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.     

Safety and immunogenicity of a new purified vero cell rabies vaccine (PVRV) administered by intramuscular and intradermal routes in healthy volunteers

Background

Rabies is 100% fatal but preventable with modern vaccines and immunoglobulins. There is a huge demand for rabies vaccines in developing countries of Asia and Africa. We have developed a new purified vero cell rabies vaccine (PVRV) and evaluated its safety and immunogenicity in healthy volunteers by intramuscular (IM) and intradermal (ID) routes of vaccination.

Methodology

Sixty adults aged between 18 and 50 years were recruited in this actively controlled Phase I clinical study and were randomized to receive three 1 ml or 0.1 ml doses of new PVRV intramuscularly or intradermally on days 0, 7 and 21. The control group received commercially available PVRV (Verorab) by intramuscular route. Adverse events (AEs) were recorded with diary cards till day 28 post-vaccination. Immunogenicity was assessed on day 0, 7, 21 and 42 by rapid fluorescence focus inhibition test (RFFIT).

Results

In all, 116 solicited local and systemic events were reported across the three groups. Most were mild and resolved without sequelae. Also the few unsolicited events, deemed unrelated to the study vaccines, caused no problems. No significant changes in the routine laboratory parameters were found. Two doses of a vaccine elicited protective titres (≥0.5 IU/ml) in all subjects, the GMTs varying between 0.57 and 0.69 IU/ml on day 7, 3.07 and 3.97 IU/ml on day 21, and 6.12 and 8.52 IU/ml on day 42 post-vaccination.

Conclusions

PVRV was well tolerated and showed good immunogenicity regardless of whether administered intramuscularly or, using a tenth of that volume, intradermally. Further studies with this new vaccine are warranted.     

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.     

A randomized non-inferiority clinical study to assess post-exposure prophylaxis by a new purified vero cell rabies vaccine (Rabivax-S) administered by intramuscular and intradermal routes

BackgroundRabies is a 100% fatal disease but preventable with vaccines and immunoglobulins. We have developed a new purified vero cell rabies vaccine (Rabivax-S) and evaluated its safety and immunogenicity in post-exposure prophylaxis by intramuscular (IM) and intradermal (ID) routes.MethodsThis was a randomized active-controlled non-inferiority study in 180 individuals (age 5 years and above) with suspected rabies exposure (90 each with WHO Category II and Category III exposures). The participants received either Rabivax-S (1 mL IM; five doses), Rabivax-S (0.1 mL ID; eight doses) or purified chick embryo cell vaccine (PCEC, Rabipur®) (1 mL IM; five doses). The IM doses were given on Day 0, 3, 7, 14 and 28 while the ID doses were given on days 0, 3, 7 and 28. Category III patients also received a human rabies immunoglobulin (HRIG) on Day 0. Adverse events (AEs) were recorded with diary cards till day 42. Rabies neutralizing antibody levels were measured on day 0, 7, 14, 28 and 42.ResultsIn both the category II and III patients, the geometric mean concentration (GMC) ratios of Rabivax-S IM and Rabivax-S ID groups to PCEC IM were more than 1, thus proving the non-inferiority. GMCs were similar or higher in Rabivax-S groups at all the time points. Seroresponse against rabies (RFFIT titre ⩾ 0.5 IU/mL) was achieved in all participants. Mostly mild local and systemic adverse events were reported across the three groups and all resolved without sequelae.ConclusionsRabivax-S was well tolerated and showed immunogenicity comparable to a licensed rabies vaccine by both IM and ID routes in post-exposure prophylaxis.Registry No.: CTRI/2012/11/003135     

Enhancing comparative rabies DNA vaccine effectiveness through glycoprotein gene modifications

Enhancing DNA vaccine effectiveness remains a challenge, especially if the desired goal is immunization efficacy after a single dose. The glycoprotein gene from the rabies virus Evelyn–Rokitnicki–Abelseth (ERA) strain was modified by mutation at amino acid residue 333 from arginine to glutamine. The modified and original unmodified glycoprotein genes were cloned separately and developed as DNA vaccines for immunization in mice. The intramuscular (IM) route using a single dose (100 μg) of a modified DNA vaccine showed virus neutralizing antibody induction by d30, and 80% of the mice survived a challenge in which 100% of unvaccinated controls succumbed. Similar results were obtained using a single dose (10 μg) by the intradermal (ID) route with one-tenth amount of the DNA administered. Administration of single dose of DNA vaccine with unmodified G did not result in the production of detectable levels of virus neutralizing antibody by d30. The results of the IM and the ID routes of administration were statistically significant (P < 0.01). Based on these preliminary results, a modified glycoprotein gene from the ERA rabies virus strain may be an ideal candidate for DNA vaccine efficacy enhancement.     

