Human Diploid Cell Rabies Vaccine Research Articles

Immunogenicity of 4-dose Essen intramuscular regimen for rabies post-exposure prophylaxis: A multi-center cross-sectional study in China

BackgroundThe 4-dose Essen intramuscular (IM) regimen for rabies post-exposure prophylaxis (PEP) has been recommended by Advisory Committee on Immunization Practices (ACIP) and World Health Organization (WHO), but the large-sample clinical evidence is still limited. MethodRabies virus neutralizing antibodies of 11,752 patients were detected from 409 rabies prevention clinics in 27 provinces in China. Patients with serum collected before or no later than 1 h after injection on the day of the fifth dose (day 28) of 5-dose Essen regimen were included in Group A to observe the immune efficacy of 4-dose Essen IM regimen, and patients with serum collected 14–28 days after injection of the fifth dose were included in Group B to observe the immune efficacy of 5-dose Essen IM regimen. ResultsFinally, 2351 cases met the inclusion and exclusion criteria, including 2244 cases in Group A and 107 cases in Group B. The antibody titer of Group A was higher than that of Group B [12.21 (4.15, 32.10) IU/ml vs. 9.41 (3.87, 27.38) IU/ml] (P = 0.002). In Group A, the median antibody titers were 4.01IU/ml, 11.63IU/ml and 29.46IU/ml in patients vaccinated with purified hamster kidney cell vaccine (PHKCV), purified Vero cell vaccine (PVRV), and human diploid cell rabies vaccine (HDCV), respectively, with statistical significance (P < 0.001). ConclusionsThe 4-dose Essen IM regimen could provide satisfactory immune effect, and HDCV induced higher antibody titer than PHKCV or PVRV.

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.

Safety and immunogenicity of three dose levels of an investigational, highly purified Vero cell rabies vaccine: A randomized, controlled, observer-blinded, Phase II study with a simulated post-exposure regimen in healthy adults

ABSTRACT A serum-free, highly purified rabies vaccine produced in Vero cells is under development. The initial formulation, PVRV-NG, was evaluated in five Phase II studies and subsequently reformulated (PVRV-NG2). This multicenter, observer-blinded Phase II study investigated the safety and immune response of three different doses (antigen content) of PVRV-NG2 versus a licensed human diploid cell rabies vaccine (HDCV; Imovax rabies®). Healthy adults (N = 320) were randomized to receive PVRV-NG2 (low, medium, or high dose), PVRV-NG, or HDCV (2:2:2:1:1 ratio), according to a five-dose Essen simulated post-exposure regimen (Days [D] 0, 3, 7, 14, and 28). All participants received human rabies immunoglobulin intramuscularly on D0. Immunogenicity was assessed at D0, 14, 28, 42, and 6 months after the final injection using the rapid fluorescent focus inhibition test. Seroconversion rates were calculated as the percentage of participants achieving rabies virus neutralizing antibody titers ≥0.5 IU/mL. All analyses were descriptive. At each timepoint, geometric mean titers (GMTs) increased with antigen content (measured using an enzyme-linked immunosorbent assay). High-dose PVRV-NG2 GMTs were the highest at all timepoints, medium-dose PVRV-NG2 GMTs were similar to those with HDCV, and low-dose PVRV-NG2 GMTs were similar to PVRV-NG. The safety profile of PVRV-NG2 was comparable to PVRV-NG; however, fewer injection site reactions were reported with PVRV-NG2 or PVRV-NG (range 36.7–47.5%) than with HDCV (61.5%). This study demonstrated a dose–effect of antigen content at all timepoints. As post-exposure prophylaxis, the safety and immunogenicity profiles of the high-dose PVRV-NG2 group compared favorably with HDCV. Clinicaltrials.gov number: NCT03145766.

