Improved serologic responses to DTaP over Tdap vaccination in adult hematopoietic cell transplant recipients.

BACKGROUND: Hematopoietic cell transplantation (HCT) recipients have reduced antibody titers to tetanus, diphtheria, and pertussis. Tdap is approved for revaccinating adult HCT recipients in the United States, whereas DTaP is not approved in this population. To our knowledge, no studies to date have compared responses to DTaP versus Tdap in adult HCT patients. We conducted a retrospective study comparing responses to DTaP versus Tdap vaccines in otherwise similar adult HCT patients in order to determine if one of these vaccines elicits superior antibody responses. METHODS: We evaluated 43 allogeneic and autologous transplant recipients as a combined cohort and as separate subsets for vaccine specific antibody titers and proportion of strong vaccine responders. Subset analysis focused on the autologous transplant recipients. RESULTS: Higher median antibody titers were found to all vaccine components among DTaP recipients (diphtheria p = .021, pertussis p = .020, tetanus p = .007). DTaP recipients also had more strong responders to diphtheria and pertussis (diphtheria p = .002, pertussis p = .006). Among the autologous HCT recipient subset, there were more strong responders to diphtheria (p = .036). CONCLUSIONS: Our data shows that post-HCT vaccination with DTaP leads to higher antibody titers and more strong responders, which suggests that DTaP is more effective than Tdap in HCT recipients.

Development of a droplet digital PCR for pertussis toxin locus copy number determination in a genetically-modified Bordetella pertussis strain.

To improve pertussis toxin (PT) yield in B. pertussis strains for vaccine production a genetically-engineered strain (gdPT 191-134 strain) with a second copy of the genetically detoxified PT (gdPT) locus was developed. The consistency of the production and genetic stability of the strain when used for vaccine production must be established. We developed two simplex ddPCR assays with PCR systems for ptxA, the target gene present in two copies, and pgm, the reference gene present as a single copy. The ddPCR assay had sufficient precision to discriminate the copy number of the PT locus accurately in two B. pertussis strains: one copy in the parent, non-genetically-engineered strain and two copies in the gdPT 191-134 strain. Using the ddPCR assays, we were able to show that the ratio of the ptxA to pgm genes decreased during serial culture passages, due to the loss of PT locus, which in turn, resulted in lower levels of PT production over time. We were then able to assess culture conditions that improved the stability of the double locus, as shown by non-significant reduction in gdPT toxin yield.

Estimating Population-Level Effects of the Acellular Pertussis Vaccine Using Routinely Collected Immunization Data.

BACKGROUND: Measuring and reporting the different population-level effects of the acellular pertussis vaccine on pertussis disease in addition to direct effects can increase the cost-effectiveness of a vaccine. METHODS: We conducted a retrospective cohort study of children born between 1 January 2008 and 31 December 2017, in King County, Washington, who were enrolled in the Washington State Immunization Information System. Diphtheria, tetanus toxoids, and acellular pertussis (DTaP) vaccination data from in the Washington State Immunization Information System was linked with pertussis case data from Public Health Seattle and King County. Census-level vaccination coverage was estimated as proportion of age-appropriately vaccinated children residing in it. Direct vaccine effectiveness was estimated by comparing pertussis risk in fully vaccinated and undervaccinated children. Population-level vaccine effectiveness (VE) measures were estimated by comparing pertussis risk in census tracts in the highest quartile for vaccination coverage with that in the lowest quartile. RESULTS: For direct protection, estimated VE was 76% (95% confidence interval, 63%-84%) in low-vaccination-coverage clusters, and it decreased to 47% (13%-68%) in high-coverage clusters, after adjustment for potential confounders. The estimated indirect VE was 45.0% (95% confidence interval, 1%-70%), the total VE 93.9% (91%-96%), and the overall VE 42.2% (19%-60%). CONCLUSION: Our findings suggest that DTaP vaccination provided direct as well as indirect protection in the highly immunized King County, Washington. Routine DTaP vaccination programs may have the potential to provide not only protection for vaccinated individuals but also for the undervaccinated individuals living in the same area.

Highlights of the 12th International Bordetella Symposium.

To commemorate the 100th anniversary of the Nobel prize being awarded to Jules Bordet, the discoverer of Bordetella pertussis, the 12th International Bordetella Symposium was held from 9 to 12 April 2019 at the Université Libre de Bruxelles, where Jules Bordet studied and was Professor of Microbiology. The symposium attracted more than 300 Bordetella experts from 34 countries. They discussed the latest epidemiologic data and clinical aspects of pertussis, Bordetella biology and pathogenesis, immunology and vaccine development, and genomics and evolution. Advanced technological and methodological tools provided novel insights into the genomic diversity of Bordetella and a better understanding of pertussis disease and vaccine performance. New molecular approaches revealed previously unrecognized complexity of virulence gene regulation. Innovative insights into the immune responses to infection by Bordetella resulted in the development of new vaccine candidates. Such discoveries will aid in the design of more effective approaches to control pertussis and other Bordetella-related diseases.

