Prevalidation of the cAMP-PTx reporter assay for quantitative assessment of pertussis toxin activity.

Testing for inactivation of pertussis toxin and reversion to toxicity in aP vaccines has historically relied on the murine histamine sensitization test, that lacks mechanistic understanding, suffers from standardization problems and is associated with severe animal suffering. Though the regulatory requirements for in vivo testing of acellular pertussis (aP) vaccine products have been waived in Europe, it is still common practice globally. Easy and quantitative in vitro methods are therefore urgently needed. One of the alternatives under development is our reporter cell line - CHO-CRE cells - that carries a cAMP-reporter construct. After exposure to pertussis toxin, cells are stimulated with a low concentration of forskolin to allow detection of pertussis toxin dependent changes in intracellular cAMP levels. Here, the results of two prevalidation studies with purified pertussis toxin and pertussis toxin spiked aP vaccines are described that were performed according to the principles of the ICH Q2(R1) guidelines for a content assay. We confirmed the assay's specificity, accuracy, precision, linearity and range. The cAMP-PTx reporter assay allows for objective, reliable and quantitative assessment of pertussis toxin levels in aP vaccines and can thereby boost broad and global replacement of the histamine sensitization test.

The Need to Optimize Adolescent Immunization.

The adolescent period heralds the pediatric patient's transition into adulthood. It is a time of dynamic development during which effective preventive care measures can promote safe behaviors and the development of lifelong health habits. One of the foundations of preventive adolescent health care is timely vaccination, and every visit can be viewed as an opportunity to update and complete an adolescent's immunizations.In the past decade, the adolescent immunization schedule has expanded to include 2 doses of quadrivalent meningococcal conjugate vaccine, 1 dose of tetanus, diphtheria, acellular pertussis, absorbed vaccine, 2 or 3 doses of human papillomavirus vaccine, depending on the child's age, and an annual influenza vaccine. In addition, during adolescent visits, health care providers can determine whether catch-up vaccination is needed to meet early childhood recommendations for hepatitis B; hepatitis A; measles, mumps, rubella; poliovirus; and varicella vaccines. New serogroup B meningococcal vaccines are now available for those at increased risk for meningococcal disease; in addition, these serogroup B meningococcal vaccines received a Category B recommendation for healthy adolescents, where individual counseling and risk-benefit evaluation based on health care provider judgements and patient preferences are indicated. This clinical report focuses on the epidemiology of adolescent vaccine-preventable diseases by reviewing the rationale for the annual universally recommended adolescent immunization schedule of the American Academy of Pediatrics, the American Academy of Family Physicians, the Centers for Disease Control and Prevention, and the American Congress of Obstetricians and Gynecologists. In addition, the barriers that negatively influence adherence to this current adolescent immunization schedule will be highlighted.

Reduced risk of pertussis among persons ever vaccinated with whole cell pertussis vaccine compared to recipients of acellular pertussis vaccines in a large US cohort.

BACKGROUND: Unexpected waning of immunity after pertussis vaccination is now well described. In this study we examined whether prior vaccination with whole-cell pertussis vaccine (wP) at any point provided superior protection contrasted with a solely acellular pertussis vaccine (aP) series. We utilized the coincidence of a large outbreak of pertussis with the termination of wP availability, providing populations of children who had been vaccinated with combinations of wP and aP. METHODS: Kaiser Permanente (KP) is an integrated healthcare system with complete electronic records and a centralized laboratory. Cases of laboratory-confirmed pertussis and vaccination data for members aged 8-20 years were retrieved. RESULTS: Among 263 496 persons aged 8-20 years, 904 cases of pertussis were identified. In patients with a full history of vaccinations administered by KP, those with 5 total doses of only aP had an 8.57 relative risk (RR) of pertussis (P < .0001) contrasted to those with ≥1 wP dose. With 6 doses of aP, the RR of disease was 3.55 (P < .0001). When external vaccine records were included, the results were similar. CONCLUSIONS: We found a markedly increased risk of disease associated with an entirely aP series. This risk was mitigated, but not eliminated, by the presence of a sixth dose of pertussis vaccine (Tdap). Receipt of 1 or more wP doses markedly augmented the durability of immunity from subsequent aP doses. It appears that a wholly acellular pertussis vaccine series is significantly less effective and durable than one that contains the traditional whole cell vaccine.

