Human Diploid Cell Vaccine Research Articles

Immunogenicity and Safety of a Purified Vero Rabies Vaccine-Serum Free, Compared With 2 Licensed Vaccines, in a Simulated Rabies Post-Exposure Regimen in Healthy Adults in France: A Randomized, Controlled, Phase 3 Trial.

A next-generation Vero cell rabies vaccine (PVRV-NG2) was developed using the same Pitman-Moore strain as in the licensed purified Vero cell vaccine (PVRV; Verorab) and the human diploid cell vaccine (HDCV; Imovax Rabies®). This dual-center, modified, double-blind, phase 3 study evaluated the immunogenic non-inferiority and safety of PVRV-NG2 with and without concomitant intramuscular human rabies immunoglobulin (HRIG) versus PVRV + HRIG and HDCV + HRIG in a simulated post-exposure prophylaxis (PEP) regimen. Healthy adults ≥18 years old (N = 640) were randomized 3:1:1:1 to PVRV-NG2 + HRIG, PVRV + HRIG, HDCV + HRIG, or PVRV-NG2 alone (administered as single vaccine injections on days [D] 0, D3, D7, D14, and 28, with HRIG on D0 in applicable groups). Rabies virus neutralizing antibodies (RVNA) titers were assessed pre- (D0) and post-vaccination (D14, D28, and D42) using the rapid fluorescent focus inhibition test. Non-inferiority, based on the proportion of participants achieving RVNA titers ≥0.5 IU/mL (primary objective), was demonstrated if the lower limit of the 95% CI of the difference in proportions between PVRV-NG2 + HRIG and PVRV + HRIG/HDCV + HRIG was >-5% at D28. Safety was assessed up to 6 months after the last injection. Non-inferiority of PVRV-NG2 + HRIG compared with PVRV + HRIG and HDCV + HRIG was demonstrated. Nearly all participants (99.6%, PVRV-NG2 + HRIG; 100%, PVRV + HRIG; 98.7%, HDCV + HRIG; 100%, PVRV-NG2 alone) achieved RVNA titers ≥0.5 IU/mL at D28. Geometric mean titers were similar between groups with concomitant HRIG administration at all time points. Safety profiles were similar between PVRV-NG2 and comparator vaccines. In a simulated PEP setting, PVRV-NG2 + HRIG showed comparable immunogenicity and safety to current standard-of-care vaccines. NCT03965962.

Safety and immunogenicity of a serum-free purified Vero rabies vaccine in comparison with the rabies human diploid cell vaccine (HDCV; Imovax® Rabies) administered in a simulated rabies post-exposure regimen in healthy adults

A new generation, serum-free, antibiotic-free, purified Vero rabies vaccine (PVRV-NG; Sanofi) has been developed based on the same Pitman-Moore viral strain used for the currently licensed purified Vero cell rabies vaccine (PVRV; Verorab®, Sanofi) and human diploid cell vaccine (HDCV; Imovax® Rabies, Sanofi). PVRV-NG has demonstrated a satisfactory safety profile and induces robust immune responses, with non-inferiority demonstrated versus PVRV when given as a three-dose pre-exposure prophylaxis (PrEP) regimen in healthy children and adults. Here, we evaluated the safety and immunogenic non-inferiority of PVRV-NG compared to HDCV when administered as simulated post-exposure prophylaxis (PEP), with concomitant administration of human rabies immunoglobulin (HRIG), in healthy adults in the USA. Participants were vaccinated according to the 5-dose Essen intramuscular regimen (4-week, 1-injection site regimen, with a single dose given on days 0, 3, 7, 14 and 28) for PEP, with concomitant HRIG administered on day 0. Rabies virus neutralising antibodies (RVNA) were evaluated on days 0, 14, 28 and 42. Non-inferiority of PVRV-NG compared with HDCV was shown if the lower limit of the 95 % confidence interval (CI) for the difference in seroconversion rates (RVNA titers ≥ 0.5 IU/mL on day 14) between PVRV-NG and HDCV was above the non-inferiority margin of –5 %. Safety was evaluated after each vaccination and monitored throughout the study. The difference in seroconversion rate between the PVRV-NG and HDCV groups was –2.8 % (95 % CI, –8.08 to 4.20), indicating that non-inferiority was not demonstrated. The seroconversion rate was < 99 % in both study groups on day 14. There were no major safety concerns identified, and PVRV-NG demonstrated a similar safety profile to HDCV.