Rabies neutralizing antibody after 2 intradermal doses on days 0 and 21 for pre-exposure prophylaxis

Pre-exposure prophylaxis is recommended for people who will be exposed to rabies virus in the laboratory or who will contact with mammals. World Health Organization recommends 2 doses of a cell-culture rabies vaccine given 1 week apart, and a third booster dose given 2–3 weeks later. Neutralizing antibody response is virtually 100%, and the individual remains sensitized indefinitely. Intradermal pre-exposure regimen for rabies prophylaxis is more economical compared with the conventional intramuscular regimen in terms of vaccine volume. However, both regimens require three clinic visits. In order to reduce non-medical expenses such as transportation to the clinics and to increase compliance, the immunogenicity and safety of two-visit intradermal regimen for pre-exposure prophylaxis were studied. Fifty-five healthy subjects aged between 18 and 24 years were enrolled and divided into two groups. Group A (n = 39) received 0.1 ml of purified Vero cell rabies vaccine (PVRV; Sanofi Pasteur, Lyon, France; Lot no. Z0996 with an antigenic value of 4.8 IU/0.5 ml vial) intradermally each at two sites on days 0 and 21. Group B (n = 16) received 0.5 ml of PVRV intramuscularly on days 0, 7 and 21, as conventional intramuscular regimen for pre-exposure prophylaxis. Rabies neutralizing antibody (Nab) titers were measured on days 0, 35, 365 and 379 (14 days after simulated post-exposure booster vaccination). All subjects from two groups had Nab titers ≥0.5 IU/ml on day 35. In addition, the difference between geometric mean titers for group A (4.51 IU/ml; range of Nab titers 1.69–13.0 IU/ml) and group B (6.74 IU/ml; range of Nab titers 2.20–14.23 IU/ml) on day 35 was not statistically significant (p > 0.05). One year after pre-exposure vaccination, all subjects in both groups received simulated post-exposure booster vaccination with 0.1 ml of PVRV ID on days 0 and 3 (day 365 and day 368 after pre-exposure vaccination). After simulated booster vaccinations with 0.1 ml PVRV ID on days 0 and 3, all subjects in groups A (GMT 14.38 IU/ml; range 2.99–308.44 IU/ml) and in group B (GMT 14.06 IU/ml; range 3.12–62.09 IU/ml) had rabies Nab titers ≥0.5 IU/ml on day 14 post-booster (p > 0.05). Mild local adverse events such as pain at injection site, pruritus and erythema were observed. Our study indicated that 2-site intradermal pre-exposure regimen on days 0 and 21 with 0.1 ml of cell-culture rabies vaccine is safe and immunogenic as the conventional intramuscular regimen.     

Safety and immunogenicity of two freeze-dried Vero cell rabies vaccines for human use in post-exposure prophylaxis

To provide basis for human rabies vaccination in China, the safety and immunogenicity of two freeze-dried Vero cell rabies vaccines for human use were assessed. A total of 250 volunteers were enrolled and divided into two groups: volunteers in Group A (n = 200) were vaccinated five doses of Speeda Vero cell rabies vaccine manufactured by Liaoning Chengda Biotechnology Co. Ltd. on day 0, 3, 7, 14, 28 after exposure. Volunteers in Group B (n = 50) were treated with Verorab Vero cell rabies vaccine manufactured by Sanofi Pasteur on the same schedule. The local and systematic adverse reactions were observed. Serum neutralizing antibody levels of 80 individuals in Group A and 50 individuals in Group B were tested with RFFIT on day 7, 14, 45, 180, 360 after the first dose. The seroconversion rates in Groups A and B were 40.3% and 37.0% on day 7 after the first dose, 95.5% and 97.7% on day 14, 100% and 100% on day 45, 100% and 100% on day 180, 89.1% and 89.5% on day 360 respectively, indicating no significant differences between the two groups. And no significant differences were found between the neutralizing antibody geometric mean titers (GMTs) of the two groups on day 7, 14, 45, 180 and 360 after the first dose, with the GMTs of day 14, 45, 180 and 360 all higher than 0.5 IU/ml. Antibody levels of the two groups peaked around 2 weeks after the full vaccination program, followed by a 55% decrease up to day 180 and another 76% decrease up to day 360. Both groups experienced occasions of transient fever, rash, edema, and scleroma after vaccination. Neither group had any severe adverse reactions. It was concluded that both vaccines showed satisfactory safety and immunogenicity. Booster vaccination is recommended following another exposure after six months since the full vaccination program.     

