Interaction of rabies vaccine with human rabies immunoglobulin and reliability of a 2-1-1 schedule application for postexposure treatment

Five commercially available rabies vaccines (HDCV, FBKC vaccine, PCEC vaccine, PVRV and PDEV) applied alone or combined with human rabies immunoglobulin (HRIG) were administered, by random allocation, to 161 volunteer vaccinees, using the abbreviated 2-1-1 postexposure immunization schedule. Protective levels of rabies antibody were demonstrated in all vaccinees by day 14, and in all but one vaccinee from day 21 to day 90. Partial inhibition of the antibody response due to HRIG was observed for three vaccines (PCEC vaccine, PVRV and PDEV). In terms of economy, reliability and rapid antibody induction, the 2-1-1 schedule proves superior to the presently recommended regimen for postexposure rabies prophylaxis.     

Tolerability and immunogenicity of an 11-valent pneumococcal conjugate vaccine in adults

We studied the safety and immunogenicity in healthy adults of an 11-valent pneumococcal conjugate vaccine. Capsular polysaccharides (PS) of serotypes 1, 4, 5, 7F, 9V, 19F and 23F were conjugated to tetanus toxoid, and of serotypes 3, 6B, 14 and 18C to diphtheria toxoid. Ten subjects received the conjugate vaccine with and the other ten subjects without aluminium hydroxide adjuvant. The reference vaccine was a marketed 23-valent PS vaccine. Safety data were recorded over 5 days after the immunisation. IgG antibody concentrations, avidity and subclass distribution were measured by EIA. The conjugate without aluminium induced more local adverse effects than the conjugate with aluminium or PS vaccine. All vaccines evoked significant antibody increases to all vaccine specific antigens. Both conjugate vaccines induced antibodies mainly of IgG(2) subclass, and adjuvanted conjugate vaccine induced IgG antibodies with increased avidity. This first administration, to man, of a mixed protein carrier 11-valent pneumococcal conjugate vaccine demonstrated its ability to induce an immune response without significant adverse effects, enabling further study on its use in paediatric populations.     

Immunogenicity and safety of low-dose intradermal rabies vaccination given during an Expanded Programme on immunization session in Viet Nam: results of a comparative randomized trial.

The World Health Organization recently recommended a rabies vaccine pre-exposure schedule using 3 intradermal (i.d.) injections of one-fifth the standard intramuscular (i.m.) dose of current cell culture vaccines as a cost-reducing alternative for developing countries. As a strategy to improve further the acceptability of childhood rabies immunization, we assessed, in a controlled, randomized trial performed in 240 Vietnamese infants, the possibility of associating i.d. administration of a one-fifth dose of purified Vero-cell rabies vaccine (PVRV) with routine Expanded Programme on Immunization vaccines given at 2, 3 and 4 months of age (diphtheria, tetanus, whole-cell pertussis and inactivated poliomyelitis combined vaccine, DTP-IPV). Safety and immunogenicity results were compared with a group of infants given 2 i.m. doses of PVRV (2, 4 months) in association with DTP-IPV (2, 3, 4 months). After i.d. injection, more infants experienced local reactions, particularly redness, but these reactions were generally mild and transient. The rate of systemic reactions was the same in both groups. Although the rabies antibody titres (rapid fluorescent focus inhibition test) were higher 1 month after the third vaccine dose in the i.m. group (30.6 IU/mL vs 12.0 IU/mL in the i.d. group), all infants in both groups had achieved WHO-acceptable protective antibody titres (> or = 0.5 IU/mL) at this time. There was no evidence for any interference between DTP-IPV and rabies vaccine, supporting the interest of a low-dose i.d. PVRV pre-exposure regimen in infants living in rabies-endemic developing countries.     

