Outer membrane vesicles derived from Bordetella pertussis are potent adjuvant that drive Th1-biased response.

For several years, we have been committed to exploring the potential of Bordetella pertussis-derived outer membrane vesicles (OMVBp) as a promising third-generation vaccine against the reemerging pertussis disease. The results of our preclinical trials not only confirm its protective capacity against B. pertussis infection but also set the stage for forthcoming human clinical trials. This study delves into the examination of OMVBp as an adjuvant. To accomplish this objective, we implemented a two-dose murine schedule to evaluate the specific immune response induced by formulations containing OMVBp combined with 3 heterologous immunogens: Tetanus toxoid (T), Diphtheria toxoid (D), and the SARS-CoV-2 Spike protein (S). The specific levels of IgG, IgG1, and IgG2a triggered by the different tested formulations were evaluated using ELISA in dose-response assays for OMVBp and the immunogens at varying levels. These assays demonstrated that OMVBp exhibits adjuvant properties even at the low concentration employed (1.5 µg of protein per dose). As this effect was notably enhanced at medium (3 µg) and high concentrations (6 µg), we chose the medium concentration to determine the minimum immunogen dose at which the OMV adjuvant properties are significantly evident. These assays demonstrated that OMVBp exhibits adjuvant properties even at the lowest concentration tested for each immunogen. In the presence of OMVBp, specific IgG levels detected for the lowest amount of antigen tested increased by 2.5 to 10 fold compared to those found in animals immunized with formulations containing adjuvant-free antigens (p<0.0001). When assessing the adjuvant properties of OMVBp compared to the widely recognized adjuvant alum, we detected similar levels of specific IgG against D, T and S for both adjuvants. Experiments with OMVs derived from E. coli (OMVE.coli) reaffirmed that the adjuvant properties of OMVs extend across different bacterial species. Nonetheless, it's crucial to highlight that OMVBp notably skewed the immune response towards a Th1 profile (p<0.05). These collective findings emphasize the dual role of OMVBp as both an adjuvant and modulator of the immune response, positioning it favorably for incorporation into combined vaccine formulations.

Bordetella pertussis isolates in Finland after acellular vaccination: serotype change and biofilm formation.

OBJECTIVES: In Finland, whole cell pertussis vaccine (wP) was introduced in 1952 and was replaced by acellular pertussis vaccine (aP) without fimbrial (FIM) antigen in 2005. We aimed to analyse the changes in serotypes of circulating Bordetella pertussis before and after acellular vaccination and to explore the relationship between biofilm formation and serotype diversity after the introduction of aP vaccine. METHODS: Serotyping of 1399 B. pertussis isolates collected at the Finnish National Reference Laboratory for Pertussis and Diphtheria in Turku, Finland, from 1974 to 2023 was performed by slide agglutination or indirect ELISA. Of 278 isolates collected after 2005, 53 were selected, genotyped for fim3 and fim2 alleles, and tested for biofilm formation. The selection criteria included maintaining a relatively equal distribution of isolates per time interval, ensuring approximately a 50:50 ratio of FIM2 (N = 26) and FIM3 (N = 27) serotypes. The reference strain Tohama I was used as a control. RESULTS: During the wP era, the majority of circulating B. pertussis exhibited the FIM2 serotype. However, FIM3 strains have appeared since 1999 and become prevalent. After the implementation of aP vaccines, the distribution of serotypes has exhibited substantial variability. FIM3 isolates displayed an enhanced biofilm formation compared to FIM2 isolates (Geometric mean value (95% CI): 0.90 (0.79-1.03) vs. 0.75 (0.65-0.85); p < 0.05). Of the 27 FIM3 isolates, 8 harboured fim3-1 and 19 fim3-2 alleles. FIM3 isolates with fim3-2 allele were significantly associated with increased biofilm formation when compared to those with fim3-1 (1.07 (0.96-1.19) vs. 0.61 (0.52-0.72); p < 0.0001). CONCLUSION: Following the implementation of aP vaccines, the distribution of serotypes in Finland has exhibited substantial variability. FIM3 isolates with the fim3-2 allele displayed an enhanced biofilm formation capability compared to FIM2 isolates.

Inequity of antenatal influenza and pertussis vaccine coverage in Australia: the Links2HealthierBubs record linkage cohort study, 2012-2017.

