Acellular Pertussis Booster Vaccine Research Articles

A novel whole blood assay to quantify the release of T cell associated cytokines in response to Bordetella pertussis antigens

BackgroundBordetella pertussis continues to cause whooping cough globally even in countries with high immunisation coverage. Booster vaccinations with acellular pertussis vaccines are thus used in children, adolescents, and adults. T cell immunity is crucial for orchestrating the immune response after vaccination. However, T cell assays can be expensive and difficult to implement in large clinical trials. In this study, a whole blood (WB) stimulation assay was developed to identify secreted T cell associated cytokines in different age groups after acellular pertussis booster vaccination. Material and methodsLongitudinal WB samples were collected from a small set of subjects (n = 38) aged 7–70 years participating in a larger ongoing clinical trial. For assay development, samples were diluted and incubated with purified inactivated pertussis toxin (PT), filamentous haemagglutinin (FHA), inactivated B. pertussis lysate, and complete medium (M) as stimulating conditions, with anti-CD28 and anti-CD49d as co-stimulants. Different timepoints around the vaccination (D0, D7, D14, D28), WB dilution factor (1:2, 1:4) and incubation time (24 h, 48 h, 72 h) were compared. Responses to 15 cytokines were tested with Luminex/multiplex immunoassay. ResultsThe optimized assay consisted of WB incubation with M, PT, and FHA (including the two co-stimulants). After 48 h incubation, supernatants were collected for measurement of seven selected T cell associated cytokines (IL-2, IL-5, IL-10, IL-13, IL-17 A, IL-17F, and IFN-y) from samples before and 28 days after vaccination. PT stimulation showed a trend for upregulation of IL-2, IL-13, and IL-17 A/F for adult subjects, whereas the responses of all cytokines were downregulated for the paediatric subjects. Furthermore, PT and FHA-stimulated WB showed diverse cytokine producing profiles. ConclusionsThe developed WB-based cytokine assay was shown to be less costly, easy to perform, and functional in differently aged individuals. Further, it requires only a small amount of fresh blood, which is beneficial especially for studies including infants. Our results support the use of this assay for other immunological studies in the future.

Safety and immunogenicity of an indigenously developed tetanus toxoid, diphtheria toxoid, and acellular pertussis vaccine (Tdap) in adults, adolescents, and children in India

ABSTRACTBackgroundThis study assessed safety and immunogenicity of Serum Institute of India Pvt Ltd (SIIPL)’s tetanus toxoid (TT), diphtheria toxoid (DT), and acellular pertussis booster vaccine (Tdap).Research Design and MethodsIn this Phase II/III, multicenter, randomized, active-controlled, open-label study, 1500 healthy individuals, aged 4–65 years, were randomized to receive a single dose of SIIPL Tdap or comparator Tdap vaccine (Boostrix®; GlaxoSmithKlines, India). Adverse events (AEs) during initial 30 minutes, 7-day, 30-day post-vaccination were assessed. Blood samples were taken before and 30 days post-vaccination for immunogenicity assessment.ResultsNo significant differences in incidence of local and systemic solicited AEs were observed between the two groups; no vaccine-related serious AEs were reported. SIIPL Tdap was non-inferior to comparator Tdap in achieving booster responses to TT and DT in 75.2% and 70.8% of the participants, respectively, and to pertussis toxoid (PT), pertactin (PRN), and filamentous hemagglutinin (FHA) in 94.3%, 92.6%, and 95.0% of the participants, respectively. Anti-PT, anti-PRN, and anti-FHA antibody geometric mean titers in both the groups, were significantly higher post-vaccination compared to pre-vaccination.ConclusionsBooster vaccination with SIIPL Tdap was non-inferior to comparator Tdap with respect to immunogenicity against tetanus, diphtheria, and pertussis and was well tolerated.

Prior exposure to B. pertussis shapes the mucosal antibody response to acellular pertussis booster vaccination

Bordetella pertussis (Bp), the causative agent of pertussis, continues to circulate despite widespread vaccination programs. An important question is whether and how (sub)clinical infections shape immune memory to Bp, particularly in populations primed with acellular pertussis vaccines (aP). Here, we examine the prevalence of mucosal antibodies against non-vaccine antigens in aP-primed children and adolescents of the BERT study (NCT03697798), using antibody binding to a Bp mutant strain lacking aP antigens (Bp_mut). Our study identifies increased levels of mucosal IgG and IgA binding to Bp_mut in older aP-primed individuals, suggesting different Bp exposure between aP-primed birth cohorts, in line with pertussis disease incidence data. To examine whether Bp exposure influences vaccination responses, we measured mucosal antibody responses to aP booster vaccination as a secondary study outcome. Although booster vaccination induces significant increases in mucosal antibodies to Bp in both cohorts, the older age group that had higher baseline antibodies to Bp_ mut shows increased persistence of antibodies after vaccination.