Purified Vero cell rabies vaccine and human diploid cell strain vaccine: comparison of neutralizing antibody responses to post-exposure regimens

Neutralizing antibody responses to conventional rabies post-exposure regimens of human diploid cell strain vaccine (HDCSV) and the new purified Vero cell rabies vaccine (PVRV) were compared in 58 healthy Thai veterinary students. The geometric mean titres (GMTs) of the group given HDCSV were slightly higher than those given PVRV, but on day 28 the peak GMTs of the two groups were statistically similar. The early antibody response to PVRV was unaffected by the addition of passive immunization, whereas the level of HDCSV response was reduced on day 14, so that there was no difference on that day between the GMTs of the two vaccine groups given HRIG. However, by day 91 the GMT of those given PVRV and HRIG was lower than in those given HDCSV alone or with HRIG. The appearance of antibody was less rapid than was observed in previous studies using multiple-site intradermal vaccination. Side effects were trivial. Our results confirm the promise of this new, potentially more economical tissue culture vaccine, but they suggest that the regimen could be improved.     

What happens if intradermal injections of rabies vaccine are partially or entirely injected subcutaneously?

Reported are the results of a study with the Thai Red Cross two-site intradermal purified Vero-cell rabies vaccine (PVRV) schedule that was deliberately injected into subcutaneous tissue. The 44 healthy nonimmune Thai adults who were enrolled in the study were randomly assigned to the following groups and given PVRV as shown: group A (two intradermal injections on days 0, 3, and 7); group B (one intradermal and one subcutaneous injection on days 0, 3, and 7); and group C (two subcutaneous injections on days 0, 3, and 7). Neutralizing antirabies antibody titres were determined on day 14 using the rapid fluorescent focus inhibition test. High rabies antibody titres were obtained for all three groups. These results suggest that the economical and safe Thai Red Cross intradermal PVRV regimen could be used in selected general health care facilities.     

Humoral and cellular immunity induced by antigens adjuvanted with colloidal iron hydroxide

The immunopotentiating activities of colloidal iron hydroxide, a novel, experimental mineral adjuvant, and of aluminium hydroxide. the licensed adjuvant for human vaccines, were compared. Our studies revealed that colloidal iron hydroxide and aluminium hydroxide behaved comparably with respect to supporting induction of an antibody response to tetanus toxoid. Furthermore, mice immunized with both, the experimental vaccine (tick-borne encephalitis virus (TBEV) antigen adsorbed to colloidal iron hydroxide) or with a commercially available TBEV vaccine (adjuvanted with aluminium hydroxide), developed long-lasting antibody responses which protected the animals from TBEV infection even one year after vaccination. The use of colloidal iron hydroxide as adjuvant had the additional advantage to reproducibly support induction of HIV-1 envelope-specific cytotoxic T lymphocytes (CTL), when used as adjuvant for a HIV-1 env-carrying recombinant fowlpox virus and being applied via the subcutaneous route. Aluminium hydroxide was much less active in this respect. Non-adjuvanted recombinant fowlpox elicited CTLs only when given intravenously or intraperitoneally, vaccination routes considered not to be suitable for routine use in humans. Further studies to evaluate the use of colloidal iron as possible alternative and/or supplement for routinely used mineral adjuvants may therefore be warranted.     

Co-expression of tetanus toxin fragment C in Escherichia coli with thioredoxin and its evaluation as an effective subunit vaccine candidate

The receptor-binding domain of tetanus toxin (THc), which mediates the binding of the toxin to the nerve cells, is a candidate subunit vaccine against tetanus. In this study one synthetic gene encoding the THc was constructed and highly expressed in Escherichia coli by co-expression with thioredoxin (Trx). The purified THc-vaccinated mice were completely protected against an active toxin challenge in mouse models of disease and the potency of two doses of THc was comparable to that of three doses of toxoid vaccine. And a solid-phase assay showed that the anti-THc sera inhibited the binding of THc or toxoid to the ganglioside GT1b as the anti-tetanus toxoid sera. Furthermore, mice were vaccinated once or twice at four different dosages of THc and a dose-response was observed in both the antibody titer and protective efficacy with increasing dosage of THc and number of vaccinations. The data presented in the report showed that the recombinant THc expressed in E. coli is efficacious in protecting mice against challenge with tetanus toxin suggesting that the THc protein may be developed into a human subunit vaccine candidate designed for the prevention of tetanus.     

