Model-based estimates of risks of disease transmission and economic costs of seven injection devices in sub-Saharan Africa

OBJECTIVE: To investigate and compare seven types of injection devices for their risks of iatrogenic transmission of bloodborne pathogens and their economic costs in sub-Saharan Africa. METHODS: Risk assumptions for each device and cost models were constructed to estimate the number of new hepatitis B virus (HBV) and human immunodeficiency virus (HIV) infections resulting from patient-to-patient, patient-to-health care worker, and patient-to-community transmission. Costs of device purchase and usage were derived from the literature, while costs of direct medical care and lost productivity from HBV and HIV disease were based on data collected in 1999 in Côte d''Ivoire, Ghana, and Uganda. Multivariate sensitivity analyses using Monte Carlo simulation characterized uncertainties in model parameters. Costs were summed from both the societal and health care system payer''s perspectives. FINDINGS: Resterilizable and disposable needles and syringes had the highest overall costs for device purchase, usage, and iatrogenic disease: median US dollars 26.77 and US dollars 25.29, respectively, per injection from the societal perspective. Disposable-cartridge jet injectors and automatic needle-shielding syringes had the lowest costs, US dollars 0.36 and US dollars 0.80, respectively. Reusable-nozzle jet injectors and auto-disable needle and syringes were intermediate, at US dollars 0.80 and US dollars 0.91, respectively, per injection. CONCLUSION: Despite their nominal purchase and usage costs, conventional needles and syringes carry a hidden but huge burden of iatrogenic disease. Alternative injection devices for the millions of injections administered annually in sub-Saharan Africa would be of value and should be considered by policy-makers in procurement decisions.     

Incremental cost-effectiveness of supplementary immunization activities to prevent neonatal tetanus in Pakistan

OBJECTIVE: This study aimed to estimate the incremental cost-effectiveness of supplementary immunization activities to prevent neonatal tetanus in the Loralai district of Pakistan. The supplemental immunization activities were carried out in two phases during 2001-03. METHODS: A state-transition model was used to estimate the effect of routine vaccination with tetanus toxoid as well as vaccination with tetanus toxoid during supplementary immunization activities.The model follows each woman in the target population from birth until the end of her childbearing years, using age-specific fertility data and vaccination history to determine the number of births at risk for neonatal tetanus. Recently published data on the incidence of neonatal tetanus from Loralai were used to determine the number of cases occurring with and without supplementary immunization activities. Data on the costs of the activities were collected from the UNICEF office in Balochistan and from the Provincial Health Department. FINDINGS: Using base-case assumptions we estimated that the supplementary immunization activities would prevent 280 cases of neonatal tetanus and 224 deaths from neonatal tetanus between 2001 and 2034. Implementation of the supplementary activities was relatively inexpensive. The cost per tetanus toxoid dose delivered was 0.40 U.S. dollars. In the base-case analysis the cost per death averted was 117.00 U.S. dollars (95% confidence interval (CI) = 78-205 U.S. dollars) and the cost per disability-adjusted life year (DALY) averted was 3.61 U.S. dollars (95% Cl = 2.43-6.39 U.S. dollars). CONCLUSION: Compared with similar analyses of other interventions, the cost per DALY averted is a favourable cost-effectiveness ratio. However, if routine diphtheria-tetanus-pertussis vaccination coverage in the Loralai district had been higher (at a coverage rate of about 80%) the cost-effectiveness of the intervention would have been even more favourable, at 2.65 U.S. dollars per DALY averted.     

Jet gun or syringe? A trial of alternative methods of BCG vaccination

In a trial of alternative methods of BCG vaccination, 628 children were vaccinated by syringe and needle and 690 by needleless jet injector. The lesions produced by vaccination with the jet injector were significantly smaller than those resulting from intradermal injection by syringe and needle and only 31 (4%) of the lesions from the jet injector had failed to heal by 3 months, compared with 311 (50%) from the syringe and needle. All but one of the children vaccinated by jet injector developed scars of 4 mm or more in diameter but only one had a scar in excess of 10 mm, compared with 41 scars of this size among those vaccinated by syringe and needle. There was a significant difference in tuberculin conversion rates for the two vaccination methods in one of the districts possibly related to differing vaccine reconstitution techniques.The cost of vaccination per 1000 children by jet injector was less than 40% of the costfor syringe and needle, using a new disposable syringe and needle for each child.In terms of acceptability to the children, freedom from complications and lower cost vaccination the jet injector proved to be the better method.     

