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 and Germany), purified vero cell rabies vaccine (Verorab, France; Indirab, India) and human diploid cell vaccine (MIRV, France). The potency of these vaccines varied from 0.55 IU to 2.32 IU per intradermal dose of 0.1 ml per site. The vaccines were administered to 1,011 subjects 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).
rabies vaccines; intradermal route; antigenicity; immunogenicity; metaanalysis
The antibody responses of 194 volunteers were studied for up to 3 years after primary immunization with one, two or three doses of human diploid cell rabies vaccine, administered either in 0.1 ml volumes intradermally (i.d.) or as 1.0 ml intramuscularly (i.m.). Sero-conversion occurred in 95% of subjects after the first injection and in 100% after the second. The highest titres and most durable antibody responses were induced by three injections of vaccine. Booster doses were administered either by the subcutaneous (s.c.) or i.d. route, after 6, 12 or 24 months to randomly grouped volunteers; these induced responses greater than or equal to 5.0 i.u. per ml in 95% of subjects. The responses were rapid and were neither influenced by the primary regimen nor by the timing and route of the booster dose. Antibody titres after i.d. immunization were only two-fold lower than those induced by the larger volume of vaccine. The findings suggest that the i.d. route is both effective and economic.
The antirabies human diploid cell vaccine produced by 1'Institute Merieux, Lyon, France, was administered intradermally to 35 high-risk volunteers using 0.2-ml amounts and various immunization schedules. Three groups never before vaccinated against rabies developed virus-neutralizing antibodies, the titer of which was dose dependent. A single injection stimulated the formation of antibodies. Four inoculations induced the highest antibody levels and the longest persistence of antibody. The administration of a single intradermal booster inoculation was sufficient, even in the case of low-persisting antibody, to elicit a rapid increase of antibodies to high levels. A primary inoculation course of two injections induced a sufficient antibody level which, in case of exposure, could apparently be rapidly elevated by a 0.2-ml intradermal booster inoculation. Adverse side reactions were observed in 7 of 14 individuals after a 1- or 1.5-year intradermal booster inoculation. We therefore suggest that the intramuscular and subcutaneous routes continue to be used for primary vaccinations and that the highly effective intradermal route be restricted to booster inoculations. This is the first long term study of this vaccine and should be a guideline for the pre-exposure treatment of high-risk personnel.
In 1978, 22 staff members of the National Institute of Virology, Pune, India, were given two doses of human diploid cell antirabies vaccine (HDCV) for primary pre-exposure prophylactic immunization; the interval between the two doses being approximately 4 weeks. Eighteen of these 22 vaccinees were given a booster dose 1 year later. All 18 vaccinees developed protective levels of antibody; most of them had antibody levels exceeding 10 IU/ml. In 1984, 5 years after the booster dose, 11 (79.0%) of 14 vaccinees tested still possessed neutralizing antibody levels ranging from 0.5 IU/ml to 10 IU/ml. Fourteen days after the administration of a booster dose, the antibody levels ranged from 10 to greater than or equal to 100 IU/ml for all except one vaccine (5.2 IU/ml). These findings demonstrate that the majority of vaccines retained detectable neutralizing antibody after pre-exposure prophylaxis for as long as 5 years and that a single booster dose thereafter evoked a good antibody response.
In a field study, rabies virus neutralizing antibody titres were determined by the microtest modification of the rapid fluorescent focus inhibition test before and after primary vaccination in 30 puppies, and before and after booster vaccination in 59 previously vaccinated dogs. A commercial modified live virus vaccine was used. Three weeks after primary vaccination the mean antibody titre was 102 ± 90, but only 24 dogs presented for booster vaccination had detectable antibody levels (mean titre 12 ± 16). The antibody responses three weeks after booster vaccination (mean 380 ± 216) were significantly greater than the responses to primary vaccination. It was concluded that previously vaccinated dogs could have an anamnestic response to booster vaccination, even when antibodies were not detected in their sera before revaccination.