Acellular pertussis vaccines in China.

In China, whole-cell pertussis (Pw) vaccines were produced in the early 1960s and acellular pertussis (Pa) vaccines were introduced in 1995. Pa vaccines have now almost completely replaced Pw vaccines in the national immunization program. To strengthen the regulation of vaccines used in China, a vaccine lot release system was established in 2001 and Pa vaccines have been included in the system since 2006. This paper mainly described the current status of production and the quality control measures in place for Pa vaccines; and analyses quality control test data accumulated between 2006 and 2010.

Economic impact of the introduction of an acellular pertussis vaccine in Canada: a 6-year analysis.

BACKGROUND: Between July 1997 and April 1998, Canadian public health agencies switched from the whole cell vaccine to the acellular vaccine for pertussis immunization. The acellular vaccine provided better efficacy and fewer adverse events than the whole cell vaccine did. OBJECTIVE: To determine the economic impact of replacing the whole cell vaccine with an acellular vaccine in Canada. METHODS: A decision analytic model was developed comparing costs and outcomes of pertussis vaccination for Canadian children born in the years 1991-2004. Effectiveness was measured as number of avoided pertussis cases as well as the number of avoided hospital admissions. Incremental costs per avoided pertussis case and per avoided hospital admission were calculated for Ministry of Health (MoH) and societal (SOC) perspectives. Various one-way sensitivity analyses as well as a Monte Carlo simulation were performed by varying key model parameters. RESULTS: The switch in immunization programs resulted in an incremental cost to the MoH of CAD $108 per pertussis case avoided (CAD $0.96 per child-year). From the SOC perspective, there was a savings of CAD $184 per pertussis case avoided (CAD $0.13 per child-year). The one-way sensitivity analyses provided incremental cost-effective ratios (ICERs) ranging from an incremental cost of CAD $1034 per avoided pertussis case from the MoH perspective to a saving of CAD $1583 per avoided case from the SOC perspective. The Monte Carlo simulation confirmed the robustness of these results. CONCLUSIONS: Pertussis vaccination with AcE was cost-saving from the societal perspective and cost-effective from the Ministry of Health perspective.

The distribution over time of costs and social net benefits for pertussis immunization programs.

The cost of a six-dose pertussis immunization programs for children and adolescents is investigated in relation to estimators of the price of acellular vaccine, the value of a child's life, levels of vaccination rate and discount rates. We compare the cost of the program maintained over time at 90% with three alternative strategies, each involving a decrease in vaccination coverage. Data from England and Wales, 1966-2005, is used to formalize a delay in occurrence of pertussis cases as a result of a fall in coverage. We first apply the criterion of minimization of the total social cost of pertussis to identify the best cost saving immunization strategy. The results are also discussed in form of the discounted present value of the total social net benefits. We find that the discounted present value of the total social net benefit is maximized when a stable vaccination program at 90% is compared to a gradual decrease in vaccination coverage leading to the lowest vaccination rate. The benefits to society of providing sustained immunization strategy, vaccinating the highest proportion of children and adolescents, are systematically proved on the basis of the second optimisation criterion, independently of the level of estimators applied during economic evaluation for the cost variables.

Boostrix: a reduced-dose acellular pertussis vaccine for use in adolescents and adults.

