Routine Childhood Vaccines Given From 1 through 18 Years of Age.

In addition to the vaccines due in the first year of life, the US Advisory Committee on Immunization Practices recommends that children continue to receive vaccines regularly against a variety of infectious diseases. Starting at 12 to 15 months of life, these include the two-dose measles-mumps-rubella vaccine series and the two-dose varicella vaccine series. Also in the second year of life, infants should begin the two-dose hepatitis A vaccine series and complete the Haemophilus influenzae type B vaccine series as well as the pneumococcal conjugate vaccine series. Before 19 months of life, infants should receive the third dose of the poliovirus vaccine and the fourth dose of diphtheria-tetanus-acellular pertussis (DTaP) vaccine. The final doses of poliovirus and tetanus-diphtheria-acellular pertussis vaccines are both due at 4 to 6 years of life. Before each influenza season, every child should receive the influenza vaccine. Those less than 9 years of age who previously received less than two doses need two doses a month apart. At 11 to 12 years of life, all should get two doses of the human papillomavirus vaccine, the adolescent/adult version of the tetanus-diphtheria-acellular pertussis vaccine, and begin a two-dose series of meningococcal ACWY vaccine. Each of these vaccines is due when the vaccine works to protect against both an immediate risk as well as to provide long-term protection. Each vaccine-preventable disease varies in terms of the nature of exposure, the form of the morbidity, the risk of mortality, and potential to prevent or ameliorate its harm.

Collaborative study on saccharide quantification of the Haemophilus influenzae type b component in liquid vaccine presentations.

Before release onto the market, it must be demonstrated that the total and free polysaccharide (poly ribosyl-ribitol-phosphate, PRP) content of Haemophilus influenzae type b (Hib) vaccine complies with requirements. However, manufacturers use different methods to assay PRP content: a national control laboratory must establish and validate the relevant manufacturer methodology before using it to determine PRP content. An international study was organised by the World Health Organization (WHO), in collaboration with the Biological Standardisation Programme (BSP) of the Council of Europe/European Directorate for the Quality of Medicines & HealthCare (EDQM) and of the European Union Commission, to verify the suitability of a single method for determining PRP content in liquid pentavalent vaccines (DTwP-HepB-Hib) containing a whole-cell pertussis component. It consists of HCl hydrolysis followed by chromatographic separation and quantification of ribitol on a CarboPac MA1 column using high-performance anion exchange chromatography coupled with pulsed amperometric detection (HPAEC-PAD). The unconjugated, free, PRP is separated from the total PRP using C4 solid-phase extraction cartridges (SPE C4). Ten quality control laboratories performed two independent analyses applying the proposed analytical test protocol to five vaccine samples, including a vaccine lot with sub-potent PRP content and very high free PRP content. Both WHO PRP standard and ribitol reference standard were included as calibrating standards. A significant bias between WHO PRP standard and ribitol reference standard was observed. Study results showed that the proposed analytical method is, in principle, suitable for the intended use provided that a validation is performed as usually expected from quality control laboratories.

Lot-to-lot Consistency, Safety, Tolerability and Immunogenicity of an Investigational Hexavalent Vaccine in US Infants.

BACKGROUND: This multicenter phase III study (NCT01340937) evaluated the consistency of immune responses to 3 separate lots of diphtheria-tetanus toxoids-acellular pertussis 5, inactivated poliovirus vaccine, Haemophilus influenzae type b, and hepatitis B (DTaP5-IPV-Hib-HepB), an investigational hexavalent vaccine (HV). METHODS: Healthy infants were randomized (2:2:2:1) to receive HV or Pentacel (Control). Groups 1, 2 and 3 received HV at 2, 4 and 6 months, and Control at 15 months. Group 4 received Control at 2, 4, 6 and 15 months, plus Recombivax HB (HepB) at 2 and 6 months. Concomitant Prevnar 13 was given to all groups at 2, 4, 6 and 15 months; pentavalent rotavirus vaccine (RV5) was given to all groups at 2, 4 and 6 months. Blood specimens (3-5 mL) were collected immediately before administration of dose 1, postdose 3, immediately before toddler dose, and after toddler dose. Adverse events were recorded after each vaccination. RESULTS: The 3 manufacturing lots of HV induced consistent antibody responses to all antigens. Immunogenicity of HV was noninferior to Control for all antibodies, except for pertussis filamentous hemagglutinin geometric mean concentration postdose 3, and pertussis pertactin (PRN) geometric mean concentration after toddler dose. Postdose 3 immunogenicity of concomitantly administered Prevnar 13 was generally similar (except for serotype 6B) when given with HV or Control. Adverse events of HV were similar to Control, except for a higher rate of fever ≥38.0°C [49.2% vs. 35.4%, estimated difference 13.7% (8.4, 18.8)]. CONCLUSIONS: HV demonstrated lot-to-lot manufacturing consistency; safety and immunogenicity were comparable with the licensed vaccines. HV provides a new combination vaccine option within the US 2-month, 4-month and 6-month vaccine series.

