Safety and Immunogenicity of Purified Vero Cell Rabies Vaccine ...

Philippine Journal of Internal Medicine

Clinical Trial

Safety and Immunogenicity of Purified Vero Cell Rabies Vaccine Versus Purified Chick Embryo Cell Rabies Vaccine Using Pre-Exposure and Post Exposure Regimen Among Healthy Volunteers in San Lazaro Hospital Edna A. Miranda, M.D.*; Talitha Lea V. Lacuesta, M.D.*; Jason T. Suquila, M.D.*; Minda A. Manalo, M.D.; Efren M. Dimaano, M.D.

Abstract

Objective: This is a prospective, randomized openlabeled clinical study to demonstrate the safety and immunogenicity of Purified Vero Cell Rabies Vaccine (PVRV) Freeze-Dried using pre-exposure and postexposure regimen utilizing Modified Thai Red Cross schedule (Modified TRC) in comparison with Purified Chick Embryo Cell (PCEC) Rabies Vaccine among healthy volunteers in San Lazaro Hospital. Methodology: A total of 189 healthy Filipino volunteers were randomized into three groups: Group A received PVRV 0.1 ml intradermally (ID) using the pre-exposure regimen (Day 0, 7, 28). Group B and Group C were given PVRV 0.1 ml ID and PCEC 0.1 ml ID, respectively, using the Modified TRC on days 0, 3, 7 and 30. The statistical tables and graphs were generated using Microsoft ® Excel ® 2010. SPSS® version 13 for Windows™ was used for descriptive statistics (geometric mean, arithmetic mean, standard deviation and percentages) and inferential statistics (χ2 test, one-way ANOVA and two-way mixed factorial ANOVA). Results: The results revealed that the percentage seroconversion of both PRVR and PCEC post-exposure groups in this clinical study were 100% on days 14 and 90. The PRVR pre-exposure group achieved 96% seroconversion on Day 28 with Geometric Mean titers

I ntroduction Burden of Disease. Rabies, one of the vaccinepreventable diseases, remains a major public health problem, causing at least 55,000 deaths every year globally 1 and about 300 deaths per year locally, 2,3 despite vaccine development and increased awareness in the community. This had been attributed to inconsistent availability (or inadequacy of supplies), inaccessibility and cost. According to the World Health Organization, animal bite cases have been increasing in the Philippines, with at least 328,459 persons in 2011 alone being bitten by animals. The country is among the top 10 countries with rabies as a public health problem.3 Rabies Prophylaxis. Although rabies is a 100%

*San Lazaro Hospital, Manila, Philippines

(GMT) of 1.96 IU/ml (95% CI: 1.45 - 2.65), which is comparable to other similar studies on pre-exposure rabies vaccination. There was no overall difference in all three groups for the whole duration of the study (p = 1.000). The geometic mean titers (GMT) for post-exposure PRVR and PCEC groups on days 14, 30 and 90 were all above 0.5 IU/ml. There was no significant difference between these two post-exposure groups (p = 0.052). The proportion of the subjects in the three groups who experienced local (pain and tenderness at the injection sites, erythema and itching) or systemic reactions (low grade fever, dizziness and headache) during follow-up period were not significantly different (p = 0.134). There were no serious adverse events (SAEs) reported during the follow-up period. Conclusion: The Asian manufactured PVRV is safe, tolerable, immunogenic and comparable with PCEC and therefore, the Asian manufactured PVRV can be an economical alternative for rabies post-exposure treatment using the modified TRC regimen and for pre-exposure prophylaxis. Keywords: Speeda™, Rabipur™, rabies, vaccine, PVRV, PCEC, safety, immunogenicity, Modified Thai Red Cross, clinical study, San Lazaro Hospital practically fatal disease, it is preventable with timely and proper usage of modern immunologicals (vaccines and immunoglobulins). Prophylaxis against rabies is of two types. One is the post-exposure prophylaxis (PEP) i.e., initiation of treatment after exposure. This is the most common type of prophylaxis that is encountered by the physicians. The other type is the pre-exposure (PreP) vaccination in which modern anti-rabies vaccines are given even before the exposure occurs. The cell culture vaccines have proven to be more efficacious and safe in comparison to the egg-derived vaccines. The safety of the Vero cell rabies vaccine is now firmly established, and it maintains significant protective efficacy for a minimum of three years and may be protective even after 10 years. Post-exposure Prophylaxis. Treatment for the prevention of rabies in humans exposed to rabies should begin as soon as possible after the exposure occurs.

