies vaccination (a preliminary one year study) Pakamatz Khawplod a,∗ , Wipaporn Jaijaroensup a , Artikaya Sawangvaree a , Sompop Prakongsri a , Henry Wilde b a
Queen Saovabha Memorial Institute, the Thai Red Cross Society, Bangkok 10330, Thailand WHO Collaborating Centre for Research and Training on Viral Zoonoses, Department of Medicine (Neurology) and Molecular Biology Centre for Neurological Diseases, Chulalongkorn University Hospital, Bangkok, Thailand b
a r t i c l e
i n f o
Article history: Received 22 March 2011 Received in revised form 1 December 2011 Accepted 5 December 2011 Available online 15 December 2011 Keywords: Rabies pre-exposure vaccination Single dose 4-Sites ID booster Tissue culture rabies vaccine
a b s t r a c t We performed an abbreviated prospective study of rabies pre-exposure (PREP) vaccination in 109 volunteers. Group 1, the control group, received the conventional 3 intradermal injections on days 0, 7 and 21. Group 2 received one rabies vaccine injection (0.1 ml intradermally) at 2 sites on a single day. Group 3 was given one full ampule intramuscularly. One year later, all 3 groups received booster injections (0.1 ml at 4 sites) intradermally at one time or 2 injections intramuscularly on days 0 and 3. All subjects achieved a vigorous anamnestic antibody response 7 days after the boosters. These data suggest that one time immunization of one full dose intramuscularly or 2 site injections of 0.1 intradermally on a single day are adequate to prime immune memory and obtain an accelerated immune response one year later. © 2011 Elsevier Ltd. All rights reserved.
1. Introduction Purified potent tissue and chick embryo rabies vaccines have been in use for more than 3 decades. The original six doses intramuscular post-exposure prophylaxis regimens (PEP) are expensive, complicated and some required injections for as long as 3 months. With decades of experience, it has become evident that PEP schedules can be shortened; saving time, compliance and costs of vaccines and travel expenses. The original “Essen” PEP regimen has now been shortened from 6 injections to five and then to 4 administered within 2 weeks [1,2]. The so-called “Zagreb” or “2-1-1” intramuscular PEP schedule takes only 3 weeks to complete [2]. The Thai Red Cross intradermal schedule went from 5 clinic visits over 3 months to 4 visits over one month [2–4]. Current studies, still in progress, are likely to reduce it to one week [5]. The “Oxford” or “Eight Site” intradermal post-exposure schedule required 3 months for completion and was rarely used [2]. Pre-exposure (PREP) vaccination for potentially exposed subjects requires 3 injections over 3–4 weeks [2,6]. It might be possible to reduce it to even less vaccine and fewer injections [7,8]. The 4-site intradermal one clinic visit booster schedule has been found to result in an accelerated antibody response equal to or
∗ Corresponding author at: Queen Saovabha Memorial Institute, The Thai Red Cross Society, 1871 Rama 4 Rd., Bangkok 10330, Thailand. Tel.: +66 22520161; fax: +66 22540212. E-mail address: [email protected] (P. Khawplod). 0264-410X/$ – see front matter © 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2011.12.028
