Quantitative analysis of pertussis, tetanus, and diphtheria antibodies in sera and breast milk from Tdap vaccinated women using a qualified multiplex assay.

Pertussis (whooping cough) is a reemergent, highly contagious respiratory infection of public health concern. Infants prior to initiation of their primary vaccination series are the most vulnerable to severe infection, and even death. Vaccination during pregnancy is an efficacious means of reducing infection in infants. This approach relies on boosting maternal immunity and passive transfer of antibodies to the infant via placenta and breast milk. Similarly, maternal vaccination post-partum can enhance maternal-infant immunity. To support the analysis of pertussis immunity in the context of maternal-infant immunization, we developed a high throughput multiplex assay for simultaneous quantification of serum IgG antibodies against pertussis vaccine antigens: pertussis toxin (PT), filamentous hemagglutinin (FHA), pertactin (PRN), and fimbriae (FIM2/3), and against tetanus (TT) and diphtheria toxoids (DT), using the Meso Scale Discovery (MSD) platform. The assay was qualified, and specificity, sensitivity, accuracy, precision, linearity, and robustness were demonstrated. The assay was subsequently adapted for quantification of IgG and IgA in breast milk. Applied to a serological survey of pregnant women living in the United States and sub-Saharan Africa, this method revealed differences in magnitude and breadth of antibody profile, consistent with history of vaccination. A longitudinal analysis of Tdap responses in women vaccinated post-partum demonstrated a rapid increase in serum IgG that remained elevated for up to 24 months. Likewise, high levels of vaccine-specific IgA and IgG antibodies were present in breast milk, although they exhibited faster decay. This multiplex MSD assay is a reliable and practical tool for quantification of pertussis, tetanus, and diphtheria antibodies in serum and breast milk in serosurveys or vaccine studies. IMPORTANCE: Pertussis (whooping cough) has reemerged in recent years. Vaccination during pregnancy is an effective approach to prevent illness during the first months of life. We developed a multiplex assay for quantification of pertussis, tetanus, and diphtheria serum antibodies using the Meso Scale Discovery (MSD) platform; the method was qualified, and specificity, precision, accuracy, linearity, and limits of quantification were defined. It was also adapted for quantification of antibodies in breast milk. We successfully determined serostatus in women from different regions and with different vaccination histories, as well as responses to Tdap in blood and breast milk post-partum. This is the first description of a multiplex assay for the quantification of pertussis, tetanus, and diphtheria antibodies in breast milk.

Risk of New Retinal Vascular Occlusion After mRNA COVID-19 Vaccination Within Aggregated Electronic Health Record Data.

Importance: New-onset retinal vascular occlusion (RVO) occurring acutely after messenger RNA (mRNA) COVID-19 vaccination has been described in recent literature. Because RVO can cause vision loss or blindness, an epidemiologic investigation evaluating this potential association is of great importance to public health. Objective: To investigate how often patients are diagnosed with new RVO acutely after the mRNA COVID-19 vaccine compared with influenza and tetanus, diphtheria, pertussis (Tdap) vaccines. Design, Setting, and Participants: A retrospective population-based cohort design using the TriNetX Analytics platform, a federated, aggregated electronic health record (EHR) research network containing the deidentified EHR data of more than 103 million patients, was used to examine aggregate EHR data. Data were collected and analyzed on October 20, 2022. Data on patients within the TriNetX Analytics platform were searched for the presence of vaccination Common Procedural Technology codes, and instances of newly diagnosed RVO within 21 days of vaccination were recorded and reported. Propensity score matching based on demographic characteristics (age, sex, race and ethnicity) and comorbidities (diabetes, hypertension, and hyperlipidemia) was performed between vaccination groups for evaluation of relative risks (RRs). Main Outcomes and Measures: The appearance of a new-encounter diagnosis of RVO within 21 days of the mRNA COVID-19 vaccination was the primary outcome. Historical comparison cohorts of patients receiving influenza and Tdap vaccinations allowed for evaluation of the RRs for RVO. Results: Of 3 108 829 patients (mean [SD] age at vaccination, 50.7 [20.4] years; 56.4% women) who received the mRNA COVID-19 vaccine, 104 (0.003%; 95% CI, 0.003%-0.004%) patients had a new diagnosis of RVO within 21 days of vaccination. After propensity score matching, the RR for new RVO diagnosis after the first dose of COVID-19 vaccination was not significantly different from that after influenza (RR, 0.74; 95% CI, 0.54-1.01) or Tdap (RR, 0.78; 95% CI, 0.44-1.38) vaccinations, but was greater when compared with the second dose of the COVID-19 vaccination (RR, 2.25; 95% CI, 1.33-3.81). Conclusions and Relevance: The findings of this study suggest that RVO diagnosed acutely after mRNA COVID-19 vaccination occurs extremely rarely at rates similar to those of 2 different historically used vaccinations, the influenza and Tdap vaccines. No evidence suggesting an association between the mRNA COVID-19 vaccination and newly diagnosed RVO was found.

