Pertussis vaccination in mixed markets: Recommendations from the Global Pertussis Initiative.

The Global Pertussis Initiative is an expert scientific forum that publishes consensus recommendations concerning pertussis for many regions of the world. Here, we give recommendations for the primary vaccination of infants in those countries where whole-cell pertussis (wP)- and acellular pertussis (aP)-containing combination vaccines are used in parallel. A selective literature review was performed concerning the influence on safety, immunogenicity, and effectiveness of mixing wP- and aP-containing vaccines for primary immunization of infants. In addition, local data were collected from various countries and the results discussed in a face-to-face meeting. Very few data addressing issues of mixing combination vaccines were identified, and no data were available concerning the effectiveness or duration of protection. It was also found that pharmacovigilance data are scarce or lacking in those countries where they would be needed the most. We then identified frequent problems occurring in low- and middle-income countries (LMICs) where both vaccine types are used. Relying on local knowledge, we give practical recommendations for a variety of situations in different settings. Specific needs for additional data addressing these issues were also identified. International bodies, such as the World Health Organization (WHO), as well as vaccine producers should try to find ways to highlight the problems of mixing wP- and aP-containing combination vaccines with robust data. Countries are urged to improve on their pharmacovigilance for vaccines. For practicing physicians, our recommendations offer guidance when wP- and aP-containing vaccines are used in parallel during primary immunization.

Pertussis surveillance by small serosurveys of blood donors.

Serosurveys have established data about the distribution of immunoglobulin G (IgG)-antibodies to pertussis toxin (PT) in various populations. We tried to detect whether small serosurveys in blood donors could serve as a simple and inexpensive means to collect information about the circulation of Bordetella pertussis. We screened every donation in 307 adult blood donors aged 19-69 years for IgG-anti-PT by standardised enzyme-linked immunosorbent assays (ELISA), and the donors were followed between 2014 and 2016 for a total of 426 person-years. When we used a vertical survey with cut-offs of 100, 62.5 and 40 IU/ml, respectively, as an indicator for recent contacts with B. pertussis, nine (2.9%), 22 (7.2%) and 54 (17.6%) of donors had IgG-anti-PT titres above the respective levels. During the horizontal observation period of 426 person years, six significant increases and two conversions were found, which lead to an estimate of 1878 contacts/100.000 person-years (1.9% per year). Median and mean IgG-anti-PT concentrations remained relatively stable from year to year during the observation period. Our findings show that small serosurveys of blood donors offer a simple and cheap method for the surveillance of B. pertussis.

Latent class analysis of diagnostic tests for adenovirus, Bordetella pertussis and influenza virus infections in German adults with longer lasting coughs.

Laboratory tests in adult outpatients with longer lasting coughs to identify a potential causal pathogen are rarely performed, and there is no gold standard for these diagnostic tests. While the diagnostic validity of serological tests for pertussis is well established their potential contribution for diagnosing adenovirus and influenza virus A and B infections is unclear. A sentinel study into the population-based incidence of longer lasting coughs in adults was done in Rostock (former East Germany) and Krefeld (former West Germany). A total of 971 outpatients who consulted general practitioners or internists were included. Inclusion criteria were coughing for ⩾1 week and no chronic respiratory diseases. We evaluated the performance of polymerase chain reaction (PCR) as well as IgG and IgA serology, applying a latent class model for diagnosing infections with adenovirus, B. pertussis, and influenza virus A and B. The adult outpatients first sought medical attention when they had been coughing for a median of 3 weeks. In this situation, direct detection of infectious agents by PCR had a low sensitivity. Modelling showed that additional serological tests equally improved sensitivity and specificity for diagnosis for adenovirus, B. pertussis and influenza virus A and B infections. The combination of serology and PCR may improve the overall performance of diagnostic tests for B. pertussis and also for adenovirus, and influenza virus A and B infections.

Analysis of Bordetella pertussis clinical isolates circulating in European countries during the period 1998-2012.