One-week intramuscular or intradermal pre-exposure prophylaxis with human diploid cell vaccine or Vero cell rabies vaccine, followed by simulated post-exposure prophylaxis at one year: A phase III, open-label, randomized, controlled trial to assess immunogenicity and safety

Shorter rabies pre-exposure prophylaxis (PrEP) regimens may offer improved convenience and feasibility over classic 3-week regimens, for example in regions with poor access to vaccines or for travelers to rabies-endemic regions. In this multicenter, open-label, controlled trial, 570 healthy participants aged 2–64 years were randomized to receive: 1-week PrEP (vaccination days [D]0 and 7; Group 1) or classic 3-week PrEP regimen (D0, D7, and D21; Group 2) with one 1.0 mL intramuscular [IM] dose of human diploid cell culture rabies vaccine (HDCV) at each visit; 1-week PrEP with two 0.1 mL intradermal (ID) HDCV doses at each visit (Group 3); or 1-week PrEP with one 0.5 mL IM dose (Group 4) or two 0.1 mL ID doses (Group 5) of Vero cell rabies vaccine (PVRV) at each visit. Participants received simulated post-exposure prophylactic (PEP) vaccination (two IM or ID doses of HDCV or PVRV three days apart) one year later. Rabies virus neutralizing antibody titers and seroconversion (titers ≥ 0.5 IU/mL) rates were assessed 14 days and up to 1 year post-PrEP, and pre- and post-PEP. Safety was assessed throughout the study. Seroconversion rates were high 14 days post-last PrEP injection (ranging from 96.7 % to 97.2 % across groups 1, 3–5; 1-week PrEP) and reached 100 % in Group 2 (3-week PrEP). Non-inferiority of Group 1 versus Group 2 in terms of seroconversion rates 14 days post-last PrEP injection (primary objective) was not demonstrated. After simulated PEP, all groups showed rapid and robust immune responses, with all but one participant achieving seroconversion (titers ≥ 0.5 IU/mL). There were no safety concerns, and the tolerability profiles of the vaccines were similar across the groups.A 1-week, IM or ID PrEP regimen with HDCV or PVRV provided efficacious priming, enabling rapid robust anamnestic responses to simulated PEP 1 year later across age groups.ClinicalTrials.gov number: NCT03700242.WHO Universal Trial Number (UTN): U1111-1183-5743.

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.

Immunogenicity and safety of human diploid cell vaccine (HDCV) vs. purified Vero cell vaccine (PVRV) vs. purified chick embryo cell vaccine (PCECV) used in post-exposure prophylaxis: a systematic review and meta-analysis

ABSTRACT This study comprehensively evaluated and compared three human rabies vaccines. Seven electronic databases were systematically searched. The Cochrane Handbook v5.1.0 was used to assess the risk of bias. A random-effects model was used to combine individual rates, and network meta-analysis was used for pairwise comparisons. Twenty-seven articles were included, with a total of 18,630 participants. The pooled incidence of the total adverse reaction to HDCV was significantly lower than that of PCECV. HDCV administration resulted in a lower incidence of local pain, fever, and weakness than purified Vero cell vaccine. HDCV caused a lower incidence of local pain and fever than PCECV. No significant difference was observed in terms of the seroconversion rate on day 7 or the rabies virus-neutralizing antibody titer on day 14. HDCV demonstrated superiority in terms of safety compared with the other two rabies vaccines, while the same was not observed in terms of immunogenicity.

