Enhanced memory B-cell immune responses after a second acellular pertussis booster vaccination in children 9 years of age

Whooping cough has made its comeback and the incidence of pertussis in countries with widespread pertussis vaccination is most prominent in individuals above 9 years of age. To control the burden of infection, several countries already introduced acellular pertussis (aP) booster vaccination in adolescents and/or adults. However, antibody levels wane rapidly after vaccination even at older age. In this longitudinal study we investigated the effect of a second aP booster on the pertussis-specific memory B-cell immunity in children 9 years of age that have previously been vaccinated according to the national immunization program. Longitudinal blood samples were taken before, one month and one year after the booster. Purified B-cells were polyclonally stimulated and frequencies of memory B-cells were identified by ELISPOT-assays specific for various pertussis antigens. In addition, IgG levels and avidity indices were measured with fluorescent bead-based multiplex immunoassays.Starting with low pertussis-specific antibody and memory B-cell levels, a typical booster response was measured at one month after vaccination with increased antibody and memory B-cell responses. Although these responses declined slightly after one year, they substantially exceeded pre-booster levels and the avidity indices of the anti-pertussis antibodies remained high. Furthermore, high numbers of pertussis-specific memory B-cells at one-month post-booster correlate quite reliably with the corresponding high antibody response at one-year follow-up. In conclusion, booster vaccination in children 9 years of age induced an enhanced pertussis-specific memory immune response that sustained at least for one year. Therefore, this study supports the introduction of booster vaccination in older age groups.     

IgG responses after booster vaccination with different pertussis vaccines in Dutch children 4 years of age: Effect of vaccine antigen content

Since whooping cough is reemerging in the Netherlands from 1996 onwards, several changes in the national immunization program have been implemented regarding the pertussis vaccinations. The aim of this study is to investigate IgG responses in whole cell (wP) and acellular (aP) pertussis vaccine primed children following revaccination with different pertussis booster vaccines at 4 years of age. IgG levels to pertussis toxin (Pt), filamentous heamagglutin (FHA), pertactin (Prn) and fimbriae type 2 and 3 (Fim2/3) and avidities of Pt and Prn antibodies were measured using a multiplex immunoassay.     

Seroprevalence of pertussis among children in Eastern Turkey

The aim of this cross-sectional study was to determine the immunity status of children to pertussis by socio-demographic characteristics in Eastern Turkey. The study sample consisted of 840 randomly selected and healthy children aged 0-71 months. The seroprevalence of pertussis was 30.1%. Age, parent education and economic status were not associated with the geometric mean titers (GMT) of pertussis antibody, while gender, residential area and the application number of diphtheria-tetanus-whole-cell pertussis vaccine were associated with GMT. Most preschool children are susceptible to pertussis and current vaccination efforts do not provide adequate immunization.     

The impact of additional pertussis vaccine doses on disease incidence in children and infants

Background

Pertussis remains a cause of considerable morbidity in children worldwide. Due to the resurgence of the disease, two vaccine doses for schoolchildren were added to the routine Israeli schedule. In 2005 a 5th dose was introduced for second-graders (aged 7-8), and in 2008 an additional catch-up dose in the eighth grade (13-14 year-olds).

Methods

Population-based epidemiologic study of pertussis in the Jerusalem district.

Results

1736 pertussis cases were reported from 1990 to 2009. The pertussis incidence rates increased sharply from 2.6/100,000 in 1990, to 10/100,000 in 2000, peaking at 28.8/100,000 in 2006, then declining to 22/100,000 in 2008 and to 15.7 in 2009 (2006 vs. 2009, p = 0.0001). Most cases (74.4%, 1134/1524 during 1998-2009) were under 20 years. Infants under one year had the highest average incidence rate (72.3/100,000; 12.5% of cases); specifically those under 6 months (84.3% of cases under one year). The case distribution among 1-4, 5-9, 10-14, and 15-19 year-olds was: 11%, 18%, 24.1%, and 8.9%. The vaccination status (age-appropriate) was: unvaccinated - 19.2%, partially vaccinated - 7.6%, and fully vaccinated - 73.2%. The overall hospitalization rate was 5.4%; infants - 33.5%. Household transmission occurred in 16.1% of cases.The two age groups showing significant decline were children aged 5-9 (61.5% reduction) and 10-14 years (73.9% reduction); there is as yet no significant decline in other age groups.