higher than with the conventional two intramuscular injections on days 0 and 3 [9,10]. This regimen is now regularly applied in 5116 subjects and none of them had any significant adverse reactions or reported of rabies death [11]. We conducted a preliminary study on volunteers to determine whether it might be possible to shorten PREP so it can be completed in one clinic visit. 2. Materials and methods Vaccine: We used commercial batches of Purified Chick Embryo Cell Rabies vaccine, RABIPUR® Chiron, lot 1032 with a potency of 10.23 IU/ml for pre-exposure vaccination and lot 1245 with a potency of 9.48 IU/ml for boosters. Volunteers: We recruited 109 Bangkok Rabies Control Unit staffs and veterinary students from Kasetsart and Mahanakorn University (ages 18–45 years). This study was performed under GCP guideline and was approved by the ethics committees of the Queen Saovabha Memorial Institute. Vaccination: See Table 1. Blood collection: See Table 1. Serum was separate and stored at −30 ◦ C until used for determination of rabies neutralizing antibody (NAb) using the RFFIT [12]. Statistic analysis: Student’s t-test. 3. Results None of the volunteers selected had detectable NAb before being enrolled. All volunteers in all 3 groups had detectable antibody
P. Khawplod et al. / Vaccine 30 (2012) 2918–2920
2919
Table 1 Vaccine injection and blood collection schedules. Group
n 36
1 Blood collection 2
ID 0.1 ml day 0, 7, 21 Days 0, 35
40
ID 0.1 ml (2 sites) day 0 only
33
IM day 0
Blood collection 3
Pre-exposure
Days 0, 14
Blood collection
Days 0, 14
Booster (1 year later)
n
Age
M/F
1A. IM on day 0, 3 1B. ID 0.1 ml at 4 sites on day 0 Days 0 (day 360), 7, 14
17 19
18–20 18–45
2/15 3/16
2A. IM on day 0, 3 2B. ID 0.1 ml at 4 sites on day 0
16 24
18–20 18–20
7/9 8/16
Days 0 (day 360), 7, 14 3A. IM day 0, 3 3B. ID 0.1 ml at 4 sites on day 0 Days 0 (day 360), 7, 14
17 16
18–29 18–26
7/10 7/9
Table 2 Rabies neutralizing antibody responses. r
1
2
3
* ** ***
n
Pre-exposure schedule
Booster schedule (one year later)
n
17
36 ID 0.1 ml day 0, 7, 21
1A. IM day 0, 3 Range No. subj. >0.5 IU/ml/total (%) 1B. ID 0.1 ml (4 sites) day 0 Range No. subj. >0.5 IU/ml/total (%)
19
0/17 (0%) Neg
16
Neg
40 ID 0.1 ml 2 sites day 0 only
2A. IM day 0, 3 Range No. subj. >0.5 IU/ml/total (%) 2B. ID 0.1 ml (4 sites) day 0 Range No. subj. >0.5 IU/ml/total (%)
24
0/16 (0%) Neg
3A. IM day 0, 3 Range No. subj. >0.5 IU/ml/total (%) 3B. ID 0.1 ml (4 sites) day 0 Range No. subj. >0.5 IU/ml/total (%)
17
Neg
16
0/17 (0%) Neg
33 IM day 0 only
NAb after pre-exposure
NAb after booster 1 year later day 0 (360), 7 and 14
Day 0
Day 35
Day 0 (before booster)
Day 7
Day 14
Neg
4.22* 1.25–31.05 17/17 (100%) 4.37 1.36–11.89 19/19 (100%)
0.49 0.13–2.13 5/17 (29%) 0.30 0.06–2.71 5/19 (26%)
11.27** 4.1–40.4 17/17 (100%) 42.49** 21.0–184.6 19/19 (100%)
54.53 13.6–417.7 17/17 (100%) 114.28*** 32.4–336.4 19/19 (100%)
1.07 0.40–5.69 13/16 (71%) 0.94 0.20–4.99 17/23 (74%)
0.15 <0.03–0.92 1/16 (5%) 0.10 <0.03–1.07 3/24 (13%)
9.71 1.84–130.5 16/16 (100%) 11.96** 1.01–77.6 24/24 (100%)
46.23 5.96–324.2 16/16 (100%) 54.36 10.1–402.6 24/24 (100%)
1.58 0.52–7.11 17/17 (100%) 1.50 0.40–7.71 15/16 (94%)
0.08 <0.03–2.18 1/17 (6%) 0.11 0.03–1.69 2/16 (13%)
10.13 5.0–62.5 17/17 (100%) 13.33 1.8–130.5 16/16 (100%)
18.96 5.5–124.2 17/17 (100%) 46.92*** 11.5–237.8 16/16 (100%)
0/19 (0%)
0/24 (0%)
0/16 (0%)
IU/ml. Significantly higher than group 1A and 2B (p < 0.01). Significantly higher than group 3B (p < 0.05).