Association between maternal health literacy and child vaccination in India: a cross-sectional study.

BACKGROUND: Education of mothers may improve child health. We investigated whether maternal health literacy, a rapidly modifiable factor related to mother's education, was associated with children's receipt of vaccines in two underserved Indian communities. METHODS: Cross-sectional surveys in an urban and a rural site. We assessed health literacy using Indian child health promotion materials. The outcome was receipt of three doses of diphtheria-tetanus-pertussis (DTP3) vaccine. We used multivariate logistic regression to investigate the relationship between maternal health literacy and vaccination status independently in each site. For both sites, adjusted models considered maternal age, maternal and paternal education, child sex, birth order, household religion and wealth quintile. Rural analyses used multilevel models adjusted for service delivery characteristics. Urban analyses represented cluster characteristics through fixed effects. RESULTS: The rural analysis included 1170 women from 60 villages. The urban analysis included 670 women from nine slum clusters. In each site, crude and adjusted models revealed a positive association between maternal health literacy and DTP3. In the rural site, the adjusted OR was 1.57 (95% CI 1.11 to 2.21, p=0.010) for those with medium health literacy, and OR=1.30 (95% CI 0.89 to 1.91, p=0.172) for those with high health literacy. In the urban site, the adjusted OR was 1.10 (95% CI 0.65 to 1.88, p=0.705) for those with medium health literacy, and OR=2.06 (95% CI 1.06 to 3.99, p=0.032) for those with high health literacy. CONCLUSIONS: In these study settings, maternal health literacy is independently associated with child vaccination. Initiatives targeting health literacy could improve vaccination coverage.

CDC update on pertussis surveillance and Tdap vaccine recommendations.

Pertussis is the most poorly controlled bacterial vaccine-preventable disease. Since the early 1980s there has been an increase in reported cases of pertussis. Multiple factors have likely contributed to the increase, including waning immunity, increased recognition, and changes in diagnostic testing and reporting. Of the four combination vaccines used to prevent diphtheria, tetanus, and pertussis, one dose of Tdap should be used to vaccinate preteens as well as teens and adults who have not yet received this booster dose. It is the position of NASN that immunizations, including the Tdap vaccine, are key to primary prevention of diseasefrom infancy through adulthood. The school nurse is in a critical position to create awareness and influence action-related national and state recommendations for the Tdap vaccine.

Landscape analysis of interactions between nutrition and vaccine responses in children.

The world's poorest children are likely to be malnourished when receiving their childhood vaccines. It is uncertain whether this affects vaccine efficacy and whether the coadministration of nutrient supplements with vaccines has beneficial or detrimental effects. More recently, a detrimental interaction between vitamin A (VA) supplementation (VAS) and the killed diphtheria-tetanus-pertussis vaccine given in early childhood has been suggested. This report provides a critical review of the published interactions between nutritional status and/or supplementation and vaccine responses in children. Due to an absence of evidence for most nutrients, this analysis focused on protein-energy, vitamins A and D, and iron and zinc. All vaccines were considered. Both observational studies and clinical trials that led to peer-reviewed publications in English or French were included. These criteria led to a pool of 58 studies for protein-energy malnutrition, 43 for VA, 4 for vitamin D, 10 for iron, and 22 for zinc. Our analysis indicates that malnutrition has surprisingly little or no effect on vaccine responses. Evidence for definitive adjunctive effects of micronutrient supplementation at the time of vaccination is also weak. Overall, the paucity, poor quality, and heterogeneity of data make it difficult to draw firm conclusions. The use of simple endpoints that may not correlate strongly with disease protection adds uncertainty. A detailed examination of the immunological mechanisms involved in potential interactions, employing modern methodologies, is therefore required. This would also help us understand the proposed, but still unproven, negative interactions between VAS and vaccine safety, a resolution of which is urgently required.

[Assessment of consistency of technological process using control cards on the example of analysis of information on immunogenic activity of pertussis component of DTP vaccine].