Conclusions

The recent marked decline in pertussis incidence among the 5-14 year-olds is encouraging. Young infants still constitute a significant disease burden, and the incidence in this age group should be followed closely.     

An observational,cohort, multi-centre,open label phase IV extension study comparing preschool DTAP-IPV booster vaccine responses in children whose mothers were randomised to one of two pertussis-containing vaccines or received no pertussis-containing vaccine in pregnancy in England

An antenatal pertussis vaccination programme was introduced in 2012 in the UK in the context of a national outbreak of pertussis. It has been shown that a lower antibody response to primary immunisation can be seen for certain pertussis antigens in infants born to women who received pertussis-containing antenatal vaccines, a phenomenon known as blunting. The longer-term impact of this has not been documented previously, and accordingly was evaluated in this study.Children were predominantly recruited from a previous study in which their mothers had received acellular pertussis-containing antenatal vaccines (dTaP₃-IPV [diphtheria toxoid, tetanus toxoid, three antigen acellular pertussis and inactivated polio] or dTaP₅-IPV [diphtheria toxoid, tetanus toxoid, five antigen acellular pertussis and inactivated polio]), or no pertussis-containing vaccine. Blood samples were obtained prior to and one month after the acellular pertussis-containing preschool booster (dTaP₅-IPV) was given at around age 3 years 4 months. Pre- and post-booster immunoglobulin G (IgG) geometric mean concentrations (GMCs) against pertussis toxin, filamentous haemagglutinin, fimbriae 2 & 3, and pertactin, were compared.Prior to the receipt of the preschool booster, there was no difference in the IgG GMCs against pertussis-specific antigens between children born to women vaccinated with dTaP₃-IPV and dTaP₅-IPV; however, IgG GMCs against pertussis toxin were significantly lower in children born to women vaccinated with dTaP₃-IPV compared with children born to unvaccinated women (geometric mean ratio 0.42 [95 % CI 0.22–0.78], p = 0.03). One month after the receipt of the preschool booster there was no differences between the groups.The blunting effect of antenatal pertussis vaccine on pertussis responses in children can persist until preschool age, although it is overcome by the administration of a booster dose.ClinicalTrials.gov registration number: NCT03578120     

Identifying long-term memory B-cells in vaccinated children despite waning antibody levels specific for Bordetella pertussis proteins

Whooping cough is a respiratory disease caused by Bordetella pertussis. Since the 1950s in developed countries pertussis vaccinations are included in the national immunization program. However, antibody levels rapidly wane after both whole cell and acellular pertussis vaccination. Therefore protection against pertussis may depend largely on long-term B- and T-cell immunities. We investigated long-term pertussis-specific memory B-cell responses in children who were primed at infant age with the Dutch wP-vaccine (ISRCTN65428640). Purified B-cells were characterized by FACS-analysis and after polyclonal stimulation memory B-cells were detected by ELISPOT-assays specific for pertussis toxin, filamentous haemagglutinin, pertactin and tetanus. In addition, plasma IgG levels directed to the same antigens were measured by a fluorescent bead-based multiplex immunoassay. Two and 3 years after wP priming as well as 2 and 5 years after the aP booster at the age of 4, low plasma IgG levels to the pertussis proteins were found. At the same time, however pertussis protein-specific memory B-cells could be detected and their number increased with age. The number of tetanus-specific memory B-cells was similar in all age groups, whereas IgG-tetanus levels were high 2 years after tetanus booster compared to pre- and 5 years post-booster levels. This study shows the presence of long-term pertussis protein-specific memory B-cells in children despite waning antibody levels after vaccination, which suggests that memory B-cells in addition to antibodies may contribute to protection against pertussis.     