Revisiting the epidemiology of pertussis in Canada, 1924-2015: a literature review, evidence synthesis, and modeling study.

BACKGROUND: Disease surveillance is central to the public health understanding of pertussis epidemiology. In Canada, public reporting practices have significantly changed over time, creating challenges in accurately characterizing pertussis epidemiology. Debate has emerged over whether pertussis resurged after the introduction of adsorbed pertussis vaccines (1981-1985), and if the incidence fell to its pre-1985 after the introduction of acellular pertussis vaccines (1997-1998). Here, we aim to assemble a unified picture of pertussis disease incidence in Canada. METHODS: Using publicly available pertussis surveillance reports, we collected, analyzed and presented Canadian pertussis data for the period (1924-2015), encompassing the pre-vaccine era, introduction of vaccine, changes to vaccine technology, and the introduction of booster doses. Information on age began to be reported since 1952, but age reporting practices (full, partial or no ages) have evolved over time, and varied across provinces/territories. For those cases reported without age each year, we impute an age distribution by assuming it follows that of the age-reported cases. RESULTS: Below the age of 20 years, the adjusted age-specific incidence from 1969 to 1988 is substantially higher than existing estimates. In children < 1 year, the incidence in some years was comparable to that during the 1988-1999 resurgence. CONCLUSIONS: The results presented here suggest that the surge in the average yearly incidence of pertussis that began in 1988 was weaker than previously inferred, and in contrary to the past findings, below age 5, the average yearly incidence of pertussis from 1999 to 2015 (when the incidence dropped again) has been lower than it was from 1969 to 1988.

[Evaluation of the safety of diphtheria, tetanus and acellular pertussis containing combination vaccines in Chengdu, 2015-2019].

Objective: To evaluate the safety of diphtheria, tetanus and acellular pertussis (DTaP) containing combination vaccines used in Chengdu. Methods: The AEFI reports data of DTaP vaccine, DTaP-Haemophilus influenza type b combined vaccine (DTaP-Hib) and DTaP-inactivated poliovirus-Hib combined vaccine (DTaP-IPV-Hib) in Chengdu from 2015 to 2019 were collected through the national immunization management system. Description epidemiological method was used to analyze the data. Results: From 2015 to 2019, a total of 8 234 cases of AEFI of DTaP containing combination vaccines were reported in Chengdu, with a reported incidence of 194.55/100 000 doses, including 7 897 cases of common adverse reaction (168.59 per 100 000) and 234 cases of rare adverse reaction (5.53 per 100 000). The DTaP vaccine reported 4 240 cases AEFI (140.63 per 100 000), the DTaP-Hib vaccine reported 2 490 cases AEFI (399.09 per 100 000) and the DTaP-IPV-Hib vaccine reported 1 504 cases AEFI (253.49 per 100 000). All the three vaccines had the highest incidence for the booster doses; the rare adverse reaction were mainly Anaphylactic Reaction (6.27 per 100 000). Conclusions: The AEFI monitor system had high sensitivity, and the rare adverse reaction rate was extremely low, all the vaccines had good safety profiles. The Thrombocytopenic purpura and Laryngeal Edema should be paid more attention to.

Pertussis Vaccines and Vaccination Strategies. An Ever-Challenging Health Problem.

Vaccines and vaccination against pertussis (whooping cough) have had one of the longest and most complex history, with alternating splendour and public disbelief, enthusiasm and concerns, overall resulting in changes in composition and replacement of vaccines, and associated vaccination strategies, including use of different vaccines in different countries, with no apparent equals for other bacterial vaccines. Of this both frustrating and exciting venue no end has been reached. In this note, I am shortly recapitulating the history of pertussis vaccines, from the inactivated, whole-cell vaccine to the acellular ones, with their merits and limitations, particularly concerning the debated issue of waning immunity, and a glimpse on a new vaccine proposal. Some reflections on the complexity and apparent peculiarity of this field are also made to the final scope of discussing aspects of the evolving strategies of disease control in a high-income country.

Human Immune Responses to Pertussis Vaccines.