AIM: To assess the consistency of technological process of manufacture of DTP vaccine's pertussis component on the basis of its immunogenicity using Shewhart's cards. MATERIALS AND METHODS: Published data of domestic plants belonging to public corporation Mechnikov "Biomed" and Ufa branch of scientific-production organization "Immunopreparat" ingressed in "Microgen" enterprise were used. Immunogenicity of DTP vaccine pertussis componentwas studied. RESULTS: It was revealed that technological process of manufacturing of DTP vaccine's pertussis component on production plants was not always in statistically controlled state. CONCLUSION: Obtained data showed that it is reasonable for quality control departments of manufacturing plants to use Shewhart's cards and methods of statistical management of technological processes for assessment of state of the latter.

Enfermedades susceptibles de vacunación y síndrome de Down / Immunizable diseases and Down syndrome

Las personas con síndrome de Down (SD), en especial durante su infancia, presentan una particular predisposición a padecer infecciones, debido sobretodo a la asociación del síndrome con una inmunodeficiencia primaria multifactorial. Un buen número de estas enfermedades son susceptibles de vacunación. Los estudios sobre vacunaciones en el SD son escasos y no incluyen los preparados inmunizantes más recientes. A falta de que se corrijan estas insuficiencias, los conocimientos actuales permiten sostener que las vacunas actualmente disponibles son seguras e inmunógenas en la población Down, aunque posibles respuestas algo inferiores a las habituales obligan al estricto cumplimiento de las pautas vacunales establecidas para asegurar su efectividad (AU)

People with Down syndrome (DS) are especially infection-prone, particularly during childhood. The main reason is an association of DS with multifactorial primary immune deficiency. Many of these conditions are immunizable, but studies of vaccination and DS are few and do not include recent formulations. While awaiting remediation of this gap, the present state of knowledge is that available vaccines are safe and effective for people with DS, though the possibility that response may be lower than average means that strict compliance with immunization schedules is required to ensure effectiveness (AU)

WHO Working Group on revision of the Manual of Laboratory Methods for Testing DTP Vaccines-Report of two meetings held on 20-21 July 2006 and 28-30 March 2007, Geneva, Switzerland.

This report reflects the discussion and conclusions of a WHO group of experts from National Regulatory Authorities (NRAs), National Control Laboratories (NCLs), vaccine industries and other relevant institutions involved in standardization and control of diphtheria, tetanus and pertussis vaccines (DTP), held on 20-21 July 2006 and 28-30 March 2007, in Geneva Switzerland for the revision of WHO Manual for quality control of DTP vaccines. Taking into account recent developments and standardization in quality control methods and the revision of WHO recommendations for D, T, P vaccines, and a need for updating the manual has been recognized. In these two meetings the current situation of quality control methods in terms of potency, safety and identity tests for DTP vaccines and statistical analysis of data were reviewed. Based on the WHO recommendations and recent validation of testing methods, the content of current manual were reviewed and discussed. The group agreed that the principles to be observed in selecting methods included identifying those critical for assuring safety, efficacy and quality and which were consistent with WHO recommendations/requirements. Methods that were well recognized but not yet included in current Recommendations should be taken into account. These would include in vivo and/or in vitro methods for determining potency, safety testing and identity. The statistical analysis of the data should be revised and updated. It was noted that the mouse based assays for toxoid potency were still quite widely used and it was desirable to establish appropriate standards for these to enable the results to be related to the standard guinea pig assays. The working group was met again to review the first drafts and to input further suggestions or amendments to the contributions of the drafting groups. The revised manual was to be finalized and published by WHO.

Investigation of immunity level against diphtheria and reinforcement of immunity by booster vaccination for infection control staff in Okayama prefecture.

The prevalence of immunity against diphtheria among Okayama local government staff members involved in diphtheria infection control was measured. Diphtheria booster vaccination was administered to staff members with low antitoxin levels (<0.1 IU/ml) in order to reinforce of immunity. Ninety-one (36.7%) of 248 staff members, 20-69 years of age, had fully protective antitoxin levels (> or =0.1 IU/ml), and the remaining 157 (63.3%) showed levels of <0.1 IU/ml. The rate of full protection was higher in females (44.9%) than in males (22.8%) and was also higher in the diphtheria-pertussis mixed vaccine (born in 1958-1967) and diphtheria-pertussis-tetanus mixed vaccine (born in 1968-) (58.3-61.0%) groups than in diphtheria vaccine (born in 1948-1957) and non-vaccinated (born until 1947) (7.4-18.9%) groups. Though antitoxin levels of 13 (68.4%) out of 19 staff members given booster vaccinations increased to 0.1 IU/ml, 50% of these individuals then showed levels of <0.1 IU/ml after 3 years. Most of the staff members with antitoxin levels of > or =0.1 IU/ml in the non-booster vaccination group maintained their immunity levels for 2-4 years, independent of their history of vaccination. To ensure that staff members of the local government have fully protective antitoxin levels against diphtheria, periodical confirmation of antitoxin levels and booster vaccination should both be systematically carried out.