Different IgG-subclass distributions after whole-cell and acellular pertussis infant primary vaccinations in healthy and pertussis infected children

The distribution of IgG-subclasses provides insight in the immunological mechanisms of protection against whooping cough. We investigated the effect of Dutch whole-cell pertussis and acellular pertussis vaccines administered in infancy on the IgG-subclass distributions in healthy children aged 12 months, 4 years and 9 years as well as in children who have been infected with Bordetella pertussis.A fluorescent bead-based multiplex immunoassay was used for the measurement of IgG1, IgG2, IgG3 and IgG4 responses against pertussis toxin, filamentous heamagglutinin and pertactin.Although IgG1 was the predominant subclass for all pertussis antigens in both healthy and infected children, elevated IgG4 levels were only present in children who had received repeated number of acellular pertussis vaccinations. IgG2 and IgG3 antibodies did not contribute to the IgG response. No differences in IgG-subclasses between healthy vaccinated or infected children were found.The pertussis vaccine used for priming seems to determine the IgG-subclass composition elicited after a secondary antibody response either induced by pertussis vaccination or infection. The pronounced anti-pertussis IgG4 response might reflect the Th2-skewing of the immune response after aP vaccination.     

Determination of serum neutralizing antibodies reveals important difference in quality of antibodies against pertussis toxin in children after infection

ObjectivesTo determine neutralizing antibodies to pertussis toxin (PTNAs) in children with suspected pertussis and to compare results of PTNAs and anti-PT IgG antibodies.Methods172 hospitalized children with suspected pertussis were included. Pertussis was confirmed by culture, PCR and/or serology. PTNAs were determined by Chinese hamster ovary (CHO) cell assay.ResultsA correlation between titers of PTNAs and anti-PT IgG levels was noticed in 172 patients (Spearman R = 0.68, P < 0.001). Subjects with same concentrations of anti-PT IgG antibodies could have different titers of PTNAs and the maximum difference observed reached to 1024 times in ELISA-confirmed patients. Moreover, subjects with same titers of PTNAs could have different concentrations of anti-PT IgG antibodies.ConclusionsOur results indicated that in some children high concentrations of anti-PT IgG antibodies do not always mean effective PTNAs induced after infection, stressing the importance of detecting PTNAs after infection and vaccination.Clinical trial registry: Not applicable.     

A decennial booster dose of reduced antigen content diphtheria, tetanus, acellular pertussis vaccine (Boostrix™) is immunogenic and well tolerated in adults

Reduced-antigen-content diphtheria-tetanus-acellular-pertussis (dTpa) vaccines are predominantly recommended for once-in-a-lifetime use. A second dTpa (Boostrix™, GlaxoSmithKline Biologicals) administration in 164 adults previously vaccinated with dTpa 10 years previously was evaluated. Before the decennial booster, 89.4% and 94.8% subjects were seroprotected (antibodies ≥0.1 IU/mL) for diphtheria and tetanus, respectively. One-month post-booster, all subjects were seroprotected/seropositive against all vaccine antigens. Robust GMC increases indicated a booster response similar to the first booster. The decennial booster was well tolerated without serious adverse events, consistent with product experience. This study supports replacing traditional Td boosters with dTpa, and use of Boostrix™ as a decennial booster.This study is registered at www.clinicaltrials.comNCT00548171.     

Impact of infant and preschool pertussis vaccinations on memory B-cell responses in children at 4 years of age