Pertussis still represents a major cause of morbidity and mortality worldwide. Although vaccination is the most powerful tool in preventing pertussis and despite nearly 70 years of universal childhood vaccination, incidence of the disease has been rising in the last two decades in countries with high vaccination coverage. Two types of vaccines are commercially available against pertussis: whole-cell pertussis vaccines (wPVs) introduced in the 1940s and still in use especially in low and middle-income countries; less reactogenic acellular pertussis vaccines (aPVs), licensed since the mid-1990s.In the last years, studies on pertussis vaccination have highlighted significant gaps and major differences between the two types of vaccines in the induction of protective anti-pertussis immunity in humans. This chapter will discuss the responses of the immune system to wPVs and aPVs, with the aim to enlighten critical points needing further efforts to reach a good level of protection in vaccinated individuals.

The Adjuvant Bordetella Colonization Factor A Attenuates Alum-Induced Th2 Responses and Enhances Bordetella pertussis Clearance from Mouse Lungs.

The reemergence of pertussis or whooping cough in several countries highlights the need for better vaccines. Acellular pertussis vaccines (aPV) contain alum as the adjuvant and elicit Th2-biased immune responses that are less effective in protecting against infection than the reactogenic whole-cell pertussis vaccines (wPV), which elicit primarily a Th1/Th17 response. An important goal for the field is to devise aPV that will induce immune responses similar to those of wPV. We show that Bordetella colonization factor A (BcfA), an outer membrane protein from Bordetella bronchiseptica, has strong adjuvant function and elicits cellular and humoral immune responses to heterologous and Bordetella pertussis antigens. Addition of BcfA to a commercial aPV resulted in greater reduction of B. pertussis numbers from the lungs than that elicited by aPV alone. The more-efficient pathogen clearance was accompanied by increased interleukin-17 (IL-17) and reduced IL-5 and an increased ratio of IgG2/IgG1 antibodies. Thus, our results suggest that BcfA improves aPV-induced responses by modifying the alum-induced Th2-biased aPV response toward Th1/Th17. A redesigned aPV containing BcfA may allow better control of pertussis reemergence by reshaping immune responses to resemble those elicited by wPV immunization.

Evaluation of Adenylate Cyclase Toxoid Antigen in Acellular Pertussis Vaccines by Using a Bordetella pertussis Challenge Model in Mice.

Bordetella pertussis is the primary causative agent of pertussis (whooping cough), which is a respiratory infection that leads to a violent cough and can be fatal in infants. There is a need to develop more effective vaccines because of the resurgence of cases of pertussis in the United States since the switch from the whole-cell pertussis vaccines (wP) to the acellular pertussis vaccines (aP; diphtheria-tetanus-acellular-pertussis vaccine/tetanus-diphtheria-pertussis vaccine). Adenylate cyclase toxin (ACT) is a major virulence factor of B. pertussis that is (i) required for establishment of infection, (ii) an effective immunogen, and (iii) a protective antigen. The C-terminal repeats-in-toxin domain (RTX) of ACT is sufficient to induce production of toxin-neutralizing antibodies. In this study, we characterized the effectiveness of vaccines containing the RTX antigen against experimental murine infection with B. pertussis RTX was not protective as a single-antigen vaccine against B. pertussis challenge, and adding RTX to 1/5 human dose of aP did not enhance protection. Since the doses of aP used in murine studies are not proportionate to mouse/human body masses, we titrated the aP from 1/20 to 1/160 of the human dose. Mice receiving 1/80 human aP dose had bacterial burden comparable to those of naive controls. Adding RTX antigen to the 1/80 aP base resulted in enhanced bacterial clearance. Inclusion of RTX induced production of antibodies recognizing RTX, enhanced production of anti-pertussis toxin, decreased secretion of proinflammatory cytokines, such as interleukin-6, and decreased recruitment of total macrophages in the lung. This study shows that adding RTX antigen to an appropriate dose of aP can enhance protection against B. pertussis challenge in mice.

An ELISA method to estimate the mono ADP-ribosyltransferase activities: e.g in pertussis toxin and vaccines.

ADP-ribosyltransferase activities have been observed in many prokaryotic and eukaryotic species and viruses and are involved in many cellular processes, including cell signalling, DNA repair, gene regulation and apoptosis. In a number of bacterial toxins, mono ADP-ribosyltransferase is the main cause of host cell cytotoxicity. Several approaches have been used to analyse this biological system from measuring its enzyme products to its functions. By using a mono ADP-ribose binding protein we have now developed an ELISA method to estimate native pertussis toxin mono ADP-ribosyltransferase activity and its residual activities in pertussis vaccines as an example. This new approach is easy to perform and adaptable in most laboratories. In theory, this assay system is also very versatile and could measure the enzyme activity in other bacteria such as Cholera, Clostridium, E. coli, Diphtheria, Pertussis, Pseudomonas, Salmonella and Staphylococcus by just switching to their respective peptide substrates. Furthermore, this mono ADP-ribose binding protein could also be used for staining mono ADP-ribosyl products resolved on gels or membranes.