Inhibitory effect of concomitantly administered rabies immunoglobulins on the immunogenicity of commercial and candidate human rabies vaccines in hamsters

The World Health Organization protocol for rabies post-exposure prophylaxis (PEP) recommends extensive wound washing, immediate vaccination, and administration of rabies immunoglobulin (RIG) in severe category III exposures. Some studies have shown that RIG can interfere with rabies vaccine immunogenicity to some extent. We investigated the interference of RIG on a next generation highly purified Vero cell rabies vaccine candidate (PVRV-NG) versus standard-of-care vaccines in a previously described hamster model. The interference of either human (h) or equine (e) RIG on the immune response elicited by PVRV-NG, Verorab® (purified Vero cell rabies vaccine, PVRV), and Imovax® Rabies (human diploid cell rabies vaccine; HDCV) was evaluated using the 4-dose Essen PEP regimen. The anti-rabies seroneutralizing titers and specific serum IgM titers were measured by fluorescent antibody virus neutralization test and enzyme-linked immunosorbent assay, respectively, for the vaccines administered with or without RIG. The RIG interference on PVRV-NG, observed transiently at Day 7, was similar to that on PVRV and tended to be lower than that on HDCV using both read-outs. In summary, the results generated in the hamster model showed that RIG induced similar or less interference on PVRV-NG than the standard-of-care vaccines.

Immunogenicity and Safety of A Lyophilized Purified Human Diploid Cell Rabies Vaccine .

Immunogenicity and Safety of A Lyophilized Purified Human Diploid Cell Rabies Vaccine .

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.

A CpG oligodeoxynucleotide enhances the immune response to rabies vaccination in mice

BackgroundRabies is a fatal disease that is preventable when post exposure prophylaxis (PEP) is administered in a timely fashion. CpG oligodeoxynucleotides (ODNs) can trigger cells that express Toll-like receptor 9, and their immunopotentiation activity in an inactivated aluminum-adjuvanted rabies vaccine for dogs has been identified using mouse and dog models.MethodsA human diploid cell rabies vaccine (HDCV) of humans and a CpG ODNs with cross-immunostimulatory activity in humans and mice were used to evaluate the immunogenicity and protective efficacy of CpG ODN in a mouse model that simulates human PEP.ResultsHDCV combined with CpG ODN (HDCV–CpG) stimulated mice to produce rabies virus-specific neutralizing antibody (RVNA) earlier and increased the seroconversion rate. Compared with HDCV alone, either HDCV–1.25 μg CpG or HDCV–5 μg CpG increased the levels of RVNA. In particular, 5 μg CpG ODN per mouse significantly boosted the levels of RVNA compared with HDCV alone. IFN-γ producing splenocytes generated in the HDCV-5 μg CpG group were significantly increased compared to the group treated with HDCV alone. When the immunization regimen was reduced to three injections or the dose was reduced to half of the recommended HDCV combined with CpG ODN, the RVNA titers were still higher than those induced by HDCV alone. After viral challenge, 50% of mice immunized with a half-dose HDCV–CpG survived, while the survival rate of mice immunized with HDCV alone was 30%.ConclusionsThe immunopotentiation activity of CpG ODNs for a commercially available human rabies vaccine was first evaluated in a mouse model on the basis of the Essen regimen. Our results suggest that the CpG ODN used in this study is a potential adjuvant to rabies vaccines for human use.

Immunogenicity and feasibility of intradermal vaccination against rabies in Quebec.

Preexposure vaccination against rabies is recommended for some travellers and individuals exposed to the virus through their work. At a cost of at least $150 per intramuscular (IM) dose, few follow this recommendation. In Canada, provided certain conditions are met, the National Advisory Committee on Immunization (NACI) and the Comité d'immunisation du Québec allow a more economical alternative, intradermal vaccine administration (ID) which uses 1/10 the IM dose. The purpose of this study is to assess the feasibility and immunogenicity of intradermal preexposure vaccination. Students and employees at the Faculty of Veterinary Medicine received three doses of ImovaxRage™ (Sanofi Pasteur) inactivated, human diploid cell rabies vaccine at days 0, 7 and 21 or 28. An IM or ID booster dose was administered after two years when indicated. Among the 159 participants who received three doses, 139 underwent serological testing in the year following vaccination and all achieved protective antibody levels. The antibody level was higher when measured within five weeks of the third dose. When the serological control was performed two years later, 65% of participants had a <0.5 IU/ml titre. Of the 22/30 participants who chose an ID booster, 100% responded and the average antibody titres were multiplied by 11, indicating a strong anamnestic response. ID rabies vaccination is immunogenic, economic and could be considered for the booster dose. Protective antibodies decline rapidly after primary immunization by ID, so it would seem prudent to perform a serological control one year later on individuals at high risk of occult occupational exposure. An alternative would be to give these individuals a routine ID booster dose one year after primary vaccination, which would simplify initial treatment and reduce related costs (follow-up, blood sampling, serological tests, etc.). The persistence of protective antibodies after this booster dose should be assessed to determine the need for subsequent serological tests and the ideal interval between tests.

