A comparative study on the safety and immunogenicity of purified duck embryo cell vaccine (PDEV,Vaxirab) with purified chick embryo cell vaccine (PCEC,Rabipur) and purifed vero cell rabies vaccine (PVRV,Verorab)

Rabies is a fatal but preventable disease. Cell culture vaccines (CCV) and purified duck embryo vaccines (PDEV) are currently recommended by WHO for post-exposure prophylaxis. In India, a PDEV (Vaxirab) is being manufactured and is in use since 2003. In the present study, we have evaluated the safety, immunogenicity and tolerance of this vaccine with two other WHO approved CCVs, viz., purified chick embryo cell vaccine (PCEC, Rabipur) and purified vero cell rabies vaccine (PVRV, Veroroab). This study was an open label, randomized phase IV comparative clinical trial. A total of 152 people bitten by dogs and other animals were recruited from 4 different centres from India. They were randomly assigned to receive one of the vaccines by Essen intramuscular regimen (52 subjects received Vaxirab and 50 each Rabipur and Verorab) and rabies immunoglobulin was also administered in all category III exposures. Their blood samples were collected on day 0 (prior to vaccination), 14, 28, 90 and 180. Side effects if any were monitored. The rabies neutralizing antibody titers in their blood samples were estimated by the rapid fluorescent focus inhibition test (RFFIT). Subjects in all three groups had neutralizing antibody titers by day 14 (>0.5 IU/mL) and geometric mean titers (GMT) observed for different vaccines on all days tested did not vary significantly (p > 0.5). Side effects observed were minimal and did not vary significantly among the groups. The results of the present study indicate that PDEV (Vaxirab) is as safe, tolerable and immunogenic as both PCEC (Rabipur) and PVRV (Verorab). Thus this vaccine can be a good alternative to WHO approved CCVs for rabies post-exposure prophylaxis.     

Antibody response of patients after postexposure rabies vaccination with small intradermal doses of purified chick embryo cell vaccine or purified Vero cell rabies vaccine

Although the introduction of tissue culture vaccines for rabies has dramatically improved the immunogenicity and safety of rabies vaccines, they are often prohibitively expensive for developing countries. To examine whether smaller doses of these vaccines could be used, we tested the safety and immunogenicity of purified chick embryo cell vaccine (PCECV) on 211 patients in Thailand with World Health Organization (WHO) category II and III exposures to rabies. The patients presented at two Thai hospitals and were randomized into three groups. Patients in Group 1 received 0.1 ml PCECV intradermally at two sites on days 0, 3, 7, and at one site on days 30 and 90. Group 2 was treated similarly, except that purified Vero cell rabies vaccine (PVRV) was used instead of PCECV. Group 3 received 1.0 ml PCECV intramuscularly on days 0, 3, 7, 14, 30 and 90. After 0, 3, 7, 14, 30 and 90 days serum was collected from the subjects and the geometric mean titres (GMTs) of rabies virus neutralizing antibody determined. After 14 days the GMT of 59 patients vaccinated intradermally with PCECV was equivalent to that of patients who received PVRV. Adverse reactions were more frequent in patients who received vaccines intradermally, indicating the reactions were associated with the route of injection, rather than the vaccine per se. We conclude that PCECV is a safe and highly immunogenic vaccine for postexposure rabies vaccination when administered intradermally in 0.1-ml doses using the two-site method ("2,2,2,0,1,1") recommended by WHO.     

Potency requirements of rabies vaccines administered intradermally using the Thai Red Cross regimen: investigation of the immunogenicity of serially diluted purified chick embryo cell rabies vaccine

To determine the minimum vaccine potency per intradermal dose required to elicit an adequate immune response using the Thai Red Cross (TRC) regimen (2-2-2-0-1-1), healthy volunteers received 0.1 mL volumes of PCECV containing decreasing amounts of antigen. Subjects also received HRIG to evaluate potential interference with antibody production. Results indicated that when each 0.1 mL intradermal dose of PCECV contained antigen corresponding to 0.32 IU per intramuscular dose, every subject had titers above 0.5 IU/mL by day 14. These results confirm that the current World Health Organization (WHO) recommendations for vaccine potency (2.5 IU per intramuscular dose) are sufficient for use in the Thai Red Cross intradermal regimen.     