Duration of protective immunity conferred by maternal tetanus toxoid immunization: further evidence from Matlab, Bangladesh.

OBJECTIVES: Although maternal tetanus immunization has been shown to be highly effective in the prevention of neonatal tetanus, unresolved questions remain concerning the required minimum number of doses and the resulting duration of effective immunity. This study examined the duration of effective immunity against neonatal tetanus provided by maternal tetanus immunization. METHODS: A randomized, double-blind cholera vaccine trial of 41,571 children and nonpregnant adult women carried out in 1974 in the Matlab comparison area of rural Bangladesh provided a unique opportunity to address dose and immunity issues. RESULTS: Children of women who received either 1 or 2 injections of tetanus toxoid experienced 4- to 14-day mortality levels consistently lower than those of children of unimmunized mothers. Analysis of neonatal-tetanus-related mortality showed that 2 injections of tetanus toxoid provided significant protection for subsequent durations of up to 12 or 13 years. CONCLUSIONS: The data demonstrate that a limited-dose regimen of maternal tetanus toxoid provides significant and extended protection against the risk of neonatal tetanus death.     

A controlled field trial of an aluminium phosphate-adsorbed cholera vaccine in Calcutta

A controlled field trial to determine the efficacy of a single dose of an aluminium phosphate-adsorbed cholera vaccine was conducted in Calcutta during 1975-77. An aluminium phosphate-adsorbed tetanus toxoid was used as the placebo. Follow-up of the immunized volunteers for a period of two years showed that the adsorbed cholera vaccine provided 100% protection to children under five years of age for 6 months, 88.9% for 12 months, and 91.7% for 18 months (P<0.05). The overall protection for all age groups was 58.5% for 18 months. There were no serious side effects following the anti-cholera inoculations.     

Rabies post-exposure prophylaxis vaccination with purified chick embryo cell vaccine (PCECV) and purified Vero cell rabies vaccine (PVRV) in a four-site intradermal schedule (4-0-2-0-1-1): an immunogenic, cost-effective and practical regimen

Currently, two intradermal (ID) regimens for rabies post-exposure prophylaxis (PEP) are recommended by WHO and used in countries where approved by national authorities: the Thai Red Cross (TRC) two-site ID regimen and the eight-site ID regimen. Besides these WHO recommended schedules, a new economical four-site ID regimen was evaluated that reduces the cost of PEP by up to 80%, when compared with the standard intramuscular Essen regimen, reduces the number of visits required for the patients when compared with the TRC regimen, and is more convenient than the eight-site regimen. To determine the immunogenicity of the ID four-site PEP regimen (4-0-2-0-1-1), 180 healthy volunteers were randomized to receive 0.1 mL volumes of PCECV or PVRV administered ID over both left and right shoulders and both deltoid regions on day 0, both deltoid regions on day 7 and over one deltoid region on days 30 and 90. Regardless of the vaccine, every subject developed rabies virus neutralizing antibody (RVNA) titers above 0.5 IU/mL by day 14, as determined by rapid fluorescent focus inhibition test (RFFIT) using a homologous test system. Two weeks after the last dose of vaccine, RVNA titers were all above 0.5 IU/mL (day 104). Geometric mean titers were similar throughout the study period. Both vaccines were well tolerated. These results demonstrate that a new four-site ID PEP regimen is a cost-effective and convenient alternative to IM (Essen or Zagreb) or ID (TRC or eight-site) regimens, especially using a 1 mL vial of vaccine (PCECV).     