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Miranda E, et al Treatment should follow the proper categorization as per the WHO guidelines. 4-7 Treatment consists of three important steps which include cleaning of wound, administration of rabies passive immunization and cellculture or purified embryonated egg rabies vaccination. Passive Immunization. Rabies Immunoglobulins (RIG) are of two types, Human Rabies Immunoglobulin (HRIG) and Equine Rabies Immunoglobulin (ERIG). HRIG is administered at a dose of 20 IU/Kg body weight (maximum of 1500 IU). ERIG is administered after skin sensitivity test at a dose of 40 IU/Kg body weight (maximum of 3000 IU). The RIG is infiltrated into and around the wounds whenever anatomically feasible and the products are diluted with sterile normal saline if insufficient by volume. Intradermal Rabies Vaccination (IDRV) was first started in Thailand in 1984, and was found successful. In 1992, World Health Organization (WHO) approved it for use in developing countries with problems of shortage of rabies vaccine due to paucity of funds.4 Since 1995, Purified Vero Cell Rabies Vaccine (PVRV), Purified Chick Embryo Cell Rabies Vaccine (PCEC) and Purified Duck Embryo Vaccine (PDEV) have been used for post-exposure treatment against rabies. About 40% of patients also receive RIG, when indicated. This approach has led to an important increase in the costs of vaccination. To overcome the financial burden of PET, in 1992 the WHO Expert Committee on Rabies recommended the use of the intradermal (ID) regimen of anti-rabies vaccination, especially for developing countries where the cost of vaccination is high and the supply of vaccine frequently runs out.4 The Philippines was among the first countries to adopt this ID regimen.8 According to WHO, the ID use of tissue culture vaccines can reduce the cost of PEP by as much as 60-80%.5,6 Among the different types of ID regimen, the most widely used is known as 2-site Intradermal regimen or Thai Red Cross (TRC) regimen, administered as 2-2-2-1-1. This regimen reduces the cost of anti-rabies vaccination without compromising its efficacy. However, recent observation in Thailand, suggested that Day 90 should be given on Day 30 hence, the 2-2-2-0-2 schedule came about now called Modified Thai Red Cross (Modified TRC). In 1997, the Department of Health (DOH) in the Philippines adopted the ID regimen of anti-rabies vaccination. The following year, animal bite centers were set up in all provinces and major cities in the Philippines so that effective post-exposure treatment using the ID regimen may become more available to bite victims.8 In 1992, based on the results of an earlier study, the WHO Expert Committee on Rabies recommended that each ID dose should be 0.1 ml of PVRV per dose or 0.2 ml of PCEC per dose.4 Further studies

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Safety and Immunogenicity of Purified Vero Cell Rabies Vaccine showed that the 0.1ml PCEC (with a potency of 7.0 IU/ml and is currently being used globally in pre- and post-exposure prophylaxis) is also effective and safe. It is therefore the aim of this study to investigate the efficacy and safety of the Asian manufactured PVRV in healthy Filipino volunteers using the Modified TRC regimen in order to supplement the already published researches of PVRV: Liu et. al.9 showed that Asian manufactured PVRV had similar immunogenicity with PCEC when administered via the Zagreb and Essen regimen, Wang et al10 and Yu et. al.11 demonstrated that Asian manufactured PVRV was comparable to the European manufactured PVRV in terms of immunogenicity, safety and antibody persistence when given via the Essen regimen.