Despite more than 50 years of vaccination, pertussis is still an endemic disease, with regular epidemic outbreaks. With the exception of Poland, European countries have replaced whole-cell vaccines (WCVs) by acellular vaccines (ACVs) in the 1990s. Worldwide, antigenic divergence in vaccine antigens has been found between vaccine strains and circulating strains. In this work, 466 Bordetella pertussis isolates collected in the period 1998-2012 from 13 European countries were characterised by multi-locus antigen sequence typing (MAST) of the pertussis toxin promoter (ptxP) and of the genes coding for proteins used in the ACVs: pertussis toxin (Ptx), pertactin (Prn), type 2 fimbriae (Fim2) and type 3 fimbriae (Fim3). Isolates were further characterised by fimbrial serotyping, multi-locus variable-number tandem repeat analysis (MLVA) and pulsed-field gel electrophoresis (PFGE). The results showed a very similar B. pertussis population for 12 countries using ACVs, while Poland, which uses a WCV, was quite distinct, suggesting that ACVs and WCVs select for different B. pertussis populations. This study forms a baseline for future studies on the effect of vaccination programmes on B. pertussis populations.

Investigations into the emergence of pertactin-deficient Bordetella pertussis isolates in six European countries, 1996 to 2012.

Pathogen adaptation has been proposed to contribute to the resurgence of pertussis. A striking recent example is the emergence of isolates deficient in the vaccine component pertactin (Prn). This study explores the emergence of such Prn-deficient isolates in six European countries. During 2007 to 2009, 0/83 isolates from the Netherlands, 0/18 from the United Kingdom, 0/17 Finland, 0/23 Denmark, 4/99 Sweden and 5/20 from Norway of the isolates collected were Prn-deficient. In the Netherlands and Sweden, respectively 4/146 and 1/8 were observed in a later period (2010­12). The Prn-deficient isolates were genetically diverse and different mutations were found to inactivate the prn gene. These are indications that Prn-deficiency is subject to positive selective pressure. We hypothesise that the switch from whole cell to acellular pertussis vaccines has affected the balance between 'costs and benefits' of Prn production by Bordetella pertussis to the extent that isolates that do not produce Prn are able to expand. The absence of Prn-deficient isolates in some countries may point to ways to prevent or delay the spread of Prn-deficient strains. In order to substantiate this hypothesis, trends in the European B. pertussis population should be monitored continuously.

External quality assessment of pertussis serology in Germany.

The purpose of this investigation was to test the performance of pertussis serology in diagnostic laboratories. The World Health Organization (WHO) Reference Reagent (06/142) and a sample with a low level of antibodies were sent to 200 participants of an external quality assessment (EQA) programme in Germany. The results were reported qualitatively and quantitatively, and were converted into IU/ml when possible. A total of 183 participants reported results. IgG, IgA and IgM enzyme-linked immunosorbent assays (ELISAs) with mixed antigens were used by 111, 110 and 113 participants, respectively, and 69 and 44 participants used IgG and IgA ELISAs with purified pertussis toxin (PT), respectively. IgG, IgA and IgM immunoblots were employed by 62, 63 and 11 participants, respectively. Most tests could distinguish between the positive and negative samples, but quantitative results were reported partly in non-comparable units. Only 37 % of participants used ELISAs that gave results comparable to the expected values in IU/ml and that could be interpreted according to published recommendations.

Comparison of commercially available immunoblot assays measuring IgG and IgA antibodies to Bordetella pertussis antigens.