Table 3 Rabies neutralizing antibody response in volunteers who had antibody response of less than 0.5 IU/ml at day 14. Pre-exposure schedule
Booster (1 year later)
Day 14a
Day 360b
Day 367c
Day 374d
IM day 0 only
IM day 0, 3
1.68 0.52 0.96 0.85
Neg Neg Neg 0.03
10.0 8.78 14.14 1.81
11.97 38.55 124.18 11.46
2.73 0.37 1.77 0.2
0.03 0.04 0.03 Neg
10.44 2.39 2.97 5.45
22.93 70.71 17.68 28.47
0.38 0.44 0.36 0.37 0.57 1.36 0.4
0.15 0.24 0.07 0.15 Neg 0.04 0.18
12.97 5.95 15.42 8.78 1.84 6.48 7.07
26.11 62.5 13.05 38.56 5.96 13.63 27.26
0.31 0.20 0.42 0.44 0.37
Neg Neg Neg Neg 0.05
40.53 1.01 14.8 8.41 5.00
209.5 15.52 38.56 32.42 13.36
ID 0.1 ml × 4 sites day 0 only
ID 0.1 ml (2 sites) day 0 only
IM day 0, 3
ID 0.1 ml × 4 sites day 0 only
Neg, negative or undetectable (NAb <0.03 IU/ml). a 14 days after received single dose of rabies vaccination. b One year later (day 360) after received rabies pre-exposure vaccination and before booster. c 7 days after received first booster dose. d 14 days after received first booster dose.
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P. Khawplod et al. / Vaccine 30 (2012) 2918–2920
titers 2 weeks after receiving either one or the conventional three injections (Table 2). At one year, the GMT NAb of group 1 was significantly higher than in groups 2 and 3. Nine volunteers (9/109, 8%) were found to have antibodies below the detectable test threshold (<0.03 IU/ml) on day 360 before receiving boosters. However, all responded with an accelerated immune response when tested 7 and 14 days after receiving boosters (see Tables 2 and 3) The control group (1B), which received 4 site ID boosters administered on one day, had a GMT of NAb on day 7 which was significantly higher (p < 0.01) than in the group which received 2 IM booster injections (1A). Among the one injection groups (Gr 2 and 3) there was no statistically significant difference in subjects who received 2 booster IM (2A, 3A) or one 4 sites ID series at one sitting (2B, 3B). 4. Discussions The WHO approved intramuscular or intradermal three dose PREP schedule, administered over 3–4 weeks, remains the “gold standard” for reliable long term protection [2,6]. It confers immune memory for many years and results in an accelerated immune response after booster vaccination in previous history of rabies tissue culture or nerve tissue derived vaccine [13,14]. However, an abbreviated PREP of three intradermal injections within one week is as immunogenic as the WHO approved conventional schedule administered over 3–4 weeks [7]. There is no relationship of age, interval of time since PERP and booster or the remaining antibody on level of anti-rabies antibody response after booster vaccination [13–17]. The important of booster vaccination schedule has been demonstrated in PERP vaccination particularly 4 sites ID one clinic visit booster schedule [7–10]. It may be possible to shorten PREP, with our experimental one injection IM regimen, from 3 to 4 weeks to one clinic visit; particularly when there is insufficient time to complete a full multi-visit schedule. The two abbreviated schedules studied here show promise for special situations, but will require further study and possible improvements. Our data, and those from prior work, also suggest that one clinic visit PREP immunization, using one-site or two-site intradermal 0.1 ml injections, or one full dose intramuscular one [7,8], is enough to prime the immune memory and reveal in similar immune protection. Acknowledgements Queen Saovabha Memorial Institute, the Thai Red Cross Society funded and supported this study. The authors are grateful to Prof. Visith Sitprija for the valuable support and Ms. Ratana Suttisri for