Acute motor axonal neuropathy following anti-rabies human diploid cell vaccine: A rare case and review

Rationale: Guillain Barre syndrome (GBS) is an acute neurological illness leading to quadriparesis with respiratory involvement. It can be triggered by infections, vaccinations, surgery, trauma, transplantation and drugs. Anti-rabies cell culture vaccines introduced to overcome the high rate of neurological complications associated with tissue based rabies vaccine, can be very rarely associated with GBS.Patient concerns: A 50-year-old female presented with acute severe upper back pain evolving into pure motor quadriparesis following administration of human diploid cell vaccine for rabies.Diagnosis: Acute motor axonal neuropathy variant of GBS following anti-rabies human diploid cell vaccine.Interventions: Intravenous high dose steroids.Outcomes: Patient recovered completely within 1 month.Lessons: Although anti-rabies cell culture vaccines are highly immunogenic and safe, they are rarely associated with GBS. Clinicians should be aware of this link because prompt diagnosis and treatment can result in complete recovery and avoid complications.

Pre-marketing immunogenicity and safety of a lyophilized purified human diploid cell rabies vaccine produced from microcarrier cultures: a randomized clinical trial

ABSTRACT The large-scale production of a human diploid cell (HDC) vaccine (HDCV) for rabies is limited by several technical challenges. Kanghua Biological Products Co., Ltd., has successfully used microcarrier technology for the large-scale culture of HDCs in bioreactors to develop a lyophilized and purified HDCV. In this blinded, randomized, parallel-group study conducted between July and October 2014 in Mianzhu, Sichuan Province, China, we monitored the safety and immunogenicity of this vaccine in a healthy population vaccinated according to the Essen post-exposure immunization schedule. A hamster kidney cell vaccine was used as the control. Adverse reactions were monitored 0.5, 6, 24, 48, and 72 h post vaccination to assess safety. Neutralizing antibodies in venous blood were measured on day 7, 14, and 72 to evaluate the immunogenicity of the vaccine while follow-up monitoring continued for 1 month. No serious adverse reactions were observed in any volunteer. The incidence rates of systemic and local adverse reactions were, respectively, 10.6% and 2.9% in the test group and 20.0% and 13.6% in the control group. After the third injection, the positive conversion rates of antibodies in the test and control groups were 100% and 98.82%, respectively. In addition, the average antibody titers on day 7, 14, and 42, were respectively, 1.71, 2.72, and 1.29 times higher than those in the control group. These results indicate that HDCV had a better safety profile and higher immunogenicity than the hamster kidney cell rabies vaccine. Trial registration number: 20130602.

Adverse events in vaccinations for travelers - a 1-year prospective survey in a travel clinic in Germany.

The study goal was to assess and compare adverse events (AE) of current vaccinations for travelers under 'real-life conditions'. A prospective observational online questionnaire study was performed from May 2015 till April 2016 in a travel clinic in Germany. Online questionnaire links were sent 1 week after the first vaccination date. Severity was rated on a scale from 1 to 5 (minor to very severe AE). Of 1357 vaccinees 781 (57.6%) responded to the questionnaire, corresponding to 1415 vaccinations (1-7 simultaneous vaccinations). Responders were more often female (f:m = 1.29:1). Main age groups were 20-29 years old (36.1%). Most frequent vaccinations were against rabies (277; chick embryo cell vaccine (CEC): 97, human diploid cell vaccine (HDC): 180), yellow fever (250), typhoid fever (198), meningococcal meningitis (126) and Japanese encephalitis (104). A total of 217 vaccinees (27.8%) reported AE; 82 (10.5%) rated AE as more severe (grade 3: 61, grade 4: 18, grade 5: 3). No life-threatening AE was reported. Of 157 systemic AE the most frequent were: fatigue (75), headaches (46) and pyrexia (31). Of 94 local AE most frequently reported were pain (66), myalgia (25) and swelling (12). AE after single vaccinations were more often associated with rabies vaccine (OR 2.2; 1.2-4.2). AE increased with the number of simultaneous vaccinations (single vaccination: 24.1%, 88/365; 2 vaccinations: 26.6%, 73/274, ≥3 vaccinations: 39.4%, 56/142, χ2 = 12.24, P = 0.002, CCorr = 0.18), but more severe AE showed no association with the number of vaccinations (χ2 = 5.55, P = 0.06, CCorr = 0.12). Single and simultaneous vaccinations were overall well tolerated. AE were reported more frequently with rabies vaccinations in single vaccinations. Increased numbers of simultaneous vaccinations led to some incremental AE but not to more severe AE. Simultaneous vaccinations should be encouraged to reduce missed opportunities for immunizations.