Bordetella pertussis infection is mostly diagnosed by serological tests, such as by enzyme-linked immunosorbent assays (ELISAs) or by immunoblots. We compared immunoblots from five different manufacturers. Immunoblots from Euroimmun, Mikrogen, Trinity Biotech, Viramed and Virotech were used. All kits except the kit from Trinity Biotech measured IgG and IgA antibodies separately. The kits were used according to the kit inserts. Various reference preparations from the World Health Organization (WHO), the National Institute for Biological Standards and Control (NIBSC) and the Center for Biologics Evaluation and Research/Food and Drug Administration (CBER/FDA) were analysed. Patient sera with high antibody titres in ELISA, sera from patients with compatible clinical symptoms and sera from vaccinees were compared. An algorithm for interpreting quantitative values for IgG and IgA anti-pertussis toxin (PT) from in-house ELISAs was used as a reference. The sensitivity and specificity of the assays was variable when comparing the qualitative results of immunoblots with expected values of reference preparations and ELISA interpretation of patient sera. The interpretation of semi-quantitative reading of the immunoblots did not compare well to the ELISA results. Adenylate cyclase toxin as an additional antigen in two immunoblots did not effectively distinguish between infection and vaccination. Due to the lack of quantification of antibody concentrations, IgG and IgA immunoblots are of limited value in the serological diagnosis of pertussis.

Monitoring bacterial contamination of blood components in Germany: effect of contamination reduction measures.

BACKGROUND AND OBJECTIVES: National guidelines for monitoring bacterial contamination of blood components were introduced in Germany in 1997. Between 1998 and 2002, numerous measures were implemented to prevent bacterial contamination. This study investigates their impact on contamination rates. MATERIALS AND METHODS: Culture-based testing for bacterial detection on a random sample of blood components is part of routine quality control in German blood establishments. Using standardized questionnaires, data from the production periods 1998, 2001 and 2005/2006 were collected and analysed. RESULTS: The bacterial contamination rate of RBCs was reduced from 0·157% in 1998 to 0·029% in 2005/2006 (P<0·001). While the contamination rate of apheresis PCs remained nearly unchanged over the years, it dramatically decreased for pooled PCs by 70% to a contamination rate of 0·158% (P=0·001) within the last observation period, similar to that of apheresis PCs. The contamination rate of plasma decreased from 0·100% in 1998 to 0·019% in 2005/2006 (P=0·002). CONCLUSIONS: Precautionary measures significantly reduced bacterial contamination rates of blood components. Long-term monitoring with standardized methods is appropriate to evaluate the cumulative effect of contamination-preventing measures.

What to do and what not to do in serological diagnosis of pertussis: recommendations from EU reference laboratories.

Bordetella pertussis-specific antibodies can be detected by enzyme-linked immunosorbent assays (ELISAs) or multiplex immunoassays. Assays use purified or mixed antigens, and only pertussis toxin (PT) is specific for B. pertussis. The interpretation of results can be based on dual-sample or single-sample serology using one or two cut-offs. The EU Pertstrain group recommends that: (i) ELISAs and multiplex immunoassays should use purified non-detoxified PT as an antigen, that they should have a broad linear range and that they should express results quantitatively in International Units per millilitre (IU/ml); (ii) a single or dual diagnostic cut-off for single-serum serology using IgG-anti-PT between 50 and 120 IU/ml should be used, and diagnostic serology cannot be validly interpreted for one year after vaccination with acellular pertussis (aP) vaccines; (iii) IgA-anti-PT should only be used with indeterminate IgG-anti-PT levels or when a second sample cannot be obtained. This group discourages using: (i) other antigens in routine diagnostics, as they are not specific; (ii) micro-agglutination, due to its lack of sensitivity; (iii) immunoblots for pertussis serodiagnosis, as results cannot be quantified; (iv) other methods, such as complement fixation or indirect immunofluorescence, due to their low sensitivity and/or specificity.

[Lifelong protection against pertussis]. / Lebenslanger Schutz vor Pertussis.

Pertussis is an endemic and cyclical disease. But protection from infection and through vaccination is not long-lived. Because of high vaccination coverage among infants the age distribution of pertussis has changed: adults and adolescents are now the main reservoir for Bordetella pertussis. The current recommendations of the German Standing Vaccination Committee (STIKO) are designed to achieve life-long protection, which is feasible with acellular pertussis vaccines. Vaccination of all adults with Tdap instead of dT vaccine is recommended in many countries, because this strategy may reduce the burden of disease in adults and infants, and is cost-effective.

International Bordetella pertussis assay standardization and harmonization meeting report. Centers for Disease Control and Prevention, Atlanta, Georgia, United States, 19-20 July 2007.