Small animal jet injection technique results in enhanced immunogenicity of hantavirus DNA vaccines

DNA vaccine evaluation in small animals is hampered by low immunogenicity when the vaccines are delivered using a needle and syringe. To overcome this technical hurdle we tested the possibility that a device developed for human intradermal medicine delivery might be adapted to successfully deliver a DNA vaccine to small animals. Disposable syringe jet injection (DSJI) does not currently exist for small animals. However, a commercialized, human intradermal device used to to administer medicines to the human dermis in a 0.1 mL volume was evaluated in Syrian hamsters. Here, we found that hantavirus DNA vaccines administered to hamsters using DSJI were substantially more immunogenic than the same vaccines delivered by needle/syringe or particle mediated epidermal delivery (gene gun) vaccination. By adjusting how the device was used we could deliver vaccine to either subcutaneous tissues, or through the skin into the muscle. RNA and/or antigen expression was detected in epidermal, subepidermal and fibroblast cells. We directly compared six optimized and non-optimized hantavirus DNA vaccines in hamsters. Optimization, including codon-usage and mRNA stability, did not necessarily result in increased immunogenicity for all vaccines tested; however, optimization of the Andes virus (ANDV) DNA vaccine protected vaccinated hamsters from lethal disease. This is the first time active vaccination with an ANDV DNA vaccine has shown protective efficacy in the hamster model. The adaptation of a human intradermal jet injection device for use as a method of subcutaneous and intramuscular jet injection of DNA vaccines will advance the development of nucleic acid based medical countermeasures for diseases modeled in hamsters.     

The use of jet-injectors in BCG vaccination

In mass vaccination programmes, the jet-injection of vaccine may have considerable operational advantages over the classical techniques. The technical performance of two models of jet-injector, the Dermo-Jet and the Ped-O-Jet, in BCG vaccination was assessed in a number of studies which are reviewed by the authors. It is shown that the jet-injectors do not administer the full dose for which they are calibrated and that the size of the vaccination lesion varies more than after vaccination by syringe.     

Vaccination of infants with a four-dose and a three-dose vaccination schedule

Swedish infants were vaccinated with diphtheria, tetanus and pertussis toxoids, inactivated poliovirus vaccine and a Haemophilus influenzae type b - tetanus toxoid conjugate vaccine at 2, 4, 6 and 15 months (US vaccination program, 'US arm', n=118) or at 3, 5 and 12 months of age (Swedish vaccination program, 'Swedish arm', n=103). The antigen amounts in the diphtheria and tetanus vaccines were higher in the Swedish than in the US arm while the amounts in the other vaccines were the same in both arms. There were no serious side effects. Local reactions increased with the numbers of doses but did not differ significantly between the groups. Serum was obtained at 2, 7, 15 and 16 months in the US arm and at 3, 6, 12 and 13 months of age in the Swedish arm. A fifth serum was obtained in both groups at 4 yr of age. For vaccines with the same antigen amount the following was observed: a. three doses at 2, 4 and 6 months were more immunogenic than two doses at 3 and 5 months; b. the third dose in the Swedish arm was more immunogenic than the third dose in the US arm; c. the fourth dose in the US arm induced higher antibodies than the third dose in the Swedish arm (except for pertussis toxin antibodies that were similar in both groups) and the differences tended to remain at the age of 4 yr. Children in the Swedish arm received a higher diphtheria toxoid dose (25 Lf) than in the US arm (15 Lf) which led to higher diphtheria toxin antibodies in the Swedish arm at comparable ages. Children in the Swedish arm received a higher tetanus toxoid dose (7 Lf) than in the US arm (6 Lf). Tetanus antibodies were similar at comparable ages. In conclusion, the immunogenicity of vaccines in infancy can be improved by increasing the number of doses, by prolonging the intervals between doses and by increasing the antigen amount in the vaccine.     

Deferral of routine booster doses of tetanus and diphtheria toxoids for adolescents and adults

A shortage of tetanus and diphtheria toxoids (Td) and tetanus toxoid (TT) in the United States has resulted because one of two manufacturers discontinued production of tetanus toxoid-containing products. Aventis Pasteur (Swiftwater, Pennsylvania) is the only major manufacturer of tetanus and Td in the United States. In response to the shortage, Aventis Pasteur has increased production of Td to meet national needs; however, because 11 months are required for vaccine production, the shortage is expected to last for the remainder of 2001.     