Whole blood based point-of-care assay for the detection of anti-pertussis toxin IgG antibodies

Current serological diagnosis of pertussis is usually done by ELISA to determine serum specific anti-pertussis toxin (PT) IgG antibodies. However, the ELISAs are often central-laboratory based, require trained staff, and have long turnaround times. A rapid point-of-care (POC) assay for pertussis serology would aid in both diagnosis and surveillance of the disease. In this study, a quantitative lateral flow assay (LFA) with fluorescent Eu-nanoparticle reporters was used for the detection of anti-PT antibodies from whole blood. The assay was evaluated by testing overall 141 samples including 25 before and 116 one month after acellular pertussis booster vaccination. LFA results were compared to those obtained with standardized anti-PT IgG ELISAs with paired serum samples. Correlation between the assays was high (Pearson R = 0.832), and the achieved analytical sensitivity of the LFA was 29 IU/mL, which would be sufficient for clinically relevant cutoffs for determining recent infections. The paired samples, collected pre- and post-booster, demonstrated a significant increase in anti-PT IgG antibodies similar to that detected by ELISA. The developed LFA opens up several alternatives for a suitable POC test also in middle- and low-income countries.

Age and Primary Vaccination Background Influence the Plasma Cell Response to Pertussis Booster Vaccination.

Pertussis is a vaccine-preventable disease caused by the bacterium Bordetella pertussis. Over the past years, the incidence and mortality of pertussis increased significantly. A possible cause is the switch from whole-cell to acellular pertussis vaccines, although other factors may also contribute. Here, we applied high-dimensional flow cytometry to investigate changes in B cells in individuals of different ages and distinct priming backgrounds upon administration of an acellular pertussis booster vaccine. Participants were divided over four age cohorts. We compared longitudinal kinetics within each cohort and between the different cohorts. Changes in the B-cell compartment were correlated to numbers of vaccine-specific B- and plasma cells and serum Ig levels. Expansion and maturation of plasma cells 7 days postvaccination was the most prominent cellular change in all age groups and was most pronounced for more mature IgG1+ plasma cells. Plasma cell responses were stronger in individuals primed with whole-cell vaccine than in individuals primed with acellular vaccine. Moreover, IgG1+ and IgA1+ plasma cell expansion correlated with FHA-, Prn-, or PT- specific serum IgG or IgA levels. Our study indicates plasma cells as a potential early cellular marker of an immune response and contributes to understanding differences in immune responses between age groups and primary vaccination backgrounds.

Corrigendum to ‘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’

Acknowledgements We thank all participants of the study and we acknowledge the work of all individuals at the Oxford Vaccine Group, the Turku University group, the Dutch Spaarne Hospital and RIVM who have undertaken the work of the BERT study including the administrative staff, play assistants, clinical research nurses, clinical research fellows, laboratory staff and members of the IT team. In particular, we acknowledge Jacqueline Zonneveld and Greetje van Asselts at the Spaarne Gasthuis Hospital, Hoofddorp, the Netherlands for their help in the management of clinical data and performing home visits. We are also grateful to Inge Pronk and Eleonora Lambert, who both work at the Centre for Infectious Disease Control, RIVM for their assistance in clinical trial management. PERISCOPE has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115910. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA and BMGF. DFK receives salary for support from the NIHR Oxford Biomedical Research Centre. 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 KingdomAcellular 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. Full-Text PDF Open Access