An international meeting on Bordetella pertussis assay standardization and harmonization was held at the Centers for Disease Control and Prevention (CDC), Atlanta, GA, 19-20 July 2007. The goal of the meeting was to harmonize the immunoassays used for pertussis diagnostics and vaccine evaluation, as agreed upon by academic and government researchers, regulatory authorities, vaccine manufacturers, and the World Health Organization (WHO). The primary objectives were (1) to provide epidemiologic, laboratory, and statistical background for support of global harmonization; (2) to overview the current status of global epidemiology, pathogenesis and immunology of pertussis; (3) to develop a consensus opinion on existing gaps in understanding standardization of pertussis assays used for serodiagnosis and vaccine evaluation; and (4) to search for a multicenter process for addressing these priority gaps. Presentations and discussions by content experts addressed these objectives. A prioritized list of action items to improve standardization and harmonization of pertussis assays was identified during a group discussion at the end of the meeting. The major items included: (1) to identify a group that will organize, prepare, maintain, and distribute proficiency panels and key reagents such as reference and control sera; (2) to encourage the development and identification of one or more reference laboratories that can serve as an anchor and resource for other laboratories; (3) to define a performance-based assay method that can serve as a reference point for evaluating laboratory differences; (4) to develop guidance on quality of other reagents, e.g., pertussis toxin and other antigens, and methods to demonstrate their suitability; (5) to establish an international working group to harmonize the criteria to evaluate the results obtained on reference and proficiency panel sera; (6) to create an inventory to determine the amount of appropriate and well-characterized sera that are available globally to be used as bridging reagents for vaccine licensure; and (7) to seek specific guidance from regulatory authorities regarding the expectations and requirements for the licensure of new multicomponent pertussis vaccines.

[Pertussis: incidence, symptoms and costs]. / Pertussis bei Erwachsenen: Häufigkeit, Symptome und Kosten.

BACKGROUND AND OBJECTIVE: A prospective sentinel study into the population-based incidence of pertussis in adults was done between 2001 and 2004 in Rostock (former East Germany) and Krefeld (former West Germany). PATIENTS AND METHODS: 971 outpatients, who consulted general practitioners or internists, were included. Clinical inclusion criteria were coughing for one week or more and no chronic respiratory diseases. Bordetella infection was diagnosed by PCR on nasopharyngeal swabs and ELISA for serology (IgG-anti-PT, IgA-anti-PT, IgG-anti-FHA, IgA-anti-FHA). RESULTS: We found a total of 97 cases of pertussis in this cohort. The main symptom was coughing for a median of 7-8 weeks. Population-based incidence was estimated in Krefeld at 169 cases/100000 population per year, and in Rostock at 160/100000 per year. Resource use was 120 EUR of direct medical cost and 434 euro of indirect medical cost, not including hospitalization in this study. CONCLUSIONS: Pertussis is a frequent cause of longer lasting cough in German adults, and it causes significant morbidity and costs.

Effectiveness of acellular pertussis vaccine assessed by hospital-based active surveillance in Germany.

We assessed the effectiveness of complete and partial pertussis vaccination in Germany--a country where acellular vaccine is predominantly used--for the prevention of cases of pertussis requiring hospitalization. Vaccine effectiveness was estimated by means of a screening method. Vaccine coverage of children born during the period of June 1996 through December 1998 was assessed by a telephone survey. Data from hospitalized children with pertussis in 1997-1998 and from patients with pertussis complications in 1997-2000 were acquired by a nationwide, hospital-based, active surveillance system. Age-adjusted vaccine effectiveness of completed primary vaccination was estimated to be 99.8% (95% confidence interval [95% CI], 98.9-100). After receipt of 1 dose of vaccine, vaccine effectiveness was as high as 68.0% (95% CI, 45.6-81.1), increasing to 91.8% (95% CI, 84.7-95.7) after receipt of the second dose. Vaccine effectiveness was even slightly higher for pertussis with complications. Thus, even after partial vaccination, acellular pertussis vaccine is highly effective in preventing hospitalizations for pertussis.