Rabies; rabies vaccine; vaccination; dogs
This study was done to investigate the antibody response to a Vero cell antirabies vaccine, the persistence of antibody for 5 years, and the effect of a booster dose after this interval. From August 2005 to February 2011, a total of 195 patients were enrolled into our study due to an animal bite. The Essen intramuscular (i.m.) regimen, which is recommended by the WHO for modern vaccines used in postexposure treatment, was adopted in this study. Blood samples were obtained on day 0, day 7, day 14, day 45, year 1, year 2, year 3, year 4, year 5, and year 5 plus 14 days. Immunogenicity was evaluated by the titration of neutralizing antibodies with a rapid fluorescent focus inhibition test (RFFIT). Seroconversion was expressed as the seroconversion rate (SCR). A secondary quantitative evaluation criterion, other than the seroconversion level, was the geometric mean titer (GMT). Of the 195 enrolled patients, 168 (86.4%) of them completed the whole study. No serious adverse reactions to the vaccine were reported during vaccination, the 5-year follow-up period, or revaccination. On day 14, the rabies antibody GMT value was 8.87 IU/ml in the vaccinees. During the next 5 years, the SCR in the ChengDa vaccine group gradually decreased to 34.0% at year 5, down from 90.5% at year 1. There was a significant booster effect: the GMT was 15.22 IU/ml on year 5 plus 14 days. Our findings demonstrate that the ChengDa rabies vaccine offers an alternative with a high degree of efficacy and yet limited side effects and ensures that the exposed patient will be on the safe side of the risk of rabies by the 14th day. Moreover, when followed by a booster dose 5 years later, it could boost the immunity. A further booster is effective in inducing a good neutralizing antibody response even after an interval of 5 years.
Dogs were vaccinated intradermally with vaccinia virus recombinants expressing the rabies virus glycoprotein (G protein) or nucleoprotein (N protein) or a combination of both proteins. The dogs vaccinated with either the G or G plus N proteins developed virus-neutralizing antibody titers, whereas those vaccinated with only the N protein did not. All dogs were then challenged with a lethal dose of a street rabies virus, which killed all control dogs. Dogs vaccinated with the G or G plus N proteins were protected. Five (71%) of seven dogs vaccinated with the N protein sickened, with incubation periods 3 to 7 days shorter than that of the control dogs; however, three (60%) of the five rabid dogs recovered without supportive treatment. Thus, five (71%) of seven vaccinated with the rabies N protein were protected against a street rabies challenge. Our data indicate that rabies virus N protein may be involved in reducing the incubation period in dogs primed with rabies virus N protein and then challenged with a street rabies virus and, of more importance, in subsequent sickness and recovery.
Rabies humoral antibodies were induced in eight New Zealand rabbits by a single intramuscular injection of inactivated suckling mouse brain rabies vaccine. The primary response to immunization was measured in blood samples taken at selected intervals for 6 months. The anamnestic response was measured in blood samples obtained 2 weeks after the rabbits received a booster immunization. The humoral antibody concentrations were measured by the rapid-fluorescent-focus-inhibition technique (RFFIT), indirect fluorescent-antibody assay (IFA), and indirect radioimmunoassay (RIA). The maximal neutralizing antibody titers as measured by RFFIT were attained by the 4th week and persisted into the 24th week. After booster immunization the antibody response was almost 10-fold higher than the highest level attained in the primary response. The antibody levels as measured by IFA and RIA were similar, but the titers as measured by either procedure were almost 10-fold lower than those determined by RFFIT. After booster immunizations the antibody levels, as measured by IFA and RIA, were three- and sixfold higher, respectively, than the maximal levels attained in the primary response. Twenty-two human serum specimens were tested by the same serological procedures, with disparate results. Both RIA and RFFIT effectively differentiated antirabies-positive sera from antirabies-negative sera.