Adequate 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. In addition older adults and patients with chronic diseases are more vulnerable to complications. In high-income countries, priming vaccination in infancy is usually undertaken using acellular pertussis vaccines. There is a significant between-country variation in the use of booster vaccinations which are administered at different ages and to different target populations. We investigated the effect of age on the response to acellular pertussis booster vaccination in three European countries. Methods: In total 379 participants, divided between four age groups - children (7-10y), adolescents (11-15y), young adults (20-34y), and older adults (60-70y) - received a pertussis toxoid, filamentous haemagglutinin, and pertactin containing booster vaccine. Serum IgG and IgA antibody concentrations to pertussis vaccine antigens at day 0, day 28, and one year were measured with a multiplex immunoassay. Findings: Participants from all four age groups showed high IgG antibodies to pertussis toxin at day 28. IgG antibody concentrations at 28 days and one year postvaccination were comparable between the age groups, but IgA concentrations showed an increase of antibody concentrations with age at all timepoints. Interpretation: Acellular pertussis booster vaccination induces comparable serological responses in older adults as younger age groups and could be considered for older adults in order to increase their protection. Trial Registration: The trial was registered at the EU Clinical Trial database (EudraCT number 2016-003678-42). Funding: PERISCOPE has received funding from the Innovative Medicines Initiative2 Joint Undertaking under grant agreement No 115910. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme, EFPIA and BMGF. Declaration of Interests: None of the authors received payment or service from a third part at any time, nor does anyone have a financial relationship with entities in the bio-medical arena. None of the authors have any patents relevant to the work. MVP is a member of the Portuguese National Immunisation Technical Advisory Group (Comissao Tecnica de Vacinacao da Direccao Geral de Saude). Ethics Approval Statement: The trial was approved by the Medical Research Ethics Committees United (MEC-U, NL60807.100.17-R17.039) in the Netherlands, the South Central - Hampshire B Research Ethics Committee (REC, 19/SC/0368) in the UK, and the MREC UTU (ETMK Dnro: 129/1800/2017) in Finland. Written informed consent was obtained from all adult participants, and parents or legal guardian of minors, at the start of the study.

Pertussis specific cell-mediated immune responses ten years after acellular pertussis booster vaccination in young adults

BackgroundOne of the reasons for pertussis resurgence is waning immunity. Both humoral and cell mediated immunity (CMI) are essential for protection. The aim of this study was to evaluate CMI responses after acellular pertussis vaccination in young adults. MethodsFifty-seven young adults were followed for ten years after a diphtheria-tetanus acellular pertussis (dTpa) booster vaccination. A second booster was administrated at year 10. CMI was determined from peripheral blood mononuclear cells (PBMC) stimulated with vaccine antigens pertussis toxin (PT), filamentous hemagglutinin (FHA) and pertactin (PRN) before and one month after the second vaccination, using proliferation and IFN-γ and IL-17 ELISpot. In addition, the response to ten selected cytokines was measured from 14 subjects. ResultsBefore the booster dose, positive proliferation was recognized in 51%, 53% and 89% of the subjects against PT, PRN and FHA, respectively. One month after, the positivity rate increased to 81%, 81% and 96%. Although the number of IFN-γ and IL-17 secreting cells was increased, the expression of most of the tested cytokines was found to be downregulated. After PT stimulation, only one (7.1%) subject had increased production in all cytokines, whereas six (42.9%) had decreased production of all cytokines. Ten subjects (71.4%) had decreased concentration of IFN-γ, the cytokine important for pertussis protection. ConclusionsCMI persists even when antibodies have decayed, and acellular pertussis vaccine enhances the CMI response. Further studies are needed to illustrate what factors cause the low production of some important cytokines.

Pertussis, a Disease Whose Time Has Come

In the United States, major epidemics of pertussis or whooping cough have occurred in the last 5 years making this disease a major public health issue. The adolescent and adult populations are the major transmitters of disease to the community. However, these epidemics have had the greatest effect on the young infant population resulting in high rates of hospitalizations and complications and accounting for 100% of the mortality. Optimization of vaccine recommendations is a strategy that is critically important as a method to control the disease burden and decrease the transmission of disease to the young infant population. Immunization that is focused on the close contacts of these young infants (the cocoon strategy) is felt to be one of the main cornerstones to vaccine optimization with the immunization of pregnant women being critical. Transmission studies have shown that adolescent and adult close contacts, especially new mothers, are the source of disease transmission to their young infants in more than 50% of the cases. The Centers for Disease Control and Prevention and the American College of Obstetricians and Gynecologists strongly recommend that the tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis booster vaccine be given to pregnant women during each pregnancy between 27 weeks and 36 weeks of gestation to protect their infant against pertussis disease.

