PERISCOPE: road towards effective control of pertussis.

The resurgence and changing epidemiology of pertussis in high-income countries, the high infant mortality caused by pertussis in low-income countries, and the increasing morbidity in all age groups worldwide call for a concerted effort to both improve the current vaccines and develop new vaccines and vaccination strategies against pertussis. In this Personal View, we identify several key obstacles on the path to developing a durable solution for global control of pertussis. To systematically address these obstacles, the PERtussIS Correlates Of Protection Europe (PERISCOPE) Consortium was established in March, 2016. The objectives of this consortium are to increase scientific understanding of immunity to pertussis in humans induced by vaccines and infections, to identify biomarkers of protective immunity, and to generate technologies and infrastructure for the future development of improved pertussis vaccines. By working towards the accelerated licensure and implementation of novel, well tolerated, and effective pertussis vaccines, we hope to strengthen and stimulate further collaboration and transparency between the key stakeholders, including the public, the scientific community, public health institutes, regulatory authorities, and vaccine manufacturers.

Evaluation of Adenylate Cyclase Toxoid Antigen in Acellular Pertussis Vaccines by Using a Bordetella pertussis Challenge Model in Mice.

Bordetella pertussis is the primary causative agent of pertussis (whooping cough), which is a respiratory infection that leads to a violent cough and can be fatal in infants. There is a need to develop more effective vaccines because of the resurgence of cases of pertussis in the United States since the switch from the whole-cell pertussis vaccines (wP) to the acellular pertussis vaccines (aP; diphtheria-tetanus-acellular-pertussis vaccine/tetanus-diphtheria-pertussis vaccine). Adenylate cyclase toxin (ACT) is a major virulence factor of B. pertussis that is (i) required for establishment of infection, (ii) an effective immunogen, and (iii) a protective antigen. The C-terminal repeats-in-toxin domain (RTX) of ACT is sufficient to induce production of toxin-neutralizing antibodies. In this study, we characterized the effectiveness of vaccines containing the RTX antigen against experimental murine infection with B. pertussis RTX was not protective as a single-antigen vaccine against B. pertussis challenge, and adding RTX to 1/5 human dose of aP did not enhance protection. Since the doses of aP used in murine studies are not proportionate to mouse/human body masses, we titrated the aP from 1/20 to 1/160 of the human dose. Mice receiving 1/80 human aP dose had bacterial burden comparable to those of naive controls. Adding RTX antigen to the 1/80 aP base resulted in enhanced bacterial clearance. Inclusion of RTX induced production of antibodies recognizing RTX, enhanced production of anti-pertussis toxin, decreased secretion of proinflammatory cytokines, such as interleukin-6, and decreased recruitment of total macrophages in the lung. This study shows that adding RTX antigen to an appropriate dose of aP can enhance protection against B. pertussis challenge in mice.

Vaccination against pertussis and influenza in pregnancy: a qualitative study of barriers and facilitators.

OBJECTIVES: Influenza and pertussis vaccination programmes have been in place for pregnant women in the UK since 2009 and 2012, respectively. In 2015, vaccine uptake rates were 55% for influenza and 63% for pertussis in Northern Ireland. We conducted a qualitative study with the aim of learning about the views of pregnant women and identifying potential barriers to vaccination in pregnancy. STUDY DESIGN: Qualitative study using focus groups and in-depth interviews. METHODS: We conducted focus group discussions and interviews on vaccination in pregnancy using a discussion guide developed in consultation with stakeholders and service users. Pregnant women were recruited on-street. We performed inductive coding of transcripts and thematic analysis, using a phenomenological approach. RESULTS: Sixteen pregnant women participated. We identified six key themes. Information and knowledge: Vaccinated and unvaccinated women demonstrated similar levels of knowledge and desire for information, preferring direct communication with healthcare professionals. The influence of others: Some vaccinated participants reported firm endorsements of vaccination by healthcare professionals including midwives, while some unvaccinated women recalled neutral or reticent staff. Acceptance and trust: Most women expressed trust of health professionals. Fear and distrust: Vaccinated individuals expressed concerns about side-effects more than unvaccinated women. A few unvaccinated women expressed distrust of vaccines and healthcare systems. Responsibility for the baby: Both groups prioritised protecting the baby but unvaccinated participants were concerned about vaccine-related harm. Accessing vaccination: Multiple appointments, lack of childcare, time off work and having responsibility to organise vaccination hindered some participants from getting immunised. Some women were willing to be vaccinated but did not recall being offered vaccination or were not sufficiently motivated to make arrangements themselves. CONCLUSION: Healthcare professionals appear to have a vital influential role in pregnant women's decisions about vaccination. Involving midwives and improving convenience of vaccination access may increase uptake. Strategies to develop interventions should address the aforementioned barriers to meet the pregnant women's needs.