laboratory assistance for this study. The authors have no conflicts of interest to declare. References [1] Use of a Reduced (4-Dose) Vaccine Schedule for Postexposure Prophylaxis to Prevent Human Rabies. Recommendations of the Advisory Committee on Immunization Practices. MMWR. March 19; 2010. Vol. 59/No. RR-2. [2] WHO Expert Committee on Rabies. First report. Geneva, World Health Organization; 2004 (WHO Technical Report Series, No. 931). [3] Khawplod P, Wilde H, Tepsumethanon S, Limusanno S, Tantawichien T, Chomchey P, et al. Prospective immunogenicity study of multiple intradermal injections of rabies vaccine in an effort to obtain an early immune response without the use of immunoglobulin. Clin Infect Dis 2002;35(12):1562–5. [4] 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 Apr 12;24(16):3084–6. [5] 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(January (1)):56–60. [6] WHO. Rabies vaccines, WHO position paper. Weekly Epidemiological Record; 2010; 32: 309–20. [7] Khawplod P, Wilde H, Benjavongkulchai M, Sriaroon C, Chomchey P. Immunogenicity study of abbreviated rabies preexposure vaccination schedules. J Travel Med 2007;14(May–June (3)):173–6. [8] Khawplod P, Wilde H, Sriaroon C, Chomchey P, Kamolthum T, Sitprija V. One or three intradermal injections within one week for rabies pre-exposure immunization. Dev Biol (Basel) 2008;131:393–401. [9] Tantawichien T, Benjavongkulchai M, Limsuwan K, Khawplod P, Kaewchompoo W, Chomchey P, Sitprija V. Antibody response after a four-site intradermal booster vaccination with cell-culture rabies vaccine. Clin Infect Dis 1999;28(5):1100–3. [10] Khawplod P, Benjavongkulchai M, Limusanno S, Chareonwai S, Kaewchompoo W, Tantawichien T, et al. Four-site intradermal postexposure boosters in previously rabies vaccinated subjects. Travel Med 2002;9(3):153–5. [11] 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;151(November (9)):1070–2. [12] Smith JS, Yager PA, Baer GM. A Rapid Fluorescent focus inhibition test (RFFIT) for determining rabies virus neutralizing antibody. In: Meslin FX, Kaplan MM, Koprowski H, editors. WHO. Laboratory techniques in rabies. Geneva: WHO; 1996. p. 181–93. [13] 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(November (16)):1549–52. [14] Suwuansrinon K, Wilde H, Benjavongkulchai M, Banjongkasaena U, Lertjarutorn S, Boonchang S, et al. Survival of neutralizing antibody in previously rabies vaccinated subjects: a prospective study showing long lasting immunity. Vaccine 2006;24(18):3878–80. [15] Vien NC, Feroldi E, Lang J. Long-term anti-rabies antibody persistence following intramuscular or low dose intradermalr vaccination of young Vietnamese children. Trans R Soc Trop Med Hyg 2008;10(3):294–6. [16] Strady C, Andreoletti L, Baumard S, Servettaz A, Jaussaud R, Strady A. Immunogenicity and booster efficacy of pre-exposure rabies vaccination. Trans R Soc Trop Med Hyg 2009;103(11):1159–64. [17] Brown D, Featherstone JJ, Fooks RA, Gettner S, Lloyd E, Schweiger M. Intradermal pre-exposure rabies vaccine elicits long lasting immunity. Vaccine 2008;26(31):3909–12.
Contents lists available at SciVerse ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Short communication
One clinic visit for pre-exposure rabies vaccination (a preliminary one year study) Pakamatz Khawplod a,∗ , Wipaporn Jaijaroensup a , Artikaya Sawangvaree a , Sompop Prakongsri a , Henry Wilde b a
Queen Saovabha Memorial Institute, the Thai Red Cross Society, Bangkok 10330, Thailand WHO Collaborating Centre for Research and Training on Viral Zoonoses, Department of Medicine (Neurology) and Molecular Biology Centre for Neurological Diseases, Chulalongkorn University Hospital, Bangkok, Thailand b
a r t i c l e
i n f o
Article history: Received 22 March 2011 Received in revised form 1 December 2011 Accepted 5 December 2011 Available online 15 December 2011 Keywords: Rabies pre-exposure vaccination Single dose 4-Sites ID booster Tissue culture rabies vaccine
a b s t r a c t We performed an abbreviated prospective study of rabies pre-exposure (PREP) vaccination in 109 volunteers. Group 1, the control group, received the conventional 3 intradermal injections on days 0, 7 and 21. Group 2 received one rabies vaccine injection (0.1 ml intradermally) at 2 sites on a single day. Group 3 was given one full ampule intramuscularly. One year later, all 3 groups received booster injections (0.1 ml at 4 sites) intradermally at one time or 2 injections intramuscularly on days 0 and 3. All subjects achieved a vigorous anamnestic antibody response 7 days after the boosters. These data suggest that one time immunization of one full dose intramuscularly or 2 site injections of 0.1 intradermally on a single day are adequate to prime immune memory and obtain an accelerated immune response one year later. © 2011 Elsevier Ltd. All rights reserved.