Immunogenicity and safety of BPZE1, an intranasal live attenuated pertussis vaccine, versus tetanus-diphtheria-acellular pertussis vaccine: a randomised, double-blind, phase 2b trial.

BACKGROUND: Bordetella pertussis epidemics persist as transmission remains unabated despite high acellular pertussis vaccination rates. BPZE1, a live attenuated intranasal pertussis vaccine, was designed to prevent B pertussis infection and disease. We aimed to assess the immunogenicity and safety of BPZE1 compared with the tetanus-diphtheria-acellular pertussis vaccine (Tdap). METHODS: In this double-blind, phase 2b trial at three research centres in the USA, healthy adults aged 18-50 years were randomly assigned (2:2:1:1) via a permuted block randomisation schedule to receive BPZE1 vaccination followed by BPZE1 attenuated challenge, BPZE1 vaccination followed by placebo challenge, Tdap followed by BPZE1 attenuated challenge, or Tdap followed by placebo challenge. On day 1, lyophilised BPZE1 was reconstituted with sterile water and given intranasally (0·4 mL delivered to each nostril), whereas Tdap was given intramuscularly. To maintain masking, participants in the BPZE1 groups received an intramuscular saline injection, and those in the Tdap groups received intranasal lyophilised placebo buffer. The attenuated challenge took place on day 85. The primary immunogenicity endpoint was the proportion of participants achieving nasal secretory IgA seroconversion against at least one B pertussis antigen on day 29 or day 113. Reactogenicity was assessed up to 7 days after vaccination and challenge, and adverse events were recorded for 28 days after vaccination and challenge. Serious adverse events were monitored throughout the study. This trial is registered with ClinicalTrials.gov, NCT03942406. FINDINGS: Between June 17 and Oct 3, 2019, 458 participants were screened and 280 were randomly assigned to the main cohort: 92 to the BPZE1-BPZE1 group, 92 to the BPZE1-placebo group, 46 to the Tdap-BPZE1 group, and 50 to the Tdap-placebo group. Seroconversion of at least one B pertussis-specific nasal secretory IgA was recorded in 79 (94% [95% CI 87-98]) of 84 participants in the BPZE1-BPZE1 group, 89 (95% [88-98]) of 94 in the BPZE1-placebo group, 38 (90% [77-97]) of 42 in the Tdap-BPZE1 group, and 42 (93% [82-99]) of 45 in the Tdap-placebo group. BPZE1 induced broad and consistent B pertussis-specific mucosal secretory IgA responses, whereas Tdap did not induce consistent mucosal secretory IgA responses. Both vaccines were well tolerated, with mild reactogenicity and no serious adverse events related to study vaccination. INTERPRETATION: BPZE1 induced nasal mucosal immunity and produced functional serum responses. BPZE1 has the potential to avert B pertussis infections, which ultimately could lead to reduced transmission and diminished epidemic cycles. These results should be confirmed in large phase 3 trials. FUNDING: ILiAD Biotechnologies.

Mucosal Immunization with DTaP Confers Protection against Bordetella pertussis Infection and Cough in Sprague-Dawley Rats.

Pertussis is a respiratory disease caused by the Gram-negative pathogen, Bordetella pertussis. The transition from a whole-cell pertussis vaccine (wP and DTP) to an acellular pertussis vaccine (aP, DTaP, and Tdap) correlates with an increase in pertussis cases, despite widespread vaccine implementation and coverage, and it is now appreciated that the protection provided by aP rapidly wanes. To recapitulate the localized immunity observed from natural infection, mucosal vaccination with aP was explored using the coughing rat model of pertussis. Overall, our goal was to evaluate the route of vaccination in the coughing rat model of pertussis. Immunity induced by both oral gavage and intranasal vaccination of aP in B. pertussis challenged rats over a 9-day infection was compared to intramuscular wP (IM-wP)- and IM-aP-immunized rats that were used as positive controls. Our data demonstrate that mucosal immunization of aP resulted in the production of anti-B. pertussis IgG antibody titers similar to IM-wP- and IM-aP-vaccinated controls postchallenge. IN-aP also induced anti-B. pertussis IgA antibodies in the nasal cavity. Immunization with IM-wP, IM-aP, IN-aP, and OG-aP immunization protected against B. pertussis-induced cough, whereas OG-aP immunization did not protect against respiratory distress. Mucosal immunization by both intranasal and oral gavage administration protected against acute inflammation and decreased bacterial burden in the lung compared to mock-vaccinated challenge rats. The data presented in this study suggest that mucosal vaccination with aP can induce a mucosal immune response and provide protection against B. pertussis challenge. This study highlights the potential benefits and uses of the coughing rat model of pertussis; however, further questions regarding waning immunity still require additional investigation.