The importance of involving midwives before and during the implementation of an antenatal pertussis vaccination program in New South Wales, Australia.

PROBLEM: Typically there is limited opportunity for stakeholder engagement to determine service delivery gaps when implementing an outbreak or supplementary vaccination program. BACKGROUND: In response to increasing pertussis notifications in NSW, Australia, an antenatal pertussis vaccination program was introduced offering pertussis containing vaccine to all pregnant women in the third trimester. AIM: To explore the effectiveness of consulting with midwives prior to and during a new state-wide vaccination program. METHODS: A pre-program needs analysis was conducted through an online audit of the NSW Clinical Midwifery Consultants followed by a post-implementation audit at 18 months. FINDINGS: Information received from the midwives was utilised during program planning which facilitated program implementation without any major issues in all Local Health Districts. The post-implementation audit provided feedback to program planners that that implementation was continuing consistently and Midwives were found to be very supportive and engaged. DISCUSSION: Education and support of clinicians is vital for high vaccine uptake in new vaccination programs which can be enabled through appropriate educational packages and program resources. CONCLUSION: Consulting with the midwives in advance of a new vaccination program was a new initiative and highly recommended as it was time well spent gaining essential information on program resourcing and operational needs. Conducting a post-implementation audit is also strongly recommended as a check-point for issues and recommendations, to empower frontline staff and support consistent program implementation. Frontline staff engagement before and during implementation of a new vaccination program is a powerful mechanism for effective, efficient and consistent program delivery.

Maternal Care Providers' Barriers Regarding Influenza and Pertussis Vaccination During Pregnancy in Catalonia, Spain.

Objective Maternal care providers (MCPs), obstetrician-gynaecologists and midwives are uniquely placed to increase maternal vaccination acceptance. We aimed to assess their knowledge, attitudes and practices regarding influenza and pertussis vaccination during pregnancy. Methods We conducted an online survey among MCPs working at "Attention to Sexual and Reproductive Health" (ASSIR) Units in Catalonia region. The survey included questions about current recommendations of influenza and pertussis immunization during pregnancy, reasons for not routinely recommending vaccination and several strategies to increase vaccination uptake. Results A total of 194 MCPs completed the survey, 178 (91.8%) were female and 145 (70%) were midwives. Only 61 (31.4%) stated they vaccinated themselves annually against influenza with a significant lower uptake among midwives (26.9%) than obstetrician-gynaecologists (44.9%) (p = 0.03). Overall, 53.6% of MCPs knew influenza vaccine was indicated during first trimester but only 43.3% stated they prescribed it. Almost all MCPs (98.5%) knew pertussis vaccine was recommended and 97.4% stated they prescribed it. The most important vaccination barrier found was the concern related to vaccine adverse events (25.9%) and more midwives than obstetrician-gynaecologists expressed this concern (30.8 vs. 10%) (p = 0.02). The most popular strategies were: including vaccine recommendations in the pregnancy booklet (93.8%) and receiving vaccination training (92.3%). In the adjusted analysis, the only factor significantly associated with MCPs' prescription of influenza vaccine during second/third trimester was having been vaccinated themselves (odds ratio 3.70, 95% confidence interval 1.3-13.2). Conclusions for Practice Implementation of practical tools, continuous training and clear definition of responsibilities regarding vaccination among MCPs may have a significant impact on maternal vaccination coverage.