BACKGROUND: Pregnancy and early infancy are increased risk periods for severe adverse effects of respiratory infections. Aboriginal and/or Torres Strait Islander (respectfully referred to as First Nations) women and children in Australia bear a disproportionately higher burden of respiratory diseases compared to non-Indigenous women and infants. Influenza vaccines and whooping cough (pertussis) vaccines are recommended and free in every Australian pregnancy to combat these infections. We aimed to assess the equity of influenza and/or pertussis vaccination in pregnancy for three priority groups in Australia: First Nations women; women from culturally and linguistically diverse (CALD) backgrounds; and women living in remote areas or socio-economic disadvantage. METHODS: We conducted individual record linkage of Perinatal Data Collections with immunisation registers/databases between 2012 and 2017. Analysis included generalised linear mixed model, log-binomial regression with a random intercept for the unique maternal identifier to account for clustering, presented as prevalence ratios (PR) and 95% compatibility intervals (95%CI). RESULTS: There were 445,590 individual women in the final cohort. Compared with other Australian women (n = 322,848), First Nations women (n = 29,181) were less likely to have received both recommended antenatal vaccines (PR 0.69, 95% CI 0.67-0.71) whereas women from CALD backgrounds (n = 93,561) were more likely to have (PR 1.16, 95% CI 1.10-1.13). Women living in remote areas were less likely to have received both vaccines (PR 0.75, 95% CI 0.72-0.78), and women living in the highest areas of advantage were more likely to have received both vaccines (PR 1.44, 95% CI 1.40-1.48). CONCLUSIONS: Compared to other groups, First Nations Australian families, those living in remote areas and/or families from lower socio-economic backgrounds did not receive recommended vaccinations during pregnancy that are the benchmark of equitable healthcare. Addressing these barriers must remain a core priority for Australian health care systems and vaccine providers. An extension of this cohort is necessary to reassess these study findings.

Assessing the In Vivo Effectiveness of Cationic Lipid Nanoparticles with a Triple Adjuvant for Intranasal Vaccination against the Respiratory Pathogen Bordetella pertussis.

Continuous outbreaks of pertussis around the world suggest inadequate immune protection in infants and weakened immune responses induced over time by the acellular pertussis vaccine. Vaccine adjuvants provide a means to improve vaccine immunogenicity and support long-term adaptive immunity against pertussis. An acellular pertussis vaccine was prepared with pertactin, pertussis toxin, and fimbriae 2/3 antigens combined with a triple-adjuvant system consisting of innate defense regulator peptide IDR 1002, a Toll-like receptor-3 agonist poly(I:C), and a polyphosphazene in a fixed combination. The vaccine was delivered intranasally in a cationic lipid nanoparticle formulation fabricated by simple admixture and two schema for addition of antigens (LT-A, antigens associated outside of L-TriAdj, and LAT, antigens associated inside of L-TriAdj) to optimize particle size and cationic surface charge. In the former, antigens were associated with the lipidic formulation of the triple adjuvant by electrostatic attraction. In the latter, the antigens resided in the interior of the lipid nanoparticle. Two dose levels of antigens were used with adjuvant comprised of the triple adjuvant with or without the lipid nanoparticle carrier. Formulation of vaccines with the triple adjuvant stimulated systemic and mucosal immune responses. The lipid nanoparticle vaccines favored a Th1 type of response with higher IgG2a and IgA serum antibody titers particularly for pertussis toxin and pertactin formulated at the 5 µg dose level in the admixed formulation. Additionally, the lipid nanoparticle vaccines resulted in high nasal SIgA antibodies and an early (4 weeks post vaccination) response after a single vaccination dose. The LT-A nanoparticles trended toward higher titers of serum antibodies compared to LAT. The cationic lipid-based vaccine nanoparticles formulated with a triple adjuvant showed encouraging results as a potential formulation for intranasally administered pertussis vaccines.

Pertussis Disease and Antenatal Vaccine Effectiveness in Australian Children.