O bjectives Primary Objective: To demonstrate the safety and immunogenicity of Purified Vero Cell Rabies Vaccine (PVRV) Freeze-Dried using pre-exposure regimen and post-exposure regimen utilizing Modified Thai Red Cross (TRC) schedule in comparison with Purified Chick Embryo Cell (PCEC) Rabies Vaccine among healthy volunteers. Secondary Objectives: 1. To describe the demographic profile of the healthy volunteers included in the study. 2. To determine the geometric mean titer (GMT) and percentage seroconversion of the groups of healthy volunteers in this study. 3. To establish the safety profile of the two groups of patients given 0.1 ml of PVRV using Modified TRC. a.) T o c o m p a r e p r o p o r t i o n o f t h e s u b j e c t s experiencing local or systemic reactions during follow up period. b.) To detect serious adverse events (SAEs) occurring during follow-up period.

M ethodology Selection of Study Population: A. Inclusion Criteria: 1. Healthy subjects male or female between seven to seven to 65 years old 2. Subjects have given a written informed consent or been granted one, signed by their parents (for subjects < 18 years of age) 3. Judged to be in good health on the basis of reported medical history and history-directed physical examination. 4. Plans to remain in the study area for the whole duration of the clinical trial. 5. Subject’s close family members have a

Safety and Immunogenicity of Purified Vero Cell Rabies Vaccine verifiable fixed home address and have a regular employment in Metro Manila.

Miranda E, et al and informed consent was secured prior to enrollment. Vaccines administered:



B. Exclusion Criteria: 1. Subjects who have received previous rabies immunization 2. Subjects currently receiving immunosuppressive therapy or immunotherapy, have allergies, or having any form of malignancy. 3. Subjects who suffered from rabies in their lifetime before entry in the trial 4. Subjects suffering from acute or chronic infections 5. Subjects suffering from acute febrile illnessor allergic reactions, including allergy to antibiotics 6. Subjects with occurrence of seizures at the time of vaccination 7. Subjects currently included or enrolled in other clinical trials 8. Subjects who have participated in any other clinical trial within the past three months. 9. Subjects who have clinical evidence of significant neurological, hematological, hepatic, renal, cardiac, respiratory disease or metabolic illness. 10. Pregnant or nursing women 11. Subjects with known hypersensitivity to the vaccine or any component of the vaccine. 12. Subjects treated with anti-malarial drug chloroquine in the last two months. 13. Subjects with previous history of exposure to any canine or feline bite or lick. 14. Subjects with history of alcohol, drug or any illicit substance abuse. 15. Subjects who received blood transfusion and/or plasma transfusion within the past three months.

Overall study design This is a prospective, randomized, open-labeled study enrolling 189 subjects distributed into three groups: GROUP A consisted of 63 healthy volunteers administered with PVRV (Speeda TM) 0.1 ml intradermal (ID) on one site using the pre-exposure schedule (Day 0, 7 and 28). GROUP B consisted of 63 healthy volunteers administered with PVRV (Speeda TM) 0.1 ml ID on two sites using Modified TRC schedule (2-2-2-2) on Days 0, 3, 7 and 30. GROUP C consisted of 63 healthy volunteers administered with PCEC (RabipurTM) 0.1 ml ID on two sites using Modified TRC schedule (2-2-2-2) on Days 0, 3, 7 and 30. Healthy volunteers of all groups were strictly screened