Two experiments on simulated postexposure treatment were carried out in dogs using human rabies immunoglobulin (RIGH) and human diploid cell vaccine for human use. In one experiment, when animals were challenged by injecting street virus into the masseter muscle and treated with a combination of RIGH and vaccine, 50% of the animals were protected from rabies. In the other trial, in which animals were challenged by injecting the virus into the femoral muscle, treatment with RIGH and vaccine protected all the animals against rabies. To our knowledge this is the highest rate of postexposure survival in animals reported to date. In addition, five out of eight (62.5%) dogs that received RIGH alone after the virus challenge were protected, while none of the animals receiving vaccine alone were protected from rabies. These trials suggest that animals can be protected from rabies by postexposure treatment. The route of exposure and timing of the administration of vaccine and hyperimmune serum would seem to be important.
The standard six-dose intramuscular (i.m.) rabies post-exposure vaccine regimen using a new purified chick embryo cell (PCEC) vaccine was compared with two economical multisite intradermal (i.d.) PCEC regimens, a multisite i.m. PCEC schedule and a subcutaneous regimen using a suckling mouse brain (SMB) rabies vaccine manufactured in Thailand. The neutralizing antibody results for the four-site and eight-site i.d. and the standard i.m. PCEC regimens were similar over 3 months. A three-site i.m. PCEC regimen had no advantage. The SMB vaccine gave the lowest antibody levels. Human rabies immune globulin therapy significantly increased the GMT of all groups on day 7, unlike equine antirabies serum (EARS). Both antisera suppressed antibody responses to PCEC on days 14 and 28. Three generalized reactions probably related to EARS were the only serious side effects. An eight-site i.d. PCEC vaccine regimen proved as immunogenic as the routine i.m. schedule and, if implemented as post-exposure prophylaxis, would be the cheapest widely available tissue culture vaccine regimen. The protective efficiency should now be tested in patients bitten by rabid animals.
The methods used for both pre-exposure and post-exposure immunization against rabies were studied. In pre-exposure immunization duck embryo vaccine should be used. In post-exposure immunization either duck embryo or Semple-type vaccine appears to be effective in stimulating antibody production. Both vaccines may cause neurological sequelae. A dose of vaccine should be given 20-50 days after completion of the primary course of vaccination. Immune serum should be used in all severe exposures especially of the head and neck, and in individuals in whom the commencement of vaccination has been unduly delayed. In individuals who have been previously vaccinated reinforcing doses have been found to be effective even as long as 20 years after the primary vaccination. A tissue culture vaccine has been developed and is about to undergo field trials.
Interviews to solicit information about animal bites and rabies vaccinations were completed on 1165 of 1175 non-military veterinarians in Illinois in 1968. Two hundred and sixty-one veterinarians reported 380 exposure incidents that precipitated the administration of rabies vaccine; 72 veterinarians had received two or more series of vaccine. Vaccine was administered after exposure from: examination of a patient (n = 230), bite (n = 79), necropsy (n = 17), other causes (n = 13) and unstated (n = 41). Eighty-six percent of the exposures were to dogs or cattle. In 231 veterinarians receiving postexposure vaccinations, where year of first vaccination and year of graduation from veterinary school were known, 97 (42%) were exposed in the six years spanning one year before graduation and four years after graduation. There were 296 veterinarians, including 12 receiving postexposure vaccination, who had received their first series of vaccine as preexposure prophylaxis. Twenty-one percent of all vaccinees (pre- and postexposure) reported reactions to the rabies vaccine. Seventy-two veterinarians reported they had been treated for an animal bite in the previous year.
We describe the epidemiology of human rabies postexposure prophylaxis (PEP) in four upstate New York counties during the 1st and 2nd year of a raccoon rabies epizootic. We obtained data from records of 1,173 persons whose rabies PEP was reported to local health departments in 1993 and 1994. Mean annual PEP incidence rates were highest in rural counties, in summer, and in patients 10 to 14 and 35 to 44 years of age. PEP given after bites was primarily associated with unvaccinated dogs and cats, but most (70%) was not attributable to bites. Although pet vaccination and stray animal control, which target direct exposure, remain the cornerstones of human rabies prevention, the risk for rabies by the nonbite route (e. g., raccoon saliva on pet dogs' and cats' fur) should also be considered.