A New Vaccine Delivery Vehicle and Adjuvant Candidate: Bordetella pertussis Inactivated Whole Cells Entrapped in Alginate Microspheres.

There is no doubt about the whole cell pertussis vaccine efficacy, but it is necessary to improve the vaccine quality specially to decrease its toxicity by obtaining good immunogenicity with low bacterial content. In this work, under optimum condition inactivated B. pertussis bacteria cells entrapped with alginate microparticles were fabricated and in vivo immunogenicity and ptency of new microparticle based vaccine were evaluated in mice. Microspheres loaded with inactive B. pertussis bacterium cells were prepared via an emulsification method and analyzed for morphology, size, polydispersity index, loading efficiency, loading capacity, release profile and in vivo potency. The inactivated bacterial suspension mixture prepared in this work was nontoxic and showed potent ED50 (1:333 of human dose) and preserved agglutinins 1, 2, 3. The optimum conditions for the preparation of microparticles were achieved at alginate concentration 3.8% (w/v), CaCl2 8% (w/v), PLL 0.1% (w/v), lipophilic surfactant 0.22 (%w/v), hydrophilic surfactant 3.6 (%w/v), cross linking time 3min, homogenization rate 600 rpm, and alginate to CaCl2 solution ratio 4. Both empty and B. pertussis loaded microparticles exhibited smooth surface texture and relatively spherical shape. The B. pertussis encapsulated microspheres fabricated under optimized conditions showed mean particle size 151.1 µm, polydispersity index 0.43, loading efficiency 89.6%, loading capacity 36.3%, and relatively constant release rate lasted to 15 days. In vivo immunogenicity and protection study against wild type challenge showed strongly higher potency (approximately 2.5 fold) of encapsulated B. pertussis organisms than non-encapsulated conventional aluminum hydroxide adsorbed vaccine. It can be concluded that microencapsulation of inactive B. pertussis cells appears to be a suitable approach for improving the wP vaccine quality, specially by obtaining good immunogenicity with low bacterial content.

Surveillance of infant pertussis in Sweden 1998-2012; severity of disease in relation to the national vaccination programme.

In Sweden, pertussis was excluded from the national vaccination programme in 1979 until acellular vaccination was introduced in a highly endemic setting in 1996. The general incidence dropped 10-fold within a decade, less in infants. Infant pertussis reached 40-45 cases per 100,000 in 2008 to 2012; few of these cases were older than five months. We present an observational 15-year study on the severity of infant pertussis based on 1,443 laboratory-confirmed cases prospectively identified from 1998 to 2012 in the national mandatory reporting system and followed up by telephone contact. Analyses were made in relation to age at onset of symptoms and vaccination history. Pertussis decreased in non-vaccinated infants (2003 to 2012, p<0.001), indicating herd immunity, both in those too young to be vaccinated and those older than three months. The hospitalisation rates also decreased (last five-year period vs the previous five-year periods, p <0.001), but 70% of all cases in under three month-old infants and 99% of cases with apnoea due to pertussis were admitted to hospital in 1998 to 2012. Median duration of hospitalisation was seven days for unvaccinated vs four days for vaccinated infants aged 3-5 months. Nine unvaccinated infants died during the study period.