Reduced dose pre-exposure primary and booster intradermal rabies vaccination with a purified chick embryo cell vaccine (PCECV) is immunogenic and safe in adults

Pre-exposure vaccination of persons at risk with intradermally administered reduced dose cell culture rabies vaccines remains controversial in low-enzootic countries. In a prospective clinical trial of adult volunteers (N=25), we studied the immune response to purified chick embryo cell vaccine (PCECV) administered intradermally at a reduced dose (0.1 mL) in a three-dose schedule (0, 7 and 21 days). In 10 subjects, immunogenicity of intradermally administered one-dose booster vaccination with 0.1 mL PCECV was investigated. All participants were seroconverted 3 weeks after primary and 1 week after booster vaccination (antibody titre > or = 0.5 EU/mL, measured by enzyme linked immunosorbent assay). Local adverse events such as erythema and swelling were moderate and transitory. The intradermal vaccination route offers an efficacious and cost-reducing strategy to increase the accessibility of cell culture rabies vaccines.     

Pre-exposure studies with purified chick embryo cell culture rabies vaccine and human diploid cell vaccine: serological and clinical responses in man

Clinical reactions and neutralizing antibody responses to six pre-exposure regimens of purified chick embryo cell culture rabies vaccine (PCECV) and human diploid cell strain rabies vaccine (HDCSV) were studied in 177 volunteers. Antibody kinetics, height of the response and persistence of antibody over two years were virtually identical after PCECV and HDCSV. An antibody response was detected in all subjects on day 14 when the highest titres were found after two intramuscular (i.m.) 1.0 ml doses of a schedule of immunization on days 0, 7 and 21. In comparison, a schedule of immunization on days 0, 28 and 56 ultimately evoked the highest titres 21 days after the final injection, but antibody persisted equally well over two years with either schedule. Neutralizing antibody titres were lower after intradermal (i.d.) vaccination with 0.1 ml compared to 1.0 ml i.m. on days 0, 7 and 21, but when given on days 0, 28 and 56 the responses were comparable. Three subjects with a personal or family history of atopy developed urticarial lesions after PCECV. Both vaccines were otherwise well tolerated.     

A pilot study on intradermal vaccination of Japanese rabies vaccine for pre-exposure immunization

Japanese rabies vaccine, a purified chick embryo cell vaccine manufactured by Kaketsuken (PCEC-K), is normally given subcutaneously; however, this requires a large amount of vaccine, and the pre-exposure vaccination regimen requires 6 months to complete. These factors often hamper appropriate vaccination. Therefore, we examined whether this vaccine could induce adequate level of viral neutralizing antibody (VNA) when vaccinated according to the World Health Organization (WHO) intradermal regimen. Our pilot study showed that this regimen resulted in all subjects developing adequate VNA levels. Intradermal route was effective not only for pre-exposure but also for booster vaccination. The intradermal PCEC-K regimen was found to be safe and effective in inducing adequate VNA levels with the use of a smaller quantity of vaccine and within a shorter period of time.     

Purified chick embryo cell rabies vaccine: economical multisite intradermal regimen for post-exposure prophylaxis

The standard six-dose intramuscular (i.m.) rabies post-exposure vaccine regimen using a new purified chick embryo cell (PCEC) vaccine was compared with two economical multisite intradermal (i.d.) PCEC regimens, a multisite i.m. PCEC schedule and a subcutaneous regimen using a suckling mouse brain (SMB) rabies vaccine manufactured in Thailand. The neutralizing antibody results for the four-site and eight-site i.d. and the standard i.m. PCEC regimens were similar over 3 months. A three-site i.m. PCEC regimen had no advantage. The SMB vaccine gave the lowest antibody levels. Human rabies immune globulin therapy significantly increased the GMT of all groups on day 7, unlike equine antirabies serum (EARS). Both antisera suppressed antibody responses to PCEC on days 14 and 28. Three generalized reactions probably related to EARS were the only serious side effects. An eight-site i.d. PCEC vaccine regimen proved as immunogenic as the routine i.m. schedule and, if implemented as post-exposure prophylaxis, would be the cheapest widely available tissue culture vaccine regimen. The protective efficiency should now be tested in patients bitten by rabid animals.     