Adult rhesus monkeys (Macaca mulata) were vaccinated with four inactivated rabies vaccines, including two cell culture vaccines, one zonal purified cell culture vaccine, and a 10% extracted duck embryo vaccine. The vaccines were potency tested by both National Institutes of Health (NIH) and Habel methods and passed one or both tests. However, a vaccine having acceptable potency by one method frequently failed or was marginal by the other procedure. Groups of three monkeys were inoculated with each vaccine by one of two schedules. The first consisted of four weekly 1-ml doses followed by a 1-ml booster dose at 6 months, and the second consisted of seven daily 1-ml doses of vaccine with no booster. Both zonal purified and extracted duck embryo vaccines induced detectable neutralizing antibody by day 7 with either schedule, and antibody titers elicited by the cell culture vaccine remained high through 210 days. However, antibody titers produced by the 10% duck embryo vaccine dropped sharply after their 28-day peak. Duck embryo cell culture vaccines with low or marginal potency as measured by Habel or NIH tests still produced rapid, high levels of serum-neutralizing antibody in primates. LD50 or NIH and Habel tests as measured in mice were not necessarily good indices of antibody response in the primate host. The need for a cell culture potency test that will yield a more predictable correlation with the definitive host's antibody response is discussed.
Oral vaccination is an important tool currently in use to control the spread of rabies in wildlife populations in various programs around the world. Oral rabies vaccination (ORV) of raccoons represents the largest targeted program to control wildlife rabies in the United States. Currently, the vaccinia-rabies glycoprotein recombinant virus vaccine (V-RG) is the only licensed oral rabies vaccine in the US. In the current study, captive raccoons were used to evaluate two previously described constructs of a rabies virus vaccine developed by reverse genetics (SPBNGAS and SPBNGAS-GAS) for immunogenicity and efficacy compared to the V-RG vaccine. Four of five control animals succumbed to rabies virus after severe challenge, while three of five animals vaccinated orally with SPBNGAS succumbed. No mortality was observed for animals administered SPBNGAS-GAS or the V-RG vaccine. The results of this preliminary study suggest that SPBNGAS-GAS provides comparable efficacy to V-RG. Additional studies will be needed to determine the duration of immunity and optimal dosage of SPBNGAS-GAS and to examine its efficacy in other reservoir species.
Rabies; Vaccine; Raccoons; Oral
Intradermal rabies vaccine is recommended by the World Health Organisation, but not all countries, including England, follow this recommendation. A group of 12 adults in England previously given pre-exposure intradermal rabies vaccine were considered to be non-immune to rabies because their rabies antibody titres were known to be less than 0.5 IU/mL. A cohort study examined the immunizing effect of increasing the participants'
cumulative dose of intradermal rabies to 2.0 IU. All patients subsequently demonstrated rabies antibody levels >0.5 IU·mL supporting evidence of adequate sero-conversion. No adverse effects of intradermal rabies vaccine boosting were noted. Within the limits of a small study the findings support the hypothesis that adequate levels of rabies antibody can be achieved by a schedule of intradermal injections delivered on at least three occasions with a cumulative rabies vaccine dose of 2.0 IU.
Although fatal if untreated, human rabies can be prevented through post-exposure prophylaxis (PEP), which involves a course of vaccination and immunoglobulin administered immediately after exposure. However, high costs and frequent lack of rabies vaccine and immunoglobulin lead to about 55,000 deaths per year worldwide. Using data from a detailed study of rabies in Tanzania, we calculate a cost-effectiveness ratio for PEP when the WHO-recommended Essen regimen, a 5-dose intramuscular vaccination schedule, is adopted. Our analyses indicate a cost-effectiveness ratio for PEP of $27/quality-adjusted life year (QALY) from a health care perspective and $32/QALY from a societal perspective in Tanzania. From both perspectives, it is “very cost-effective” to administer PEP to patients bitten by an animal suspected to be rabid. Moreover, PEP remains “very cost-effective” provided that at least 1% of doses are administered to people who were actually exposed to rabies.