PVRV (Speeda™) The study vaccine PVRV (Speeda™) is a purified rabies vaccine freeze dried for human use and produced from Vero cell inoculated with fixed rabies virus. After incubation, the harvested virus solution is concentrated, purified and refined with addition of aluminum hydroxide. The fixed strains of rabies are inoculated into the primary hamster kidney cells or Vero cells. After incubation, the virus solution is harvested. After concentration, inactivation refinery, purification and lyophilization with addition of suitable stabilizer, the finished product is obtained. The active ingredients are inactivated rabies viruses, 0.5 ml containing at least 5.0 IU protective activity. The inactive ingredients are DNA remains such as bovine serum, protein remains, proteins, aluminum hydroxide, and thiomerosal free formaldehyde. The finished products have aluminum hydroxide ≤ 0.10 mg/ml and free formaldehyde ≤ 0.1 mg/ml. The product is made in China, under the Liaoning Cheng Da Biotechnology Co., Ltd. and listed in the biological products of China Pharmacopoeia, 2005. The products used have the batch/lot numbers 201109234 (vaccine; contains 2.5 IU/dose of FreezeDried Powder) and 20110841 (diluent; contains 0.5 ml distilled water). When 5.0 IU of the vaccine is administered ID or IM, one vial can be used for all the doses correctly obtainable within six hours after reconstitution. After reconstitution the vaccine should be stored at 2°C - 8°C and after this period of time the vial should be discarded or not used to vaccinate subjects enrolled in the trial. Great care will be taken with aseptic technique, an appropriate dose of vaccine may be withdrawn from a vial and the remainder used for another patient, provided that the vial is kept cool and stored at the correct temperature in the refrigerator. A sterile needle and syringe must be used to draw up vaccine for each patient, to prevent cross-infection. PCEC (Rabipur™) Purified Chick Embryo Cells (PCEC) is an inactivated rabies virus from Strain Flury LEP freeze dried for human use and produced from primary chicken fibroblast cell cultures with potency of ≥ 2.5 IU. Other components of PCEC (RabipurTM) include TRIS-(hydroxymethyl-aminomethane, sodium chloride, EDTA (Titriplex III), potassium-L-glutamate, polygeline, saccharose and water. PCEC is manufactured by Chiron Behring Vaccines Pvt. Ltd. Plot No. 3502, G.I.D.C. Estate, Post Box No.

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Safety and Immunogenicity of Purified Vero Cell Rabies Vaccine

Miranda E, et al 136, Ankleshwar 393 002, Dist. Bharuch, India. This vaccine is of sufficient potency to allow its safe use in one of the WHO recommended intradermal and intramuscular post-exposure regimens. This vaccine does not contain a preservative; therefore, great care must be taken to avoid contamination of the reconstituted vaccine. Any reconstituted vaccine should be used as soon as possible. It must be stored in a refrigerator at 2°C - 8°C and used within 6 to 8 hours of reconstitution. Immunogenicity variables: Blood samples (10ml) were drawn before vaccination on days 0, 14, 28 (for Group A) or 30 (for Group B and C) and 90 to determine the rabies virus neutralizing antibodies (RVNA) using Rapid Fluorescent Focus Inhibition Test (RFFIT). The sera were extracted from the blood samples, stored at -20 oC and forwarded to Kansas State University (KSU) for RVNA titer analysis. Safety variables: Medical history was obtained and physical examination was performed for each subject. Any adverse event during the study period was carefully recorded in an index card of adverse reactions checklist for a period of seven days. Statistical Methods and Determination of Sample Size Statistical Plans. The statistical tables and graphs were generated using Microsoft ® Excel ® 2010. SPSS ® version 13 for Windows™ was used for descriptive statistics (geometric mean, arithmetic mean, standard deviation and percentages) and inferential statistics (χ2 test, one-way ANOVA and two-way mixed factorial ANOVA). All tables for demography, efficacy, immunogenicity and safety analysis were presented for all study subjects. Analysis of Efficacy and Immunogenicity Data. All subjects whose RVNA titers were measurable by Day 0 (≥ 0.1 IU/ml) were not included in the analysis. This analysis was performed on a descriptive and inferential level for all the groups. All tables and graphs were done for all study subjects included in the analyses. Location parameter estimates of rabies antibody on Day 0, 14, 30 (day 28, in the case of PVRV pre-exposure) and 90 were calculated separately for each visit, e.g. geometric mean titer (GMT) and percentage of seroconversion. Log-transformation prior to determination of descriptive statistics was done to determine the 95% confidence interval (95% CI) for the GMT. For ease of computation of parametric statistics

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(one-way ANOVA, two-way mixed factorial ANOVA), RVNA titers of < 0.1 IU/ml and > 15 IU/ml were conservatively assigned with discrete values of 0.04 IU/ml and 15.1 IU/ml, respectively. Analysis of Safety Data. The number of adverse events was counted individually per vaccine group. The adverse events from both PVRV pre-exposure and post-exposure groups were combined. The percentages of adverse events from PVRV and PCEC were compared using χ2 test. Determination of Sample Size. The sample size of this prospective, randomized, open-labeled phase IV clinical study was not formally calculated on the basis of power. However, the number of subjects were already used in clinical trials with other rabies vaccines 9,12-14 and provided data that were considered adequate. The number was also thought to be enough to give good estimates of vaccine efficacy.