Immediate Hypersensitivity Reaction Related to Rabies Post-Exposure-Prophylaxis in Thailand with Subsequent Rabies Vaccine Change to Avoid Polygeline Vaccine Excipient with Successful Challenge and Treatment Tolerance in the United States

Background Untreated rabies is fatal, globally killing 60,000 persons/years. Rabies vaccine (RV) is life-saving, of various types and used in high-risk rabies exposure (HRRE) as a post-exposure prophylaxis (PEP) series of initial (RV-i) and completion (RV-c) doses. Polygeline has been implicated in immediate allergic reactions to tick-borne encephalitis vaccine and is an excipient in Rabipur, a purified chick embryo vaccine (PCECV) as part of Thai Red Cross (TRC) RV protocol. In United States, RVs are Rabavert (PCECV), containing polygeline, and Imovax Rabies, a human diploid cell vaccine (HDCV) that does not. RV-associated adverse reactions occur up to 6% as mostly non-IgE/skin-limited or immune complex and rarely nonfatal anaphylaxis. We describe TRC-RV-immediate allergic reaction in a male child traveling in Thailand and how after his return to United States , we were able to overcome RV-PEP delays and demonstrate safe treatment tolerance with a different RV.Methods Review of literature, Thai/US RV and Allergy Protocols, Pink Book/RV InsertsResultsA healthy 4-years old US boy had HRRE from feral cat bite in Thailand with immediate disseminated hives at 1 hour post-TRC-RVi (Day 0), resolved with oral antihistamine. Upon US return (Days 3-8), clinicians stopped RV-PEP due to RV allergy fears; Day 6 rabies-immunoglobulin given. On Day 9, US academic Allergist/Infectious Disease referral done: no other medical problems found; HDCV skin prick test (negative); TRC-RV (not available); two-step HDCV-RV challenge performed (10%, then full); Days 13 and 20, HDCV-RV-c full tolerated; Days 30+, asymptomatic; serum tryptase 3.2 ng/ml; Rapid Fluorescent Foci Inhibition Test (RFFIT)Conclusion RV type I hypersensitivity reactions are uncommon, components to RVs vary worldwide and such adverse RV reactions should not stop RV-PEP. Analysis of vaccine content, exposures, and relevant testing is critical to deducing likely reaction type and candidate antigens as excipients in non-RVs and across RV types. IgE-vaccine tests may not be reliable/possible and mid-series RV change to non-polygeline type may be a viable option when RV-c must be done to reach timely RV-c-PEP treatment tolerance and avoid hypersensitivity reactions.Disclosures All authors: No reported disclosures.

Post-Marketing Surveillance of Human Rabies Diploid Cell Vaccine (Imovax) in the Vaccine Adverse Event Reporting System (VAERS) in the United States, 1990‒2015.

BackgroundIn 1980, human diploid cell vaccine (HDCV, Imovax Rabies, Sanofi Pasteur), was licensed for use in the United States.ObjectiveTo assess adverse events (AEs) after HDCV reported to the US Vaccine Adverse Event Reporting System (VAERS), a spontaneous reporting surveillance system.MethodsWe searched VAERS for US reports after HDCV among persons vaccinated from January 1, 1990–July 31, 2015. Medical records were requested for reports classified as serious (death, hospitalization, prolonged hospitalization, disability, life-threatening-illness), and those suggesting anaphylaxis and Guillain-Barré syndrome (GBS). Physicians reviewed available information and assigned a primary clinical category to each report using MedDRA system organ classes. Empirical Bayesian (EB) data mining was used to identify disproportional AE reporting after HDCV.ResultsVAERS received 1,611 reports after HDCV; 93 (5.8%) were serious. Among all reports, the three most common AEs included pyrexia (18.2%), headache (17.9%), and nausea (16.5%). Among serious reports, four deaths appeared to be unrelated to vaccination.ConclusionsThis 25-year review of VAERS did not identify new or unexpected AEs after HDCV. The vast majority of AEs were non-serious. Injection site reactions, hypersensitivity reactions, and non-specific constitutional symptoms were most frequently reported, similar to findings in pre-licensure studies.