Study on the Quality of Lyophilized Human Diploid Cell Rabies Vaccine Using Microcarrier Technology

&lt;p&gt;The aim is to study the potency, purity, safety, and stability of the lyophilized human diploid cell rabies vaccine (HDCV). The viruses were harvested from infected human diploid cells (MRC-5 strain) which were cultured in a microcarrier bioreactor. After harvest, purification, inactivation and lyophilization, HDCV was produced. The potency of vaccines was measured by NIH method; the bovine serum protein residual content and the antibiotic residues were tested by ELISA method; the endotoxin content was detected by semi quantitative gel method; the safety of vaccine was determined &lt;em&gt;in vivo&lt;/em&gt;. Among 6 batches of HDCV, the lowest immunizing potency was 4.79 IU/ml, whilst the highest was 6.03 IU/ml; the lowest bovine serum protein residual content was 12.41 ng/dose, whilst the highest was 31.74 ng/Dose; the content of antibiotic residues was from 2.20 ng/ml to 4.00 ng/ml; endotoxin levels were all lower than 50 EU/dose. All the mice and guinea pigs vaccinated were all alive, and the body weight of each mouse also increased. The stability was investigated by determining the water content and potency of the vaccine placed in 37±1 °C for 4 weeks and 2-8 °C for 48 months, respectively. The results indicate all the quality index accords with the standards of “Pharmacopoeia of the People's Republic of China 2010, 3 Volumes”. HDCV shows satisfactory potency, purity, safety, and stability.&lt;/p&gt;

Assessment of inactivated human rabies vaccines: Biochemical characterization and genetic identification of virus strains

The World Health Organization (WHO) recommends the periodic evaluation of the purity of the cell lines used in the production of rabies vaccines, as well as the antigenic identity of the virus strains. Here, we analyzed seventeen marketed inactivated human rabies virus vaccines for viral and non-viral proteins by SDS-PAGE and Coomassie/silver staining. Mass spectrometric analysis of an abundant 60–70kDa signal indicated that in most vaccines serum albumin of human origin (HSA) was the major component. Quantification of HSA in the vaccines revealed a mean concentration of 22mg HSA/dose in all tested PVRV (purified vero cell rabies vaccine), HDCV (human diploid cell rabies vaccine) and PHK (primary hamster kidney) vaccines. In contrast, 1000-fold lower HSA levels and no HSA were detected in PCECV (purified chick embryo cell-culture vaccine) and PDEV (duck embryo rabies vaccine), respectively. Western blot analyses further confirmed a high bias in the HSA content, whereas the virus protein levels were rather similar in all tested vaccines. In addition, the vaccine viruses were sequenced within the N- and G-genes to identify the strain. In the majority of sequenced vaccines, the declared vaccine strain was confirmed. However, some discrepancies in the genetic identification were observed, supporting WHO's recommendation for the molecular characterization of vaccine seed strains. This research highlights the variation in purity found between different human rabies virus vaccines, and suggests that further research is needed to establish the impact non-active components have on the potency of such vaccines.

The Immunogenicity of a Modified Intradermal Pre‐exposure Rabies Vaccination Schedule—A Case Series of 420 Travelers

Current Australian recommendations for rabies pre-exposure vaccination involve the use of cell-culture-based rabies vaccines, which are administered via intramuscular (IM) or intradermal (ID) routes. ID vaccination is more affordable for travelers, but is only recommended if there is sufficient time to perform serology 2 to 3 weeks post-vaccination and confirm immunity prior to travel. We report the immunogenicity of a modified ID schedule that can be completed in less time than the standard ID schedule, and allow more travelers to be vaccinated prior to departure. Travelers were offered a modified schedule if they were unable to afford standard IM vaccinations, and did not have time to complete a standard ID course. The modified schedule consisted of two ID injections of 0.1 mL of human diploid cell rabies vaccine administered on days 0 and 7, and serology was performed to determine immune status at a time between day 21 and 28. A total of 420 travelers aged between 10 and 65 years were vaccinated using the modified ID course. The overall seroconversion rate was 94.5%, with 397 travelers developing antibody levels of >0.5 IU/mL when tested at approximately 21 days post-vaccination. The modified ID schedule used in this case series was highly effective, had similar immunogenicity to the standard ID schedule, and should be considered in travelers who are unable to complete standard IM or standard ID courses of rabies vaccines.