R esults

and Discussion

Baseline Characteristics A total of 189 healthy adult volunteers were equally randomized in 3 groups. There were no drop-outs from the study. However, 7 subjects (11%) from PVRV pre-exposure group and 7 subjects (11%) from PVRV post-exposure group had measurable RVNA titers (≥ 0.1 IU/ml) on day 0, and thus were excluded from the analysis. The demographic profiles of each group are presented below (Table I).

Table I: Demographic Profile of Healthy Volunteers of PVRV and PCEC groups PVRV Pre-exposure (n = 56)

PVRV Post-exposure (n = 56)

PCEC Post-exposure (n = 62)

pvalue

Gender (M/F)

28/28

25/31

19/43

0.086*

Age (mean ± SD)

30.39 ± 15.39

27.46 ± 13.44

24.45 ± 11.75

0.062†

*χ2 test; †one-way analysis of variance (ANOVA)

Safety Although none of the subjects in this study had any serious adverse events (SAEs) or anaphylactic reactions during the study, there were a few subjects in all groups receiving the study vaccines who experienced adverse events (Table II). Phanuphak et. al. 15 and Briggs et. al. 16 noted that although there was a higher incidence of local adverse reaction with intradermal route as compared to intramuscular route of vaccine administration, reactions from intradermal

Miranda E, et al

Safety and Immunogenicity of Purified Vero Cell Rabies Vaccine route were usually mild. A total of six adverse events (four local, two systemic) came from the combined PVRV groups (n = 112), while a total of seven adverse events (one local, six systemic) came from the PCEC group (n = 63). On the basis of nature of adverse events, there were fewer systemic adverse events from PVRV as compared to the number of systemic adverse events from PCEC; conversely, there were fewer local adverse events from PCEC as compared to the number of local adverse events from PVRV. On the basis of number of adverse events, PVRV was not significantly different from PCEC (p = 0.134). Over-all, the adverse events reported in this study were relatively few, minor and transient that were comparable to other clinical trials involving PVRV, 910,12-13,15,17-19 therefore, the Asian manufactured PVRV is considered safe and tolerable.

Table II: Number of Subjects (in %) with Local and Systemic Reactions and Time of Appearance of PVRV vs PCEC*†

Location

local

systemic

PVRV (pre-exposure) n = 56

PVRV (post-exposure) n = 56

PCEC (postexposure) n = 63

Time of Apearance 24hr

Time of Apearance 24hr

Time of Apearance 24hr

Pain/ Tenderness

1

-

-

-

1

-

Erythema

2

-

-

-

-

-

Itching

-

-

1

-

-

-

Low-Grade Fever

2

-

-

-

-

-

Dizziness

-

-

-

-

4

1

Headache

-

-

-

-

1

-

Adverse Reaction

*total number of subjects with local and systemic reactions: PVRV (pre and post) = 6/112 (5.4%), PCEC (post) = 7/63 (11.1%) †p-value (over-all) = 0.134 (χ2 test)

Efficacy Forty-one out of 56 (73%) subjects in PVRV preexposure group, 56/56 subjects in PVRV post-exposure group, and 63/63 subjects in PCEC post-exposure group seroconverted by day 14 with an RVNA titer of ≥ 0.05 IU/ml. By day 30 (day 28 for PVRV pre-exposure group), 54/56 (96%) subjects in PVRV pre-exposure group, 55/56 (98%) subjects in PVRV post-exposure group, and all 63 subjects in PCEC post-exposure group had an RVNA titer of ≥ 0.05 IU/ml. By day 90, 41/56 (73%) subjects in PVRV preexposure group, all 56 subjects in PVRV post-exposure group, and all 63 subjects in PCEC post-exposure group had an RVNA titer of ≥ 0.05 IU/ml. This showed the sustained RVNA titer of ≥ 0.05 IU/ml in both PVRV and PCEC post-exposure groups.