Effectiveness of experimental and commercial pertussis vaccines in the elimination of Bordetella pertussis isolates with different genetic profiles in murine model.

The aim of this study was to compare the elimination of Bordetella pertussis clinical isolates, representing different genotypes in relation to alleles encoding virulence factors (MLST-multi-locus antigen sequence typing), MLVA type (multi-locus variable-number tandem repeat analysis) and PFGE group (pulsed-field gel electrophoresis) from the lungs of naive mice or mice were immunised with the commercial whole-cell pertussis vaccine, the acellular pertussis vaccine and the experimental whole-cell pertussis vaccine. Molecular data indicate that the resurgence of pertussis in populations with high vaccine coverage is associated with genomic adaptation of B. pertussis, to vaccine selection pressure. Pertactin-negative B. pertussis isolates were suspected to contribute to the reduced vaccine effectiveness. It was shown that one of the isolates used is PRN deficient. The mice were intranasally challenged with bacterial suspension containing approximately 5 × 10 7 CFU/ml B. pertussis. The immunogenicity of the tested vaccines against PT (pertussis toxin), PRN (pertactin), FHA (filamentous haemagglutinin) and FIM (fimbriae types 2 and 3) was examined. The commercial whole-cell and acellular pertussis vaccines induced an immunity effective at eliminating the genetically different B. pertussis isolates from the lungs. However, the elimination of the PRN-deficient isolate from the lungs of mice vaccinated with commercial vaccines was delayed as compared to the PRN ( +) isolate, suggesting phenotypic differences with the circulating isolates and vaccine strains. The most effective vaccine was the experimental vaccine with the composition identical to that of the strains used for infection.

Immunogenicity and Safety of a Tetravalent Dengue Vaccine Administered Concomitantly or Sequentially With Tdap Vaccine: Randomized Phase IIIb Trial in Healthy Participants 9-60 Years of Age in the Philippines.

BACKGROUND: Incorporating dengue vaccination into existing childhood vaccination programs could increase vaccine coverage. This study assessed the safety and immunogenicity of concomitant versus sequential administration of the combined tetanus toxoid, reduced diphtheria toxoid and acellular pertussis (Tdap) vaccine and the tetravalent dengue vaccine (CYD-TDV). METHODS: This phase IIIb, randomized, open-label, multicenter study was conducted in the Philippines in individuals 9-≤60 years of age (NCT02992418). Participants were to receive 3 CYD-TDV doses 6 months apart, the first dose administered either concomitantly or sequentially (28 days post-Tdap). Antibody levels were measured at baseline and 28 days post-first doses of Tdap vaccine and CYD-TDV, using enzyme-linked immunosorbent assay (pertussis, tetanus), micrometabolic inhibition test-toxin neutralization assay (diphtheria) and plaque reduction neutralization test (dengue). Immunogenicity was assessed for all participants, and statistical analysis reported for baseline dengue seropositive participants. Safety was assessed throughout. RESULTS: Among 688 randomized participants, 629 (91.4%) were baseline dengue seropositive (concomitant group, n = 314 and sequential group, n = 315). After the first dose, non-inferiority of immune responses between concomitant and sequential vaccination was achieved; between-group geometric mean antibody concentration ratios were close to 1 for anti-PT, anti-FHA, anti-PRN and anti-FIM, between-group differences in percent achieving seroprotection (titers ≥0.1 IU/mL) were 0.26% (diphtheria) and 0.66% (tetanus), and between-group geometric mean antibody titer ratios were close to 1 for dengue serotypes 1-4. Safety profiles in both study groups were comparable. CONCLUSIONS: CYD-TDV and Tdap vaccine administered concomitantly or sequentially in baseline dengue seropositive participants elicited comparable immunogenicity and safety profiles.

Knowledge, Attitudes, and Practices Associated with Pertussis Vaccination during Pregnancy: Japan, 2016-2017.

Neonatal pertussis can potentially cause severe complications and even death. Mothers have been most frequently identified as the source of neonatal pertussis. Approximately a dozen countries have implemented pertussis vaccination programs for pregnant women to protect neonates; however, in Japan, this has not been implemented. The aim of this questionnaire-based study was to ascertain the willingness of women to be vaccinated during pregnancy and the factors associated with willingness. The subjects were 977 pregnant women who visited either of the two selected hospitals for maternity health checks. Most of the women were in their first pregnancy (96%), and approximately half of them considered a physician to be the most reliable source of information about vaccination (481/977, 49%). "Willingness to receive pertussis vaccination" was significantly associated with the factors "no fear of receiving vaccination" (odds ratio [OR] = 3.10, 95% confidence interval [CI]: 2.21-4.34), "necessary to prevent pertussis" (OR = 8.70, 95% CI: 6.17-12.28), "effective in pregnancy" (OR = 5.46, 95% CI: 3.94-7.56), and "no concern about the side effects after vaccination" (OR = 3.03, 95% CI: 1.66-5.55). Pregnant women are likely to consider vaccination if they have a good understanding of the disease and its outcomes. Physicians are well positioned to improve knowledge and attitudes toward pertussis vaccination during pregnancy.