Safety and efficacy of novel dermal and epidermal microneedle delivery systems for rabies vaccination in healthy adults

In the present pilot study, intradermal ID delivery systems with a BD microneedle from 1 to 3 mm in length, and epidermal delivery (BD skin abrader) through abraded skin surface relative to standard intramuscular injection were evaluated. Circulating neutralizing antibodies were measured against the rabies virus after the Vero cells rabies vaccine was administered at D0, D7, D21 and D49. This clinical evaluation in 66 healthy volunteers shows that ID delivery using BD microneedle technology of 1/4 the IM antigen dose is safe, efficient and reliable, resulting in a protective seroconversion rate. In contrast, the epidermal delivery route did not produce an immune response against the rabies vaccine.     

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,tolerability and efficacy of intradermal rabies immunization with DebioJect™

In a single-center study, 66 healthy volunteers aged between 18 and 50 years were randomized to be immunized against rabies with three different injection routes: intradermal with DebioJect™ (IDJ), standard intradermal with classical needle (IDS), also called Mantoux method, and intramuscular with classical needle (IM). “Vaccin rabique Pasteur®” and saline solution (NaCl 0.9%) were administered at D0, D7 and D28. Antigen doses for both intradermal routes were 1/5 of the dose for IM. Tolerability, safety and induced immunogenicity of IDJ were compared to IDS and IM routes. Pain was evaluated at needle insertion and at product injection for all vaccination visits. Solicited Adverse Event (SolAE) and local reactogenicity symptoms including pain, redness and pruritus were recorded daily following each vaccination visit. Adverse events (AE) were recorded over the whole duration of the study. Humoral immune response was measured by assessing the rabies virus neutralizing antibody (VNA) titers using Rapid Fluorescent Focus Inhibition Test (RFFIT). Results demonstrated that the DebioJect™ is a safe, reliable and efficient device. Significant decreases of pain at needle insertion and at vaccine injection were reported with IDJ compared to IDS and IM. All local reactogenicity symptoms (pain, redness and pruritus) after injection with either vaccine or saline solution, were similar for IDJ and IDS, except that IDJ injection induced more redness 30 min after saline solution.No systemic SolAE was deemed related to DebioJect™ and classical needles. No AE was deemed related to DebioJect™. No Serious Adverse Event (SAE) was reported during the study.At the end of the study all participants were considered immunized against rabies and no significant difference in humoral response was observed between the 3 studied routes.     

Immunogenicity and safety of intradermal versus intramuscular route of influenza immunization in infants less than 6 months of age: A randomized controlled trial

We aimed to explore intradermal influenza vaccination in infants <6 months. One hundred twenty-six infants 2–3 months of age were randomized to receive either two doses, 1 month apart, of 0.25 ml of a trivalent inactivated influenza vaccine (7.5 μg of hemagglutinin per strain) via the intramuscular (IM) route or 0.1 ml of the same vaccine (3 μg of hemagglutinin per strain) via the intradermal (ID) route. The vaccine was well tolerated. Only four infants had hemagglutination inhibition (HAI) titer <40 against ≥1 vaccine-covered antigen pre-vaccination. There was no difference in fold-rise of HAI titer response between those in the IM or ID group. We documented maintenance of HAI titers above seroprotective levels against all three vaccine antigens in 97.6% of subjects regardless of vaccination methods over a time of waning maternal antibodies.     

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.     

The immunogenicity of intradermal influenza vaccination in COPD patients

We evaluated the immunogenicity of a reduced-dose intradermal trivalent, inactivated, split-virion seasonal influenza vaccine compared to that of a conventional intramuscular vaccination in chronic obstructive pulmonary disease (COPD) patients. One hundred and fifty-six COPD patients randomly received either 0.2 ml (6 μg hemagglutinin (HA) per strain) split into two-site intradermal (ID) injections or a single 0.5 ml (15 μg HA per strain) intramuscular (IM) injection. Geometric mean titers, seroconversion factors, seroconversion rates and seroprotection rates at 4 weeks post-vaccination in the ID group were less than those in the IM group. Only the seroconversion factor to influenza B in the ID group was statistically less than in the IM group (18.8 in the ID group, n = 81 versus 37.3 in the IM group, n = 75, p = 0.045). Nevertheless, each strain of the ID vaccination met all the Committee for Proprietary Medicinal Products (CPMP) criteria. Seroprotection rates were above 60% throughout the year in influenza A (H3N2), for at least 6 months in influenza A (H1N1) and at least 4 weeks in influenza B in both ID and IM groups. The reduced-dose intradermal vaccination may be considered for use in COPD patients in a vaccine shortage situation.     