Whooping cough, caused by Bordetella pertussis, is reemerging in the vaccinated population. Antibody levels to pertussis antigens wane rapidly after both whole-cell (wP) and acellular pertussis (aP) vaccination and protection may largely depend on long-term B- and T-cell immunity. We studied the effect of wP and aP infant priming at 2, 3, 4 and 11 months according to the Dutch immunization program on pertussis-specific memory B-cell responses before and after a booster vaccination with either a high- or low-pertussis dose vaccine at 4 years of age.Purified B-cells were characterized by FACS-analysis and after polyclonal stimulation, memory B-cells were detected by ELISPOT-assays specific for pertussis toxin, filamentous haemagglutinin and pertactin.Before and after the booster, higher memory B-cell responses were measured in aP primed children compared with wP primed children. In contrast with antibody levels, no dose-effect was observed on the numbers of memory B-cell responses. In aP primed children a fifth high-dose aP vaccination tended to induce even lower memory B-cell responses than a low-dose aP booster. In both wP and aP primed children, the number of memory B-cells increased after the booster and correlated with the pertussis-specific antibody concentrations and observed affinity maturation.This study indicates that aP vaccinations in the first year of life induce higher pertussis-specific memory B-cell responses in children 4 years of age compared with Dutch wP primary vaccinations. Since infant aP vaccinations have improved protection against whooping cough in children despite waning antibody levels, this suggests that an enhanced memory B-cell pool induction may have an important role in protection. However, the pertussis-dose of the preschool booster needs to be considered depending on the vaccine used for priming to optimize long-term protection against whooping cough.     

Invasive pneumococcal disease in Singapore children

INTRODUCTION: Our retrospective study examined community-acquired invasive pneumococcal disease (IPD) in children admitted to KK Women's and Children's Hospital, Singapore. METHODS: All pneumococcal isolates from sterile sites from 1997 to 2004 were surveyed. RESULTS: There were 147 positive pneumococcal isolates with a mean age of 45 months. The estimated incidence of IPD was 13.6 per 10(5) children under 5 years old. Diagnoses at presentation were: Pneumonia 63.3% (included 14.3% empyema), bacteremia 17%, meningitis 15.6% (included 2.8% meningitis and pneumonia), 4.1% others. The morbidity rate was 25.2%, mortality rate was 6.1%. Antibiotic resistance was: Penicillin 44%, ceftriaxone 15%, erythromycin 62%, trimethoprim-sulfamethoxazole 67%. A separate serotype analysis (n=93, 63%) showed that the current 7valent pneumococcal conjugate vaccine (PCV7) would cover 78.1% of vaccine serotypes and 89% of vaccine-related serotypes for children under 5 years old.     

Fully vaccinated children are rare: immunization coverage and seroprevalence in Austrian school children

Vaccination coverage for vaccine-preventable diseases in Austria as well as in many Central European countries has been reported to be too low to eradicate such diseases and prevent further outbreaks. Austria lacks an adequate surveillance system to monitor prevalence of the diseases, the vaccination coverage and seroconversion. School children aged 10–14 years (n = 1077) were recruited in all four schools in the city of Schwaz, Austria, to present their vaccination documents and to give blood for serological testing (diphtheria, pertussis, measles, mumps, rubella, varicella). All participants received a report with a personal guideline for (re-) vaccination. Overall vaccination coverage was 86.4% for measles, 85.5% for mumps and 35.0% for rubella. Tetanus vaccination coverage was 98.4% for the first, 97.8% for the second and 96.7% for the third dose, while 55.4% of the study subjects received the recommended two booster injections. For diphtheria the corresponding vaccination coverage was found to be almost identical. Pertussis coverage was lower in general (first dose: 90.9%; second dose: 89.0%; third dose: 86.5%). Oral poliomyelitis vaccination showed a coverage of 98.6, 96.5, 95.3%, with 78.7% receiving the fourth dose. Overall 38.7% were classified as fully vaccinated. Seropositivity for measles was found in 90.4%, for mumps in 61.8%, for rubella in 82.3%, for diphtheria in 65.8%, for pertussis in 35.6% and for varicella in 95.0%. In summary, fully vaccinated children are rare and intensive public health efforts will be necessary to reach higher levels of immunity and prevent further outbreaks.     

微生态制剂治疗小儿腹泻病的疗效观察

目的 探讨微生态制剂对小儿腹泻病的影响.方法 选取68例腹泻患儿,随机分成治疗组34例和对照组34例,治疗组在常规治疗方案基础上,同时给予微生态制剂;对照组给予一般常规治疗.结果 同时应用微生态制剂治疗组疗效明显优于对照组(x2=10.846,P＜0.01).平均腹泻消失时间和平均住院时间均明显少于对照组(t=3.265,t=2.663,P＜0.05).结论 微生态制剂尤其是益生菌应用于腹泻病的预防和治疗起到协同作用.     