Stability of an antifertility vaccine consisting of gonadotropin subunits linked to tetanus toxoid

The shelf life and thermal stability of an antifertility vaccine, in which gonadotropin subunits are linked to carriers such as tetanus toxoid and cholera toxin chain B and has successfully completed phase-I clinical trials at five centres in India, was studied. The vaccine adsorbed on alum was stored at three temperatures, 4 degrees C, room temperature (20-30 degrees C) and at 40 degrees C, for a period of up to 1 year. The human chorionic gonadotropin (hCG) binding capacity of antibodies (peak titres) induced in rodents by the vaccine after 6 months of storage at 40 degrees C and at room temperature were 1430 +/- 201 (mean +/- s.e.m.) and 1291 +/- 152 ng ml-1 respectively as compared to 1075 +/- 185 ng ml-1 for the vaccine stored at 4 degrees C. The difference was not statistically significant. After 12 months of storage, the immunogenic properties of the vaccine were nearly the same irrespective of the temperature at which the vaccine was kept. The findings show that the vaccine adsorbed on alum can withstand storage up to at least one year at room temperature and at 40 degrees C. These observations have implications for the current thoughts on storage of tetanus toxoid and diphtheria toxoid at 4-8 degrees C, the two vaccines widely used in immunoprophylaxis, and suggest that similar investigations on these vaccines as cold chain facilities are not universally available in developing countries.     

Evaluation of typhoid vaccines in the laboratory and in a controlled field trial in Poland: Preliminary report

In 1961 a controlled field trial of anti-typhoid vaccines was carried out in 25 regions in Poland. Four types of vaccine were studied: (1) bacterial acetone-killed and -dried vaccine (two kinds), (2) bacterial formol-killed phenol-preserved vaccine, (3) Westphal''s endotoxin adsorbed on aluminium hydroxide, and (4) Grasset''s vaccine (autolysate of typhoid bacilli adsorbed on aluminium hydroxide). The control vaccine was tetanus toxoid. A total of 690 655 persons received two inoculations. Prior to the field trial, laboratory tests were carried out on the vaccines, postvaccinal reactions were studied, and a serological examination was made of randomly selected blood samples. The vaccination was followed by a two-year survey of cases of typhoid and other diseases. Among children aged 5-14 years, the formol-killed phenol-preserved vaccine was found to be the most effective and Grasset''s vaccine the least. Among adults aged 15-60 years, no conclusive evidence for the effectiveness of the vaccines could be obtained owing to the small number of cases. This may be due to the maintenance of immunity through repeated annual vaccination with bacterial vaccines.     

A β-mannan trisaccharide conjugate vaccine aids clearance of Candida albicans in immunocompromised rabbits

A β-(1→2)-linked mannose trisaccharide epitope that is the optimal inhibitor of two protective monoclonal antibodies specific for the Candida albicans cell wall phosphomannan was used to create a synthetic conjugate vaccine. Two injections of the trisaccharide-tetanus toxoid conjugate administered with alum induced a robust secondary antibody response in rabbits with trisaccharide specific IgG ELISA titers in excess of 1:100,000. Fluorescent labeling studies demonstrated these antibodies (i) recognized the cell wall β-mannan of C. albicans on hyphae and budding cells and (ii) C. albicans incubated with immune sera bound complement factor C3. The synthetic conjugate vaccine but not the carrier protein, tetanus toxoid reduced Candida load in vaccinated rabbits subsequently rendered leukocytopenic by injection of cyclophosphamide and then challenged with live C. albicans. These data support the contention that antibody mediated immunity plays a role in combating C. albicans infections and suggests that a surprisingly simple, readily accessible synthetic conjugate vaccine may have therapeutic potential.     

Controlled field trials and laboratory studies on the effectiveness of typhoid vaccines in Poland, 1961-64: Final report

In recent years studies of the effectiveness of different typhoid vaccines have been sponsored by the World Health Organization in British Guiana, the USSR, and Yugoslavia. A similarly sponsored study has been made in Poland under the auspices of the Polish Typhoid Committee. In the controlled field trial four types of vaccine were used: (1) bacterial acetone-killed and -dried (vaccines K and P), (2) bacterial formol-killed phenol-preserved (vaccine N), (3) Westphal''s endotoxin adsorbed on aluminium hydroxide (vaccine S), and (4) Grasset''s vaccine (autolysate of typhoid bacilli adsorbed on aluminium hydroxide; vaccine T). The control vaccine was tetanus toxoid (vaccine O). Laboratory tests were also carried out.     