BACKGROUND: Population-level studies of severe pertussis extending beyond infancy are sparse, and none in the context of antenatal vaccination. We compared hospitalized pertussis cases from birth to 15 years of age before and after introduction of antenatal immunization. METHODS: Active surveillance of laboratory-confirmed pertussis hospitalizations in a national network of pediatric hospitals in Australia January 2012 to June 2019. Impact of maternal vaccination was assessed by vaccine effectiveness (VE) in cases and test-negative controls with <2 months of age and by before-after comparison of age distribution of cases. Among cases eligible for one or more vaccine doses, we examined proportions age-appropriately immunized and with comorbidities by age group. RESULTS: Among 419 eligible cases, the proportion <2 months of age significantly decreased from 33.1% in 2012 to 2014 compared with 19.6% in 2016 to 2019 when mothers of only 4 of 17 (23.5%) cases <2 months of age had received antenatal vaccination. VE was estimated to be 84.3% (95% CI, 26.1-96.7). Across all years (2012-2019), of 55 cases 4-11 months of age, 21 (38%) had ≥2 vaccine doses, whereas among 155 cases ≥12 months of age, 122 (85.2%) had ≥3 vaccine doses. Prevalence of comorbidities (primarily cardiorespiratory) increased from 5 (2.1%) <6 months of age to 36 (24.2%) ≥12 months of age (P < 0.001), with 6/16 (38%) cases ≥12 months of age who required intensive care having comorbidities. CONCLUSIONS: Below the age of 12 months, prevention of severe pertussis will be maximized by high maternal antenatal vaccine uptake and timeliness of infant vaccine doses. Despite full immunization, we found children ≥12 months of age accounted for 27% of hospitalizations <15 years, with 24% having comorbities, suggesting new vaccine strategies, such as additional doses or more immunogenic vaccines, require evaluation.

The optimal strategy for pertussis vaccination: a systematic review and meta-analysis of randomized control trials and real-world data.

OBJECTIVE: Severe pertussis infection has been reported in infants before receiving routine immunization series. This problem could be solved by vaccinating mothers during pregnancy or children at birth. This study aimed to conduct a systematic review and meta-analysis of randomized controlled trials (RCTs) and real-world evidence to evaluate the optimal strategy for pertussis vaccination. DATA SOURCES: PubMed, Embase, and the Cochrane Library databases were searched until December 2020. STUDY ELIGIBILITY CRITERIA: RCTs, cohort studies, case-control studies, and case series were included if they investigated the efficacy, immunogenicity, and safety of acellular pertussis vaccine during pregnancy and at birth. METHODS: Number of pertussis cases, severe adverse events (SAEs), and pertussis antibody concentration in infants before and after they receive routine vaccination series were extracted and random-effect model was used to pool the analyses. RESULTS: Overall, 29 studies were included. Our meta-analysis revealed that pertussis immunization during pregnancy significantly increased the concentrations of 3 pertussis antibodies and reduced the incidence rates of infected infants below 3 months of age (odds ratio, 0.22; 95% confidence interval, 0.14-0.33). Similarly, infants vaccinated at birth had higher levels of pertussis antibody than those who were not. No significant difference in rates of severe adverse events was seen in all vaccination groups (during pregnancy [risk ratio, 1.18; 95% confidence interval, 0.76-1.82] and at birth [risk ratio, 0.72; 95% confidence interval, 0.34-1.54]). CONCLUSION: Pertussis vaccination during pregnancy could protect infants against pertussis disease before the routine vaccination. Pertussis immunization at birth would be an alternative for infants whose mothers did not receive pertussis vaccines during pregnancy.

Pertussis immunisation in infancy and atopic outcomes: A protocol for a population-based cohort study using linked administrative data.

INTRODUCTION: The burden of IgE-mediated food allergy in Australian born children is reported to be among the highest globally. This illness shares risk factors and frequently coexists with asthma, one of the most common noncommunicable diseases of childhood. Findings from a case-control study suggest that compared to immunisation with acellular pertussis vaccine, early priming of infants with whole-cell pertussis vaccine may be associated with a lower risk of subsequent IgE-mediated food allergy. If whole-cell vaccination is protective of food allergy and other atopic diseases, especially if protective against childhood asthma, the population-level effects could justify its preferential recommendation. However, the potential beneficial effects of whole-cell pertussis vaccination for the prevention of atopic diseases at a population-scale are yet to be investigated. METHODS AND ANALYSIS: Analyses of population-based record linkage data will be undertaken to compare the rates of admissions to hospital for asthma in children aged between 5 and 15 years old, who were born in Western Australia (WA) or New South Wales (NSW) between 1997 and 1999 (329,831) when pertussis immunisation in Australia transitioned from whole-cell to acellular only schedules. In the primary analysis we will estimate hazard ratios and 95% confidence intervals for the time-to-first-event (hospital admissions as above) using Cox proportional hazard models in recipients of a first dose of whole-cell versus acellular pertussis-containing vaccine before 112 days old (~4 months of age). Similarly, we will also fit time-to-recurrent events analyses using Andersen-Gill models, and robust variance estimates to account for potential within-child dependence. Hospitalisations for all-cause anaphylaxis, food anaphylaxis, venom, all-cause urticaria and atopic dermatitis will also be examined in children who received at least one dose of pertussis-containing vaccine by the time of the cohort entry, using analogous statistical methods. Presentations to the emergency departments will be assessed separately using the same statistical approach.