Safety and immunogenicity of a serum-free purified Vero rabies vaccine in healthy adults: A randomised phase II pre-exposure prophylaxis study

A serum-free, highly purified Vero cell rabies vaccine (PVRV-NG) is under development. We previously demonstrated that pre-exposure prophylaxis (PrEP) with PVRV-NG had a satisfactory safety profile and was immunogenically non-inferior to the licensed purified Vero cell rabies vaccine in adults. Here, we evaluated the safety and immunogenic non-inferiority of PrEP with PVRV-NG compared to the licensed human diploid cell vaccine (HDCV) in healthy adults (NCT01784874). Participants received three vaccinations (days 0, 7, and 28) as PrEP with or without a booster injection after 12 months. Rabies virus neutralising antibodies (RVNA) were evaluated on days 0, 28 (subgroup only), and 42, and Months 6, 12, and 12 + 14 days (booster group only). Non-inferiority (first primary objective) was based on the proportion of participants with RVNA titres ≥ 0.5 IU/mL (World Health Organization criteria for seroconversion) on day 42, expected to be ≥ 99% (second primary objective). Safety was evaluated after each dose and monitored throughout the study. At day 42, PVRV-NG was non-inferior to HDCV and the first primary objective was met; seroconversion was observed for 98.3% of PVRV-NG recipients and 99.1% of HDCV recipients. As < 99% of participants in the PVRV-NG group had RVNA titres ≥ 0.5 IU/mL, the second primary objective was not met. Booster vaccination produced a strong increase in RVNA titres for all groups, primed with PVRV-NG or HDCV. RVNA geometric mean titres tended to be higher for HDCV than PVRV-NG primary vaccine recipients. In a complementary evaluation using alternative criteria for seroconversion (complete virus neutralization at 1:5 serum dilution), 99.6% and 100% of participants in the PVRV-NG and HDCV groups, respectively, achieved seroconversion across the vaccine groups. No major safety concerns were observed during the study. PVRV-NG was well tolerated, with a similar safety profile to HDCV in terms of incidence, duration, and severity of adverse events after primary and booster vaccinations.ClinicalTrials.gov number: NCT01784874.     

精制Vero细胞狂犬病疫苗的研制及免疫学效果观察

目的　以Vero细胞为基质，研制新一代精制Vero细胞狂犬病疫苗。方法　以CTN-1V10为生产毒株，以＜150代Vero细胞为培养基质，采用转瓶旋转培养，按不同时间收获病毒液，经过澄清、浓缩、纯化、灭活制成精制Vero细胞狂犬病疫苗。从以此工艺制备的疫苗中选取一批做为免疫学效果观察的受试疫苗。按暴露后免疫程序接种63人，其中受试疫苗接种33人，法国维尔博狂犬病疫苗接种30人，观察不良反应和测定中和抗体。结果　新研制的精制Vero细胞狂犬病疫苗各项指标完全符合WHO的有关质量要求。两种疫苗全程免疫后中和抗体阳转率均为100%，中和抗体受试组为11.94IU/ml;维尔博疫苗对照组为11.69IU/ml。结论　精制Vero细胞狂犬病疫苗不但制造工艺合理，而且副反应轻微，免疫原性良好。     

A single center,open label study of intradermal administration of an inactivated purified chick embryo cell culture rabies virus vaccine in adults

In the USA, rabies vaccines (RVs) are licensed for intramuscular (IM) use only, although RVs are licensed for use by the intradermal (ID) route in many other countries. Recent limitations in supplies of RV in the USA reopened discussions on the more efficient use of available biologics, including utilization of more stringent risk assessments, and potential ID RV administration. A clinical trial was designed to compare the immunogenic and adverse effects of a purified chicken embryo cell (PCEC) RV administered ID or IM. Enrollment was designed in four arms, ID Pre-Exposure Prophylaxis (Pre-EP), IM Pre-EP, ID Booster, and IM Booster vaccination. Enrollment included 130 adult volunteers. The arms with IM administration received vaccine according to the current ACIP recommendations: Pre-EP, three 1 mL (2.5 I.U.) RV doses, each on day 0, 7, and 21; or a routine Booster, one 1 ml dose. The ID groups received the same schedule, but doses administered were in a volume of 0.1 mL (0.25 I.U.). The rate of increase in rabies virus neutralizing antibody titers 14–21 days after vaccination were similar in the ID and correspondent IM groups. The GMT values for ID vaccination were slightly lower than those for IM vaccination, for both naïve and booster groups, and these differences were statistically significant by t-test. Fourteen days after completing vaccination, all individuals developed RV neutralizing antibody titers over the minimum arbitrary value obtained with the rapid fluorescent focus inhibition test (RFFIT). Antibodies were over the set threshold until the end of the trial, 160 days after completed vaccination. No serious adverse reactions were reported. Most frequent adverse reactions were erythema, induration and tenderness, localized at the site of injection. Multi use of 1 mL rabies vaccine vials for ID doses of 0.1 was demonstrated to be both safe and inmunogenic.     