Pertussis remains a serious problem in many countries. Even in countries with high vaccine coverage and a long vaccination history, pertussis outbreaks occur periodically. Rather than being a disease of young children, pertussis has shifted to affect adolescents and adults. Increased pertussis burden in adolescents and adults is the major source of severe infection for young infants. An effective vaccine is needed to control the spread of pertussis beyond preschool children. Boostrix is a reduced-dose acellular pertussis vaccine with diphtheria and tetanus toxoids, and is designed for use in adolescents and adults. Current evidence suggests that Boostrix is immunogenic and well tolerated. The pertussis component of Boostrix has been shown to be efficacious in a large-scale Phase III trial. More than 50 countries have given permit to the use of Boostrix, and many of them formally recommend the use of Boostrix in adolescents and adults. Designed as a vaccine for adolescence and adults, Boostrix has a long way to go to achieve large-scale use in those target groups. Nevertheless, we expect that the advent of Boostrix will lead to a much better control of pertussis in the general population.

[Pertussis: data collection and vaccinal strategy]. / La coqueluche : collecte de données et choix des stratégies vaccinales.

UNLABELLED: Renacoq is a pediatric hospital-based surveillance network in France, set up in April 1996 to monitor the trend of pertussis among children and the impact of vaccination strategies. METHOD: The authors studied the link between data collection and public health policy. Microbiologists from 43 hospitals notify diagnosis of pertussis among children less than 16 years of age. Pediatricians complete a questionnaire for infants less than 6 months of age fulfilling the case definitions. Positive cultures are sent to the National reference laboratory to validate biological results. Data collected from 1996 to 2007 was analyzed, as well as its interaction with changes in pertussis vaccine policy. RESULTS: The introduction of adolescent and adult boosters was largely supported by Renacoq data but this was not the case for interruption of whole cell vaccine use. The impact of adolescent booster is moderate because of a limited vaccine coverage. There was no observed impact of the adult booster but the coverage is very weak. The introduction and then the sole use of acellular vaccine did not have any impact on Renacoq data. DISCUSSION: The study illustrates the burden of the disease among infants and the link between surveillance data collection and public health decision. It highlights the difficulty to implement new vaccine strategies and the importance of data collection, stressing the need for a better consideration of hospital practitioners involved in public healthcare surveillance.

[Experimental, clinical and immunologic assessment of acellular staphylococcal vaccine "Staphylovac"].

Results of experimental, clinical and immunological effects of acellular dry staphylococcal vaccine "Staphylovac" developed in Mechnikov Research Institute of Vaccines and Sera are presented. Original mildly virulent strains of Staphylococcus aureus having high immunogenicity, and intra- and interspecies protective activity against different representatives of opportunistic microflora were used for construction of the preparation. Low-toxicity and weak anapylactogenicity of the vaccine were established. In experiments on mice, guinea pigs and rabbits significant protective, antigenic and immunomodulate activity of the preparation was revealed with low sensitization of animals. Clinical trials performed in different centers showed that inclusion of vaccinotherapy in complex treatment of chronic staphylococcal infections (chronic pyodermia, lung abscess etc.) resulted in prolonged pathologic locus, decrease of number and severity of exacerbations, prolongation of remission, and complete recovery in significant number of patients. Activation of innate and adaptive immunity was revealed in the same patients. It was shown on the large group of athletes that administration of the vaccine by aerosol route prevents disruption of immunologic adaptation occurring due to excess physical activity and stress situations during competitions.

Use of a new combined vaccine in pediatric practices.