Humoral immune responses to a protective peptide-conjugate against measles after different prime-boost regimens

The current live-attenuated measles vaccine leaves many children unprotected until they reach the recommended age of vaccination. We have previously shown that the short peptide corresponding to the hemagglutinin noose epitope (HNE) of the measles virus (MV) hemagglutinin protein induced virus-neutralizing antibodies even in the presence of protective levels of anti-whole virus-specific antibodies. Here we investigate the immunogenicity of HNE peptide-conjugates of diphtheria or tetanus toxoid in mice after active and passive priming with antibodies against the peptide, toxoids and conjugates. Both conjugates induced high titers of peptide antibodies which crossreacted with the virus and protected against a lethal intracranial challenge with a rodent-adapted measles virus, even after active priming with homologous or heterologous toxoid or conjugate. Peptide-specific epitopic suppression was stronger after passive priming with carrier or conjugate antibodies, but diphtheria toxoid as a carrier was less susceptible to suppression than tetanus toxoid and suppression was overcome by an additional boost. Furthermore, prior immunization with peptide-conjugate did not interfere with the development of a complete response to a subsequent injection of MV, suggesting that the benefits of a follow-up vaccination with the current live-attenuated vaccine would not be lost. These results underline the potential of these peptide-based conjugates as vaccine candidates for use in early infancy to close the window of susceptibility before the live-attenuated vaccine can be administered.     

Immunoenhancement with combined rabies and aluminium-adjuvanted tetanus vaccines

The effect of combining tetanus toxoid in the same syringe with purified Vero cell rabies vaccine (PVRV) was investigated in the 2-1-1 regimen of PVRV. The 2-1-1 regimen alone was as immunogenic as the five-dose regimen, while saving one dose of vaccine and two clinic visits. When aluminium hydroxide-adsorbed tetanus toxoid was used to dissolve PVRV on days 0 (one of the two doses) and 21, the anti-rabies antibody was significantly increased. Aluminium-free tetanus toxoid was ineffective, suggesting that immunoenhancement was due to aluminium adjuvant. In addition, anti-tetanus antibody was unaffected and the side-effects were not increased by such mixing.     

Licensure of a diphtheria and tetanus toxoids and acellular pertussis adsorbed, inactivated poliovirus, and haemophilus B conjugate vaccine and guidance for use in infants and children

On June 20, 2008 the Food and Drug Administration (FDA) licensed a combined diphtheria and tetanus toxoids and acellular pertussis adsorbed (DTaP), inactivated poliovirus vaccine (IPV), and Haemophilus influenzae type b conjugate (tetanus toxoid [TT] conjugate) vaccine, DTaP-IPV/Hib (Pentacel, Sanofi Pasteur, Swiftwater, Pennsylvania), for use as a four-dose series in infants and children at ages 2, 4, 6, and 15-18 months. This report summarizes the indications for Pentacel and provides guidance from the Advisory Committee on Immunization Practices (ACIP) for its use.     

Syncope after vaccination--United States, January 2005-July 2007

Syncope (vasovagal reaction), or fainting, can be triggered by various stimuli, including medical procedures. Syncope has been documented to occur after vaccination, most commonly among adolescents, and can result in hospitalization for a medical evaluation or because of injury. During 2005 and 2006, the Advisory Committee on Immunization Practices (ACIP) recommended use of three newly licensed vaccines for adolescents: the quadrivalent human papillomavirus recombinant vaccine (HPV) (Gardasil(R), Merck & Co., Inc., Whitehouse Station, New Jersey) in a 3-dose series, the quadrivalent meningococcal conjugate vaccine (MCV4) (Menactra, Sanofi Pasteur, Inc., Swiftwater, Pennsylvania) in a single dose, and the tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Tdap) (Adacel, Sanofi Pasteur; Boostrix, GlaxoSmithKline Biologicals, Research Triangle Park, North Carolina) in a single dose. To describe trends in occurrence of postvaccination syncope, CDC and the Food and Drug Administration (FDA) analyzed data from the Vaccine Adverse Event Reporting System (VAERS) for January 1, 2005-July 31, 2007, and compared the results with VAERS reports received during January 1, 2002-December 31, 2004. The findings indicated that, since 2005, reports to VAERS regarding postvaccination syncope have increased, primarily among females aged 11-18 years, and rarely, subsequent serious injuries have occurred. To prevent syncope-related injuries, vaccine providers should follow the ACIP recommendation to strongly consider observing patients for 15 minutes after vaccination.     