Differences in avidity of IgG antibodies to pertussis toxin after acellular pertussis booster vaccination and natural infection

BackgroundPertussis toxin (PT) is a specific virulence factor of Bordetella pertussis and it is included in all acellular pertussis vaccines (aP). Although immunity after infection seems to persist longer than that after vaccination, the exact mechanism(s) is not known. Primary aim of this study was to develop an ELISA method for measuring avidity index (AI) of IgG-anti-PT antibodies and to compare antibody responses after booster vaccination and infection. Secondary aim was to evaluate if the AI-ELISA has potential in the serodiagnosis of pertussis. MaterialSerum samples from a total of 409 subjects were included in the study. Paired sera were taken from 97 adolescents who received booster vaccine ten years ago (dTpa-004) and from 80 young adults who received a second booster dose ten years after the previous booster vaccine (dTpa-040). Thirty-two paired sera from culture-confirmed pertussis patients, 161 single sera from serologically diagnosed patients and 39 single sera from healthy controls were included. AI of IgG-anti-PT antibodies were determined with newly developed ELISA using diethylamine (DEA) as a bond breaking agent. The IgG-anti-PT antibodies were measured by standardized ELISA. ResultsA significant increase was found in antibody concentrations and AI between PRE and one month POST vaccination ten years ago [GMC for antibody: 7.9IU/ml vs. 98.3IU/ml (p=0.0001); for AI: 40.4% vs. 56.1% (p=0.0001)]. Similar result was observed after the second booster dose [GMC for antibody: 9.2IU/ml vs. 92.4IU/ml (p=0.0001); for AI: 36.1% vs. 59.5% (p=0.0001)] and between the first and second sera of culture-confirmed patients [GMC for antibody: 6.9IU/ml vs. 285.1IU/ml (p=0.0001); for AI: 40.5% vs. 68.4% (p=0.0001)]. Healthy controls showed lower levels of both antibodies and AI. ConclusionsOur results suggest that there may be difference in quality and quantity of antibodies to PT after vaccination and after infection. Furthermore, AI could be a help for vaccine studies.

Pertussis Circulation Has Increased T-Cell Immunity during Childhood More than a Second Acellular Booster Vaccination in Dutch Children 9 Years of Age

Here we report the first evaluation of T-cell responses upon a second acellular pertussis booster vaccination in Dutch children at 9 years of age, 5 years after a preschool booster vaccination. Blood samples of children 9 years of age were studied longitudinally until 1 year after the second aP booster and compared with those after the first aP booster in children 4 and 6 years of age from a cross-sectional study. After stimulation with pertussis-vaccine antigens, Th1, Th2 and Th17 cytokine responses were measured and effector memory cells (CCR7-CD45RA-) were characterized by 8-colour FACS analysis. The second aP booster vaccination at pre-adolescent age in wP primed individuals did increase pertussis-specific Th1 and Th2 cytokine responses. Noticeably, almost all T-cell responses had increased with age and were already high before the booster vaccination at 9 years of age. The enhancement of T-cell immunity during the 5 year following the booster at 4 years of age is probably caused by natural boosting due to the a high circulation of pertussis. However, the incidence of pertussis is high in adolescents and adults who have only received the Dutch wP vaccine during infancy and no booster at 4 years of age. Therefore, an aP booster vaccination at adolescence or later in these populations might improve long-term immunity against pertussis and reduce the transmission to the vulnerable newborns.Trial RegistrationControlled-Trials.com ISRCTN64117538

Gene Polymorphism in Toll-like Receptor 4: Effect on Antibody Production and Persistence After Acellular Pertussis Vaccination During Adolescence

Toll-like receptors play an important role in the regulation of adaptive immunity. This study aimed to investigate whether Toll-like receptor 4 (TLR4) polymorphisms influence the production and persistence of antibodies after acellular pertussis booster vaccination during adolescence. Seventy-five subjects received a single dose of diphtheria and tetanus toxoids and acellular pertussis vaccine 10 years ago, during adolescence. The same cohort was followed up at 3, 5, and 10 years after this booster vaccination. Pyrosequencing was used for detecting polymorphism in TLR4. Concentrations of anti-pertussis vaccine antibodies were measured by standardized enzyme-linked immunosorbant assay and published elsewhere. The fold increase in antibodies to pertussis toxin after original vaccination 10 years ago was significantly lower in subjects with TLR4 polymorphism than in those without (55% vs 86%; P = .028). At the 3-year follow-up evaluation, geometric mean concentrations of anti-pertussis vaccine antibodies were significantly lower in subjects with TLR4 polymorphism, compared with those without the polymorphism (for pertussis toxin, P = .028; for filamentous hemagglutinin, P = .047; and for pertactin, P = .046). This study suggests that TLR4 Asp299Gly polymorphism might influence production and persistence of antibodies after pertussis booster vaccination in adolescents. However, the results should be interpreted with caution as the number of subjects included in this study was limited.

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.