El papel de la matrona en la «estrategia de nido» como prevención de la tos ferina / The role of the midwife in the "cocoon strategy" for prevention of pertussis

La tos ferina es un importante problema de salud pública que afecta especialmente a la mujer gestante y a los recién nacidos, y que es susceptible de prevención y control mediante la vacunación. El aumento en los últimos años del número de casos hace necesario poner en práctica la «estrategia de nido» (vacunación de las personas del entorno del lactante que puedan actuar como fuente de infección), que ha demostrado ampliamente su eficacia. La matrona, como personal directamente implicado en la salud de la mujer y del recién nacido, es el profesional de elección para liderar esta estrategia, actuando en cuatro momentos claves: 1. Consulta preconcepcional: vacunación de la mujer y su pareja; 2. Primera consulta de control de embarazo: revisión del estado de vacunación de la mujer y la pareja. Planificación de la administración de la vacuna. Información; 3. Preparación al parto: información de la estrategia de nido; 4. Visita puerperal: vacunación de la mujer y la pareja

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Factors associated with vaccination for hepatitis B, pertussis, seasonal and pandemic influenza among French general practitioners: a 2010 survey.

Our objectives were to describe the vaccine coverage (VC(1)) for some occupational vaccines (hepatitis B, pertussis, seasonal and pandemic influenza) among French General Practitioners (GPs(2)) and to study the factors associated with being vaccinated for each of these four diseases. We surveyed a representative national sample of 1431 self-employed GPs in France. Self-reported VC was 76.9% for 2009/10 seasonal influenza, 73.0% for hepatitis B, 63.9% for pertussis and 60.8% for A/H1N1 pandemic influenza. The factors associated with reporting being vaccinated were quite different from one vaccine to another. For some or all four vaccines, we found a significant positive association (p<0.05) with the following factors in the multivariate analysis: GP's male gender, high volume of activity, no particular mode of exercise (e.g. homoeopathy), no use of Internet at the practice, Continuing Medical Education sessions, discussing the benefits and risks of vaccination with the patients and performing prevention investigations for oneself (lipid profile). Being vaccinated for one vaccine also increased the VC for some or all three other studied vaccines. All these findings argue for public health campaigns using messages adapted to each vaccine.

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 vaccine].

Protective, immunogenic, toxic, and sensitizing properties of acellular pertussis vaccine (aPV) developed according to original technology were studied, aPV had marked protective activity which lasted more than 2 years. Sera of mice immunized by aPV also possess protective properties, and they were more prominent than in sera of mice immunized by pertussis bacteria suspension (PS). Immune sera to aPV neutralized cytopathogenic effect of pertussis toxin (PT) on ovarian Chinese hamster cells in 1:250 dilution, whereas neutralizing activity of sera to PS was very low. Level of antibodies to PT was higher in rabbits immunized, according to schedules and dosage recommended for children, by aPV than by PS. High immunogenicity of aPV was proved also by levels of IgG to PT in sera of mice immunized three times by aPV in human dosage. During experiments on mice and guinea pigs aPV had mild toxicity, did not induce autoimmune process, did not have anaphylactogenic properties compared with bacterial suspension characterized by high anaphylactogenic activity. Histamine-sensitizing abilityof aPVwas 40 times lower than that of PS. Assessment of pyrogenic properties of aPV and PS performed on rabbits showed that aPV was 1,000 times less pyrogenic than PS. Obtained results demonstrate high protective and immunogenic properties of domestic acellular pertussis vaccine and its low toxic and sensitizing characteristics.

Improving the cellular pertussis vaccine: increased potency and consistency.

Although Europe, Canada and the US have switched from cellular to acellular pertussis vaccines, most developing countries will continue to use the more cost effective cellular vaccine. Consistency of production however is the typical problem inherent to cellular vaccines. Optimising the production process of cellular pertussis bulk suspensions using product potency as a measure is not possible, since the mandatory animal test to measure potency has little discriminatory power. To circumvent this problem, this study focussed on measuring process parameters related to consistency and potency instead, even though the extent of those relationships could not be quantified. Critical evaluation and modification of individual process steps lead to 2 optimised production processes, NVP-96 and NVP-THIJS. These were compared to the original NVP production process in terms of antigen and biomass content, potency, toxicity and immunogenicity in mice. The batch to batch variation for both optimised products was clearly less than the original product for all parameters tested. The biomass content of the NVP-THIJS product was 15% lower than that of the NVP-96 product, while the immunogenicity in mice was twofold to threefold higher. The stability of the NVP-THIJS product remained higher than the NVP-96 product over a period of 2 years, while the decline of the potency of both suspensions was comparable.