Pertussis Vaccine Candidate Based on Outer Membrane Vesicles Derived From Biofilm Culture.

Outer membrane vesicles (OMV) derived from Bordetella pertussis-the etiologic agent of the resurgent disease called pertussis-are safe and effective in preventing bacterial colonization in the lungs of immunized mice. Vaccine formulations containing those OMV are capable of inducing a mixed Th1/Th2/Th17 profile, but even more interestingly, they may induce a tissue-resident memory immune response. This immune response is recommended for the new generation of pertussis-vaccines that must be developed to overcome the weaknesses of current commercial acellular vaccines (second-generation of pertussis vaccine). The third-generation of pertussis vaccine should also deal with infections caused by bacteria that currently circulate in the population and are phenotypically and genotypically different [in particular those deficient in the expression of pertactin antigen, PRN(-)] from those that circulated in the past. Here we evaluated the protective capacity of OMV derived from bacteria grown in biofilm, since it was observed that, by difference with older culture collection vaccine strains, circulating clinical B. pertussis isolates possess higher capacity for this lifestyle. Therefore, we performed studies with a clinical isolate with good biofilm-forming capacity. Biofilm lifestyle was confirmed by both scanning electron microscopy and proteomics. While scanning electron microscopy revealed typical biofilm structures in these cultures, BipA, fimbria, and other adhesins described as typical of the biofilm lifestyle were overexpressed in the biofilm culture in comparison with planktonic culture. OMV derived from biofilm (OMVbiof) or planktonic lifestyle (OMVplank) were used to formulate vaccines to compare their immunogenicity and protective capacities against infection with PRN(+) or PRN(-) B. pertussis clinical isolates. Using the mouse protection model, we detected that OMVbiof-vaccine was more immunogenic than OMVplank-vaccine in terms of both specific antibody titers and quality, since OMVbiof-vaccine induced antibodies with higher avidity. Moreover, when OMV were administered at suboptimal quantity for protection, OMVbiof-vaccine exhibited a significantly adequate and higher protective capacity against PRN(+) or PRN(-) than OMVplank-vaccine. Our findings indicate that the vaccine based on B. pertussis biofilm-derived OMV induces high protection also against pertactin-deficient strains, with a robust immune response.

Pertussis (Whooping Cough).

Pertussis (whooping cough) is a respiratory infection caused by Bordetella pertussis. All ages are susceptible. In the prevaccine era, almost all children became infected. Pertussis is particularly dangerous in young infants, who account for practically all hospitalizations and deaths, but clinical disease is burdensome at any age. Widespread use of pertussis vaccines dramatically reduced cases, but concern over adverse reactions led to the replacement of standard whole-cell by acellular pertussis vaccines that contain only a few selected pertussis antigens and are far less reactogenic. Routine administration of acellular pertussis vaccines combined with diphtheria and tetanus toxoids is recommended in infancy with toddler and preschool boosters, at age 11, and during pregnancy. Boosting in the second half of every pregancy is critical to protection of the newborn. Waning of vaccine immunity over time has become an increasing concern, and several new pertussis vaccines are being evaluated to address this problem.

Associations Between Maternal Immunisation and Reduced Rates of Preterm Birth and Stillbirth: A Population Based Retrospective Cohort Study.