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.

Impacto en niños menores de un año del programa de vacunación con dTpa en embarazadas en Castelló / Impact in children under the age of one of Tdap vaccination programme on pregnant women in Castelló

INTRODUCCIÓN: Se analiza el cambio en las tasas de incidencia de tosferina en menores de un año en Castelló, antes y después de la introducción de la vacunación a embarazadas en enero de 2015. MÉTODOS: Se han comparado las tasas de incidencia del periodo postvacunal (2015-2018) con el prevacunal (2011-2014) en todas las edades, niños de 3 a 11 meses y menores de 3 meses. Se han calculado los riesgos relativos y sus intervalos de confianza al 95%. RESULTADOS: La tasa global fue superior en el periodo postvacunal que en el prevacunal (0,23 vs. 0,15 por 1.000 personas-año), pero disminuyó en los menores de 3 meses. Los riesgos relativos fueron: 1,56 (IC 95% 1,34-1,82) para todas las edades; 1,73 (IC 95% 0,87-3,57) para 3 a 11 meses, y 0,35 (IC 95% 0,16-0,69) para menores de 3 meses. Un patrón similar se observó para niños hospitalizados. CONCLUSIONES: La tasa de incidencia en menores de 3 meses se redujo en un 65%, y el riesgo de hospitalización en un 71%, lo que evidencia que la medida ha sido efectiva. Esta reducción de la incidencia ocurrió de forma específica en este grupo de edad y no en otros

INTRODUCTION: The objective was to compare incidence rates of pertussis in children under the age of one in Castelló, before and after the introduction of vaccination of pregnant women in January 2015. METHODS: The incidence of the post-vaccine period (2015-2018) was compared with the pre-vaccine period (2011-2014) in all ages, in children from 3 to 11 months and under 3 months. The relative risks and their 95% confidence intervals (95% CI) were calculated. RESULTS: The overall rate of pertussis in all ages was higher in the post-vaccine period than in the pre-vaccine period (0.23 vs. 0.15 per 1.000 person-years), but decreased in those under 3 months. The relative risks were: 1.56 (95% CI 1.34-1.82) in all ages; 1.73 (95% CI 0.87-3.57) for children aged 3 to 11 months, and 0.35 (95% CI 0.16-0.69) for children under 3 months. A similar pattern was observed for hospitalised children. CONCLUSIONS: The incidence rate in children under 3 months was reduced by 65% in the period after the intervention, and the hospitalisation risk rate by 71%, suggesting that the measure has been effective and specific for this age group

Update on Transplacental Transfer of IgG Subclasses: Impact of Maternal and Fetal Factors.

Transplacental antibody transfer from mother to fetus provides protection from infection in the first weeks of life, and the four different subclasses of IgG (IgG1, IgG2, IgG3, and IgG4) have diverse roles in protection against infection. In this study, we evaluated concentrations and transplacental transfer ratios of the IgG subclasses in a healthy UK-based cohort of mother-cord pairs, and investigated associations with maternal, obstetric, and fetal factors. In agreement with previous studies, we found a strong association between maternal and cord IgG for all subclasses. We report a transfer efficiency hierarchy of IgG1>IgG3>IgG4=IgG2 in our study population, and our review of the literature demonstrates that there is no consensus in the hierarchy of subclass transfer, despite the commonly made statement that the order is IgG1>IgG4>IgG3>IgG2. We report additional data regarding negative associations between elevated maternal IgG concentrations and maternal/cord transfer ratios, finding an effect on IgG1, IgG2, and IgG3 subclasses. Levels of IgG subclasses were the same between venous and arterial blood samples from the umbilical cord, but there was a significantly higher level of total IgG in arterial blood. We found no correlation between placental FcRn protein levels and IgG transfer in our cohort, suggesting that IgG is the main determinant of observed differences in transplacental transfer ratios at term. Neonatal IgG1 and IgG4 levels were increased with later gestation at delivery, independent of any increase in transplacental transfer, indicating that the benefit of later gestation is through accumulation of these subclasses in the fetus. Neonatal IgG2 levels and transfer ratios were reduced in rhesus-negative pregnancies, suggesting that administered anti-D antibodies may compete for transplacental transfer of this subclass. Maternal influenza vaccination resulted in elevated maternal and neonatal levels of IgG4, whereas maternal Tdap vaccination had no impact on neonatal levels of the subclasses, nor transfer. However, within Tdap vaccinated pregnancies, later gestation at Tdap vaccination was associated with higher transplacental transfer. Our study provides information regarding levels and transfer of IgG subclasses in healthy term pregnancies and demonstrates the importance of recording detailed clinical information in studies of antibody transfer, including parity, ethnicity, and timing of maternal vaccine delivery.