Cost-effectiveness; Rabies; Post-exposure prophylaxis
The cost-benefit of raccoon rabies control strategies such as oral rabies vaccination (ORV) are under evaluation. As an initial quantification of the potential cost savings for a control program, the collection of selected rabies cost data was pilot tested for five counties in New York State (NYS) in a three-year period.
Rabies costs reported to NYS from the study counties were computerized and linked to a human rabies exposure database. Consolidated costs by county and year were averaged and compared.
Reported rabies-associated costs for all rabies variants totalled $2.1 million, for human rabies postexposure prophylaxes (PEP) (90.9%), animal specimen preparation/shipment to laboratory (4.7%), and pet vaccination clinics (4.4%). The proportion that may be attributed to raccoon rabies control was 37% ($784,529). Average costs associated with the raccoon variant varied across counties from $440 to $1,885 per PEP, $14 to $44 per specimen, and $0.33 to $15 per pet vaccinated.
Rabies costs vary widely by county in New York State, and were associated with human population size and methods used by counties to estimate costs. Rabies cost variability must be considered in developing estimates of possible ORV-related cost savings. Costs of PEPs and specimen preparation/shipments, as well as the costs of pet vaccination provided by this study may be valuable for development of more realistic scenarios in economic modelling of ORV costs versus benefits.
Rabies, the most fatal of all infectious diseases, remains a major public health problem in developing countries, claiming the lives of an estimated 55,000 people each year. Most fatal rabies cases, with more than half of them in children, result from dog bites and occur among low-income families in Southeast Asia and Africa. Safe and efficacious vaccines are available to prevent rabies. However, they have to be given repeatedly, three times for pre-exposure vaccination and four to five times for post-exposure prophylaxis (PEP). In cases of severe exposure, a regimen of vaccine combined with a rabies immunoglobulin (RIG) preparation is required. The high incidence of fatal rabies is linked to a lack of knowledge on the appropriate treatment of bite wounds, lack of access to costly PEP, and failure to follow up with repeat immunizations. New, more immunogenic but less costly rabies virus vaccines are needed to reduce the toll of rabies on human lives. A preventative vaccine used for the immunization of children, especially those in high incidence countries, would be expected to lower fatality rates. Such a vaccine would have to be inexpensive, safe, and provide sustained protection, preferably after a single dose. Novel regimens are also needed for PEP to reduce the need for the already scarce and costly RIG and to reduce the number of vaccine doses to one or two. In this review, the pipeline of new rabies vaccines that are in pre-clinical testing is provided and an opinion on those that might be best suited as potential replacements for the currently used vaccines is offered.
The ERA strain of rabies vaccine virus failed to propagate or cause clinical manifestations when instilled into the mammary gland of lactating goats. However, the virus did produce neutralizing antibodies in this gland as a result of repetitive viral stimulation, a “sham infection”. The protective property of the concentrated and partly purified milk serum antibody was assessed in mice. In the first trial, protective activity was observed when a single dose of milk serum antibody was administered at intervals up to three days after exposure to virulent rabies virus. In the second trial, using a more concentrated milk serum antibody, about half of the mice were protected when the milk serum was administered up to ten days after exposure to virulent virus.
The duration of hepatitis B vaccine-induced immunity was studied in a group of 54 seronegative health professionals who received plasma-derived hepatitis B vaccine (Merck's Heptavax) in 1978 and 1979. Five to seven years later, 52 vaccinees received a booster dose of yeast recombinant hepatitis B vaccine (Merck's Recombivax). Of 54 vaccinees, 47 (87 percent) had a favorable anti-HBs response (greater than 10 S/N RIA units) and 7 (13 percent) had low (2.1-10 S/N) or undetectable levels (less than 2.1 S/N) one year after primary immunization. After five to seven years, the anti-HBs values had declined to undetectable levels in 25 percent and to low levels in 23 percent. A booster dose of vaccine induced an anamnestic response in 90 percent of vaccinees by two weeks. The results of this study indicate that persons who respond favorably to primary immunization may be protected for at least seven years.