Reduction in Corticosteroid Use Among Patients Receiving Omalizumab in Real World Settings: A Systematic Literature Review of Non-Randomized Studies

Sarah W. Spriet, DO, Taylor A. Banks, MD, Cecilia Mikita, MD, MPH, FAAAAI; Walter Reed National Military Medical Center, Bethesda, MD. RATIONALE: Rabies post-exposure treatment is a medical necessity. Two rabies vaccines are available in the United States; purified chick embryo cell culture vaccine (PCECV, RabAvert ) and gelatin-free human diploid cell vaccine (HDCV, Imovax ). We report a case of PCECV-triggered anaphylaxis. METHODS: After clinical evaluation, patient and a volunteer control underwent skin prick and intradermal testing to the rabies vaccines, vaccine components, and rabies immunoglobulin. Vaccine challenge was then performed. RESULTS: A healthy 15 year old male presented to the Emergency Department after a live bat was found in his home, captured, and found to have rabies.Mucousmembrane exposure could not be ruled out and human rabies immunoglobulin (ImogamRabies – HT ) and PCECVwere administered. Within minutes, he developed dyspnea, stridor and generalized hives. Symptoms resolved within one hour after treatment with antihistamines and IV corticosteroids and he was referred to AllergyImmunology. On day 3 post-exposure, patient and control underwent skin prick testing to undiluted PCECV, egg, gelatin, HDCVand Imogam. Skin prick was positive to PCECV and gelatin. Intradermal testing (IDT) using 0.02 mL of 1:100 dilution to HDCV and Imogam was negative. IDT using 0.02 mL of 1:10 dilution was negative to Imogam, positive to HDCV; however, considered an irritating dose given identical results in control. Patient tolerated a 10/90 challenge to HDCV and completed post-exposure series using this vaccine. CONCLUSIONS: Skin test results and successful challenge to HDCV suggest gelatin allergy. Awareness of the potential for IgE-mediated reactions to rabies vaccine is important. Challenge to HDCV should be considered in select patients.

Infectious Diseases Associated with Caves

In recent times, caving has become increasingly popular, with almost 2 million people visiting national park caves each year in the United States. Although the 2 million tourist visits are extremely low risk, smaller numbers of sport cavers are at risk for some high risk conditions, and expedition cavers are at risk for some obscure infections. Infectious diseases like histoplasmosis, rabies, leptospirosis, and tick-borne relapsing fever may be transmitted by the underground fauna. To reduce the risk of illness or injury while caving, knowledge of potential risks before engaging in this activity is important. Caving preparation needs to be carefully planned and executed, including vaccinations, prophylactic medications, and advice regarding safe conduct and behaviors.

Rabies-Prevention Policy Update: New Reduced-Dose Schedule

The Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention recommends reducing the number of doses from 5 to 4 of human diploid cell vaccine or purified chick embryo cell vaccine required for postexposure prophylaxis to prevent rabies in humans. The vaccine doses should be given on day 0 (first day of prophylaxis) and days 3, 7, and 14 after the first dose. For persons with immune suppression, the 5-dose regimen should continue to be used. Recommendations for the use of human rabies immunoglobulin remain unchanged. The American Academy of Pediatrics endorses these recommendations.