Recommendations are needed for adolescent and adult pertussis immunisation: rationale and strategies for consideration.

Pertussis vaccination of infants has dramatically reduced disease, complications and deaths in infancy and early childhood. But there is still a major public health challenge--to deal with the morbidity and economic burden of illness in older children, adolescents and adults. Furthermore, it is these groups that form a major source of infection for non-immunised and partially immunised infants who are at high risk of severe complications. Adult-type acellular pertussis vaccine confers safe and effective protection against pertussis. There are several strategies to consider for immunising older individuals. Universal vaccination of all age groups would be the best available strategy for protecting individuals. It would also reduce the potential for transmitting the disease to other susceptibles, particularly infants. However, such a policy may be difficult both logistically and economically at this time. More easily achievable as a first step would be a strategy of universal adolescent booster vaccination combined with a programme targeted at adults most likely to have contact with very young babies including healthcare and childcare workers, parents and close family contacts. There is also potential for offering vaccination to adults (and their carers and close contacts) whose medical conditions or advanced age may place them at increased risk of more severe pertussis disease. Specific details of immunisation programmes must be made on a country by country basis depending on local circumstances.

Pertussis in Germany: regional differences in management and vaccination status of hospitalized cases.

The incidence of pertussis requiring hospitalization in children younger than 16 years was estimated by the use of an active surveillance-system. Of special interest were differences between West and East Germany following different vaccination strategies before reunification. In 1997 and 1998, 754 pertussis cases required a total of 11,151 hospital inpatient days. The incidence of hospitalized pertussis was 2.68/100,000 person years and this was significantly higher in East than in West Germany. In East Germany an unusually high percentage of hospitalized cases was found in children aged 6-15 years (45% versus 13% in West Germany). The difference between the regions may be due either to a different perception of the disease or to an increased immunity induced by prior disease or vaccination. In East Germany, pertussis was rare until reunification but it has increased significantly since then. Older children may thus represent a population at risk of pertussis having not had previous exposure to pertussis antigens.

Stability of antibodies to Bordetella antigens in German adults.

To estimate the rate of asymptomatic exposure to Bordetella pertussis antigens in the German adult population and to evaluate the stability of antibodies to these antigens, antibody levels against Bordetella antigens and their variability over time were measured in German adult blood donors. One hundred forty-six regular blood donors (41 females, 105 males) were tested repeatedly for antibodies of isotypes IgG and IgA to pertussis toxin, filamentous hemagglutinin (FHA) and pertactin over a period of 2-5 years. Overall, 86% and 56% had IgG or IgA antibodies to pertussis toxin, respectively, 100% and 92% had IgG or IgA antibodies to FHA, respectively, and 83% and 93% had IgG or IgA antibodies to pertactin, respectively. One significant titer increase of both IgG anti-FHA and IgG anti-pertactin, one of IgG anti-FHA, and two of IgA anti-FHA as well as one significant decrease of IgG anti-pertussis toxin were observed during an observation period of 480.5 person-years. Antibody concentrations in men and women were not different. The data show that the level of antibodies to pertussis toxin, FHA, and pertactin remains stable over several years. Furthermore, depending on the definition of serological evidence, the rate of significant increases or decreases suggesting unrecognized exposure to Bordetella antigens was estimated to be between <0.2 and 1.0 per 100 person-years in the population studied.

Epidemiological typing of Bordetella pertussis isolates: recommendations for a standard methodology.

Pertussis is re-emerging in vaccinated populations, and to gain insight into the reasons for this development population-based studies are necessary. Unfortunately, various techniques are used to study Bordetella pertussis populations, hampering comparison between studies. A standard methodology for epidemiological typing of Bordetella pertussis isolates is proposed which is based on serotyping, pulsed-field gel electrophoresis and gene typing. Such a standard approach will allow comparisons between studies performed in different laboratories. Comparisons may reveal whether the epidemiological differences observed between countries are due for instance to different Bordetella pertussis populations or different vaccines used.