Pakamatz Khawplod

Failure of Multiple-Site Intradermal Postexposure Rabies Vaccination in Patients with Human Immunodeficiency Virus with Low CD4+ T Lymphocyte Counts

Human immunodeficiency virus (HIV)-infected patients with low CD4(+) T lymphocyte counts had a poor neutralizing antibody response to pre- and postexposure rabies vaccination. This study of HIV-infected patients with CD4(+) T lymphocyte counts < 200/microL indicated that patients had a poor response after 4-site intradermal vaccinations (4-4-4-0-2-2, doubling the intradermal doses of cell-culture rabies vaccine).

What is an acceptable delay in rabies immune globulin administration when vaccine alone had been given previously

Rabies immune globulins (RIG) are not always available. Rabies-exposed patients often present to medical centers, particularly in canine rabies infested regions, after a vaccine series has been started without immune globulin administration. It is known that rabies immune globulin can result in suppression of the neutralizing antibody response which usually yields detectable antibodies by day 7. We have shown that it can be administered with a delay of up to 5 days after the start of vaccine treatment without significant antibody suppression within the first month. This study utilized the WHO approved multisite Thai Red Cross intradermal postexposure regimen. Effective use of rabies immune globulin in severe and multiple wounds, particularly in small children, may require dilution of the RIG in normal saline to provide a volume adequate for infiltration of all wounds.

Inhibition of rabies virus replication by multiple artificial microRNAs.

The RNA interference (RNAi) technology has been recognized as a promising antiviral therapy for a few years. One of the potential limitations for applying this technology against wild type rabies virus is its high rate of genetic variation. Recently, an RNAi vector system that incorporated modified dsRNA within microRNA structure [or artificial miRNAs(amiRNAs)] has been described. This allowed expression of multiple amiRNAs of single or multiple targets from a single construct. In this study, we evaluated a benefit of using amiRNA vector against different rabies strains. We found that applying single targeting amiRNA against challenged rabies virus standard (CVS) rabies nucleocapsid (N) mRNA resulted in more than 90% reduction of viral genome in Neuro2A cells up to 72 h after infection. Multiple amiRNAs aiming at single or multiple NmRNA target(s) yielded comparable inhibitory results as with a single amiRNA against perfectly matched target. Although the level of each mature miRNA generated from multiple amiRNA construct was slightly reduced as assessed by stem-loop RT and real-time PCR techniques, its effectiveness remained unchanged even when an ineffective or scrambled amiRNA was also included in the transcript. Against highly pathogenic wild type virus, single amiRNA construct activity was reduced when mismatching with target sequence occurred at critical site whereas multiple targeting amiRNA construct remained highly effective. Our results suggest the benefit of using multiple targeting amiRNAs when confronting with wild type rabies virus, the sequence of which is not completely known.

Postexposure Rabies Prophylaxis Completed in 1 Week: Preliminary Study

BACKGROUND Patients exposed to a rabid animal often travel long distances to receive postexposure prophylaxis (PEP), which requires 4 or 5 visits. Reducing the number of clinic visits would not only reduce costs for the patient but may also help increase compliance to receive complete PEP. We made an effort to develop PEP completed in 1 week. METHODS We administered the 4-site intradermal injections of 0.1 mL of purified Vero cell rabies vaccine to the deltoids and thighs on days 0, 3, and 7, with and without equine rabies immunoglobulin (40 IU/kg). A control group received the World Health Organization-approved and widely used Thai Red Cross regimen (2-site intradermal injections on days 0, 3, and 7 and 1 injection on days 28 and 90) with equine rabies immunoglobulin. We then determined rabies neutralizing antibody (NAb) up to day 360. RESULTS Geometric mean titers for subjects receiving the 4-site intradermal regimen, with or without equine rabies immunoglobulin, had significantly higher NAb values than did the control group on day 14 and 28 (P<.001). All subjects in all groups had a NAb value > or =0.5 IU/mL on days 14 and 28. The percentages of subjects who had a NAb value > or =0.5 IU/mL from days 0 through 360 were not significantly different among the 3 groups. CONCLUSIONS After any PEP regimen, World Health Organization recommendations require a NAb value > or =0.5 IU/mL on days 14 and 28. The 1-week PEP regimen, therefore, appears promising. It increased immunogenicity over the 2-site intradermal schedule, and it is convenient and can be used in small clinics, because it consumes almost the entire supplied vaccine ampoule volume.

Postexposure Treatment of Rabies Infection: Can It Be Done without Immunoglobulin?

The last remaining international manufacturer of equine rabies immunoglobulin (ERIG) discontinued production in 2001. However, ERIG remains an essential biological that has no substitute other than human rabies immunoglobulin (HRIG), which is in short supply and virtually unaffordable in developing countries. Physicians in regions where canine rabies is endemic and neither ERIG nor HRIG is available are providing less-than-optimal treatment to patients exposed to rabies. If no immunoglobulin is available, they have only 1 therapy option: use of a vaccine schedule that produces the highest and, hopefully, earliest neutralizing antibody response. However, treatment failures must still be expected. Early, aggressive wound cleansing and more intensive efforts at canine control and are ever more important. Countries that have the resources to manufacture their own rabies immunoglobulins must be encouraged to do so.