1. Introduction Purified potent tissue and chick embryo rabies vaccines have been in use for more than 3 decades. The original six doses intramuscular post-exposure prophylaxis regimens (PEP) are expensive, complicated and some required injections for as long as 3 months. With decades of experience, it has become evident that PEP schedules can be shortened; saving time, compliance and costs of vaccines and travel expenses. The original “Essen” PEP regimen has now been shortened from 6 injections to five and then to 4 administered within 2 weeks [1,2]. The so-called “Zagreb” or “2-1-1” intramuscular PEP schedule takes only 3 weeks to complete [2]. The Thai Red Cross intradermal schedule went from 5 clinic visits over 3 months to 4 visits over one month [2–4]. Current studies, still in progress, are likely to reduce it to one week [5]. The “Oxford” or “Eight Site” intradermal post-exposure schedule required 3 months for completion and was rarely used [2]. Pre-exposure (PREP) vaccination for potentially exposed subjects requires 3 injections over 3–4 weeks [2,6]. It might be possible to reduce it to even less vaccine and fewer injections [7,8]. The 4-site intradermal one clinic visit booster schedule has been found to result in an accelerated antibody response equal to or
∗ Corresponding author at: Queen Saovabha Memorial Institute, The Thai Red Cross Society, 1871 Rama 4 Rd., Bangkok 10330, Thailand. Tel.: +66 22520161; fax: +66 22540212. E-mail address: [email protected] (P. Khawplod). 0264-410X/$ – see front matter © 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2011.12.028
higher than with the conventional two intramuscular injections on days 0 and 3 [9,10]. This regimen is now regularly applied in 5116 subjects and none of them had any significant adverse reactions or reported of rabies death [11]. We conducted a preliminary study on volunteers to determine whether it might be possible to shorten PREP so it can be completed in one clinic visit. 2. Materials and methods Vaccine: We used commercial batches of Purified Chick Embryo Cell Rabies vaccine, RABIPUR® Chiron, lot 1032 with a potency of 10.23 IU/ml for pre-exposure vaccination and lot 1245 with a potency of 9.48 IU/ml for boosters. Volunteers: We recruited 109 Bangkok Rabies Control Unit staffs and veterinary students from Kasetsart and Mahanakorn University (ages 18–45 years). This study was performed under GCP guideline and was approved by the ethics committees of the Queen Saovabha Memorial Institute. Vaccination: See Table 1. Blood collection: See Table 1. Serum was separate and stored at −30 ◦ C until used for determination of rabies neutralizing antibody (NAb) using the RFFIT [12]. Statistic analysis: Student’s t-test. 3. Results None of the volunteers selected had detectable NAb before being enrolled. All volunteers in all 3 groups had detectable antibody
P. Khawplod et al. / Vaccine 30 (2012) 2918–2920
2919
Table 1 Vaccine injection and blood collection schedules. Group
n 36
1 Blood collection 2
ID 0.1 ml day 0, 7, 21 Days 0, 35
40
