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Background: The Swedish school-based vaccination programme offers HPV vaccine to girls born ≥1999 in 5-6th grade. In 2012, all counties introduced free-of-charge catch-up vaccination campaigns targeting girls born 1993-1998. Varying vaccine uptake in the catch-up group by December 2012 suggested that some implementation strategies were more successful than others. In order to inform future vaccination campaigns, we assessed the impact of different implementation strategies on the county-level catch-up vaccine uptake., Methods: We conducted an ecological study including all Swedish counties (n = 21), asking regional health offices about the information channels they used and where vaccination of the catch-up target group took place in their counties. The uptake of ≥1 dose by 30 September 2014 was estimated using data from the voluntary national vaccination register. We investigated associations between counties' catch-up vaccine uptake, information channels and vaccination settings by calculating incidence rate ratios (IRR) and 95% confidence intervals (CI), using negative binomial regression models., Results: County level catch-up vaccine uptake varied between 49-84%. All counties offered vaccination through primary health care settings. Apart from this eight (34%) also offered the vaccine in some of their schools, four (19%) in all their schools, and two (10%) in other health care centres. The information channels most frequently used were: information at the national on-line health care consulting web-page (100%), letter/invitations (90%), and advertisement (81%). Counties offering vaccination to girls in all schools and counties offering vaccination in some of their schools, reached higher vaccine uptake compared to counties not offering vaccination in any of their schools (all schools adjusted IRR: 1.3, 95% CI: 1.1-1.5, some schools adjusted IRR: 1.2, 95% CI: 1.1-1.3)., Conclusion: Counties offering HPV vaccination to catch-up groups in schools reached the highest vaccine uptake. No information channel explained differences in county-level vaccine uptake. Our findings suggest that catch-up vaccination outside the national vaccination program can reach a high uptake at the population level if it is implemented primarily with an organized delivery (e.g. in schools).

Background: Concerns have been raised that HPV-vaccination might affect women's cervical screening behavior. We therefore investigated the association between opportunistic HPV-vaccination and attendance after invitation to cervical screening., Methods: A cohort of all women resident in Sweden, born 1977-1987 (N=629,703), and invited to cervical screening, was followed October 2006 - December 2012. Invitations to screening were identified via the National Quality Register for Cervical Cancer Prevention, as was the primary outcome of a registered smear. Vaccination status was obtained from two nationwide health data registers. Hazard ratios (HR) were estimated using Cox regression adjusted for age, education level and income (HRadj). Women were individually followed for up to 6 years, of which the first and second screening rounds were analyzed separately., Results: Screening attendance after three years of follow-up was 86% in vaccinated women (N=4,897) and 75% in unvaccinated women (N=625,804). The crude HR of screening attendance in vaccinated vs. unvaccinated women was 1.31 (95% CI 1.27-1.35) in the first screening round. Adjustment for education and income reduced but did not erase this difference (HRadj=1.09, 95% CI 1.05-1.13). In the second screening round, attendance was likewise higher in HPV-vaccinated women (crude HR=1.26, 95% CI 1.21-1.32; HRadj=1.15, 95% CI 1.10-1.20)., Conclusions: HPV-vaccination is so far associated with equal or higher attendance to cervical screening in Sweden in a cohort of opportunistically vaccinated young women. Most but not all of the difference in attendance was explained by socioeconomic differences between vaccinated and unvaccinated women. HPV vaccine effectiveness studies should consider screening attendance of HPV-vaccinated women when assessing incidence of screen-detected cervical lesions.

Objective: This study describes the prevalence of vaccine hesitancy associated with the Catalan systematic childhood vaccination calendar and some related psychosocial determinants among paediatric primary care nurses in Barcelona (Spain). Methods: Cross-sectional descriptive study. In 2017 we invited the paediatric nurses (N = 165) working in Barcelona public primary health centres with paediatric departments (N = 41) to participate. They answered a questionnaire with sociodemographic and behavioural variables: severity and perceived probability of contracting the diseases of the vaccines in the vaccination schedule; safety and protection offered by each vaccine; and beliefs, social norms, and knowledge about vaccines. Outcome variable was vaccine hesitancy, dichotomized into not hesitant (nurses who would vaccinate their own offspring), and hesitant (including those who would not vaccinate them, those who had doubts and those who would delay the administration of one or more vaccines). We performed bivariate analysis and adjusted logistic regression models. Results: 83% of paediatric nurses (N = 137) agreed to participate. 67.9% had the intention to vaccinate their children of all the vaccines in the systematic schedule. 32.1% of nurses experienced vaccine hesitancy, especially about the HPV (21.9%) and varicella (17.5%) vaccines. The multivariate analysis suggests associations between hesitancy and low perception of the severity of whooping cough (aOR: 3.88; 95%CI:1.32–11.4), low perception of safety of the HPV vaccine (aOR:8.5;95%CI:1.24–57.8), the belief that vaccines are administered too early (aOR:6.09;95%CI:1.98–18.8), and not having children (aOR:4.05;95%CI:1.22–13.3). Conclusions: Although most paediatric nurses had the intention to vaccinate their own children, almost one-third reported some kind of vaccine hesitancy, mainly related to doubts about HPV and varicella vaccines, as well as some misconceptions. These factors should be addressed to enhance nurses' fundamental role in promoting vaccination to families. [ABSTRACT FROM AUTHOR]