Safety review of the purified chick embryo cell rabies vaccine: Data from the Vaccine Adverse Event Reporting System (VAERS), 1997-2005

On October 20, 1997, the U.S. Food and Drug Administration (FDA) licensed Purified Chick Embryo Cell (PCEC, RabAvert) vaccine against rabies in humans following clinical trials demonstrating safety and efficacy. From October 1997 through December 2005, the Vaccine Adverse Event Reporting System (VAERS) received 336 reports of adverse events (AEs) following vaccination with PCEC vaccine in the U.S.; there were no death reports. Serious events, including 20 hospitalizations and 13 neurological events, were described in 24 (7%) reports. There was no pattern among the 13 neurological AEs suggesting a plausible relationship to vaccination. A total of 20 AEs, 3 serious, were classified as possible anaphylaxis. There were 312 non-serious AEs (93%). Nineteen reports (6%) described that the vaccination series was discontinued because of non-serious AEs. Most reported AEs are non-serious and consistent with pre-licensure safety data. The rabies risk must be carefully considered before vaccine discontinuation.     

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

Systemic allergic reactions following booster immunizations have complicated rabies pre-exposure prophylaxis with the human diploid cell rabies vaccine licensed in the US (conventional HDCV). We conducted two studies comparing an HDCV purified by zonal centrifugation to conventional HDCV. In a study of primary pre-exposure immunization, volunteers received one of four regimens: three 1.0-ml intramuscular (i.m.) or 0.1-ml intradermal (i.d.) doses of conventional or purified HDCV over 28 days. Although volunteers vaccinated i.m. had significantly greater rabies neutralizing antibody titres (VNA) 49 days, 91 days and 26 months after immunization began than volunteers vaccinated i.d. (p less than 0.005-p less than 0.05), there were no significant differences between vaccines. In a study of booster immunizations, 77 volunteers immunized with conventional HDCV 2 years earlier received a 0.1-ml i.d. booster with either conventional or purified HDCV. VNA was significantly greater with the conventional HDCV on days 7 and 28 after booster, but not on day 365. A moderate or severe reaction was reported by 5 (13%) of the 40 persons who received boosters with conventional HDCV, versus none of 37 who received the purified HDCV (p = 0.03). Purified HDCV appears to be preferable to conventional HDCV for booster vaccination.     

A serum-free,purified vero cell rabies vaccine is safe and as immunogenic as the reference vaccine Verorab™ for pre-exposure use in healthy adults: Results from a randomized controlled phase-II trial

Background

Verorab™ was licensed in 1985 for both pre- and post-exposure prophylaxis of rabies. The next generation purified Vero cell rabies vaccine (PVRV-NG) is a highly purified vaccine. We performed a phase II clinical study in adults in France to assess its immunological non-inferiority and clinical safety for pre-exposure prophylaxis.

Methods

In a randomized phase-II trial, 384 healthy adult subjects were randomized (2:1) to receive a three-dose primary series of PVRV-NG or Verorab. One year later, the PVRV-NG group received a PVRV-NG booster while the Verorab group participants were randomized to receive a booster of PVRV-NG or Verorab for. Rabies virus neutralizing antibodies (RVNA) were evaluated on days 0, 28 (subgroup), 42, months 6, 12 and 12 + 14 days. Safety was evaluated for seven days after each dose. Adverse event between doses, until 28 days after the final dose was recorded. Serious adverse events were recorded up to 6 months after the last dose.

Results

The criterion for non-inferiority was met in the per-protocol analysis set and confirmed in the full analysis set (FAS). In the FAS, 99.6% and 100% of subjects had RVNA titers ≥0.5 IU/mL in PVRV-NG and Verorab groups, respectively. While RVNA levels gradually decreased over the 12-month period, at 6 and 12 months after vaccination >89% and >77%, respectively, in both groups had RVNA titers ≥0.5 IU/mL. The PVRV-NG booster induced a strong response, irrespective of the vaccine given for the primary series. PVRV-NG was safe and well tolerated and its safety profile was similar to Verorab for unsolicited adverse events and solicited systemic reactions. The incidence of solicited injection-site reactions was lower with PVRV-NG than with Verorab after the primary series and the booster dose.