Mixing is required for uniform reconstitution of filter-dried protein antigens in a single-injection vaccine formulation

Ambient temperature filter dried vaccine formulations have been proposed to simultaneously achieve thermostability and offer a ready-to-use immunisation device that combines reconstitution and injection. Vaccine concentration should be uniform at the point of injection, but the uniformity following direct reconstitution of filter-dried vaccines has not been reported. We present here a study of vaccine mixing and release following dissolution of filter-dried model protein and toxoid antigens within a single syringe, filter and needle unit. Release was better for filters made from glass than cellulose. Without additional mixing, uniformity was poor and only 41% of input protein was released from protein filter-dried onto glass fiber. In contrast, adding a simple glass bead and mixing by inversion, 100% release antigen solution was achieved, with uniform concentration at exit from the needle throughout a simulated injection. Adsorption onto alum adjuvant had no detectable effect on vaccine dissolution and mixing. The uniformity and yield of low doses of diphtheria and tetanus toxoid was also improved by mixing, albeit with a lower yield of 60–68%. We conclude that uniformity and mixing should be studied to ensure safety and efficacy of directly reconstituted filter-dried vaccine formulations.     

Comparative study of reactions and serological response to cholera vaccines in a controlled field trial conducted in the USSR

This article presents the results of a comparative study of the reactogenicity and the serological response induced by a number of cholera vaccines. Conducted in the USSR on 998 adults aged 18 years and over, the study covered whole-cell heat-killed and formalin-inactivated cholera vaccines, whole-cell heat-killed El Tor vaccine, and a new partially purified toxoid preparation proposed for the immunoprophylaxis of cholera—all administered by hypodermic syringe or jet injector. The most marked reactions were found to occur with the formalin-inactivated cholera vaccine and the least marked with the partially purified toxoid. It was also established that the toxoid was no less effective than the whole-cell vaccine in inducing the intense production of antibodies to the Inaba serotype and, in somewhat lesser degree, to the Ogawa serotype of the El Tor vibrio. It was the only preparation to give rise to intense production of specific antitoxins in 95-98% of cases. The reactions to and immunogenic properties of the cholera vaccines did not show any statistically significant difference whether administered by hypodermic syringe or by jet injector.     

Immunogenicity study of a combined diphtheria, tetanus, acellular pertussis, inactivated poliomyelitis vaccine used to reconstitute a freeze-dried Haemophilus influenzae type b vaccine (DTaP-IPV//PRP-T) administered simultaneously with a hepatitis B vaccine at two, three and four months of life

This study was designed to assess the immunogenicity of a vaccine combining diphtheria and tetanus toxoids, acellular pertussis vaccine, and inactivated poliovirus vaccine reconstituting Haemophilus influenzae type b polysaccharide conjugated to tetanus protein (DTaP-IPV//PRP-T; Pasteur Mérieux Connaught, Lyon, France) administered simultaneously in association with hepatitis B vaccine (RECOMBIVAX (?trade mark omitted?) Merck, Sharp & Dohme, West Point, PA, USA) for the primary immunization of infants. The vaccines were administered at two, three and four months of age. One hundred and sixty-two healthy infants, aged 8-10 weeks, were enrolled in the study. Blood samples were taken before the first dose and 4 weeks after the third dose. The infants were observed for 15 minutes after vaccination for any immediate reaction. Adverse events requiring a medical consultation were recorded by the parents in a diary over the 7 days following vaccination. Four weeks after the third immunization, the percentages of infants fulfilling seroconversion criteria were 98.9% for pertussis toxin, 95.9% for filamentous haemagglutinin, 100.0% for tetanus, 100.0% for diphtheria, 99.3% for poliovirus type 1, 100.0% for both poliovirus types 2 and 3, 98.0% for Haemophilus influenzae type b, and 100% for hepatitis B surface antigen. No vaccine-related serious adverse event was reported. The simultaneous administration of DTaP-IPV//PRP-T and hepatitis B vaccines at two, three and four months of age yielded clinically satisfactory immune responses to all antigens compared with historical controls and gave a good safety profile.     

Recall of Tripedia vaccine

On January 27, 1999, the Food and Drug Administration initiated a voluntary recall of Tripedia diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP), lot number 0916490, manufactured by Pasteur Merieux Connaught USA. Routine post-release stability testing completed in January 1999 indicated that the potency of the diphtheria toxoid component of this lot was below specification. The potency of the tetanus and pertussis components of this lot was acceptable.     