Induction of humoral immunity in response to immunization with recombinant Mycobacterium bovis BCG expressing the S1 subunit of Bordetella pertussis toxin.

Two recombinant Mycobacterium bovis BCG (rBCG) vaccine strains were developed for the expression of cytoplasmically located S1 subunit of pertussis toxin, with expression driven by the hsp60 promoter of M. bovis (rBCG/pPB10) or the pAN promoter of Mycobacterium paratuberculosis (rBCG/pPB12). Both strains showed stable expression of equivalent levels of recombinant S1 in vitro and induced long-term (up to 8 months) humoral immune responses in BALB/c mice, although these responses differed quantitatively and qualitatively. Specifically, rBCG/pPB12 induced markedly higher levels of IgG1 than did rBCG/pPB10, and mice immunized with the former strain developed specific long-term memory to S1, as indicated by the production of high levels of S1-specific IgG in response to a sublethal challenge with pertussis toxin 15 months after initial immunization. When considered in combination with previous studies, our data encourage further evaluation of rBCG as a potential means of developing a low-cost whooping cough vaccine based on defined antigens.

[Evaluation of the stability of pertussis vaccine OCO-3 standard]. / Otsenka stabil'nosti standarta kokliushnoi vaktsiny OCO-3.

The evaluation of the immunogenic activity and residual toxicity of the National Standard of pertussis vaccine (OCO-3) was carried out. As shown by observations lasting for a period of 25 years, the preparation possesses stable immunogenicity and its toxicity remained unchanged, which makes it possible to use OCO-3 for the routine control of the pertussis component of commercial lots of adsorbed DPT vaccine.

[New acellular pertussis vaccine, containing glucosaminylmuramyldipeptide]. / Sozdanie novoi beskletochnoi kokliushnoi vaktsiny, vkliuchaiushchei gliukozaminilmuramildipeptid.

As shown in this work, the synthetic immunomodulator glucosaminylmuramyldipeptide (GMDP) can be included into acellular pertussis vaccine (APV). The optimal doses of GMDP, ranging from 0.001 to 0.0001 microg, have been found. These doses enhance the protective activity of APV, especially its low-active doses. GMDP decrease the manifestations of toxic, anaphylactogenic and pyrogenic properties of APV, which may lead to the decrease of the antigenic load of APV on the body of the vaccines and thus to lessening the side-effects of vaccination. GMDP has been shown to considerably increase, in comparison with common pertussis vaccine and APV, the percentage of phagocytizing leukocytes by day 14. The immunization of mice with APV with and without GMDP in doses of 0.01 and 0.001 microg leads to a change in T-lymphocyte/B-lymphocyte ratio in the population of spleen lymphocytes.

[The patterns of the corrective action of a natural immunomodulator on the secondary immunological defect caused by a corpuscular pertussis vaccine]. / Zakonomernosti korrigiruiushchego deistviia prirodnogo immunomoduliatora na vtorichnyi immunologicheskii defekt, vyzvannyi korpuskuliarnoi kokliushnoi vaktsinoi.

Purified staphylococcal toxoid (PST) was shown to be capable of preventing the development of secondary antigen-nonspecific immune deficiency in mice, immunized with whole-cell pertussis vaccine. The immunocorrective action of PST was manifested after its injection before (on day -1), simultaneously with and after (on day +1) the injection of whole-cell pertussis vaccine. Correction was either complete or partial, depending on the scheme of the experiment and the dose of PST.

[The use of pharmacological screening for characterizing the toxicity of pertussis vaccines]. / Ispol'zovanie farmakologicheskogo skrininga dlia kharakteristiki toksichnosti kokliushnykh vaktsin.