Stillbirth and preterm birth (PTB) remain two of the most important, unresolved challenges in modern pregnancy care. Approximately 10% of all births are preterm with nearly one million children dying each year due to PTB. It remains the most common cause of death among children under five years of age. The numbers for stillbirth are no less shocking with 2.6 million babies stillborn each year. With minimal impact on the rate of these adverse birth outcomes over the past decade there is an urgent need to identify more effective interventions to tackle these problems. In this retrospective cohort study, we used whole-of-population data, to determine if maternal immunization during pregnancy against influenza and/or pertussis, is associated with a lower risk of PTB, delivering a small-for-gestational age (SGA) infant, developing preeclampsia or stillbirth. Women with a singleton pregnancy at 28 or more weeks' gestation delivering in Victoria, Australia from July 2015 to December 2018 were included in the analysis. Log-binomial regression was used to measure the relationship between vaccination during pregnancy against influenza and against pertussis, with preterm birth, SGA, preeclampsia and stillbirth. Variables included in the adjusted model were maternal age, body mass index, first or subsequent birth, maternal Indigenous status, socio-economic quintile, smoking, public or private maternity care and metropolitan or rural location of the hospital. Women who received influenza vaccine were 75% less likely to have a stillbirth (aRR 025; 95% CI 0.20, 0.31), and 31% less likely to birth <37 weeks (aRR 0.69; 95% CI 0.66, 0.72). Women who received pertussis vaccine were 77% less likely to have a stillbirth (aOR 0.23; 95% CI 0.18, 0.28) and 32% less likely to birth <37 weeks gestation (aRR 0.68; 95% CI 0.66, 0.71). Vaccination also reduced the odds of small for gestational age by 13% and reduced the odds of pre-eclampsia when restricted to primiparous women. This association was seen over four different influenza seasons and independent of the time of year suggesting that any protective effect on obstetric outcomes afforded by maternal vaccination may not be due to a pathogen-specific response but rather due to pathogen-agnostic immune-modulatory effects.

Evaluation of Anti-PT Antibody Response after Pertussis Vaccination and Infection: The Importance of Both Quantity and Quality.

Pertussis toxin (PT) is considered the main virulence factor causing whooping cough or pertussis. The protein is widely studied and its composition was revealed and sequenced already during the 1980s. The human immune system creates a good response against PT when measured in quantity. However, the serum anti-PT antibodies wane rapidly, and only a small amount of these antibodies are found a few years after vaccination/infection. Therefore, multiple approaches to study the functionality (quality) of these antibodies, e.g., avidity, neutralizing capacity, and epitope specificity, have been investigated. In addition, the long-term B cell memory (Bmem) to PT is crucial for good protection throughout life. In this review, we summarize the findings from functional PT antibody and Bmem studies. These results are discussed in line with the quantity of serum anti-PT antibodies. PT neutralizing antibodies and anti-PT antibodies with proper avidity are crucial for good protection against the disease, and certain epitopes have been identified to have multiple functions in the protection. Although PT-specific Bmem responses are detectable at least five years after vaccination, long-term surveillance is lacking. Variation of the natural boosting of circulating Bordetella pertussis in communities is an important confounding factor in these memory studies.

Molecular epidemiology of Bordetella pertussis and analysis of vaccine antigen genes from clinical isolates from Shenzhen, China.

BACKGROUND: Although pertussis cases globally have been controlled through the Expanded Programme on Immunization (EPI), the incidence of pertussis has increased significantly in recent years, with a "resurgence" of pertussis occurring in developed countries with high immunization coverage. Attracted by its fast-developing economy, the population of Shenzhen has reached 14 million and has become one of the top five largest cities by population size in China. The incidence of pertussis here was about 2.02/100,000, far exceeding that of the whole province and the whole country (both < 1/100,000). There are increasing numbers of reports demonstrating variation in Bordetella pertussis antigens and genes, which may be associated with the increased incidence. Fifty strains of Bordetella pertussis isolated from 387 suspected cases were collected in Shenzhen in 2018 for genotypic and molecular epidemiological analysis. METHODS: There were 387 suspected cases of pertussis enrolled at surveillance sites in Shenzhen from June to August 2018. Nasopharyngeal swabs from suspected pertussis cases were collected for bacterial culture and the identity of putative Bordetella pertussis isolates was confirmed by real-time PCR. The immunization history of each patient was taken. The acellular pertussis vaccine (APV) antigen genes for pertussis toxin (ptxA, ptxC), pertactin (prn) and fimbriae (fim2 and fim3) together with the pertussis toxin promoter region (ptxP) were analyzed by second-generation sequencing. Genetic and phylogenetic analysis was performed using sequences publicly available from GenBank, National Institutes of Health, Bethesda, MD, USA ( https://www.ncbi.nlm.nih.gov/genbank/ ). The antimicrobial susceptibility was test by Kirby-Bauer disk diffusion. RESULTS: Fifty strains of Bordetella pertussis were successfully isolated from nasopharyngeal swabs of 387 suspected cases, with a positivity rate of 16.79%, including 28 males and 22 females, accounting for 56.0% and 44.0% respectively. Thirty-eight of the 50 (76%) patients were found to be positive for B. pertussis by culture. Among the positive cases with a history of vaccination, 30 of 42 (71.4%) cases had an incomplete pertussis vaccination history according to the national recommendation. Three phylogenetic groups (PG1-PG3) were identified each containing a predominant genotype. The two vaccines strains, CS and Tohama I, were distantly related to these three groups. Thirty-one out of fifty (62%) isolates belonged to genotype PG1, with the allelic profile prn2/ptxC2/ptxP3/ptxA1/fim3-1/fim2-1. Eighteen out of fifty (36%) isolates contained the A2047G mutation and were highly resistant to erythromycin, and all belonged to genotype PG3 (prn1/ptxA1/ptxP1/ptxC1/fim3-1/fim2-1), which is closely related to the recent epidemic strains found in northern China. CONCLUSIONS: The positive rate of cases under one-year-old was significantly higher than that of other age groups and should be monitored. The dominant antigen genotypes of 50 Shenzhen isolates are closely related to the epidemic strains in the United States, Australia and many countries in Europe. Despite high rates of immunization with APV, epidemics of pertussis have recently occurred in these countries. Therefore, genomic analysis of circulating isolates of B. pertussis should be continued, for it will benefit the control of whooping cough and development of improved vaccines and therapeutic strategies.