In Poland, primary care physicians are the most used and most trusted source of information on immunisation. We aimed to explore factors influencing support for vaccinations among physicians employed in the childhood immunisation programme, in order to inform education of healthcare workers and programme organization. In June-July 2017, we carried out a national cross-sectional survey of physicians working in randomly selected primary healthcare practices, and interviewed them by telephone. We assessed support for vaccinations using an ordinal scale (0–6) comprised of three equally weighted questions on the respondent support of the programme and vaccination of self and family. We also created a scale (0–3) based on correct answers to vaccination myths. We used ordered logistic regression to investigate factors independently influencing support for vaccinations, reporting the proportional odds ratios and 95% confidence intervals for one unit increase in the support score. Of 2,609 respondents contacted, we interviewed 500 (19%). The median vaccination support score (0–6) was 5 (IQR 2). After adjusting for other variables, we did not find significant effects of sex, medical specialty, adhering to recommendations, attending a conference in previous year, using non-scientific sources of information and self-assessed knowledge on vaccination support score. Age over 60 years, correctly addressing vaccination myths and use of one or more than one scientific sources of knowledge, significantly improved support for vaccinations (aOR = 1.97, 1.57, 3.09 and 2.68, respectively). We recommend to increase the amount, quality and accessibility of evidence-based educational materials for primary care physicians working with childhood immunisations. [ABSTRACT FROM AUTHOR]

The bivalent killed whole-cell oral cholera vaccine (BivWC) is being increasingly used to prevent cholera. The presence of O-antigen-specific memory B cells (MBC) has been associated with protective immunity against cholera, yet MBC responses have not been evaluated after BivWC vaccination. To address this knowledge gap, we measured V. cholerae O1-antigen MBC responses following BivWC vaccination. Adults in St. Marc, Haiti, received 2 doses of the BivWC vaccine, Shanchol, two weeks apart. Participants were invited to return at days 7, 21, 44, 90, 180 and 360 after the initial vaccination. Serum antibody and MBC responses were assessed at each time-point before and following vaccination. We observed that vaccination with BivWC resulted in significant O-antigen specific MBC responses to both Ogawa and Inaba serotypes that were detected by day 21 and remained significantly elevated over baseline for up to 12 months following vaccination. The BivWC oral cholera vaccine induces durable MBC responses to the V. cholerae O1-antigen. This suggests that long-term protection observed following vaccination with BivWC could be mediated or maintained by MBC responses. [ABSTRACT FROM AUTHOR]

The memory B-cell (MBC) ELISpot assay is the main technique used to measure antigen-specific MBCs as a readout of humoral immune memory. This assay relies on the ability of MBCs to differentiate into antibody-secreting cells (ASC) upon polyclonal stimulation. The total number of IgG+ ASCs generated by mitogen-stimulation is often used as a reference point; alternatively antigen-specific MBCs are expressed as a frequency of post-culture peripheral blood mononuclear cells (PBMC) as a surrogate for absolute frequencies. Therefore, it is important to know whether IgG+ B-cells are uniformly expanded during the preceding mitogen-culture as a true reflection of MBC frequencies ex vivo. We systematically compared B-cell phenotype and proportions before and after mitogen stimulation in cultures of 269 peripheral blood mononuclear cell samples from 62 volunteers by flow cytometry and analyzed the number of resulting ASCs. Our data show that the number of total IgG+ ASCs detected by ELISpot after mitogen stimulation correlates with the proportion of IgG+ MBCs ex vivo, highlighting its general robustness for comparisons of study cohorts at group level. The expansion of total and IgG+ B-cells during mitogen-stimulation, however, was not identical in all cultures, but influenced by size and composition of the ex vivo B-cell compartment. The uncorrected readout of antigen-specific MBCs per million post-culture PBMCs therefore only preserves the quality, but not the magnitude of differences in the ex vivo MBC response between groups or time points, particularly when comparing samples where the B-cell compartment substantially differs between cohorts or over time. Therefore, expressing antigen-specific cells per total IgG+ ASCs is currently the best measure to correct for mitogen-culture effects. Additionally, baseline information on the size and composition of the ex vivo B-cell compartment should be supplied to additionally inform about differences or changes in the size and composition of the ex vivo MBC compartment. [ABSTRACT FROM AUTHOR]