Antibody persistence, 32 years after post-exposure prophylaxis with human diploid cell rabies vaccine (HDCV)

In 1975–1976 forty-five persons severely bitten by rabid wolves and dogs in Iran were treated successfully against rabies with HDCV. In this study contact was made with 26 of 45 above persons, 32 years after their initial treatment and all had rabies neutralizing antibody ranging from 0.3 to 2.69 IU/ml of serum. Of the 26 persons, 17 had received a booster dose of HDCV, 28 years ago and the remaining 9 persons, who had not received any booster since the initial treatment, were given one booster dose of HDCV. All 9 of these patients developed an anamnestic response after their booster inoculation. This study confirms the persistence of rabies neutralizing antibody in persons that received post-exposure vaccination with HDCV, 32 years previously. Furthermore, a single booster inoculation with HDCV resulted in anamnestic response in all individuals.

Efficacy of RTS,S/AS01E malaria vaccine and exploratory analysis on anti-circumsporozoite antibody titres and protection in children aged 5–17 months in Kenya and Tanzania: a randomised controlled trial

SummaryBackgroundRTS,S/AS01E is the lead candidate malaria vaccine. We recently showed efficacy against clinical falciparum malaria in 5–17 month old children, during an average of 8 months follow-up. We aimed to assess the efficacy of RTS,S/AS01E during 15 months of follow-up.MethodsBetween March, 2007, and October, 2008, we enrolled healthy children aged 5–17 months in Kilifi, Kenya, and Korogwe, Tanzania. Computer-generated block randomisation was used to randomly assign participants (1:1) to receive three doses (at month 0, 1, and 2) of either RTS,S/AS01E or human diploid-cell rabies vaccine. The primary endpoint was time to first clinical malaria episode, defined as the presence of fever (temperature ≥37·5°C) and a Plasmodium falciparum density of 2500/μL or more. Follow-up was 12 months for children from Korogwe and 15 months for children from Kilifi. Primary analysis was per protocol. In a post-hoc modelling analysis we characterised the associations between anti-circumsporozoite antibodies and protection against clinical malaria episodes. This study is registered with ClinicalTrials.gov, number NCT00380393.Findings894 children were assigned, 447 in each treatment group. In the per-protocol analysis, 82 of 415 children in the RTS,S/AS01E group and 125 of 420 in the rabies vaccine group had first or only clinical malaria episode by 12 months, vaccine efficacy 39·2% (95% CI 19·5–54·1, p=0·0005). At 15 months follow-up, 58 of 209 children in the RTS,S/AS01E group and 85 of 206 in the rabies vaccine group had first or only clinical malaria episode, vaccine efficacy 45·8% (24·1–61·3, p=0·0004). At 12 months after the third dose, anti-circumsporozoite antibody titre data were available for 390 children in the RTS,S/AS01E group and 391 in the rabies group. A mean of 15 months (range 12–18 months) data were available for 172 children in the RTS,S/AS01E group and 155 in the rabies group. These titres at 1 month after the third dose were not associated with protection, but titres at 6·5 months were. The level of protection increased abruptly over a narrow range of antibody concentrations. The most common adverse events were pneumonia, febrile convulsion, gastroenteritis, and P falciparum malaria.InterpretationRTS,S/AS01E confers sustained efficacy for at least 15 months and shows promise as a potential public health intervention against childhood malaria in malaria endemic countries.FundingPATH Malaria Vaccine Initiative (MVI), GlaxoSmithKline.