Pertussis immunisation during pregnancy: Antibody levels and the impact of booster vaccine.

Pertussis (whooping cough) is a highly infectious disease caused by Bordetella pertussis. Mothers lacking adequate immunity and contracting the disease represent the biggest risk of transmission to new-borns, for which the disease is often a threat. The aim of the study was to estimate the frequency of pertussis susceptibility among pregnant women, in order to point out the need for a vaccine recall during pregnancy, and to evaluate the antibody response in already vaccinated women. A cross-sectional observational study was conducted in the blood test centre of "St. Anna" Obstetrics and Gynaecology Hospital in Turin (Piedmont, Italy). Eligibility criteria included pregnant women coming to the centre for any blood test, aged 18 or above and with gestational age between 33 and 37 weeks at the moment of the blood draw. The data collection was carried out from May 2019 to January 2020 and the concentration of anti-Pertussis Toxin (anti-PT) IgG was measured through the Enzyme-Linked Immunosorbent Assay (ELISA) technique. Two-hundred women (median age 35) were enrolled: 132 (66%) had received at least one dose of pertussis vaccine, 82 of which during pregnancy. Recently vaccinated women had significantly higher antibody titres (even 12-15 times as high) compared to those vaccinated more than 5 years before or never vaccinated at all (p < 0.0001). Moreover, 95.1% of recently vaccinated women had anti-PT IgG levels above 10 IU/ml, and 85.4% above 20 IU/ml, while the same proportions were as low as 37% and 21% (respectively) in the group of women not vaccinated in pregnancy. This study confirmed that the vaccination is greatly effective in ensuring high antibody titres in the first months after the booster vaccine, with considerable differences in anti-PT IgG compared to women vaccinated earlier or never vaccinated at all, and therefore vaccinating pregnant women against pertussis still represents a valuable strategy.

Asymptomatic Bordetella pertussis infections in a longitudinal cohort of young African infants and their mothers.

Recent pertussis resurgence in numerous countries may be driven by asymptomatic infections. Most pertussis surveillance studies are cross-sectional and cannot distinguish asymptomatic from pre-symptomatic infections. Longitudinal surveillance could overcome this barrier, providing more information about the true burden of pertussis at the population level. Here we analyze 17,442 nasopharyngeal samples from a longitudinal cohort of 1320 Zambian mother/infant pairs. Our analysis has two elements. First, we demonstrate that the full range of IS481 qPCR CT values provides insight into pertussis epidemiology, showing concordance of low and high CT results over time, within mother/infant pairs, and in relation to symptomatology. Second, we exploit these full-range qPCR data to demonstrate a high incidence of asymptomatic pertussis, including among infants. Our results demonstrate a wider burden of pertussis infection than we anticipated in this population, and expose key limitations of threshold-based interpretation of qPCR results in infectious disease surveillance.