The influence of pertussis preparations, introduced by oral and parenteral routes, on the detoxifying function of the liver and the state of the nervous system of the animals was studied by methods used in pharmacology and toxicology. The use of these methods made it possible to find out side effects produced by corpuscular pertussis vaccine, introduced parenterally, on the detoxifying function of the liver and the state of the nervous system of the animals. The negative influence on the nervous system was more pronounced after the injection of the commercial adsorbed diphtheria-pertussis-tetanus vaccine used in this investigation than after the injection of pertussis monovaccine. The oral administration of corpuscular pertussis vaccine exerted no negative influence on the above-mentioned body functions of the animals.

Experimental autoimmune uveoretinitis in mice. Induction by a single eliciting event and dependence on quantitative parameters of immunization.

Experimental autoimmune uveoretinitis (EAU) in the mouse is a recently developed model of ocular autoimmunity. Dependence of disease induction on qualitative and quantitative parameters of immunization was studied in B10.A mice immunized with interphotoreceptor retinoid-binding protein (IRBP). It was found that use of Bordetella pertussis adjuvant as well as its mode of preparation was of critical importance for disease induction; no disease was induced if pertussis adjuvant was omitted. The minimal effective protocol for EAU induction when the vaccine form of B. pertussis adjuvant was used consisted of pretreatment with cyclophosphamide, two divided doses of IRBP in complete Freund's adjuvant (CFA), and two divided doses of B. pertussis vaccine. Any reduction in the immunization schedule resulted in reduced incidence of disease. In contrast, substituting purified B. pertussis toxin (PTX) for the vaccine allowed reduction of the immunization schedule to a single dose of IRBP in CFA and omission of the cyclophosphamide pretreatment. Severity and incidence of disease could be quantitatively controlled by varying the respective doses of IRBP and PTX. In addition, a chronic or an acute clinical course of EAU could be obtained by using either a low-dose or a high-dose immunization, respectively. Establishment of a single dose induction protocol and the quantitation of the immunopathogenic response as a function of the variables of immunization lay the foundation for the further development and utilization of this promising model of ocular autoimmunity.

[Prevention in pediatrics in the Nord-Cotentin. Prospective study of 255 cases]. / Quelques aspects de la prévention en pédiatrie dans le Nord-Cotentin. Etude prospective sur 255 dossiers.

Over a 4 month period, the medical records of 255 children with an age range of 6 months to 3 years and who had been admitted to the Cherbourg Hospital Department of Pediatrics were prospectively studied. Ninety-nine % had received BCG vaccination but only 71% had a positive skin test. Ninety-two % were vaccinated against diphtheria, tetanus, whooping cough and poliomyelitis and 61% against measles. Seventy-eight % of parents said that they had correctly administered vitamin D, at least up to 18 months of age. Seventy % of children were fed cow's milk during the second half of the first year and at least 35% had at least one hematological sign of iron deficiency. The promotion of routine immunizations as well as vaccination against rubella-mumps-measles seems to be desirable goals. There is a need for the widespread use of adapted milk formulas up to 1 year of age and for systematic iron supplementation of pregnant women and of infants presenting with evidence of iron deficiency or on cow's milk.

Acellular and whole-cell pertussis vaccines in Japan. Report of a visit by US scientists.

Since the introduction of acellular pertussis vaccines in Japan late in 1981, more than 20 million doses have been administered, mostly to children 2 years of age and older. Clinical studies indicate that mild local and febrile reactions are less frequent after administration of acellular pertussis vaccines than after whole-cell vaccines. Serious adverse events with sequelae occurred in 2-year-old children at approximately the same low rate during the period 1975 through August 1981, when whole-cell vaccines were used, and during August 1981 through 1984, when acellular vaccines were used exclusively. Five household contact studies have yielded vaccine efficacy estimates ranging from 78% to 92% in children 1 year of age or older. In addition, there has been a continuing decrease in reported pertussis incidence from the epidemic peak in 1979. Additional data on the safety and efficacy of acellular pertussis vaccines administered to infants would be useful in consideration of acellular pertussis vaccine licensure in the United States.