OBJECTIVE: On December 13, 2002, Pediarix, a combination vaccine that contains diphtheria, tetanus, acellular pertussis; hepatitis B; and inactivated polio vaccines, was licensed by the Food and Drug Administration for use in the primary immunization series. Use of this vaccine decreases the number of injections that children receive when completing their primary immunization series at the 2-, 4-, and 6-month well-child visits. The objective of this study was to determine the factors that influence the use of this combined vaccine in private pediatric practices, with particular attention to the perceived economic impact of Pediarix and actions taken to address this impact within the private pediatric setting. METHODS: A mail survey study was conducted of a random sample of 565 practicing pediatricians that was obtained from the American Medical Association Masterfile. Frequency distributions were developed for all responses, and the vaccine financing policies of the state of practice for each respondent were determined. Chi2 analysis was performed to assess any associations of the predictor variables with the outcome variables of interest, use or consideration of use of the Pediarix vaccine. Logistic regression was used to determine the independent association of the predictor variables with use or consideration of use of Pediarix. Regression models that did and did not include practice ownership as a predictor variable were developed. RESULTS: Response rate was 63% (N = 355). A total of 39% (n = 123) of the respondents' practices were purchasing Pediarix for use with their private patients. An additional 18% (n = 55) were considering purchasing the vaccine. Those who were in practices that were owned by hospitals or health systems were more likely than those who were in solo or group practices to purchase Pediarix for their private patients. Approximately half of the remaining respondents order Pediarix through their state immunization program. Among the 52% of respondents who did not, 23% reported that the vaccine was not yet available through their state program, and 47% stated that they did not want to use different vaccines for their public and private patients. Only 11% believed that Pediarix was not compatible with their other vaccine products. Physicians that currently were purchasing or considering purchasing Pediarix were more likely to be influenced by both parental and provider desire to decrease the number of injections at a single visit and the reduced time for immunization delivery. Fewer than 1% of respondents reported either having experienced or expecting to experience a significant decrease in practice revenue as a result of the use of Pediarix. CONCLUSIONS: Although use of the vaccine results in fewer administration fees for most physicians, the magnitude of the change seemed not to be significant for the majority of respondents or was outweighed by other factors. It also is possible that larger practices or buying cooperatives were able to negotiate discounted rates for Pediarix relative to the constituent products. This may have been a strategy of manufacturers and/or distributors to provide incentive for practices to switch to the combination product. Of note was the appreciation of respondents for the preferences of patients for fewer vaccines and, to a lesser degree, for the decrease in office staff time required to provide vaccination with multiple antigens when using Pediarix. Also, the role of the availability of a given vaccine through the Vaccines for Children program is important in its adoption into practice.

Acellular pertussis vaccine for adolescents.

BACKGROUND: The use of whole-cell pertussis vaccine has led to a significant decline in incidence of the disease among children. This change in the epidemiological profile led to an increased number of cases among teenagers and adults, as a result of loss of immunity to the disease or vaccine after approximately 10 years. An increased number of cases was also observed among non-immunized or partially immunized infants. Licensure of the DTP vaccine against diphtheria, tetanus, and acellular pertussis formulated specifically for patients over 10 years of age (Tdap) suggests the possibility of controlling pertussis in the most affected age groups over the past few years. SOURCES OF DATA: Data were collected from MEDLINE. The research was limited to the period between January 1995 and January 2006. SUMMARY OF THE FINDINGS: In some countries there are two Tdap vaccines licensed for patients over 10 years of age. One of them contains five immunogenic components of Bordetella pertussis (pertussis toxin, filamentous hemagglutinin, fimbriae 2 and 3, and pertactin), and the other contains three components (pertactin, filamentous hemagglutinin, and inactivated pertussis toxin), the latter being the only one licensed in Brazil up to now. Although the composition of the two vaccines differs, studies show that they have similar effectiveness and immunogenicity. Some authors, however, emphasize that it is difficult to make a precise assessment of the immunological response to the vaccine and its duration. Several countries currently recommend the use of Tdap vaccine for adolescents. Canada has extended the target population up to 54 years of age. The guideline is that this group should receive one dose of the vaccine to reinforce the basic immunization scheme. This is based on study results that show that the vaccine-induced immunity lasts for around 6 to 12 years. Assessments of the economic impact of routine use of the vaccine in adolescents showed a positive cost-benefit ratio. Results of the epidemiological impact depend on the quality of diagnosis so that data reflect the reality of the disease. CONCLUSIONS: Although some questions remain to be clarified, the literature indicates the possibility of solving the "reappearance" of whooping cough (pertussis) with the use of Tdap vaccine. Perhaps the strategy of using a second booster dose in adolescence to replace the double diphtheria and tetanus vaccine should be adopted immediately.

Shift in the epidemiology of pertussis infection: an indication for pertussis vaccine boosters for adults?