Lymphocyte subpopulations and antibody levels in immunized malnourished children

1. The proportions of lymphocyte subpopulations (by rosette tests) and the serum antibody levels (using haemagglutination techniques) were estimated in malnourished and well fed Nigerian children before and up to 21 d after immunization with tetanus toxoid or measles virus vaccine. 2. Significantly diminished (P less than 0.01) mean percentage T lymphocyte levels and considerably higher mean percentage null cell levels were observed in the malnourished children before immunization with either of the vaccines. 3. There was comparable in vivo increases in percentage T lymphocytes in malnourished and control children following the administration of each antigen. 4. The mean percentage B lymphocyte levels were similar in the control and malnourished children before and after the immunization. 5. There was a slight depression in the tetanus antibody levels (P greater than 0.2) but a significant diminution (P less than 0.01) in measles virus antibody concentrations in the malnourished children. 6. Rise in mean percentage T lymphocytes corresponded with the elevation in mean tetanus antibody levels in both malnourished and control children following tetanus toxoid immunization. This was however not the situation in the malnourished children following immunization with measles virus. 7. The observed depressed T lymphocyte number in malnourished children may in practice affect their handling of antigens such as measles virus in vivo.     

Recombinant cholera toxin B subunit (rCTB) as a mucosal adjuvant enhances induction of diphtheria and tetanus antitoxin antibodies in mice by intranasal administration with diphtheria-pertussis-tetanus (DPT) combination vaccine

Recombinant cholera toxin B subunit (rCTB) which is produced by Bacillus brevis carrying pNU212-CTB acts as a mucosal adjuvant capable of enhancing host immune responses specific to unrelated, mucosally co-administered vaccine antigens. When mice were administered intranasally with diphtheria-pertussis-tetanus (DPT) combination vaccine consisting of diphtheria toxoid (DTd), tetanus toxoid (TTd), pertussis toxoid (PTd), and formalin-treated filamentous hemagglutinin (fFHA), the presence of rCTB elevated constantly high values of DTd- and TTd-specific serum ELISA IgG antibody titres, and protective levels of diphtheria and tetanus toxin-neutralizing antibodies but the absence of rCTB did not. Moreover, the addition of rCTB protected all mice against tetanic symptoms and deaths. DPT combination vaccine raised high levels of serum anti-PT IgG antibody titres regardless of rCTB and protected mice from Bordetella pertussis challenge. These results suggest that co-administration of rCTB as an adjuvant is necessary for induction of diphtheria and tetanus antitoxin antibodies on the occasion of intranasal administration of DPT combination vaccine.     

An adult formulation of a five-component acellular pertussis vaccine combined with diphtheria and tetanus toxoids is safe and immunogenic in adolescents and adults