Assessing the relationship between antigenicity and immunogenicity of human rabies vaccines when administered by intradermal route

The metadata of 10 published studies and 3 vaccine trial reports comprising of 19 vaccine cohorts from four countries conducted over a period of 23 years (1986 - 2009) was used for metaanalysis. The vaccines studied were purified chick embryo cell vaccine (Rabipur, India & Germany), purified vero cell rabies vaccine (Verorab, France; Indirab, India) & human diploid cell vaccine (MIRV, France).The potency of these vaccines varied from 0.55 IU to 2.32 IU per intradermal dose of 0.1ml per site. The vaccines were administered to 1011subjects comprising of 19 cohorts and using five different ID regimens. The immunogenicity was measured by assays of rabies virus neutralizing antibody (RVNA) titres using rapid fluorescent focus inhibition test (RFFIT) [15 cohorts] and mouse neutralization test (MNT) [4 cohorts]. The statistical analysis of the data was done by Karl Pearson’s correlation coefficient to measure the relationship between antigenicity and immunogenicity. It was revealed that, there was no significant linear relationship between antigenicity and immunogenicity of rabies vaccines when administered by intradermal route. (p> 0.230 and p>0.568)

Preventing rabies with the Verorab ® vaccine: 1985–2005 : Twenty years of clinical experience

Purified rabies vaccine cultured on Vero cells (Verorab, sanofi pasteur) is WHO-approved for pre- and post-exposure prophylaxis by intradermal and intramuscular routes. During 20 years of use, over 40 million doses of Verorab have been administered in more than 100 countries. No serious adverse event due to Verorab has been reported in clinical trials involving 3937 persons, and Verorab is better tolerated than human diploid cell vaccine (HDCV). Pre-exposure prophylaxis is confirmed immunogenic in 1437 subjects by all routes, with prompt responses following boosting; Verorab boosts effectively subjects pre-immunized with HDCV. Unlike HDCV, Verorab is not associated with post-boosting serum sickness. In the absence of data in immunodeficient/HIV-positive individuals, pre-exposure immunization is urged as early as possible. Essen, Zagreb, Thai Red Cross Intradermal (TRC-ID) and other post-exposure intramuscular and intradermal regimens are documented. Two thousand one hundred and eighty-three subjects received post-exposure prophylaxis, including 874 high risk, severe or confirmed rabid attacks. Co-administration of rabies immune globulin (RIG) does not affect neutralizing antibody levels when Essen or TRC-ID regimens are employed; levels are lower with the Zagreb regimen. Verorab has been administered safely and effectively post-exposure to 251 pregnant women, without any increase in congenital malformations or spontaneous abortions. From a pediatric perspective, safety and efficacy have been demonstrated in 759 children (0-15 years). Intradermal post-exposure Verorab is an effective and inexpensive option for developing countries. Inadvertent subcutaneous administration does not reduce immunogenicity. WHO already strongly recommends the replacement of nerve tissue vaccines with modern vaccines. Extensive clinical experience supports the use of Verorab for intramuscular and intradermal pre- and post-exposure prophylaxis, including in special situations.

Immunogenicity of Two Modern Tissue Culture RabiesVaccines in Pre-Exposure Prophylaxis

Pre-exposure prophylaxis was given to employees supposed to be involved in rabies vaccine production in India. Prior to availability of the manufacturer’s own human diploid cell (HDC) vaccine (Rabivax®), immunization was executed with a chick embryo cell (CEC) vaccine (Rabipur®). This constellation gave an opportunity to compare retrospectively immunogenicity of these two vaccines. The data was collected by retrospective analysis over more than 3 years at the clinic of Serum Institute of India Ltd. As per the standard protocol, persons with negative rabies vaccination history receive a dose of 1 ml of rabies vaccine intramuscularly on day 0, 7 and 28, and the virus anti-glycoprotein antibodies are measured one month after the third dose. The antibody levels ≥ 0.5 IU/ml are considered protective. The CEC and HDC vaccines were used during the analysis period. In all, 43 individuals received the CEC vaccine, 106 the HDC vaccine. The mean age of recipients was 33 years 5 months (Rabipur®) and 30 years 3 months (Rabivax®). All subjects in both groups were males. Five commercial batches of the CEC vaccine (129 doses) and seven batches of the HDC vaccine (318 doses) were used. 99% of the HDC and 93% of the CEC vaccine recipients were protected after the standard 3 dose schedule. Geometric mean titre was significantly greater for the HDC than CEC vaccine, being 5.05 IU/ml and 2.90 IU/ml, respectively (P=0.0002). The HDC vaccine showed a good lot-to-lot consistency with respect to GMT both by ANOVA test and Nonparametric ANOVA test. On the other hand, the CEC vaccine demonstrated a variation in titres, when the lots were compared. Three out of four low-responders accepted a booster vaccination, and regardless of whether Rabipur® or Rabivax® was used, all three responded well 1 month after the booster. The Indian HDC vaccine compares well with the CEC vaccine in terms of immunogenicity. With HDC vaccines, cost has been an issue. However, since the new HDC vaccine has a comparable cost to the CEC vaccine, it may be possible to use it in large-scale vaccinations.