Smallpox vaccination by intradermal jet injection. I. Introduction, background and results of pilot studies

Jet injection has met with great success in the rapid and effective mass administration of several immunizing agents. The recent development of a jet injector nozzle specifically designed for intradermal inoculation suggested the possible extension of jet injector methodology to mass smallpox vaccination. A total of 156 volunteer subjects, 16 unvaccinated and 140 vaccinated more than 5 years previously, received either undiluted smallpox vaccine by the multiple-pressure technique, or 0.1 ml of various dilutions of smallpox vaccine by jet injector using the new nozzle. Cutaneous and serological responses in revaccinees revealed that jet injection of diluted vaccine with a titre of 10⁷ TCID₅₀/ml was as effective as multiple-pressure inoculation of undiluted vaccine. Among the small number of primary vaccinees, jet injection of diluted vaccine with a titre of 10⁶ TCID₅₀/ml appeared as effective as multiple-pressure inoculation of undiluted vaccine. No complications of vaccination occurred.     

Immunogenicity of a combined diphtheria-tetanus-acellular pertussis vaccine in adults

Two clinical studies were undertaken to evaluate the immunogenicity of an adult-type dTpa booster vaccine (Boostrix by GlaxoSmithKline Biologicals). Blood samples taken prior to vaccination showed that 24.4 and 13.0% of subjects were seronegative for diphtheria and tetanus antibodies, respectively. Moreover, about one-third of the vaccinees had no detectable levels of antibodies to pertussis toxoid (PT) or pertactin (PRN). One month post-vaccination, more than 93% of all individuals, regardless of age or type of vaccine received, had seroprotective antibody levels for diphtheria and tetanus (> or = 0.1IU/ml). In those individuals vaccinated with the adult-type dTpa vaccine (Boostrix), more than 98% were found to be seropositive for antibodies to all three pertussis antigens (PT, filamentous haemogluttin (FHA), and PRN). These data suggest that immunity to diphtheria, tetanus and pertussis (DTP) in adults wanes and that booster vaccination with an adult-type combined dTpa vaccine would boost the serological response to diphtheria antitoxin, tetanus antitoxin and antibodies to Bordetella pertussis PT, FHA and PRN.     

Immunogenicity of a combination vaccine containing pneumococcal conjugates and meningococcal PorA OMVs

The pre-clinical immunogenicity of a combination vaccine containing 13-valent pneumococcal conjugate (13vPnC) vaccine (serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F conjugated to CRM197) and nine-valent meningococcal B PorA vaccine (NonaMen; serosubtypes P1.7,16; P1.5-1,2-2; P1.19,15-1; P1.5-2,10; P1.12-1,13; P1.7-2,4; P1.22,14; P1.7-1,1 and P1.18-1,3,6), and any potential immunological interference between pneumococcal and MenB components of the vaccine were evaluated. NIH mice were immunized twice subcutaneously with the vaccines combined in one syringe, or given individually. Combining 13vPnC vaccine with NonaMen vaccine in one syringe had no negative effect on the induced antibody response against any MenB serosubtypes compared to separate injection of the vaccines, and the anti-pneumococcal antibody responses were enhanced. Furthermore, co-administration of the combination vaccine with a combined diphtheria/tetanus/acellular pertussis/inactivated poliomyelitis vaccine/Haemophilus influenzae type b-TT conjugate (DTaP/IPV-Hib) vaccine to New Zealand white rabbits at a different injection site did not affect the anti-pneumococcal polysaccharide and anti-PorA antibody titres. We conclude that no immunological interference was observed by combined administration of pneumococcal conjugate and meningococcal B vaccines in one syringe.     

Tetanus immunisation policy in England and Wales--an overview of the literature

Current UK policy on immunisation for tetanus has changed in the light of evidence that five doses of vaccine probably provides sufficient protection as long as high-risk wounds are managed with tetanus immunoglobulin. This paper reviews the evidence base for tetanus immunisation policy in England and Wales: the epidemiology of tetanus, vaccination coverage and response to tetanus toxoid, and population immunity to tetanus. The paper highlights gaps in our current knowledge of tetanus vaccination and policy implementation, and makes recommendations for further investigations.     

Shortage of tetanus and diphtheria toxoids

A temporary shortage of adult tetanus and diphtheria toxoids (Td) in the United States has resulted from two coincident situations: 1) a decrease in the number of lots released by Wyeth Lederle (Pearl River, New York), and 2) a temporary decrease in inventory of vaccine following routine maintenance activities at the production facilities by Aventis Pasteur (Swiftware, Pennsylvania) that lasted longer than anticipated. Approximately one half of the usual number of Td doses has been distributed this year. Although there have been no decreases in production of tetanus toxoid (TT), availability is low because of increased use during the Td shortage. On the basis of information provided by Aventis Pasteur, the Public Health Service expects vaccine supplies to be restored early in 2001. Until then, Aventis Pasteur will be limiting orders to assure the widest possible distribution of available doses.