Pertussis is increasingly being recognized as an important cause of cough illness in adolescents and adults. To evaluate the safety and immunogenicity of an adult formulation of a five-component (pertussis toxoid, filamentous hemagglutinin, pertactin, fimbriae 2 and 3) acellular pertussis vaccine combined with diphtheria and tetanus toxoids, we randomly allocated 749 healthy adolescents and adults from 12-54 years of age recruited from five Canadian communities to receive either tetanus-diphtheria vaccine (Td), acellular pertussis vaccine (aP) or combined diphtheria-tetanus-acellular pertussis vaccine (TdaP). Subjects and personnel were unaware of the vaccine allocation. Antibody levels were measured before and one month postimmunization; adverse events were collected at 24 and 72 h and 8 to 10 days. Adverse events were reported in similar frequency amongst the three vaccine groups. Moderate pain at the injection site was reported less frequently in the aP group than the TdaP group (10.7% compared to 19.4%; relative risk 0.6, 95% confidence interval 0.3-0.9). Chills were reported less frequently after Td (5.3%) than after TdaP (12.5%; relative risk 0.4, 95% confidence interval 0.2-0.9). There were no statistically significant differences between recipients of Td and TdaP in tetanus and diphtheria antitoxin levels achieved. Antibody response against Bordetella pertussis antigens was vigorous in all groups although recipients of aP alone had higher levels of antibody levels against pertussis toxoid, fimbriae, and agglutinins and lower antibody levels against pertactin than did TdaP recipients. We conclude that this adult formulation 5-component acellular pertussis vaccine is safe and immunogenic in adolescents and adults and is a candidate vaccine for adolescent and adult immunization programs.     

百白破联合疫苗基础免疫后不同时间的抗体水平研究

为了解全细胞百白破联合疫苗 (DTwP)基础免疫后抗体持续时间 ,对DTwP免疫 3针后间隔 1个月和 2个月的百日咳、白喉、破伤风抗体水平的变化进行了初步研究 ,结果表明 :免疫后 2个月 ,白喉、破伤风抗体滴度 ,与免疫前相比 ,差异均有显著的统计学意义 ,并且仍然远 >0 0 1HAU的保护水平。百日咳疫苗免疫后 2个月 ,其抗体滴度仅为免疫后 1个月抗体滴度的 2 5 %左右 ,免疫后 1个月和 2个月抗体滴度间差异有非常显著的统计学意义。     

Revision of the Thai Red Cross intradermal rabies post-exposure regimen by eliminating the 90-day booster injection

The Thai Red Cross intradermal post-exposure rabies prophylaxis regimen (TRC-ID) is being used in Thailand, the Philippines, Sri Lanka and is making inroads in India. It consists of two injections of 0.1 mL of any World Health Organization recommended tissue culture rabies vaccine intradermally at two sites on days 0, 3, 7, followed by one injection on days 28 and 90. Two decades of experience had shown that approximately 11% of 187,000 possibly rabies exposed subjects who received the TRC-ID schedule, did not return for the 90-day booster. No rabies deaths had, however, been reported from this group. This stimulated two studies to determine whether the 90-day booster can be abolished. They demonstrated that, if the single 28-day 0.1 mL injection is increased to two at two sites, a comparable antibody response can be achieved and the 90-day booster can be omitted. The tissue culture rabies vaccine used in the preliminary study was purified chick embryo vaccine (PCEC Chiron) and for this study it was chromatography purified Vero cell vaccine (CPRV, Aventis-Pasteur). CPRV had been previously shown to be as immunogenic and effective as purified Vero cell rabies vaccine (PVRV).     

Immunogenicity of IRIV- versus alum-adjuvanted diphtheria and tetanus toxoid vaccines in influenza primed mice

The immunogenicity and protectivity of two different toxoid vaccines were compared in mice. In one formulation, toxoids (diphtheria or tetanus) were adsorbed to alumoxid, whereas in the other formulation the toxoids were crosslinked to immunopotentiating reconstituted influenza virosomes (IRIVs). A preimmunization with influenza antigens is necessary for a good anti-toxoid antibody response when the IRIV formulation was administered. After two immunizations with the IRIV- or alum-based vaccines, the IRIV-based formulation induced a higher humoral immune response than toxoids adsorbed to alum. Using an in vitro test, diphtheria toxin neutralizing antibodies were tested. Di-IRIV induced a significantly (p = 0.002) higher titer of diphtheria toxin neutralizing antibodies than Di-alum. Tetanus challenge experiments showed, that the IRIV-based tetanus vaccine induced a threefold higher titer of protective antibodies than the tetanus toxoid adsorbed to alum. Therefore, the IRIV-based formulations appeared to be superior to the alum-based vaccines in terms of immunogenicity and protectivity.