Table III: Comparison of Seroconversion Proportions of PVRV vs PCEC* Day 0

Day 14

Day 30

Day 90

PVRV (Pre-exposure)

0/56 (0%)

41/56 (73%)

54/56 (96%)†

41/56 (73%)

PVRV (Post-exposure)

0/56 (0%)

56/56 (100%)

55/56 (98%)

56/56 (100%)

PCEC (Post-exposure)

0/63 (0%)

63/63 (100%)

63/63 (100%)

63/63 (100%)

*p-value(over-all) = 1.000 (χ2 test) †Day 28

The seroconversion curves of all groups are shown (Figure 1). The seroconversion rates of both postexposure PVRV and PCEC were almost the same. A similar pattern was observed for pre-exposure PVRV; however, this group achieved 73% seroconversion on Day 14, 96% on Day 28 and 73% on Day 90. The GMT on Day 28 is comparable with Dong et al’s study20 regarding RVNA response of PVRV following pre-exposure schedule (1.96 IU/ml vs 2.13 IU/ml [PVRV]). Moreover, the seroconversion rate on Day 28 is also comparable with Shaw et al’s study21 on intradermal pre-exposure rabies immunization (96% vs 95.1% [PCEC]). With fewer doses needed for ID (as compared to IM) and with the Asian manufactured PVRV being less expensive than the European manufactured PVRV (by 62.9%) or PCEC (by 85%) per vial, this Asian manufactured PVRV may be considered as an economical pre-exposure prophylaxis for rabies. However, like other studies on pre-exposure prophylaxis2,20-22, the seroconversion rate decreases over time (Figure 1), and it is recommended to have at least a booster injection at 1 year to increase the levels of the RVNA titers of the vaccinees to ≥ 0.5 IU/ml 22. The over-all comparison of proportions of seroconversion revealed no statistically significant difference (χ2 = 0.00, df = 4, p = 1.000) (Table III). Seroconversion is defined by the WHO as an RVNA titer of ≥ 0.5 IU/ml so that it confers adequate rabies protection; thus, it is important to determine the percentage seroconversion by day 14. 4-7,23 Both PVRV and PCEC post-exposure prophylaxis achieved 100% seroconversion by day 14 (Table III). The GMT, standard deviation (SD) and the 95% confidence intervals of the geometric means of all groups in days 0, 14, 30 (day 28 for the PVRV preexposure group) and 90 are presented in Table IV. Looking closely at the comparison of GMT between post-exposure PVRV and PCEC over time (days 0, 14, 30 and 90) showed no statistically significant difference between these vaccines [F(2, 272) = 2.830, p = 0.052] (Table III and Figure 2).

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Safety and Immunogenicity of Purified Vero Cell Rabies Vaccine

Conclusions and Recommendation

Figure 1: Comparison of Seroconversion Rates over Time – PVRV versus PCEC Table IV: Comparison of RVNA Titers of PVRV vs PCEC In GMT ± SD (95% CI) Day 0

Day 14

Day 30

Day 90

PVRV (Pre-exposure)

-

1.08 ± 4.73 (0.70 - 1.67)

1.96 ± 4.49** (1.45 - 2.65)

0.59 ± 2.79 (0.44 - 0.81)

PVRV (Post-exposure) †

-

13.82 ± 2.55 (12.43 - 15.37)

6.65 ± 3.78 (5.48 - 8.08)

2.73 ± 3.50 (2.17 - 3.44)

PCEC (Post-exposure) †

-

14.22 ± 1.85 (13.57 - 14.89)

8.05 ± 5.10 (6.82 - 9.51)

3.78 ± 4.32 (3.06 - 4.68)

*negligible RVNA titer (< 0.1 IU/ml); †p-value(post-exposure) = 0.052 (two-way mixed factorial ANOVA) ** Day 28