ID 0.1 ml (2 sites) day 0 only
33
IM day 0
Blood collection 3
Pre-exposure
Days 0, 14
Blood collection
Days 0, 14
Booster (1 year later)
n
Age
M/F
1A. IM on day 0, 3 1B. ID 0.1 ml at 4 sites on day 0 Days 0 (day 360), 7, 14
17 19
18–20 18–45
2/15 3/16
2A. IM on day 0, 3 2B. ID 0.1 ml at 4 sites on day 0
16 24
18–20 18–20
7/9 8/16
Days 0 (day 360), 7, 14 3A. IM day 0, 3 3B. ID 0.1 ml at 4 sites on day 0 Days 0 (day 360), 7, 14
17 16
18–29 18–26
7/10 7/9
Table 2 Rabies neutralizing antibody responses. r
1
2
3
* ** ***
n
Pre-exposure schedule
Booster schedule (one year later)
n
17
36 ID 0.1 ml day 0, 7, 21
1A. IM day 0, 3 Range No. subj. >0.5 IU/ml/total (%) 1B. ID 0.1 ml (4 sites) day 0 Range No. subj. >0.5 IU/ml/total (%)
19
0/17 (0%) Neg
16
Neg
40 ID 0.1 ml 2 sites day 0 only
2A. IM day 0, 3 Range No. subj. >0.5 IU/ml/total (%) 2B. ID 0.1 ml (4 sites) day 0 Range No. subj. >0.5 IU/ml/total (%)
24
0/16 (0%) Neg
3A. IM day 0, 3 Range No. subj. >0.5 IU/ml/total (%) 3B. ID 0.1 ml (4 sites) day 0 Range No. subj. >0.5 IU/ml/total (%)
17
Neg
16
0/17 (0%) Neg
33 IM day 0 only
NAb after pre-exposure
NAb after booster 1 year later day 0 (360), 7 and 14
Day 0
Day 35
Day 0 (before booster)
Day 7
Day 14
Neg
4.22* 1.25–31.05 17/17 (100%) 4.37 1.36–11.89 19/19 (100%)
0.49 0.13–2.13 5/17 (29%) 0.30 0.06–2.71 5/19 (26%)
11.27** 4.1–40.4 17/17 (100%) 42.49** 21.0–184.6 19/19 (100%)
54.53 13.6–417.7 17/17 (100%) 114.28*** 32.4–336.4 19/19 (100%)
1.07 0.40–5.69 13/16 (71%) 0.94 0.20–4.99 17/23 (74%)
0.15 <0.03–0.92 1/16 (5%) 0.10 <0.03–1.07 3/24 (13%)
9.71 1.84–130.5 16/16 (100%) 11.96** 1.01–77.6 24/24 (100%)
46.23 5.96–324.2 16/16 (100%) 54.36 10.1–402.6 24/24 (100%)
1.58 0.52–7.11 17/17 (100%) 1.50 0.40–7.71 15/16 (94%)
0.08 <0.03–2.18 1/17 (6%) 0.11 0.03–1.69 2/16 (13%)
10.13 5.0–62.5 17/17 (100%) 13.33 1.8–130.5 16/16 (100%)
18.96 5.5–124.2 17/17 (100%) 46.92*** 11.5–237.8 16/16 (100%)
0/19 (0%)
0/24 (0%)
0/16 (0%)
IU/ml. Significantly higher than group 1A and 2B (p < 0.01). Significantly higher than group 3B (p < 0.05).
Table 3 Rabies neutralizing antibody response in volunteers who had antibody response of less than 0.5 IU/ml at day 14. Pre-exposure schedule
Booster (1 year later)
Day 14a
Day 360b
Day 367c
Day 374d
IM day 0 only
IM day 0, 3
1.68 0.52 0.96 0.85
Neg Neg Neg 0.03
10.0 8.78 14.14 1.81
11.97 38.55 124.18 11.46
2.73 0.37 1.77 0.2
0.03 0.04 0.03 Neg
10.44 2.39 2.97 5.45
22.93 70.71 17.68 28.47
0.38 0.44 0.36 0.37 0.57 1.36 0.4
0.15 0.24 0.07 0.15 Neg 0.04 0.18
12.97 5.95 15.42 8.78 1.84 6.48 7.07
26.11 62.5 13.05 38.56 5.96 13.63 27.26
0.31 0.20 0.42 0.44 0.37
Neg Neg Neg Neg 0.05
40.53 1.01 14.8 8.41 5.00
209.5 15.52 38.56 32.42 13.36
ID 0.1 ml × 4 sites day 0 only
ID 0.1 ml (2 sites) day 0 only
IM day 0, 3
ID 0.1 ml × 4 sites day 0 only
Neg, negative or undetectable (NAb <0.03 IU/ml). a 14 days after received single dose of rabies vaccination. b One year later (day 360) after received rabies pre-exposure vaccination and before booster. c 7 days after received first booster dose. d 14 days after received first booster dose.