Factores que influyen en la adherencia a la vacuna contra la tosferina en mujeres embarazadas en Uruguay / Factors that influence the uptake of pertussis vaccine in pregnant women in Uruguay

INTRODUCCIÓN: Desde 2015 se ofrece la vacunación contra tosferina de modo universal y gratuito a mujeres embarazadas del Uruguay. Si bien es obligatoria, la cobertura vacunal, aún no es completa. OBJETIVOS: Conocer la prevalencia de mujeres embarazadas de dos hospitales públicos de Uruguay que recibieron vacuna dpaT en 2017 y determinar posibles factores que influyen en la adherencia a vacunarse. MÉTODOS: Estudio observacional, transversal, descriptivo, mediante encuestas a pacientes cursando puerperio inmediato. RESULTADOS: Se analizaron 884 encuestas (edad promedio 25,2 años; 16% adolescentes; la mayoría en pareja y educación secundaria incompleta). Se vacunaron 317 mujeres (36%). Dentro de los factores que se asociaron a la no vacunación se destacan: adolescencia (OR 1,88; IC 95% 1,24-2,85), no tener pareja (OR 1,40; IC 95% 1,04-1,85), no conocer la obligatoriedad de la vacuna (OR 9,44; IC 95% 6,63-13,45), no haber sido informada sobre los beneficios de la vacuna (OR 4; IC 95% 2,43-6,41) y no creer en el beneficio de las vacunas en el embarazo (OR 6,37; IC 95% 4,61-8,78). DISCUSIÓN: La mayoría de las mujeres embarazadas no recibieron la vacuna dpaT ni tuvieron indicación médica. La falta de información sobre la obligatoriedad y su beneficio, y las creencias con respecto a la vacunación se asociaron a una disminución en la adherencia a la misma. Los profesionales de la salud que atienden mujeres gestantes deben recomendar e informar sobre el beneficio de la vacunación para ellas y el neonato y generar la percepción de riesgo necesaria, como una de las medidas para mejorar la cobertura vacunal.

BACKGROUND: Since 2015, pertussis vaccine has been offered universally and free of charge to pregnant women in Uruguay. Although it is mandatory, vaccination coverage is not yet complete. AIM: To study the pertussis vaccination coverage in 2017 in pregnant women in two state hospitals and to search for barriere for uptaking the vaccine. METHODS: We conducted an observational, descriptive and transversal study, using a survey in patients undergoing immediate postpartum period. RESULTS: 884 surveys were analyzed (mean age 25.2 years; 16% teenagers, most of them in a relationship and incomplete high school). 317 women (36%) were vaccinated. Main barriere for uptaking Tdap vaccine were: teenage and being single were associated with a greater risk for the uptake. Not being aware of the vaccine mandatoriness and not being informed about its benefits were associated with 9,44 and 4 higher risks for not uptaking the vaccine (IC 95% 6.63-13.45 and IC 95% 2.43-6.41, respectively). Not believing in the benefits of pertussis vaccine during pregnancy was associated with 6.37 higher risk (OR 6.37; IC 95% 4.61-8.78). DISCUSSION: Most pregnant women in this study during 2017 did not uptake pertussis vaccine and did not have medical indication for it. The lack of information about the obligation and benefits, and also patients' beliefs about the vaccination were identified as barriere. Health professionals who treat pregnant women should recommend and inform about the benefits of pertussis vaccine for women and the infant, and create the necessary perception of risk, in order to improve the vaccination coverage.

Acceptance of Pertussis Vaccination among Pregnant Women in Taiwan.

This cross-sectional study assessed prenatal pertussis vaccination acceptance in Taiwan. A sample of pregnant women from five private clinics in Taiwan was recruited. Demographics, experience of prenatal vaccinations, key considerations, knowledge, and attitude about pertussis and its vaccination were measured. Among 505 participants, the vaccination rate, including planned vaccination, was 29.7%. Factors associated with acceptance included clinic location, primary caregiver of the newborn, newborns with siblings, previous influenza vaccination history, knowledge and attitude toward pertussis and its vaccination. Public health agencies should provide free vaccinations, clarify misinformation, and publicize prevention information, to improve prenatal pertussis vaccination acceptance.

Correlation of Vaccine Responses.