Inactivated rabies vaccines prepared from common vaccine strains of virus were inoculated into foxes by the intramuscular and intestinal route. There were differences among the vaccines in the duration of antibody produced after intramuscular administration. Inactivated vaccines deposited directly into the lumen of the duodenum by means of a fiberscope caused seroconversion in some foxes, especially following a booster dose, but the antibodies produced were for the most part of short duration. The ERA modified live virus vaccine, in contrast, produced a satisfactory and long lasting antibody after intestinal instillation.
Immunization of mice and hamsters with a cocktail of mouse MAbs specific for rabies virus nucleocapsid protein and glycoprotein protected animals not only when challenged with a lethal dose of rabies virus after immunization, but also in post-exposure situations. Hamsters treated with the MAb cocktail 3 h after virus inoculation were completely protected from lethal rabies virus infection, and 80% of the animals survived when the MAb cocktail was given 36 h after virus challenge. The potential usefulness of this MAb cocktail for the postexposure treatment of human rabies is discussed.
Background: Pertussis occurs in older children, adolescents and adults due to waning immunity after primary vaccination. Booster vaccination for pre-school children has been recommended in Italy since 1999. In this study (NCT00871000), the immunogenicity, safety and reactogenicity of a booster dose of reduced-antigen content diphtheria-tetanus-acellular pertussis-inactivated poliovirus vaccine (dTpa-IPV; GSK Biologicals Boostrix™-Polio; 3-component pertussis) vs. full-strength DTPa-IPV vaccine (sanofi-pasteur—MSD Tetravac™; 2-component pertussis) was evaluated in pre-school Italian children.
Methods: Healthy children aged 5–6 y primed in a routine vaccination setting with three doses of DTPa-based vaccines were enrolled and randomized (1:1) in this phase IIIb, booster study to receive a single dose of dTpa-IPV or DTPa-IPV; the MMRV vaccine was co-administered. Antibody concentrations/titers against diphtheria, tetanus, pertussis and poliovirus 1–3 were measured before and one month post-booster. Reactogenicity and safety was assessed.
Results: 305 subjects were enrolled of whom 303 (dTpa-IPV = 151; DTPa-IPV = 152) received booster vaccination. One month post-booster, all subjects were seroprotected/seropositive for anti-diphtheria, anti-tetanus, anti-PT, anti-FHA and anti-poliovirus 1–3; 99.3% of dTpa-IPV and 60.4% of DTPa-IPV subjects were seropositive for anti-PRN; 98–100% of subjects were seropositive against MMRV antigens post-booster. Pain at the injection site (dTpa-IPV: 63.6%; DTPa-IPV: 63.2%) and fatigue (dTpa-IPV: 26.5%; DTPa-IPV: 23.7%) were the most commonly reported solicited local and general symptoms, during the 4-d follow-up period. No SAEs or fatalities were reported.
Conclusions: The reduced-antigen-content dTpa-IPV vaccine was non-inferior to full-strength DTPa-IPV vaccine with respect to immunogenicity. The vaccine was well-tolerated and can be confidently used as a booster dose in pre-school children.
pre-school; MMRV; diphtheria-tetanus-acellular pertussis-inactivated poliovirus vaccine; Italy; 2 + 1 schedule
In May of 2010, two communities (Truenococha and Santa Marta) reported to be at risk of vampire bat depredation were surveyed in the Province Datem del Marañón in the Loreto Department of Perú. Risk factors for bat exposure included age less than or equal to 25 years and owning animals that had been bitten by bats. Rabies virus neutralizing antibodies (rVNAs) were detected in 11% (7 of 63) of human sera tested. Rabies virus ribonucleoprotein (RNP) immunoglobulin G (IgG) antibodies were detected in the sera of three individuals, two of whom were also seropositive for rVNA. Rabies virus RNP IgM antibodies were detected in one respondent with no evidence of rVNA or RNP IgG antibodies. Because one respondent with positive rVNA results reported prior vaccination and 86% (six of seven) of rVNA-positive respondents reported being bitten by bats, these data suggest nonfatal exposure of persons to rabies virus, which is likely associated with vampire bat depredation.