For a better understanding of the maintenance of immune mechanisms to Bordetella pertussis (Bp) in relation to age, we investigated the dynamic range of specific B cell responses in various age-groups at different time points after a laboratory confirmed pertussis infection. Blood samples were obtained in a Dutch cross sectional observational study from symptomatic pertussis cases. Lymphocyte subpopulations were phenotyped by flowcytometry before and after culture. Memory B (Bmem) cells were differentiated into IgG antibody secreting cells (ASC) by polyclonal stimulation and detected by an ELISPOT assay specific for pertussis antigens pertussis toxin (Ptx), filamentous haemagglutinin (FHA) and pertactin (Prn). Bp antigen specific IgG concentrations in plasma were determined using multiplex technology. The majority of subjects having experienced a clinical pertussis episode demonstrated high levels of both Bp specific IgG and Bmem cell levels within the first 6 weeks after diagnosis. Significantly lower levels were observed thereafter. Waning of cellular and humoral immunity to maintenance levels occurred within 9 months after antigen encounter. Age was found to determine the maximum but not base-line frequencies of Bmem cell populations; higher levels of Bmem cells specific for Ptx and FHA were reached in adults and (pre-) elderly compared to under-fours and schoolchildren in the first 6 weeks after Bp exposure, whereas not in later phases. This age effect was less obvious for specific IgG levels. Nonetheless, subjects' levels of specific Bmem cells and specific IgG were weakly correlated. This is the first study to show that both age and closeness to last Bp encounter impacts the size of Bp specific Bmem cell and plasma IgG levels. [ABSTRACT FROM AUTHOR]

Understanding the biological mechanisms underlying episodic outbreaks of infectious diseases is one of mathematical epidemiology’s major goals. Historic records are an invaluable source of information in this enterprise. Pertussis (whooping cough) is a re-emerging infection whose intermittent bouts of large multiannual epidemics interspersed between periods of smaller-amplitude cycles remain an enigma. It has been suggested that recent increases in pertussis incidence and shifts in the age-distribution of cases may be due to diminished natural immune boosting. Here we show that a model that incorporates this mechanism can account for a unique set of pre-vaccine-era data from Copenhagen. Under this model, immune boosting induces transient bursts of large amplitude outbreaks. In the face of mass vaccination, the boosting model predicts larger and more frequent outbreaks than do models with permanent or passively-waning immunity. Our results emphasize the importance of understanding the mechanisms responsible for maintaining immune memory for pertussis epidemiology. [ABSTRACT FROM AUTHOR]

Bordetella pertussis is the causative agent of pertussis, a highly contagious disease of the human respiratory tract. Despite high vaccination coverage, pertussis has resurged and has become one of the most prevalent vaccine-preventable diseases in developed countries. We have proposed that both waning immunity and pathogen adaptation have contributed to the persistence and resurgence of pertussis. Allelic variation has been found in virulence-associated genes coding for the pertussis toxin A subunit (ptxA), pertactin (prn), serotype 2 fimbriae (fim2), serotype 3 fimbriae (fim3) and the promoter for pertussis toxin (ptxP). In this study, we investigated how more than 60 years of vaccination has affected the Dutch B. pertussis population by combining data from phylogeny, genomics and temporal trends in strain frequencies. Our main focus was on the ptxA, prn, fim3 and ptxP genes. However, we also compared the genomes of 11 Dutch strains belonging to successful lineages. Our results showed that, between 1949 and 2010, the Dutch B. pertussis population has undergone as least four selective sweeps that were associated with small mutations in ptxA, prn, fim3 and ptxP. Phylogenetic analysis revealed a stepwise adaptation in which mutations accumulated clonally. Genomic analysis revealed a number of additional mutations which may have a contributed to the selective sweeps. Five large deletions were identified which were fixed in the pathogen population. However, only one was linked to a selective sweep. No evidence was found for a role of gene acquisition in pathogen adaptation. Our results suggest that the B. pertussis gene repertoire is already well adapted to its current niche and required only fine tuning to persist in the face of vaccination. Further, this work shows that small mutations, even single SNPs, can drive large changes in the populations of bacterial pathogens within a time span of six to 19 years. [ABSTRACT FROM AUTHOR]

Background: In many countries, the reported pertussis has increased despite high vaccination coverage. However, accurate determination of the burden of disease is hampered by reporting artifacts. The infection frequency is more reliably estimated on the basis of the prevalence of high IgG concentrations against pertussis toxin (IgG-Ptx). We determined whether the increase in reported pertussis in the last decade is associated with an increase in the number of infections. Methodology/Principal Findings: In a cross-sectional population-based serosurveillance study conducted in 2006-07, from a randomly selected age-stratified sample of 7,903 persons, serum IgG-Ptx concentrations were analyzed using a fluorescent bead-based multiplex immuno assay. In 2006-07, 9.3% (95%CI 8.5-10.1) of the population above 9 years of age had an IgG-Ptx concentration above 62.5 EU/ml (suggestive for pertussis infection in the past year), which was more than double compared to 1995-96 (4.0%; 95%CI 3.3-4.7). The reported incidence showed a similar increase as the seroprevalence between both periods. Conclusions: Although changes in the vaccination program have reduced pertussis morbidity in childhood, they have not affected the increased infection rate in adolescent and adult pertussis. Indeed, the high circulation of B. pertussis in the latter age-categories may limit the effectiveness of pediatric vaccination. [ABSTRACT FROM AUTHOR]