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titers 2 weeks after receiving either one or the conventional three injections (Table 2). At one year, the GMT NAb of group 1 was significantly higher than in groups 2 and 3. Nine volunteers (9/109, 8%) were found to have antibodies below the detectable test threshold (<0.03 IU/ml) on day 360 before receiving boosters. However, all responded with an accelerated immune response when tested 7 and 14 days after receiving boosters (see Tables 2 and 3) The control group (1B), which received 4 site ID boosters administered on one day, had a GMT of NAb on day 7 which was significantly higher (p < 0.01) than in the group which received 2 IM booster injections (1A). Among the one injection groups (Gr 2 and 3) there was no statistically significant difference in subjects who received 2 booster IM (2A, 3A) or one 4 sites ID series at one sitting (2B, 3B). 4. Discussions The WHO approved intramuscular or intradermal three dose PREP schedule, administered over 3–4 weeks, remains the “gold standard” for reliable long term protection [2,6]. It confers immune memory for many years and results in an accelerated immune response after booster vaccination in previous history of rabies tissue culture or nerve tissue derived vaccine [13,14]. However, an abbreviated PREP of three intradermal injections within one week is as immunogenic as the WHO approved conventional schedule administered over 3–4 weeks [7]. There is no relationship of age, interval of time since PERP and booster or the remaining antibody on level of anti-rabies antibody response after booster vaccination [13–17]. The important of booster vaccination schedule has been demonstrated in PERP vaccination particularly 4 sites ID one clinic visit booster schedule [7–10]. It may be possible to shorten PREP, with our experimental one injection IM regimen, from 3 to 4 weeks to one clinic visit; particularly when there is insufficient time to complete a full multi-visit schedule. The two abbreviated schedules studied here show promise for special situations, but will require further study and possible improvements. Our data, and those from prior work, also suggest that one clinic visit PREP immunization, using one-site or two-site intradermal 0.1 ml injections, or one full dose intramuscular one [7,8], is enough to prime the immune memory and reveal in similar immune protection. Acknowledgements Queen Saovabha Memorial Institute, the Thai Red Cross Society funded and supported this study. The authors are grateful to Prof. Visith Sitprija for the valuable support and Ms. Ratana Suttisri for
laboratory assistance for this study. The authors have no conflicts of interest to declare. References [1] Use of a Reduced (4-Dose) Vaccine Schedule for Postexposure Prophylaxis to Prevent Human Rabies. Recommendations of the Advisory Committee on Immunization Practices. MMWR. March 19; 2010. Vol. 59/No. RR-2. [2] WHO Expert Committee on Rabies. First report. Geneva, World Health Organization; 2004 (WHO Technical Report Series, No. 931). [3] Khawplod P, Wilde H, Tepsumethanon S, Limusanno S, Tantawichien T, Chomchey P, et al. Prospective immunogenicity study of multiple intradermal injections of rabies vaccine in an effort to obtain an early immune response without the use of immunoglobulin. Clin Infect Dis 2002;35(12):1562–5. [4] 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 Apr 12;24(16):3084–6. [5] 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(January (1)):56–60. [6] WHO. Rabies vaccines, WHO position paper. Weekly Epidemiological Record; 2010; 32: 309–20. [7] Khawplod P, Wilde H, Benjavongkulchai M, Sriaroon C, Chomchey P. Immunogenicity study of abbreviated rabies preexposure vaccination schedules. J Travel Med 2007;14(May–June (3)):173–6. [8] Khawplod P, Wilde H, Sriaroon C, Chomchey P, Kamolthum T, Sitprija V. One or three intradermal injections within one week for rabies pre-exposure immunization. Dev Biol (Basel) 2008;131:393–401. [9] Tantawichien T, Benjavongkulchai M, Limsuwan K, Khawplod P, Kaewchompoo W, Chomchey P, Sitprija V. Antibody response after a four-site intradermal booster vaccination with cell-culture rabies vaccine. Clin Infect Dis 1999;28(5):1100–3. [10] Khawplod P, Benjavongkulchai M, Limusanno S, Chareonwai S, Kaewchompoo W, Tantawichien T, et al. Four-site intradermal postexposure boosters in previously rabies vaccinated subjects. Travel Med 2002;9(3):153–5. [11] 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;151(November (9)):1070–2. [12] Smith JS, Yager PA, Baer GM. A Rapid Fluorescent focus inhibition test (RFFIT) for determining rabies virus neutralizing antibody. In: Meslin FX, Kaplan MM, Koprowski H, editors. WHO. Laboratory techniques in rabies. Geneva: WHO; 1996. p. 181–93. [13] 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(November (16)):1549–52. [14] Suwuansrinon K, Wilde H, Benjavongkulchai M, Banjongkasaena U, Lertjarutorn S, Boonchang S, et al. Survival of neutralizing antibody in previously rabies vaccinated subjects: a prospective study showing long lasting immunity. Vaccine 2006;24(18):3878–80. [15] Vien NC, Feroldi E, Lang J. Long-term anti-rabies antibody persistence following intramuscular or low dose intradermalr vaccination of young Vietnamese children. Trans R Soc Trop Med Hyg 2008;10(3):294–6. [16] Strady C, Andreoletti L, Baumard S, Servettaz A, Jaussaud R, Strady A. Immunogenicity and booster efficacy of pre-exposure rabies vaccination. Trans R Soc Trop Med Hyg 2009;103(11):1159–64. [17] Brown D, Featherstone JJ, Fooks RA, Gettner S, Lloyd E, Schweiger M. Intradermal pre-exposure rabies vaccine elicits long lasting immunity. Vaccine 2008;26(31):3909–12.