[Development studies of lyophilized standard diphtheria-tetanus-pertussis vaccines]. / Liyofilize standart difteri-tetanoz-bogmaca asilari gelistirme çalismalari.

In this study, diphtheria, tetanus and pertussis vaccine components were prepared as the formulations of diphtheria-tetanus-pertussis (DTP), diphtheria-tetanus (DT) for children, diphtheria-tetanus (Td) for adults, and tetanus toxoid (TT), respectively. Alhydrogel-adsorbed vaccines prepared to contain the stabilizing substances were lyophilized and the immunogenicity tests were carried out both in vivo and in vitro. The potencies of the tetanus component of the vaccines were obtained by the lethal challenge test in mice. The values were found as 144.86 IU/ml for lyophilized adsorbed (LA)-DTP, 116.5 IU/ml for LA-DT, 98.25 IU/ml for LA-Td and 96.2 IU/ml for LA-TT. Anti-tetanus IgG and anti-diphteria IgG levels determined by ELISA method were found high in the sera taken from the mice immunized with the above-mentioned vaccines. Anti-B.pertussis fimbria IgG antibody levels were also high by both ELISA and microagglutination tests. The test preparations were then compared to adsorbed liquid vaccines and it was shown that the components were quite stable in the lyophilized formulations. It was concluded that the formulations prepared in this study can be used as standard vaccines after being calibrated against World Health Organization standards.

Potency of pertussis component in the DTP vaccine--an overview of three decade study in Poland.

In Poland, similar to many highly immunized Western countries, a recent increase in cases of pertussis has been observed. This study aims to evaluate the level of potency fluctuations of the pertussis component of Polish-produced DTP vaccine due to the changes having occurred in production and potency testing procedures. We compared the potency of the pertussis component of DTP vaccine lots produced and evaluated in similar periods and with similar production and testing procedures. Records of Kendrick test results performed over a 30-year period were available for analysis. This study confirms the role of different manufacturers, changes in vaccine strain compositions, in-house reference preparations used as reference vaccines in the Kendrick tests, and in mice of single strain sources in the potency values obtained. In addition, the comparisons performed revealed a downtrend in potency levels since 1992. Potency decrease in vaccine lots produced during 1992-1997 has been positively correlated to the lowering of the number of IOU/dose. Strain compositions of the DTP vaccine pertussis component and in-house references have been found to be associated with the fluctuation in potency estimations, and confirmed their crucial role in ensuring vaccine efficacy. Our study reveals that relative efficacy of the DTP vaccine produced in 1992-1997 might be lower than that of vaccines produced in other periods. This might in turn explain the increase in pertussis cases among children aged 5-15 years which is presently being observed in Poland.

Diphtheria-tetanus-pertussis (DTP) combination vaccines and evaluation of pertussis immune responses.

Diphtheria-tetanus-pertussis (DTP) combination vaccines based on inactivated whole-cell Bordetella pertussis (DTPw) or purified acellular pertussis components (DTPa) facilitate vaccine administration and will allow further co-administration such as with pneumococcal conjugates. Safety and immunogenicity studies are needed to demonstrate non-inferiority between combinations and the separate vaccines. The immunological non-inferiority is based on threshold antibody levels that represent correlates of protection. However, in case of pertussis, correlates of protection have not been defined or accepted. We describe the clinical evaluation of DTPa- and DTPw-based combinations and demonstrate their immunological non-inferiority as compared to their separately administered licensed counterparts. With respect to antibody responses against pertussis, a number of evaluations (vaccine response rates and geometric mean concentrations (GMCs) for anti-PT, anti-FHA, anti-PRN or anti-BPT; reverse cumulative distribution curves) are described. We also demonstrate that the B. pertussis mouse lung clearance model is able to predict clinical efficacy of licensed DTPa and DTPw vaccines and represents a useful tool to evaluate new combination vaccines.

[Increase in the incidence of pertussis and quality of whole-cell pertussis component of the DTP vaccine produced in Poland. Part I. Potency of DTP vaccine]. / Wzrost zachorowan na krztusiec a wyniki analizy jakosci komponentu krztuscowego polskiej szczepionki DTP. Czesc I: Moc szczepionki DTP.