Introduction: The humoral response to vaccinations varies widely between individuals. There is no data available on the correlation between responses to different vaccines. In this study, we investigated the correlation of antibody responses between routine vaccine antigens in infants. Methods: One and seven months after the 6-month vaccinations and one month after the 12-month vaccinations, antibody concentrations to diphtheria, tetanus, pertussis, polio (serotypes 1-3), Haemophilus influenzae type b (Hib), pneumococcus (13 serotypes), meningococcus C, measles, mumps and rubella were measured using fluorescent bead-based multiplex immune-assays. For the correlation of antibody responses, Spearman's rank correlation coefficients (ρ) with 95% confidence intervals (CI) were calculated between responses to each vaccine antigen. Results: The correlation between concentrations of antibodies to the vaccinations ending at 6 months of age was higher one month compared to seven months after vaccination. The strongest correlations at both time points were observed between antibody responses to different polio serotypes, certain pneumococcal serotypes and between responses to diphtheria and pneumococcal (conjugated to a diphtheria toxoid) vaccine antigens. Correlation between responses to tetanus, Hib, pertussis, polio and other vaccine antigens were weak. The correlation between antibody responses to the 12-month vaccine antigens was weaker than to the 6-month vaccine antigens and there was a negative correlation between responses to measles, mumps, rubella vaccine and non-live vaccine antigens (meningococcus C, tetanus and Hib). There was only weak correlation between antibody responses to vaccines of the same type (e.g. conjugated polysaccharide or toxoid vaccines). Conclusion: Correlation between antibody responses to similar antigens in the same vaccine (such as different serotypes of a bacteria or virus), as well as responses to antigens conjugated to similar carrier proteins, are strong. In contrast, correlation between responses to other vaccines are weak. Measuring antibody responses to one or a few vaccine antigens therefore does not offer a reliable surrogate marker of responses to unrelated vaccines.

Responses to an acellular pertussis booster vaccination in children, adolescents, and young and older adults: A collaborative study in Finland, the Netherlands, and the United Kingdom.

BACKGROUND: Pertussis can lead to serious disease and even death in infants. Older adults are more vulnerable to complications as well. In high-income countries, acellular pertussis vaccines are used for priming vaccination. In the administration of booster vaccinations to different age groups and target populations there is a substantial between-country variation. We investigated the effect of age on the response to acellular pertussis booster vaccination in three European countries. METHODS: This phase IV longitudinal intervention study performed in Finland, the Netherlands and the United Kingdom between October 2017 and January 2019 compared the vaccine responses between healthy participants of four age groups: children (7-10y), adolescents (11-15y), young adults (20-34y), and older adults (60-70y). All participants received a three-component acellular pertussis vaccine. Serum IgG and IgA antibody concentrations to pertussis antigens at day 0, 28, and 1 year were measured with a multiplex immunoassay, using pertussis toxin concentrations at day 28 as primary outcome. This trial is registered with ClinicalTrialsRegister.eu (2016-003,678-42). FINDINGS: Children (n = 109), adolescents (n = 121), young adults (n = 74), and older adults (n = 75) showed high IgG antibody concentrations to pertussis toxin at day 28 with GMCs of 147 (95% CI 120-181), 161 (95% CI 132-196), 103 (95% CI 80-133), and 121 IU/ml (95% CI 94-155), respectively. A significant increase in GMCs for vaccine antigens in all age groups by 28 days was found which had decreased by 1 year. Differences in patterns of IgG GMCs at 28 days and 1 year post-vaccination did not have a consistent relationship to age. In contrast, IgA antibodies for all antigens increased with age at all timepoints. INTERPRETATION: Acellular pertussis booster vaccination induces significant serum IgG responses to pertussis antigens across the age range which are not uniformly less in older adults. Acellular boosters could be considered for older adults to reduce the health and economic burden of pertussis.

Effect of a postpartum prescription for pertussis vaccine: a before-and-after study.

BACKGROUND: Among the strategies to encourage pregnant women to be vaccinated against pertussis in the postpartum period, that of giving them a prescription has been evaluated only sparsely. OBJECTIVE: To measure the effect of giving women who are not immunized against pertussis a prescription for the vaccine at discharge from the maternity unit. MATERIAL AND METHODS: Single-center before-and-after study (2011: before; 2015: after). All women received both oral and written information about vaccination against pertussis. During the after period, they were also specifically asked their immunization status during pregnancy. Those currently unimmunized received a written prescription for it at discharge. RESULTS: Among the women unimmunized at delivery, the percentage who were vaccinated postpartum climbed from 17 to 42% between 2011 and 2015 (p < 0.001), while the percentage of their unimmunized partners who were vaccinated remained stable (27 and 29%, p = 0.74). During this time, the percentage of women immunized against pertussis at the beginning of pregnancy rose from 32 to 52% (p < 0.001). Finally, the percentage of all women protected against this disease postpartum climbed from 44 to 72% between these two periods (p < 0.001). CONCLUSIONS: In the postpartum period, giving a prescription for pertussis vaccine to women unimmunized is accompanied by a significant elevation in their vaccination rate. Nevertheless, this rate remains low and better strategies have to be implemented.