Rabies Antibody Seroprotection Rates Among Travelers in Nepal: “Rabies Seroprotection in Travelers”

Rabies preexposure immunization is recommended for international travelers who are at risk for exposure to rabid animals, especially in areas where postexposure treatment may be limited. Rabies antibody seroprotection rates among international travelers has not been previously investigated. To assess preexisting rabies seroprotection among travelers presenting to a health clinic in Nepal. A prospective convenience sample of international travelers evaluated at a health center in Kathmandu, Nepal during a 2-month period. Subjects were eligible for inclusion if they had received rabies preexposure vaccination within the previous 5 years. Demographic information and vaccination records of rabies preexposure prophylaxis were obtained. Consenting subjects provided serum for rabies antibody measurement measured using the rapid fluorescent focus inhibition test. A dilution greater than or equal to 1:5 (0.5 IU/mL) was considered positive. Data were analyzed using chi-squares and two-sample t-tests with unequal variances. A total of 43 patients consented to enroll. Complete data were available for 38 patients. Subjects had received human diploid cell vaccine (HDCV) or purified Vero cell rabies vaccine (PVRV) vaccine, either via the intradermal or intramuscular route. All patients had adequate antibody titers except one, who had a titer below 0.5 IU/mL. There was no statistically significant relationship between antibody titer and type of vaccine, route of administration, time since vaccination, number of vaccinations, or patient age. Among 38 travelers to Nepal who had received documented preexposure rabies HDCV or PVRV vaccination series, 37 demonstrated adequate titers of > or =0.5 IU/mL and would be considered boostable if exposed to rabies virus. One traveler had a titer of <0.5 IU/mL. Type of vaccine, method of administration, number of vaccinations, and time since vaccination did not influence rabies antibody titer. Rabies vaccination with HDCV and PVRV vaccine was effective in stimulating adequate seroprotection in this sample of travelers.

Safety and Immunogenicity of a New Chromatographically Purified Rabies

Although human diploid cell vaccine (HDCV) has been available for over two decades and has a proven record of efficacy, it is very expensive to produce and can only be made in small quantities. In this trial, we compared the safety and immunogenicity of a new, chromatographically purified rabies vaccine (CPRV) with those of HDCV. One hundred and thirty-five healthy veterinary students were randomized in a 2:1 ratio between CPRV and HDCV respectively. Each student subsequently received an intramuscular injection of 0.5 mL of CPRV or 1mL of HDCV on days 0, 7, and 28, according to the standard preexposure regimen. Local safety data were collected for 7 days following each dose and systemic safety data for 42 days following the first dose. Vaccine administration and safety evaluation were performed by different site personnel. Sera for immunogenicity analysis were collected on days 0 (prevaccination), 28 and 42. All subjects achieved an antirabies antibody titer greater than or equal to the World Health Organization (WHO) accepted threshold level of seroconversion of 0.5 IU/mL after only two of three doses of vaccine in both groups. The geometric mean titers (IU/mL) in the CPRV and HDCV groups respectively were 6.54 (range 0.50 to 64.80) and 10.22 (range 0.70 to 51.40) on day 28, and 40.51 (range 5.40 to 278.00) and 37.71 (range 5.40 to 278.00) on day 42. The percentage of subjects experiencing local reactions within 3 days after any dose ranged from 65.2% to 80.9% in the CPRV group and from 77.3% to 84.4% in the HDCV group. The local reaction reported by the greatest percentage of subjects after each dose was pain/tenderness at the injection site, and most reactions were mild. Most of the reported local reactions resolved within 0 to 3 days postvaccination. Systemic reactions decreased from 76.4% after dose 1 to 36.0% after dose 3 in the CPRV group, and similarly from 55.6% to 31.8% in the HDCV group. For all postdose periods, the systemic reaction reported by the highest percentage of subjects was myalgia. No subjects experienced an immediate local or systemic reaction. In healthy adults, vaccination with CPRV using a preexposure schedule resulted in a safety and immunogenicity profile similar to that of HDCV.