This study aimed to identify and to evaluate the level of potency fluctuations of the pertussis component of Polish-produced DTP vaccine lots produced within 1972-2001 due to the changes having occurred in production and potency testing procedures. The study confirms that higher potency values were obtained for vaccine lots produced since 80-ties, e.g. after changes of: references lots (1975), vaccine strains (1978) and source of animals used in Kendrick tests (1979). Additionally, the comparisons performed revealed a down trend in potency levels within 1992-1999 correlating to the lowering of the number of IOU/dose.

[Increase in the incidence of pertussis and quality of whole-cell pertussis component of the DTP vaccine produced in Poland. Part II. Consistency of control and production]. / Wzrost zachorowan na krztusiec a wyniki analizy jakosci komponentu krztuscowego polskiej szczepionki DTP. Czesc II: Jednorodnosc badan i produkcji.

This study aimed to identify and to evaluate the level of potency fluctuations of the pertussis component of Polish-produced DTP vaccine lots produced within 1972-2001 due to the changes having occurred in production and potency testing procedures. Obtained results showed high consistency of the production and control tests confirming relevant quality of country-produced DTP vaccine.

Risk of vaccine failure after Haemophilus influenzae type b (Hib) combination vaccines with acellular pertussis.

An increase in invasive Hib disease incidence in the UK has coincided with the distribution of combination vaccines that contain acellular pertussis (DTaP-Hib). These vaccines have been associated with reduced immunogenicity of the Hib component, although there is little agreement on the clinical relevance of this finding. We retrospectively compared vaccine formulations given to fully vaccinated Hib cases with those administered to fully immunised age-matched controls using conditional logistic regression. More cases than controls received all three doses of their infant primary course as DTaP-Hib, compared with two or three doses of another Hib vaccine (conditional odds ratio 6.77 [95% CI 3.26-14.07]).

Development and clinical testing of multivalent vaccines based on a diphtheria-tetanus-acellular pertussis vaccine: difficulties encountered and lessons learned.

The widespread use of whole-cell pertussis vaccines in the second half of the 20th century have reduced the incidence of the disease significantly. However, in some countries, concerns about the reactogenicity and potential neurological damage associated with whole-cell vaccines led to a decrease in vaccine acceptance and an increase in morbidity and mortality of pertussis in several countries. This prompted the development of less reactogenic acellular pertussis vaccines combined with diphtheria and tetanus toxoids, initially in Japan and later in other countries. In Europe, the improved diphtheria, tetanus and acellular pertussis (DTPa) vaccine was first introduced in March 1994. The pertussis component of this DTPa vaccine, developed by Glaxo SmithKline, consists of pertussis toxoid, filamentous haemagglutinin and pertactin. The vaccine is well tolerated, with a lower incidence of adverse reactions than after administration of whole-cell vaccines. The long-lasting efficacy and effectiveness of DTPa vaccines have been extensively documented and these are now the cornerstone of a large range of combined vaccines including DTPa-hepatitis B (HBV), DTPa-inactivated polio (IPV) and DTPa-HBV-IPV. A lyophilised Haemophilus influenzae type b (Hib) vaccine can be reconstituted with all of these liquid combinations. The introduction of well-tolerated and efficacious DTPa vaccines and their more polyvalent combinations has improved the acceptance and simplified the implementation of childhood immunisation. This paper is a review of the technical and scientific difficulties encountered and the lessons learned over the 10-year period that it took to develop and introduce six multivalent vaccines using the Glaxo SmithKline DTPa as a building block.

Issues in selection of DTwP-based combination vaccines.

This study examines regulatory, supply, acceptance and financing issues of combinations based on diphtheria-tetanus-pertussis (whole cell) vaccines (DTwP). These combination vaccines are currently produced in Europe mostly for export. Future regulatory oversight issues could have an impact on their availability. Before use of acellular pertussis-containing vaccines, the number of doses of DTwP vaccines offered in response to United Nations agency procurement tenders far exceeded the projected demand. Current demand and supply are converging. Most of that supply comes from developing country manufacturers, a potential new source of combination vaccines as well. The expected development and use of DTwP-based combination vaccines raises antigen allocation issues that could further affect supply. These combination vaccines have strong programmatic advantages, but pose complex selection issues involving disease burden, presentation, and availability of long-term financing. Vaccine price is not the major driving factor. A model examining important selection factors for regional country groupings provides predictions that have been validated by decisions on use of DTwP-based combination vaccines. This model may be useful in providing long-term uptake projections for other combination vaccines.