A systematic review of the burden of pertussis disease in infants and the effectiveness of maternal immunization against pertussis.

Introduction Infants too young to be fully immunized are the most vulnerable to severe pertussis disease. To close this susceptibility gap, passive infant immunization through vaccination of pregnant women against pertussis was first introduced in 2011 in the United States and has been extended since then to more than 40 countries. Areas covered We conducted two systematic literature searches to describe the worldwide burden of pertussis disease in infants <6 months of age since 2005, and the effectiveness and impact of maternal pertussis vaccination in preventing infant pertussis since 2011. Expert opinion Pertussis disease incidence rates in infants aged <2-3 months were substantial in all countries with available data, exceeding 1000 cases per 100,000 population during outbreaks. Virtually all pertussis deaths occurred in this age group. Data from Africa, Eastern Mediterranean, and Asia were limited, but suggest a similar or higher disease burden than in Europe or the Americas. Estimates of effectiveness of second/third trimester pertussis vaccination in preventing pertussis disease in <2-3 months old infants were consistently high (69%-93%) across the observational studies reviewed, conducted in various settings with different designs. Maternal vaccination programs appear to be achieving their goal of reducing the burden of disease in very young infants. Plain language summary What is the context? Pertussis, also known as whooping cough, is a highly contagious disease of the respiratory tract. Infants too young to be fully vaccinated are at the highest risk of severe pertussis disease, hospitalization, and death. Vaccinating pregnant women against pertussis with a Tdap vaccine is recommended in more than 40 countries as a safe and effective strategy to protect infants for the first months of life. What is new? This review summarizes recent literature describing the burden of pertussis disease in infants worldwide prior to the introduction of maternal vaccination programs; pertussis disease incidence rates in infants aged <2-3 months were substantial in all countries with available data, exceeding 1000 cases per 100,000 population during outbreaks. Immunization of pregnant women with a Tdap vaccine can prevent about 70-90% of pertussis disease and up to 90.5% of pertussis hospitalizations in infants under 3 months of age. What is the impact? Limited available data suggest that incidence rates of pertussis disease after the introduction of Tdap maternal immunization have declined in infants. Current knowledge supports the implementation of Tdap maternal immunization programs.

Effect of FHA and Prn on Bordetella pertussis colonization of mice is dependent on vaccine type and anatomical site.

Bordetella pertussis vaccine escape mutants that lack expression of the pertussis antigen pertactin (Prn) have emerged in vaccinated populations in the last 10-20 years. Additionally, clinical isolates lacking another acellular pertussis (aP) vaccine component, filamentous hemagglutinin (FHA), have been found sporadically. Here, we show that both whole-cell pertussis (wP) and aP vaccines induced protection in the lungs of mice, but that the wP vaccine was more effective in nasal clearance. Importantly, bacterial populations isolated from the lungs shifted to an FHA-negative phenotype due to frameshift mutations in the fhaB gene. Loss of FHA expression was strongly selected for in Prn-deficient strains in the lungs following aP but not wP vaccination. The combined loss of Prn and FHA led to complete abrogation of bacterial surface binding by aP-induced serum antibodies. This study demonstrates vaccine- and anatomical site-dependent adaptation of B. pertussis and has major implications for the design of improved pertussis vaccines.

Immune interference (blunting) in the context of maternal immunization with Tdap-containing vaccines: is it a class effect?

INTRODUCTION: Maternal immunization with reduced antigen content tetanus-diphtheria-acellular pertussis (Tdap)-containing vaccines has been recommended to prevent infant pertussis. However, maternal antibodies may interfere with infant responses to routine immunization with diphtheria-tetanus-acellular pertussis (DTaP)-containing vaccines, raising concerns of suboptimal protection after infant vaccination. We performed a narrative literature review to assess whether blunting occurs regardless of the manufacturer of maternal and infant vaccines. Because internationally agreed correlates of protection are lacking, the clinical significance of blunting is not yet fully understood. We have reviewed the evidence available to date. AREAS COVERED: Thirteen studies that evaluated blunting after maternal immunization and infant primary/booster series were identified. Blunting was observed with various combinations of Tdap- and DTaP-containing vaccines for maternal and pediatric immunization. Studies assessing the effectiveness of maternal Tdap immunization beyond the primary infant immunization series in England and in the United States suggested no evidence of a clinically relevant blunting effect so far. EXPERT COMMENTARY: This review indicates that the phenomenon of blunting does not depend on the manufacturer/brand of the pertussis-containing vaccines used for immunizing mothers or children. Currently, there is no epidemiological evidence that children whose mothers received Tdap are at increased risk of pertussis after pediatric vaccinations, although longer follow-up is required.