Pertussis vaccination of young children has been effective in reducing the overall disease burden due to Bordetella pertussis in many countries. However, the disease has not been eliminated, although humans are the only known host of this pathogen. In fact, in some countries, the number of reported cases has increased dramatically from their nadir and epidemics routinely occur. In areas where >80% of children <2 years of age have been vaccinated, the burden of disease has shifted from elementary school-aged children (who are presumably protected by vaccination) to young infants (<6 months of age) and individuals >11 years of age. With the recent availability of acellular pertussis vaccines for older children to adults, consideration of a change in current vaccination policy is necessary in order to provide better disease control.

Acellular pertussis vaccines for adolescents.

BACKGROUND: The epidemiology of pertussis is changing, with a clear increase in the number of cases diagnosed in adolescents and adults. This development has spurred studies and anticipated licensure of safer diphtheria, tetanus, acellular pertussis combined (Tdap) vaccines for this older population. METHODS: Literature review. RESULTS: Tdap vaccines are safe and immunogenic when administered to adolescents and adults. Correlates of immunity to pertussis after Tdap vaccination have not been established, but various combinations of antibody to pertussis antigens (pertussis toxin, filamentous hemagglutinin, pertactin, and fimbriae) provide protection. The importance of the number of antigens in Tdap vaccines for protection against mild pertussis disease is unclear. Pertussis vaccination establishes herd immunity after sufficient uptake within communities and countries. As experience with TdaP vaccines has accumulated, a 1-2% occurrence of large, local injection-site reactions with all TdaP vaccine products have been observed for booster doses in children 4-6 years of age. The frequency of large local reactions appears lower in adolescents and adults. The pathophysiologic mechanisms for the local reactions are not established, but a majority appears to be immunoglobulin E-mediated-reactive edema, and a minority appears to be immunoglobulin G-mediated Arthus-type reactions. CONCLUSIONS: Tdap vaccines appear safe and immunogenic. The economic impact of pertussis provides a cost-benefit justification for widespread use of Tdap vaccine boosting in adolescents.

The cost of epidemiological transition: a study of a decrease in pertussis vaccination coverage.

Based on a transfer function intervention model applied to epidemiological data of pertussis incidence and pertussis vaccination in England and Wales, the consequences of pertussis vaccination strategies were estimated in terms of health effects and economic direct costs. It was established that sixth dose pertussis vaccination programs at 90% coverage were the most cost saving for short-term and for long-term vaccination prevention strategies. We considered two alternative strategies with whole-cell or acellular vaccines for primary course and acellular vaccine for two booster doses in children and one booster in adolescents. As a rule, programs based on exclusive use of acellular vaccines for all the doses were more expensive. Direct costs of programs with the vaccination rate at 90% remained systematically lower than the expected cost of pertussis disease in the case of non prevention. The stability over time of the vaccination coverage at a constant level of 90% made it possible to ensure the largest cost saving strategy during the period of 14 years of analysis. Transitions to programs with a lower proportion of vaccinated children systematically incurred an incremental direct cost for society. The amount of that cost rose with the size of the drop in the new vaccination coverage and diminished, due to the J-curve optimistic effect, when the fall in vaccination rate generated a delayed increase in notification cases of pertussis.

Adult tetanus, diphtheria and pertussis immunization: knowledge, beliefs, behavior and anticipated uptake.

BACKGROUND: Lifetime protection against pertussis has been adopted as a goal of immunization programs in Canada. To anticipate adult coverage with a combined product containing tetanus (T) and diphtheria (d) toxoids and acellular pertussis (aP) vaccine as a booster dose, we conducted a survey of households in British Columbia, Canada. METHODS: In a random telephone survey involving 800 adults, 25 years of age and older, we assessed current behaviors related to adult Td immunization and beliefs regarding pertussis vaccine under various scenarios relevant to adult decision-making. RESULTS: Forty-five percent of participants reported having received tetanus vaccine within the previous 10 years; this rate was lowest amongst elderly persons 65 years of age or more (28%). On multi-variate analysis, being up-to-date with tetanus immunization was independently associated with belief that an adult should be immunized against tetanus and perception that tetanus is life-threatening and inversely associated with being elderly. At baseline, 59% of respondents indicated willingness to receive pertussis immunization if provided free; this increased to 76% following sequential information about communicability and severity of pertussis illness and safety, efficacy and convenience of vaccine and up to 87% if accompanied by physician or nurse recommendation. Sixty-three percent of adults indicated they would receive the vaccine if required to pay $40.00 (Cdn) for it. CONCLUSIONS: Personal risk perception, public funding and physician recommendation are important to adults when considering tetanus and pertussis immunization. These factors may be relevant as immunization programs are expanded to include more adults generally.