Assessing adolescent immunization options for pertussis in Canada: A cost-utility analysis

BackgroundAdolescent tetanus, diphtheria and pertussis (Tdap) immunization helps prevent pertussis infection. Timing of Tdap receipt represents an important facet of successful adolescent pertussis immunization. Potential strategies for timing of vaccine administration are each associated with different benefits – including disease prevention – and costs. The objective of this study was to assess the cost-utility of adolescent pertussis immunization strategies in Canada.MethodsA cost-utility analysis was conducted using a pertussis disease history-simulating Markov model, with adolescents (beginning at age 10 years) as the cohort of interest. The model assessed three Tdap vaccination strategies: (1) immunization of 10 year olds, (2) removal of adolescent vaccination, and (3) immunization of 14 year olds (status quo). The analysis was conducted from a healthcare payer perspective and used a lifetime time horizon. Primary outcomes included life years, quality-adjusted life years (QALYs), health system costs, and an incremental cost-effectiveness ratio (ICER). Costs and outcomes were discounted at 1.5 percent annually. Deterministic and probabilistic sensitivity analyses were performed to assess parameter uncertainty.ResultsThe current recommended adolescent immunization strategy (at age 14) resulted in an average of 40.4432 expected QALYs and $26.28 per individual. This strategy was dominated by immunization at 10 years and no immunization. Compared to no immunization, immunizing adolescents at age 10 had an ICER of $74,899 per QALY. Results were most sensitive to the incidence of pertussis and the utility of moderate or severe pertussis. At a cost-effectiveness threshold of $50,000/QALY, removal of adolescent vaccination represented the most cost-effective strategy in 78% of simulations.ConclusionAnalysis assumes a policy context where immunization of pregnant women is recommended. Findings suggest that alternate adolescent Tdap vaccine strategies – either immunization of 10 year olds, or removal of the adolescent vaccine – are more cost-effective than the current practice of immunizing 14 year olds.     

Pertussis vaccine for adults: Knowledge,attitudes, and vaccine receipt among adults with children in the household

BackgroundPertussis is a highly contagious vaccine preventable disease resulting in significant infant morbidity and mortality. Despite the recommendations for pertussis vaccine (Tdap) in adults, coverage rates in this age group remain suboptimal. We sought to determine factors associated with Tdap receipt among adults with children in the household who live in central New York.MethodsThe study team surveyed Tdap immunization status of adults who accessed medical services for their children provided by Golisano Children's Hospital, Syracuse, New York. Adults who did not know their Tdap vaccine status were excluded. Each participant was asked a standard set of questions to determine factors associated with Tdap receipt. Logistic regression was used to calculate simple and adjusted odds ratios for Tdap receipt in relation to adults’ demographic characteristics, knowledge of Tdap and physician recommendations.ResultsEight hundred twenty four participants were included in this study; 34% had received Tdap in the past 5 years; 58% reported that their provider or child's pediatrician recommended adult Tdap vaccination. Tdap receipt was associated with knowing the symptoms of pertussis infection, female gender, younger age, and provider recommendation (p < 0.05). Participants whose provider recommended Tdap vaccine were 24.6 times more likely to receive vaccine when compared to those whose providers did not recommend vaccine (95% CI: 16.3, 37.2, p < 0.05).ConclusionTdap coverage rates are low among this study population, with provider recommendation most strongly associated with Tdap receipt. Future steps to improve vaccine coverage should include both increasing community awareness and determining barriers to provider recommendation.     