Immunogenicity, safety and lot consistency in adults of a chromatographically purified Vero-cell rabies vaccine: a randomized, double-blind trial with human diploid cell rabies vaccine

The immunogenicity and safety of a chromatographically purified rabies vaccine (CPRV) was evaluated using US veterinary medical students. In the first study, 242 healthy adults were enrolled in a randomized, modified double-blind, multicenter trial and received five doses of either CPRV or human diploid cell vaccine (HDCV) by intramuscular injection on days 0, 3, 7, 14, and 28 concurrently with human rabies immunoglobulin in a simulated post-exposure prophylaxis regimen. Post-immunization titers in the CPRV and HDCV groups reached 0.5 IU/ml (the WHO-recommended minimally acceptable titer) or greater in all subjects in both vaccine groups by day 14 and remained above that level through day 90. In the second study, 438 healthy adults were enrolled in a randomized, double-blind, multicenter trial and assigned to receive five doses from one of three lots of CPRV by intramuscular injection on days 0, 3, 7, 14, and 28 in a simulated post-exposure prophylaxis regimen to evaluate lot consistency. Post-immunization titers rapidly increased to over 0.5 IU/ml by day 14 for all subjects and remained above that level through day 42 when the study was terminated. The three lots were considered equivalent. The percentage of subjects with at least one local reaction during the five-dose regimen was slightly lower in the CPRV group than in the HDCV group (P=0.06). The most frequently reported local reaction for all doses of vaccine was pain at the injection site. Headache, myalgia, and malaise were the most frequently reported systemic events. The percentage of subjects with at least one systemic event was significantly lower for CPRV (P=0.0084). No vaccine-related serious adverse reaction was reported in these studies. The results of these studies indicate that CPRV administered intramuscularly to healthy adults is immunogenic and is associated with fewer local and systemic reactions than HDCV.     

A randomized open-label trial of 2-dose or 3-dose pre-exposure rabies prophylaxis among Thai children

BackgroundWorld Health Organization changed the recommendation for pre-exposure rabies prophylaxis from 3-dose to 2-dose regimen in 2018. Given limited data of 2-dose regimens in pediatric population, this study aimed to compare the immunogenicity between 2-dose and 3-dose pre-exposure rabies immunization.MethodsThis study was conducted among healthy children aged 2–12 years. They were randomized to 2-dose vaccination (2D) on days 0 and 28 or 3-dose vaccination (3D) on days 0, 7, and 28. Purified Vero cell rabies vaccine (PVRV-Verorab™) was administered intramuscularly. Rabies virus neutralizing antibody (RVNA) titers were measured at 3 time points: 14-day after complete vaccination, 1-year pre-booster vaccination, and 7-day post-booster dose to mimic scenario of rabies exposure. RVNA titers ≥0.5 IU/ml were considered adequate antibody. T cell specific response to rabies vaccine antigen was measured using the interferon-gamma enzyme linked immunospot assay.ResultsFrom September to October 2017, 107 participants (51% males), 78 in 2D group and 29 in 3D group were enrolled. Median age was 5.8 years (IQR 4.4–7.3). All participants had RVNA titers ≥0.5 IU/ml after primary vaccination [GMT 2D: 18.6 (95%CI 15.9–21.8) and 3D: 16.3 (95%CI 13.2–20.1 IU/ml), p = 0.35]. At 1-year prior to receiving the booster, only 80% of the children in 2D group maintained RVNA titers ≥0.5 IU/ml compared to 100% of the children in 3D group (p = 0.01). However, all participants in both groups had RVNA ≥0.5 IU/ml at 7-day post booster vaccination [GMT 2D: 20.9 (95%CI 17.4–25.3) and 3D: 22.2 (95%CI 15.8–31.4) IU/ml (P = 0.75)]. The median number of IFN-γ secreting cells at 7-day post-booster dose was 98 and 128 SFCs per 10⁶ PBMCs in the 2D and 3D groups, respectively (P = 0.30).ConclusionsTwo-dose primary rabies immunization provided adequate antibody at post primary vaccination and post booster. The results support 2-dose regimen of pre-exposure rabies immunization in the pediatric population.     