Conclusions

PVRV-NG was shown to be at least as immunogenic as Verorab and to present a similar safety profile.     

An immunogenicity study of a newly introduced purified Vero cell rabies vaccine (Abhayrab) manufactured in India

Purified Vero cell culture rabies vaccine "Abhayrab" manufactured by Human Biologicals Institute, Ooty, India was subjected for immunogenicity studies. Pre-exposure study was undertaken on 60 healthy volunteers (Group I) with vaccination on days 0, 7 and 21. A group of 75 patients of category II (Group II), 67 of category III (Group III) were given post-exposure prophylaxis and 88 patients of category III were administered with rabies immunoglobulins (Group IV) along with post-exposure prophylaxis as per World Health Organization (WHO) recommendations with a booster on day 90. The volunteers and patients vaccinated showed very few adverse side effects. The blood samples collected from volunteers (Group I) on days 14, 35 and 365 and patients (Group II-IV) on days 14, 30, 90 and 365 showed geometric mean titres (GMT) of >0.5 IU/ml. The study indicated new rabies vaccine manufactured in India was found to be safe and immunogenic.     

Evaluation of a human diploid cell strain rabies vaccine: final report of a three year study of pre-exposure immunization.

The antibody responses of 194 volunteers were studied for up to 3 years after primary immunization with one, two or three doses of human diploid cell rabies vaccine, administered either in 0.1 ml volumes intradermally (i.d.) or as 1.0 ml intramuscularly (i.m.). Sero-conversion occurred in 95% of subjects after the first injection and in 100% after the second. The highest titres and most durable antibody responses were induced by three injections of vaccine. Booster doses were administered either by the subcutaneous (s.c.) or i.d. route, after 6, 12 or 24 months to randomly grouped volunteers; these induced responses greater than or equal to 5.0 i.u. per ml in 95% of subjects. The responses were rapid and were neither influenced by the primary regimen nor by the timing and route of the booster dose. Antibody titres after i.d. immunization were only two-fold lower than those induced by the larger volume of vaccine. The findings suggest that the i.d. route is both effective and economic.     

浓缩狂犬疫苗与纯化狂犬疫苗全程免疫后抗体水平比较分析

为了解人被狗、猫、鼠等哺乳类动物咬、抓伤后进行狂犬疫苗全程免疫后的抗体水平 ,更好地预防狂犬病的发生 ,本文于 2 0 0 1年对全程注射浓缩狂犬疫苗和纯化狂犬疫苗者进行免疫效果观察 ,结果如下。1　材料和方法1 1　调查对象　 2 0 0 1年被狗、猫、鼠等哺乳类动物咬、抓伤后注射浓缩狂犬疫苗者和注射纯化狂犬疫苗者。1 2　调查方法　调查对象进行狂犬疫苗全程免疫后 1个月抽取血清 ,用狂犬抗体酶联免疫吸附目测法检测抗体 ,试剂为兰州生物制品研究所生产。2　结果　　浓缩狂犬疫苗全程免疫的 32人当中抗体阳性有 2 9人 ,阳性率为 90 6 3%…     

国产与进口冻干无佐剂人用狂犬病疫苗的安全性和免疫原性比较

目的评价国产冻干人用无佐剂狂犬病纯化疫苗(Vero细胞)的安全性和免疫原性。方法对600名健康人随机分为两组,480人(A组)接种冻干无佐剂人用狂犬病纯化疫苗(Vero细胞)和120人(B组)作为对照接种巴斯德公司生产的冻干无佐剂狂犬病纯化疫苗,采用0、3、7、14和28天免疫程序。观察每针次接种后72小时内局部和全身反应及14天、45天的免疫应答水平。结果所有接种对象均未出现严重局部和全身副反应。首剂免疫14天,A、B组抗体阳性率分别均达到98.06%和96.49%,几何平均滴度为5.0IU/ml和3.79IU/ml。免疫后45天,A、B组抗体阳性率均达到100%,抗体几何平均滴度分别上升至7.97IU/ml和7.61IU/ml。结论国产人用狂犬病无佐剂纯化疫苗(Vero细胞)具有良好安全性和免疫原性。