An immunogenicity, safety and post-marketing surveillance of a novel adsorbed human diploid cell rabies vaccine (Rabivax®) in Indian subjects

In 1999, Serum Institute of India indigenously developed an adsorbed human diploid cell rabies vaccine (Rabivax). During 2000 – 04, this new vaccine was subjected to a series of immunogenecity and safety studies. Initially, an experimental batch of Rabivax (adsorbed) was assessed on 10 healthy adult volunteers and its response was comparable with that of Merieux inactivated rabies vaccine (MIRV, lyophilized) which was used as a control. Subsequently, Rabivax (adsorbed) was assessed on forty-five suspect rabid dog bite cases with MIRV as control. The vaccine was found to be equally safe and immunogenic as MIRV and showed better rabies virus neutralizing antibody (RVNA) response on day 90 than MIRV. A post-licensing study conducted on 150 cases of suspect rabid animal bites showed it to be safe and immunogenic. To assess its long-term sero-efficacy some of these subjects tested after one year of follow up showed that 84% of them had adequate RVNA titers. In addition, a routine post-marketing surveillance done on 1608 animal bite cases demonstrated that Rabivax (adsorbed) was safe and efficacious. The adverse events to Rabivax (adsorbed) included pain at injection site (3.4%), swelling with induration (2.8%), fever and headache (1.4%). No serious adverse event was reported from the studies. In conclusion, Rabivax (adsorbed) is an immunogenic, safe, and efficacious vaccine for rabies prophylaxis in humans.

Duration of Immunity: An Anamnestic Response 14 Years After Rabies Vaccination With Purified Chick Embryo Cell Rabies Vaccine

ecent cases of human rabies imported to Eu-rope by travelers visiting India and Morocco demonstrate the relevance and value of receiving proper education regarding rabies prevention, in-cluding both preexposure vaccination and postex-posure prophylaxis, prior to leaving for canine rabies – endemic countries. 1,2 This is especially rele-vant for travelers planning on visiting countries in Asia and Africa where the majority of human rabies cases occur. 3 Modern cell culture vaccines recommended by the World Health Organization (WHO), including purifi ed chick embryo cell vac-cine (PCECV), purifi ed Vero cell rabies vaccine, and human diploid cell rabies vaccine (HDCV), provide a safe means by which travelers can be pro-tected in the event of exposure to rabies virus. These vaccines have been licensed for several decades, but there are limited published data regarding the length of time after a person has received his or her primary rabies vaccination, for which they will continue to develop an anamnestic response after a booster dose of rabies vaccine has been adminis-tered. 4,5 The vaccination recommendations for a person who has been vaccinated previously with a cell culture rabies vaccine and is subsequently exposed to a rabid animal include the administra-tion of two booster doses of vaccine (one dose on day 0 and the other on day 3) without the adminis-tration of rabies immunoglobulin (RIG). However, the limited amount of available data has led to some confusion regarding booster recommendations in previously vaccinated persons who are subse-quently exposed to rabid animals. 6,7 To determine how long individuals would be able to mount an anamnestic response after primary vac-cination, we contacted all veterinarians who had ini-tially received PCECV as students enrolled in a clinical trial initiated in 1986. 8 The veterinarians who agreed to participate in this booster study veri-fi ed and confi rmed that they had not received a rabies booster vaccination for 14 years since the clin-ical trial was completed, and all agreed to provide their serum samples for serological evaluation before and after receiving a booster dose of rabies vaccine. In the initial clinical trial conducted in 1986, 78 individuals were vaccinated with either HDCV or PCECV intramuscularly or intradermally as a pri-mary three-dose series. 8 In 1988, 68 of the 78 subjects received a single 1.0 mL of PCECV in tramuscularly. After the booster dose in 1988, the mean titer for subjects who received intradermal dosage initially was 1,106 (range: 270 – 6,800) and for subjects who received intramuscular dosage for their initial series was 1,859 (range: 1,100 – 9,500). For comparison purposes, a reciprocal titer of 1:25 is approximately equal to a titer of 0.5 IU/mL. Fourteen years later, 15 of those who initially received PCECV and a dose of intramuscular booster 1 year after their primary se-ries and who had not received any additional rabies vaccination since the 1988 booster were enrolled in this study. After approval of the study by the ethics committee and obtaining informed consent from the subjects, a blood sample was obtained and a single

Early Rabies Antibody Response to Intramuscular Booster in Previously Intradermally Immunized Travelers Using Human Diploid Cell Rabies Vaccine