Madhusudana et. al.13 and Briggs et. al.14 used TRC regimen (2-2-2-0-1-1) for both PVRV and PCEC. The GMT for both PVRV (13.83 IU/ml vs 4.6 IU/ml) and PCEC (14.22 IU/ml vs 4.3 IU/ml) in this study is considerably higher on day 14 as compared to the GMT achieved in Madhusudana’s study. However, compared to Briggs’ study, it is lower for both PVRV (13.83 IU/ml vs 28.9 IU/ml) and PCEC (14.22 IU/ml vs 28.5 IU/ml) on Day 14. The discrepancies in GMT may be due to differences in population, assay technique and even the potency of the vaccine.15 Liu et. al.9 used PVRV but administered thru IM route (Essen and Zagreb regimen). The GMT for PVRV on day 14 is comparable in this study (13.83 IU/ml [TRC] vs 14.57 IU/ml [Zagreb] vs 14.25 IU/ml [Essen]). Jaiiaroensup et. al.17 and Kulkarni et. al.19 showed that PVRV, regardless of IM or ID route, achieved good immunogenicity.

Figure 2: Comparison of RVNA titers of PVRV (Post-exposure) Vs PCEC (Post-exposure)

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B a s e d o n t h e a bo v e da t a , t h e r e was no significant difference between PVRV and PCEC in terms of the computed GMT and most especially on the percentage seroconversion. Likewise, the safety profile was comparable between PVRV and PCEC. The Asian manufactured PVRV proves to be comparable with PCEC in terms of safety, tolerability and immunogenicity. Thus, the Asian manufactured PVRV should be considered as a more economical alternative for rabies post-exposure treatment using the modified TRC regimen and for pre-exposure prophylaxis. With the safety and immunogenicity results cited, the only limitation of this study is the non-inclusion of persistence of the GMT above 0.05 IU/ml, and the authors recommend follow up of these patients given sufficient funding in the future.

References 1. Shanbag P, Shah N, Kulkarni M, Juvekar M, Madhusudana SN, Vakil HB and Malerczyk C. “Protecting Indian schoolchildren against rabies” Hum Vaccines 2008 Sept/ Oct; 4(5):365-9. 2. Dimaano EM, Scholand SJ, Alera MT, Belandres DB. “Clinical and epidemiological features of human rabies cases in the Philippines: a review from 1987 to 2006” Int J Infect Dis 2011 Jul; 15(7):e495-9. 3. Rabies in the Philippines. WHO Western Pacific Region website. http://www.wpro.who.int/philippines/areas/ communicable_diseases/rabies/en/ Date accessed: May 23, 2014. 4. “Eighth Report of the WHO Expert Committee on Rabies” WHO Technical Report Series, No. 824. Geneva: World Health Organization, 1992. 5. WHO recommendations on rabies post-exposure treatment and the correct technique of intradermal immunization against rabies. Geneva: World Health Organization, 1997. 6. “Intradermal application of rabies vaccines” Report of WHO Consultation. Bangkok, Thailand. June 2000. 7. Recommendations of the WHO Interregional Consultation on strategies for the control and elimination of rabies in Asia. Geneva: World Health Organization, 17-20 July 2001. 8. New Guidelines on the Management of Rabies Exposures. Administrative Order 2014-0012. Manila, Philippines: Department of Health, 2014. 9. Liu H, Huang G, Tang Q, Li J, Cao S, Fu C, Cao Q, Liu B, Pan H and Wang M. “The immunogenicity and safety of vaccination with purifies vero cell rabies vaccine (PVRV) in China under a 2-1-1 regimen” Hum Vaccines 2011 Feb; 7(2):220-4. 10. Wang LY, Sun MP, Zhang XC, Suo LD, Xu RH, Zou YJ, Zuo LB and Qi H. “Safety and immunogenicity of two freeze-dried Vero cell rabies vaccines for human use in post-exposure prophylaxis” Vaccine 2011 Mar 24; 29(15):2679-81. 11. Yu P, Huang Y, Zhang Y, Tang Q and Liang G. “Production and evaluation of a chromatographically purified Vero cell rabies vaccine (PVRV) in China using microcarrier technology” Hum VaccinImmunother. 2012 Sep; 8(9):1230-5.

Safety and Immunogenicity of Purified Vero Cell Rabies Vaccine

Miranda E, et al

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Volume 52 Number 2 April-June, 2014

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