Immunogenicity and safety of a DTaP-IPV/Hib pentavalent vaccine given as primary and booster vaccinations in healthy infants and toddlers in Japan.

BACKGROUND: Globally, the use of single DTaP-IPV/Hib vaccines that combine DTaP-IPV and Hib is widespread, but in Japan vaccination is usually concomitant at separate sites. The immunogenicity and safety of a primary vaccination series and booster of a combined pentavalent DTaP-IPV/Hib vaccine were evaluated and compared to separate administration of DTaP-IPV and Hib in Japanese infants. METHODS: Healthy Japanese infants were administered DTaP-IPV/Hib (Group A: N = 207) or DTaP-IPV + Hib (Group B: N = 207) by the subcutaneous (SC) or DTaP-IPV/Hib by the intramuscular (IM) route (Group C: N = 10). All subjects received a 3-dose primary vaccination series and a booster. Non-inferiority (Group A versus Group B) was tested post-primary series and subsequent post hoc analyses were performed for anti-Hib. Safety was assessed by parental reports. RESULTS: Non-inferiority for SC administration of Group A versus Group B for the primary series was demonstrated for antibody responses to all antigens except Hib using the threshold of 1.0 µg/mL. Post hoc analyses for anti-Hib demonstrated non-inferiority for the primary series response using 0.15 µg/mL, and for pre-booster antibody persistence and the booster response using 0.15 µg/mL and 1.0 µg/mL. The immune response was similar for each antigen following SC or IM administration. There were no safety concerns in any group, and a lower incidence of injection sites for the IM route was observed as expected. CONCLUSIONS: These data show the good immunogenicity and safety profile of the DTaP-IPV/Hib vaccine as a 3-dose infant primary series followed by a booster in the second year of life in Japan.

Tetanus, diphtheria and acellular pertussis (Tdap) vaccine for prevention of pertussis among adults aged 19 years and older in the United States: A cost-effectiveness analysis.

Currently, the Advisory Committee on Immunization Practices recommends one-time tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccination for all adults 19 years and older. This study is designed to evaluate the cost-effectiveness of Tdap vaccination for Tdap-eligible adults aged 19 through 85 in the United States. A cost-effectiveness model was developed to compute costs and health outcomes associated with pertussis among 100,000 Tdap-eligible persons of each age cohort. From the societal perspective, the cost per quality-adjusted life-year (QALY) saved was evaluated under the vaccination scenarios. Sensitivity analyses were also conducted to evaluate the impacts of changes in key variables. All costs were adjusted to 2018 US$ with an annual discount rate of 3% applied to costs and outcomes. The incremental cost-effectiveness ratios (ICERs) for vaccinating US adults aged 19 to 85 with Tdap ranged from $248,000/QALY to $900,000/QALY. The lowest cost per QALY was found to be $248,000 for the age 65 cohort, followed by $332,000 for the cohort of age 19, and followed by $477,000 for the age 50 cohort. Sensitivity analysis showed the most dramatic changes in ICER occurred when changing the underreporting factor, vaccine effectiveness and vaccination costs. While Tdap vaccination may not be as cost effective as predicted earlier, it remains the best available preventive measure against pertussis. Further investigation of the true burden of pertussis disease among adults and the effectiveness of Tdap vaccination in this population is needed to better estimate the impact of Tdap vaccination.

Tetanus, diphtheria, and pertussis vaccine (Tdap) in pregnancy and risk of major birth defects in the offspring.

BACKGROUND: The tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine is recommended during pregnancy to protect newborns against pertussis infection in the months prior to their primary pertussis vaccination. Although research on the safety of the vaccine has been reassuring, most previous studies have considered major malformations as a single outcome, and have not examined potential risks for specific malformations. METHODS: Using data from the Slone Epidemiology Center Birth Defects Study collected between 2006 and 2015, we identified exposures to Tdap vaccine in both early and late pregnancy and examined potential risks for specific malformations. We used logistic regression models to calculate propensity score-adjusted odds ratios (aORs) and 95% confidence intervals (CIs). RESULTS: We identified 2,357 women exposed to Tdap during pregnancy. For first trimester exposures, the risk estimate for malformations overall was 1.0 (0.7, 1.5). We had power to examine nine specific malformations and found adjusted odds ratios ranging from 0.7 to 1.3, none of which had confidence intervals that excluded 1.0. For second or third trimester exposures, we examined 15 malformations with potential late pregnancy etiology, and calculated adjusted risk estimates for nine of these. Risk estimates ranged from 0.5 to 1.9, with no lower confidence bounds that excluded 1.0. CONCLUSIONS: We observed no evidence of appreciable risks for selected specific major malformations associated with Tdap vaccine exposure during early or late pregnancy. As pertussis remains a public health concern and Tdap vaccination levels in pregnancy remain below desired levels, these data provide further reassurance regarding the current recommendations for Tdap vaccination in pregnancy.