Postexposure treatment (PET) of travelers who may have had a potential rabies exposure is simpler, safer, and cheaper if the traveler is preimmunized. Preimmunization can be done with human diploid cell rabies vaccine (HDCV) administered intramuscularly or intradermally. Some authorities, however, are now advocating that travelers vaccinated by the intradermal (ID) route should be treated as if they are not immunized. A particular concern raised is that travelers who have received pre-exposure rabies vaccination intradermally, may have a delayed response to postexposure boosters. This study is designed to elucidate whether a single intramuscular (IM) HDCV booster will provoke an early (day 5) immune response in individuals given pre-exposure ID HDCV. Twenty-nine travelers who had received a course of three 0.1 mL ID HDCV between 12 and 24 months previously were given a single 1.0 mL IM booster of HDCV. Rabies antibody levels were compared 5 days later to those before the booster. Twenty-five of the 29 subjects (86%) showed an adequate rise in virus neutralizing antibody (VNA) titer 5 days after booster. Nine of the 29 subjects (31%) had inadequate antibody levels prior to the simulated postexposure booster. Five days after the postexposure booster, 27 of 29 (93%) had adequate antibody levels. The other 2 travelers were subsequently shown to have adequate VNA levels when tested 4 and 6 weeks later, respectively. For travelers who were given pre-exposure ID HDCV vaccination within the last 2 years and received one IM postexposure booster dose of HDCV, most mounted an adequate early immune response. This data does not support a change in current recommendations for rabies PET in this group. Further research to ascertain the duration of protection of pre-exposure ID rabies immunization is required.

Rabies human diploid cell vaccine elicits cross-neutralising and cross-protecting immune responses against European and Australian bat lyssaviruses

The ability of antibodies elicited against the rabies human diploid cell vaccine (HDCV) to neutralise European bat Lyssaviruses (EBLV types-1 and -2), Australian bat Lyssavirus and classical rabies virus (RABV) has been evaluated using modified fluorescent antibody virus neutralisation (mFAVN) assays. Ninety-six percent (48 of 50) of the human post-vaccinated sera tested cross-neutralised these viruses (≥0.5 IU/ml). Cross-protection experiments using inbred mice (RIII, k/k haplotype) were also assessed. Mice were given HDCV (twice by the intra-peritoneal route) and challenged (intra-cranially or peripherally) with a lethal dose (25 MLD 50) of the individual viruses. The vaccine conferred statistically significant protection in 80–100% of animals challenged via the peripheral route. Levels of protection were lower following intra-cranial (i.c.) challenge. Our data provides strong evidence for broad spectrum cross-neutralisation and cross-protection of phylogroup I lyssaviruses using rabies HDCV.

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.

Immunologic and virologic evaluation of HIV-1-infected children after rabies vaccination

Background: One-third of Thai children experience a dog bite by the time they are 15 years old, and HIV-1 infection in children is also not uncommon. Previous study has shown that rabies vaccination of HIV-1-infected children may not result in a satisfactory antibody response when CD4+ T cells are less than 15%. The objective of this prospective clinical study is to evaluate the immunologic response and effect on viral load after rabies vaccination in HIV-infected children. Methods: Thirteen HIV-1-infected children were vaccinated with the intramuscular rabies pre-exposure regimen using human diploid cell rabies vaccine (HDCV) on days 0, 7 and 28. CD4+ and CD8+ lymphocyte counts were performed on days 0, 7 and 28. Plasma viral loads were determined on days 0, 7, 14, 60, 90, 180 and 360. Results: There were no significant change in serial measurements of CD4+/CD8+ lymphocytes during a period of 1 month and in plasma viral load during 1 year. There was no associated clinical deterioration or any adverse reactions attributable to vaccine. Conclusions: Rabies vaccination in HIV-1-infected children appears to be safe but did not significantly change the levels of plasma HIV RNA, CD4+ and CD8+ cell counts.

Successful Protection of Humans Exposed to Rabies Infection: Postexposure Treatment with the New Human Diploid Cell Rabies Vaccine and Antirabies Serum

Please refer to JAMA, Vol. 236, No. 24, December 13, 1976, pp. 2751-2754 for a copy of this article.