A phase I evaluation of inactivated influenza A/H5N1 vaccine administered by the intradermal or the intramuscular route

In a phase I clinical trial, one hundred healthy young adults were randomized to receive two doses 28 days apart of an inactivated, subvirion vaccine containing 15 or 45 μg of influenza A/H5N1 hemagglutinin (HA) by the intramuscular (IM) route, or 3 or 9 μg of H5 HA by the intradermal(ID) route. Seventy-seven subjects received a third dose. All regimens were safe and well tolerated. Antibody responses after two or three doses were low (≤20% or ≤38%, respectively) and similar in groups given 3 or 9 μg ID or 15 μg IM, and were significantly lower than those given 45 μg IM. Higher dosages of H5 HA and/or inclusion of adjuvant will be required to enhance immunogenicity by the ID route.     

Incidence and variables associated with inadequate antibody titers after pre-exposure rabies vaccination among veterinary medical students

Background

This study sought to determine the proportion of subjects with inadequate antibody titers at two years after pre-exposure rabies vaccination and identify variables associated with inadequate antibody titers.

Methods

A retrospective chart review of vaccination records of veterinary students in Michigan, 2004–2009, was conducted. Antibody titers <0.5 IU/ml as estimated by rapid fluorescent focus inhibition test were classified as inadequate. Variables were compared between the two groups to identify factors associated with inadequate titers at two years.

Results

A total of 603 subjects (mean age 24.1 ± 4.2 years, male:female 106:497) were included. Nearly one third (177/603, 29.4%) had inadequate titers at two years. Male gender (adjusted odds ratio (AOR) 1.87, 1.07–3.27; p = 0.029), vaccine manufacturer (AOR 1.49, 1.16–1.92; p = 0.002), BMI >25 (AOR 1.61, 1.02–2.54; p = 0.043), and duration between first and third doses of vaccine >21 days (AOR 2.49, 1.26–4.97; p = 0.009) were independently associated with inadequate titers.

Conclusions

Twenty-nine percent of subjects had inadequate antibody titers against rabies at 2 years. Gender, vaccine type/manufacturer, BMI of 25 or greater, and more than 21 days between the first and third doses of vaccine were independently associated with inadequate antibody titers at two years. Our data would support modifying the recommendations, so the third dose is recommended at 21 days rather than 21–28 days.     

人用Vero细胞狂犬病疫苗暴露前免疫的安全性和免疫效果观察

目的为观察人用Vero细胞狂犬病疫苗暴露前免疫程序的安全性和效果。方法征集志愿者65人,暴露前接种3剂人用Vero细胞狂犬病疫苗,分别于第0d、7d、28d肌内注射。次年第1针免疫后的第365d加强1剂。用小鼠脑内中和试验测定其抗狂犬病病毒抗体。结果所有志愿者均未出现局部反应、全身反应和严重不良反应。65名志愿者在第1次接种前,除1名血清抗体为0.5IU/ml外,其余均未测出抗体。第45d、365d、385d的血清抗体阳转率分别为100.00%、90.57%、100.00%,几何平均滴度分别为12.82IU/ml、1.57IU/ml、40.49IU/ml。结论人用Vero细胞狂犬病疫苗在暴露前免疫程序安全且效果好。     

Neutralizing antibody response after intradermal rabies vaccination in hemodialysis patients

Abnormal immune function in chronic hemodialysis (HD) patients could impair immunologic responsiveness to various vaccinations. Such inadequate response makes the HD patients to be at risk of certain fatal but preventable diseases including rabies. Although the effectiveness of rabies vaccination has been established in healthy subjects, the responsiveness of the current rabies vaccination has never been examined in HD patients. The effectiveness of post-exposure rabies vaccine was assessed in 20 stable thrice-a-week chronic HD patients who received adequate dialysis and did not have history of rabies vaccination during the last 20 years. All participants received the standard intradermal Thai Red Cross post-exposure rabies vaccination. Blood samples were obtained for determination of rabies neutralizing antibody (Nab) before the first dose (day 0) and on days 14 and 90 after vaccination. Prior to simulated vaccination, six of twenty patients already had Nab titers above the protective levels of 0.5 IU/mL while the remaining fourteen patients showed undetectable Nab. All subjects reached Nab titers above 0.5 IU/mL(acceptable level for rabies protection) by days 14 after vaccination. The geometric mean titers (GMTs) on days 14 after vaccination were 3.2 + 3.1 IU/mL (range 0.81–9.17 IU/mL). At day 90 after vaccination, 13 of 14 patients had Nab titers above the protective levels, resulting in the response rate of 92.8%. The GMTs of Nab on day 90 after vaccination were 5.09 + 1.79 IU/mL (0.42–25.0 IU/mL). There were no correlations between Nab titers and patient characteristics. No serious adverse reactions were detected. In conclusion, chronic HD patients receiving adequate dialysis have excellent protective immunological response after intradermal post-exposure rabies vaccination as WHO recommendation.