Using the North Dakota IIS to Assess the Response of Health Care Providers to the ACIP Recommendation for Tdap Vaccination During Pregnancy.

OBJECTIVES: To evaluate the response of North Dakota health care providers to follow the recommendation set forth by the Advisory Committee on Immunization Practices (ACIP) to administer a dose of tetanus, diphtheria, and acellular pertussis (Tdap) vaccine to women during each pregnancy using the North Dakota Immunization Information System (NDIIS). METHODS: Data from the NDIIS for North Dakota infants born during calendar years 2013-2018 were extracted. Mother's name was taken from the newborn records and matched to NDIIS female client records to identify the population of mothers of newborns who would have been recommended to receive Tdap during their pregnancy. Doses of Tdap vaccine administered after October 1, 2012, were extracted from the NDIIS, and the dose records were matched back to the mother's record. The time from baby's birthdate back to the doses of Tdap vaccine administered to the mother was measured to find any doses that would have been administered during pregnancy. RESULTS: The percentage of women receiving Tdap vaccine during pregnancy increased from 31.5% in 2013 to 60.6% in 2018. Of those women who received Tdap during pregnancy, 94% received the vaccine during the ACIP-recommended interval of 27 to 36 weeks' gestation, using the assumption that all babies were born at 40 weeks' gestation. CONCLUSIONS: North Dakota health care providers have responded positively to the recommendation of the ACIP to administer a dose of Tdap vaccine to women during each pregnancy and have increased their administration of the vaccine to their patients.

[Adverse reactions after repeated doses of anti-tetanus vaccine: scientific evidences]. / Reazioni avverse dopo dosi ravvicinate di vaccino anti-tetanico nell'adulto: una ricerca sulle evidenze scientifiche.

The possible risk of hyperimmunization after tetanus vaccination is currently discussed after the National Vaccine Prevention Plan 2017-2019 confirmed the recommendation of a booster dose every ten years. Due to the ubiquitous nature of tetanus spores and the inability to obtain herd-immunity through vaccination, efforts to reduce the incidence of tetanus aim at eliminating the disease. The only way to prevent infection is vaccination followed by recommended periodic booster doses. Between 2012 and 2016, Italy notified 45% (252/564) of all cases reported by the 26 EU Member States, most of them in the over 65 age group, generally women in the rural areas. The recommendation of the antipertussis vaccine, combined with anti-tetanus, in pregnancy and the indications for antitetanic prophylaxis by vaccination or specific immunoglobulins in emergency setting, gives rise to doubts about the risk of hyperimmunization. Studies generally agree on the safety of diphtheria-tetanus-pertussis combined vaccines during the third trimester of pregnancy, and the time elapsed since the previous tetanus vaccination seems not to be related to significant differences in the incidence of adverse events or obstetrical complications. In the emergency wards, given the relatively high incidence of tetanus in Italy, the risk/benefit ratio often leads to prefer vaccination to no-intervention. The administration of tetanus immunoglobulins in subjects not vaccinated in the last 10 years seems justified by the epidemiology of tetanus in Italy.

Vacuna antitetánica adyuvada en alúmina en inmunización simultánea por vías mucosa y parenteral / Alum adjuvant tetanus vaccine in simultaneous immunization by mucosal and parenteral routes

El tétanos es causado por Clostridium tetani, bacteria Gram+ esporulada que produce una potente neurotoxina. Las vacunas parenterales producen IgG antitoxina tetánica (anti TT) protectores en múltiples dosis inductoras y de reactivación; vax-TET® es una vacuna cubana parenteral adsorbida en alúmina. La IgAS (secretora), principal anticuerpo protector mucoso, sólo es inducida por la vía mucosa. La vía oral, la inducción de IgA y su papel protector no han sido exploradas. SinTimVaS se aplica por vía mucosa y parenteral simultánea que induce IgG sistémica similares a la vía parenteral y adiciona de respuesta de IgA mucosa. Evaluamos el efecto de vax-TET® aplicado en SinTimVaS en ratones Balb/c y exploramos la influencia del adyuvante sobre la inducción de IgA anti TT. SinTimVaS indujo similares respuestas de IgG anti TT séricas que dos dosis de vax-TET® intramusculares; pero superiores a una dosis. Tres dosis de vax-TET® orales no indujeron IgG anti TT sérica, mientras que la adyuvación con el adyuvante Finlay Cocleato 1 (AFCo1) sí la indujeron. No se logró determinar la inducción de IgA anti TT mucosa con ninguna de las formulaciones adjuvadas con alúmina; pero si con la formulación AFCo1+TT. Podemos concluir que vax-TET® en SinTimVaS funcionó de forma similar a la inmunización parenteral establecida, por lo que sería posible reducir los esquemas multidosis con formulaciones de adyuvantes más potentes y se confirma que se requieren potentes adyuvantes para inducir IgA mucosa(AU)