The safety and reactogenicity of a reduced-antigen-content diphtheria-tetanus-acellular pertussis (dTpa) booster vaccine in healthy Vietnamese children

Despite effective infant immunization against pertussis, the disease continues to circulate due to waning immunity. Booster vaccinations against pertussis beyond infancy are widely recommended. In Vietnam, however, no recommendations for pertussis boosters beyond the second year of life exist. This open-label, single-centre study was designed to assess the safety of a single booster dose of reduced-antigen-content-diphtheria-tetanus-acellular-pertussis vaccine (dTpa) in 300 healthy Vietnamese children (mean age 7.9 years), who had completed primary vaccination against diphtheria, tetanus and pertussis. Solicited symptoms were recorded for 4 days and unsolicited and serious adverse events (SAEs) for 31 days post-vaccination. Pain and fatigue were the most common solicited local and general symptoms in 35.0% and 14.0% of children, respectively. Grade 3 swelling occurred in 3 children; no large injection site reactions or SAEs were reported. The dTpa booster vaccine was well tolerated and this study supports its administration in school age Vietnamese children.     

Immunogenicity and reactogenicity of co-administered tetanus-diphtheria-acellular pertussis (Tdap) and tetravalent meningococcal conjugate (MCV4) vaccines compared to their separate administration

In the United States, co-administration of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis (Tdap) vaccine and tetravalent meningococcal conjugate vaccine (MCV4) is recommended in adolescents. In this clinical study, 1341 adolescents received Tdap (Boostrix® GlaxoSmithKline) and MCV4 (Menactra®, Sanofi-Pasteur) simultaneously or sequentially one month apart. Co-administration of Tdap + MCV4 was well tolerated and immunogenic, resulting in high levels of antibodies against diphtheria, tetanus, pertussis and meningococcal serogroup A,C,W-135 and Y antigens. The data provide support for current recommendations for co-administration of Tdap and MCV4 vaccines at the same office visit.     

Epidemiology of pertussis in a country with high vaccination coverage

Introduction

Pertussis has been a preventable disease in Catalonia since 1965, but the annual number of cases remains high. The aim of this study was to analyze the epidemiology of pertussis in Catalonia and its implications for control purposes.

Methods

An epidemiological study was carried out in Catalonia between 2004 and 2008. Pertussis cases reported to the Department of Health were collected and disease reports were filled out with the case information. Incidence rates, rate ratios (RR) and their 95% confidence intervals (CI) were calculated.

Results

963 cases were reported: 555 (57.6%) were confirmed and 408 (42.4%) were suspected cases. The reported incidence rate was 2.01 × 10⁻⁵ person years in 2004 and 4.34 in 2008. The biggest increase in cases between 2004 and 2008 was observed in the ≥35 years age group (RR: 6.98; 95%CI: 2.11-36.36). 303 (31.5%) patients were hospitalized, of whom 93.7% were aged <1 year. Clinical differences were observed in paroxysmal cough (83.8% in suspected and 76.4% in confirmed cases, p = 0.005), posttussive vomiting (47.1% and 36.1%, respectively, p = 0.001), apnoea (13.7% and 21.3%, respectively, p = 0.003) and fever (20.1% and 12.4%, respectively, p = 0.001).

Conclusion

Pertussis incidence rates increased during the study period, with the greatest increase occurring in the ≥35 years age group. A booster dose of vaccine in young people could reduce the circulation of B. pertussis in adolescents and adults and indirectly reduce the incidence in children.     

Seroepidemiology of pertussis infection in an urban childhood population in Cameroon

In 1989, the prevalence of IgG antibodies to pertussis toxin (PT) in a sample of 367 unvaccinated apparently healthy children 5–14 years old was estimated by ELISA in Kumba City (Cameroon). Children were recruited using a systematic random sampling from six primary schools located in different districts of the city. The sample was representative of the various socio-economic classes.The overall prevalence was 75%; it increased from 62% in 5 year old children to 81% in children 12–14 years old (P < 0.01). IgG antibody prevalence was positively related to the family size. Children belonging to households of nine or more members had a 2.2-fold risk (C.I. 95 per cent =1.1–4.6) of previous exposure to B. pertussis infection. No association was found with the father's occupation (O.R. = 1). These findings demonstrate a great impact of pertussis infection in Cameroon, with a nearly total exposure by late childhood.Corresponding author.