The effectiveness of intradermal pre-exposure rabies vaccination in an Australian travel medicine clinic.

The objective of the study was to assess the effectiveness of intradermal (ID) rabies vaccination and to determine whether any difference in response with age or gender exists. No published Australian data on the subject is available and controversy continues to surround the use of ID rabies vaccination for pre-exposure prophylaxis. Vaccinated travelers requiring postexposure treatment are sometimes considered unvaccinated. By confirming their immunity prior to travel, this problem may be avoided. The data was collected by retrospective analysis over 2 years at a specialized travel medicine clinic in Perth, Western Australia. The standard protocol is three ID injections of 0.1 mL, given on days 0, 7, and 28 with a booster after 12 months. The vaccine used was the Pasteur Merieux human diploid cell vaccine. Serology was performed 3 weeks after completion of the primary course or after a booster. Antibody levels were measured using the rapid fluorescent focus inhibition test, and levels of >0.5 IU/mL were considered protective. A total of 164 travelers were included in the study, of which 144 had completed the three primary ID doses, and 20 had received an ID booster after a previous primary ID course. The mean age was 34.75 years, and gender distribution was equal. The median time between vaccination and serology was 23 days. The antibody levels ranged from 0 to 50 IU/mL with a mean of 8.42 IU/mL. Three travelers had no detectable antibodies giving a seroconversion rate of 98.2%. No statistically significant correlation between age or gender and antibody levels was present. We have found that ID rabies vaccination is effective in a travel clinic with nurses experienced in the technique. The lower cost of ID rabies vaccination makes it accessible to a larger number of travelers. Further studies will be required to determine the duration of protection after ID vaccination and antibody response after postexposure boosters. We will continue to recommend ID rabies vaccination if there is sufficient time for serology to be performed and for results to be available prior to departure.

Assessing the Relationship between Antigenecity and Immunogenecity of Human Rabies Vaccines: Results of a Meta-Analysis

A meta-analysis was done to study the relationship between antigenecity and immunogenecity of human rabies vaccines. The data of ten cell culture human rabies vaccine studies conducted at a single center during 1993- 2004 was used in the study. The vaccines studied included Purified Chick Embryo Cell Vaccine (Kaketsuken, Japan and Rabipur, India), Purified Vero cell Rabies Vaccine (Verorab, France), Human Diploid Cell Vaccine (MIRV, France and Rabivax, Adsorbed and Lyophilized, India) and Rhesus Diploid Rabies Vaccine (adsorbed, USA). Interestingly, it was revealed that an higher antigenecity of rabies vaccines viz. potency of ? 5 IU per single intramuscular dose did not result in significantly higher immunogenecity, as measured by rabies virus neutralizing antibody (RVNA) titers in the vaccinees, both on day14 (t=0.42, p> 0.66, GMR=1.06, 95%CI of GMR=0.82, 1.37) and day 90 (t = 0.80, p > 0.43, GMR=1.15, 95%CI of GMR=0.74, 1.14). However, as there are no reports of meta-analysis of cell culture human rabies vaccine trials, to confirm this observation the authors recommend further studies in this regard.