Effect of a Prepregnancy Pertussis Booster Dose on Maternal Antibody Titers in Young Infants

To examine the influence of a pertussis booster vaccination on the transfer of maternal antibodies, 24 nonpregnant women received a tetanus, diphtheria, acellular pertussis booster vaccine between 2 consecutive pregnancies. Blood was drawn from mothers and off-spring. Efficient transplacental antibody transfer and significantly higher antibody titers against 3 pertussis antigens were observed in cord blood and in blood of 1-month-old infants born after a maternal booster vaccination compared with results in their siblings born before the booster administration.

Keeping Vulnerable Children Safe from Pertussis Preventing Nosocomial Pertussis Transmission in the Neonatal Intensive Care Unit

To examine the impact of different acellular pertussis booster vaccination strategies on the probability of a nosocomial pertussis outbreak occurring and the distribution of outbreak sizes observed for each intervention strategy. Neonatal intensive care unit. We developed a stochastic, agent-based simulation model to examine the impact of booster vaccination strategies for pertussis on health care-related transmission. Our results demonstrate that healthcare worker booster vaccination decreases the probability of secondary transmission from 49% (base case, no boosting) to 2% (if 95% of healthcare workers are boosted) and decreases final outbreak size. Boosting family caregivers did not have a clinically significant impact on nosocomial disease transmission. The provision of booster vaccine to healthcare workers in the neonatal intensive care unit substantially reduces the risk of hospital-centered pertussis outbreaks in a manner that enhances the health of hospitalized children. A formal health economic analysis of this finding is currently under way. Policies to protect patient safety in pediatric facilities should include compliance with the United States Advisory Committee on Immunization Practices, which recommends provision of pertussis booster vaccination to healthcare workers.

Clinical and Economic Effects of Pertussis Outbreaks

The reported incidence of pertussis is increasing, especially among the adolescent population. Current outbreak management strategies include investigating cases, contact follow-up, diagnostic testing, and antibiotic prophylaxis and treatment. The cost of these methods is substantial and can be attributed to the mobilization within public health departments to control the outbreaks. Through an extensive review of the literature, the clinical and economic effects of pertussis outbreaks in various nonhousehold settings are discussed. The reported incidence of pertussis among adolescents and adults in the United States since the early 1980s continues to rise. The challenges of preventing and controlling pertussis outbreaks involve diagnosing pertussis in a timely, accurate, and standardized fashion and understanding the true burden of disease in different age and socioeconomic groups. The economic effects of pertussis have been demonstrated to be significant to individuals and communities, both locally and globally. Costs associated with pertussis often include diagnostic testing, hospitalization, emergency and/or medical office visits, antibiotic and symptomatic treatment, lost work days, and other reductions in productivity. In outbreak settings, increased surveillance, antibiotic prophylaxis, isolation of infected cases, and enhanced communication and education add to the economic burden of this disease. The potential opportunity to apply the use of pertussis booster vaccination to these populations, particularly among adolescents, likely would reduce the occurrence of pertussis and minimize the clinical and economic repercussions of pertussis outbreaks. In the near future, it is anticipated that evaluating the effects of a licensed acellular pertussis booster vaccine in persons > or =10 years of age will become routine in pertussis prevention and outbreak-control activities.

The potential cost-effectiveness of acellular pertussis booster vaccination in England and Wales

A cost-effectiveness analysis of the introduction of acellular pertussis booster doses at either 4 or 15 years of age was performed. A transmission dynamic model was used to predict the level of indirect protection in those too young to be vaccinated. Multivariate sensitivity analyses were performed. In England and Wales there are an estimated 35,000 general practitioner (GP) consultations, 5500 inpatient days, and nine deaths annually attributable to pertussis, despite high levels of coverage for the primary course (∼95%). Around 80% of the bed-days and 90% of the deaths occur in those too young to be immunised (<3 months of age). The introduction of acellular booster doses at 4 years is expected to reduce morbidity and mortality in the younger age groups by 40–100%, and at 15 years by 0–100%. From the perspective of the health care provider, roughly 50% of the simulations result in a cost per life-year gained of less than £10,000 for vaccination at 4 years, the corresponding proportion for vaccination at 15 years being only 35%. Apart from the degree of indirect protection the model was most sensitive to the discount rate, the price of the vaccine, and the mortality rate. Significant uncertainty remains regarding the epidemiology of pertussis and the impact of booster doses. Nevertheless, the introduction of acellular boosters, particularly at 4 years, has the potential to be cost-effective in the UK.