A simple and rapid immunochromatographic test kit for rabies diagnosis

In rabies endemic countries, funds and infrastructure are often insufficient to employ the approved gold standard for the definitive diagnosis of rabies: the direct fluorescent test. In the present study, two types (type 1 and 2) of an ICT kit were evaluated for detection of rabies. These were developed using monoclonal antibodies which recognize epitope II and III of the nucleoprotein of rabies virus. Both kits specifically detected all rabies virus strains and there was no cross reactivity with Lyssaviruses (Lagos, Mokola and Duvenhage), Rhabdovirus (VSV and Oita 296/1972) and other common canine‐pathogenic viruses. In type 1, a single type of monoclonal antibody was used. It was capable of detecting recombinant nucleoprotein and showed sensitivity of 95.5% (42/44) and specificity of 88.9% (32/36) using brain samples from rabid dogs. In contrast, type 2 which was made of two different monoclonal antibodies had a lower sensitivity of 93.2% (41/44) and higher specificity of 100% (36/36). These ICT kits provide a simple and rapid method for rabies detection. They need neither cold chain for transportation nor complicated training for personnel. This diagnostic test is suitable for rabies screening, particularly in areas with a high prevalence of rabies and where the fluorescent antibody test is not available.

Failure of Rabies Postexposure Prophylaxis In Patients Presenting with Unusual Manifestations

We report an atypical case of paralytic rabies presenting with trismus followed by limb weakness, areflexia, ophthalmoparesis, and bilateral ptosis. Atypical presentations and history of rabies postexposure prophylaxis led to delayed diagnosis. Nucleocapsid and glycoprotein genes of rabies viruses from the patients and biting dogs brains were of identical sequences.

Failure of Pre- and Postexposure Rabies Vaccinations in a Child Infected with HIV

We report the case of a 6-y-old HIV-infected girl with severe immune deficiency who failed to respond to intramuscular pre-exposure rabies vaccination using human diploid cell rabies vaccine on days 0, 7 and 28. She also failed to respond to an intradermal postexposure rabies regimen using purified verocell rabies vaccine at 4 sites on days 0, 3 and 7 and at 2 sites on days 30 and 90 (double the usual regimen). Sequentially monitored rabies neutralizing antibody titers were below the WHO minimum acceptable level (> 0.15 IU/ml) in all specimens. Rabies prevention in HIV-infected persons with severe immune suppression requires further study.We report the case of a 6-y-old HIV-infected girl with severe immune deficiency who failed to respond to intramuscular pre-exposure rabies vaccination using human diploid cell rabies vaccine on days 0, 7 and 28. She also failed to respond to an intradermal postexposure rabies regimen using purified verocell rabies vaccine at 4 sites on days 0, 3 and 7 and at 2 sites on days 30 and 90 (double the usual regimen). Sequentially monitored rabies neutralizing antibody titers were below the WHO minimum acceptable level (> 0.15 IU/ml) in all specimens. Rabies prevention in HIV-infected persons with severe immune suppression requires further study.

Immune Response to Simulated Postexposure Rabies Booster Vaccinations in Volunteers Who Received Preexposure Vaccinations

Several studies of the efficacy of intradermal postexposure rabies vaccination have shown that this procedure is safe, effective, and cost saving. Less is known about the reliability of the present World Health Organization (WHO)-approved intradermal preexposure regimen, which consists of three 0.1-mL doses that are generally given on days 0, 7, and 28. Previous studies have shown that neutralizing antibody responses are lower and of shorter duration in subjects given the reduced-dose intradermal regimen. Thus, it is still uncertain whether the WHO-recommended single intramuscular or intradermal booster injections given on days 0 and 3 would prevent death in all cases. In this preliminary study, we evaluated titers of neutralizing antibody in Thai student volunteers given two simulated postexposure boosters, as recommended by WHO, and we compared these volunteers to a group given vaccine intramuscularly. We observed a lower, although adequate, accelerated immune response in those given the preexposure series and postexposure boosters intradermally.

Prospective Immunogenicity Study of Multiple Intradermal Injections of Rabies Vaccine in an Effort to Obtain an Early Immune Response without the Use of Immunoglobulin

The present study sought to determine whether increasing and accelerating rabies vaccine administration would result in earlier protective levels of neutralizing antibody. Results indicated that the 8-site and double-dose Thai Red Cross intradermal regimens produced higher antibody titers by day 14 but not significantly higher titers by days 5 and 7. Administration of rabies immunoglobulin into and around bite wounds on the first day of rabies prophylaxis should remain the optimal postexposure treatment.