[Laboratory assessment problems of the efficacy of acellular pertussis vaccines]. / Problemy laboratoryjnej oceny skutecznosci bezkomórkowych szczepionek przeciw krztuscowi.

Although composition of acellular pertussis vaccines is better defined than whole-cell vaccines, differences in the formulation, content, and detoxification of pertussis vaccine antigens led to a unique character of each of differently produced acellular vaccine. Currently used methods for laboratory evaluation of whole-cell pertussis vaccine efficacy were found not suitable for acellular vaccines. There is a strong need to perform analysis and evaluation of the safety and efficacy profiles of acellular pertussis vaccines combined with other vaccine antigens (e.g. Hib) both before and after conjugation. Mechanisms of interactions seen after conjugation inducing weaker immunogenicity or efficacy are still poorly recognized.

T-cell immune response assessment as a complement to serology and intranasal protection assays in determining the protective immunity induced by acellular pertussis vaccines in mice.

The relative value of antibodies and/or T-cell immune responses to Bordetella pertussis antigens in the immunity induced by acellular pertussis (aP) vaccines is still an open issue, probably due to the incomplete knowledge on the mechanisms of protective immunity to pertussis. The relevance of T-cell immune responses in protection from pertussis has been demonstrated in murine and human models of infection; thus, in this study, the ability of different vaccine preparations of three component (pertussis toxin, filamentous hemagglutinin, and pertactin) aP vaccines to induce T-cell responses was investigated in mice. All vaccine preparations examined passed the immunogenicity control test, based on antibody titer assessment, according to European Pharmacopoeia standards, and protected mice from B. pertussis intranasal challenge, but not all preparations were able to prime T cells to pertussis toxin, the specific B. pertussis antigen. In particular, one vaccine preparation was unable to induce proliferation and gamma interferon (IFN-gamma) production while the other two gave borderline results. The evaluation of T-cell responses to pertussis toxin antigen may provide information on the protective immunity induced by aP vaccines in animal models. Considering the critical role of the axis interleukin-12-IFN-gamma for protection from pertussis, our results suggest that testing the induction of a key protective cytokine such as IFN-gamma could be an additional tool for the evaluation of the immune response induced by aP vaccines.

The potential cost-effectiveness of acellular pertussis booster vaccination in England and Wales.

A cost-effectiveness analysis of the introduction of acellular pertussis booster doses at either 4 or 15 years of age was performed. A transmission dynamic model was used to predict the level of indirect protection in those too young to be vaccinated. Multivariate sensitivity analyses were performed. In England and Wales there are an estimated 35,000 general practitioner (GP) consultations, 5500 inpatient days, and nine deaths annually attributable to pertussis, despite high levels of coverage for the primary course (approximately 95%). Around 80% of the bed-days and 90% of the deaths occur in those too young to be immunised (< 3 months of age). The introduction of acellular booster doses at 4 years is expected to reduce morbidity and mortality in the younger age groups by 40-100%, and at 15 years by 0-100%. From the perspective of the health care provider, roughly 50% of the simulations result in a cost per life-year gained of less than 10,000 pounds for vaccination at 4 years, the corresponding proportion for vaccination at 15 years being only 35%. Apart from the degree of indirect protection the model was most sensitive to the discount rate, the price of the vaccine, and the mortality rate. Significant uncertainty remains regarding the epidemiology of pertussis and the impact of booster doses. Nevertheless, the introduction of acellular boosters, particularly at 4 years, has the potential to be cost-effective in the UK.