Tetanus is caused by Clostridium tetani, a sporulated Gram+ bacterium that produces a potent neurotoxin. Parenteral vaccines produce protective tetanus antitoxin (anti TT) IgG in multiple induction and reactivation doses; vax-TET® is a Cuban parenteral vaccine adsorbed onto alumina. IgAS (secretory), the main mucosal protective antibody, is only induced by the mucous membrane. The oral route, the induction of IgA and its protective role have not been explored. SinTimVaS is applied by simultaneous mucosal and parenteral route that induces systemic IgG similar to the parenteral route and adds an IgA mucosal response. We evaluated the effect of vax-TET® applied in SinTimVaS in Balb/c mice and we explored the influence of adjuvant on the induction of anti-TT IgA. SinTimVaS induced similar serum anti TT IgG responses to two intramuscular doses of vax-TET®; but higher than one dose. Three doses of oral vax-TET® did not induce serum anti-TT IgG, whereas adjuvanted with adjuvant Finlay Cocleate 1 (AFCo1) did induce it. It was not possible to determine the IgA anti-TT mucous induction with any of the formulations adjuvanted with alumina; but with the formulation AFCo1 + TT it was induced. We can conclude that vax-TET® in SinTimVaS worked in a similar way to the established parenteral immunization, so it would be possible to reduce the multi-dose vaccination schemes with more potent adjuvant formulations and it is confirmed that powerful adjuvants are required to induce mucosal IgA(AU)

The Effect of Timing of Tetanus-Diphtheria-Acellular Pertussis Vaccine Administration in Pregnancy on the Avidity of Pertussis Antibodies.

Background: Optimal timing of gestational tetanus-diphtheria-acellular pertussis (Tdap) vaccination is not well-defined. No well-established specific anti-pertussis antibody level correlates with protection, suggesting the importance of antibody quality such as avidity. We aimed to determine the effect of timing of vaccination with Tdap in pregnancy on the avidity of cord anti-pertussis toxin (PT) immunoglobulin G (IgG). Methods: Prospective study of newborns in a tertiary hospital (Melbourne, Australia) born to women vaccinated with Tdap in pregnancy. Ammonium thiocyanate was used as a bond-breaking agent to measure the avidity of anti-PT IgG using concentrations between 0.25 M (to measure low avidity antibodies) and 3 M (to measure very high avidity antibodies). Anti-PT IgG levels achieved at each ammonium thiocyanate concentration in cord samples of women vaccinated during 28-32 weeks gestation (WG) vs. 33-36 WG, and women vaccinated 5-12 vs. 1-4 weeks prior to delivery were compared using t-tests. Results: Newborns of women vaccinated with Tdap during 28-32 WG (n = 43) had statistically significant higher concentrations of medium and high avidity anti-PT IgG compared with newborns of women vaccinated during 33-36 WG (n = 47), 11.6 IU/ml (95% CI, 8.8-15.2) IU/ml vs. 6.7 IU/ml (95% CI, 5.2-8.6) and 10.1 IU/ml (95% CI, 7.4-13.8) vs. 5.7 (95% CI, 3.6-8.9) IU/ml (p = 0.007 and p = 0.035), respectively. Newborns of women vaccinated 5-12 weeks before delivery (n = 64) had statistically significant higher concentrations of high and very high avidity anti-PT IgG compared with newborns of women vaccinated within 4 weeks before delivery (n = 25), 10.3 IU/mL (95% CI, 7.9-13.4) vs. 3.3 IU/mL (95% CI, 1.7-6.4), 12.6 IU/mL (95% CI, 9.4-16.9) vs. 4.3 IU/mL (95% CI, 2.2-8.5) (all p < 0.03), respectively. Conclusions: Quantification of levels of anti-PT IgG with different avidities demonstrated that pertussis vaccination 5-12 weeks before delivery was associated with higher anti-PT IgG avidity compared with vaccination within 4 weeks before delivery. Pertussis vaccination during 28-32 WG was associated with higher anti-PT IgG avidity compared with vaccination during 33-36 WG, supporting vaccination at 28-32 over 33-36 WG for optimal protection against pertussis in infancy.