A Population-Based Study of Recurrent Symptomatic Bordetella pertussis Infections in Children in California, 2010-2015.

BACKGROUND: Natural infection with Bordetella pertussis is thought to result in 4-20 years of immunity against subsequent symptomatic pertussis infection. However, these estimates are based on studies in unvaccinated or whole-cell pertussis-vaccinated children. We conducted a population-based study of pertussis infection and reinfection during a 5-year period in California in an cohort vaccinated exclusively with acellular pertussis (aP) vaccine. METHODS: California surveillance data were reviewed to identify all children with 2 reported incidents of pertussis with symptom onset between 1 January 2010 and 31 December 2015. Case investigation reports were reviewed, and children with ≥2 episodes of symptomatic pertussis infection that met the case definition were included. RESULTS: Of 26259 pertussis cases reported in children (aged <18 years), 27 children met the inclusion criteria. Recurrent cases occurred among children of all ages; 5 (19%) were <6 months of age at the time of their first illness. The time from initial infection to reinfection was <1 year in 11 (41%) cases. Twenty-one children (78%) had received ≥3 doses of diphtheria and tetanus toxoids and aP vaccine at the time of their first pertussis infection, 1 (4%) had received 1 dose, and 5 (19%) were unvaccinated. CONCLUSIONS: Recurrent cases of pertussis infection are extremely rare. Based on this surveillance data, approximately 0.1% of children who were infected with pertussis experienced a clinically significant second episode of pertussis within 4 years. More research is needed to understand the immune response to B. pertussis infection in children vaccinated with aP vaccines.

Expanding Pertussis Epidemiology in 6 Latin America Countries through the Latin American Pertussis Project.

The Latin American Pertussis Project (LAPP), established in 2009, is a collaboration between the Centers for Disease Control and Prevention, Pan American Health Organization, Sabin Vaccine Institute, and the ministries of health of 6 countries in Latin America. The project goal is to expand understanding of pertussis epidemiology in Latin America to inform strategies for control and prevention. Here we describe LAPP structure and activities. After an initial surveillance evaluation, LAPP activities are tailored to individual country needs. LAPP activities align with Global Health Security Agenda priorities and have focused on expanding laboratory diagnostic capacity, implementing a laboratory quality control and quality assurance program, and providing epidemiologic support to strengthen reporting of pertussis surveillance data. Lessons learned include that ongoing mentoring is key to the successful adoption of new technologies and that sustainability of laboratory diagnostics requires a regional commitment to procure reagents and related supplies.

Systematic review and meta-analysis of pertussis epidemiology in Latin America and the Caribbean: 1980-2015.

OBJECTIVES: In Latin America and the Caribbean (LAC), pertussis disease incidence has reportedly increased since 2000 despite high vaccine coverage. A systematic review of pertussis literature and a meta-analysis was conducted to understand the burden of disease in LAC. METHODS: A systematic literature review was completed, using relevant search terms. Original articles describing pertussis epidemiology and vaccine coverage in LAC published between 1980 and 2015 were identified. Applying a Bayesian meta-analysis random-effects model, we calculated pooled estimates and corresponding 95% credible intervals (95% CrIs) for pertussis incidence, case fatality ratio (CFR), pertussis prevalence among contacts, and coverage with three doses of diphtheria, tetanus, and pertussis (DTP) vaccine (DTP3). RESULTS: A total of 59 studies meeting our selection criteria were identified, representing 15 countries. Of the 59, 15 of them provided incidence data, with 7 of the 15 reporting a pertussis case definition. The pertussis incidence estimate for the 1980-1999 period was 17.8 cases per 100 000 persons (95% CrI: 5.9-29.7); for the 2000-2015 period, it was 2.5 cases per 100 000 persons (95% CrI: 1.8-3.2). For the 1980-2015 period, the CFR, in 19 studies reviewed, was 3.9% (95% CrI: 2.9%-4.9%); for that same period, in 5 studies reviewed, pertussis prevalence among contacts was 24.9% (95% CrI: 13.7%-36.1%). Pooled DTP3 vaccine coverage estimates, in a total of 20 studies reviewed for the following three time periods, were: 1980-1990, 72.4% (95% CrI: 64.6%-80.2%); 1991-2000, 79.0% (95% CrI: 66.1%-91.9%); and 2001-2015, 90.0% (95% CrI: 87.7%-92.3%). CONCLUSION: A decrease in pertussis incidence and an achievement of moderately high DTP3 vaccine coverage since the early 2000s was observed. The review highlights the need for increased publication of pertussis data at the country level and for LAC as a whole in order to better understand the true burden of the disease. Application of a standardized case definition and use of active case finding would aid in obtaining more accurate estimates of the disease burden in LAC.

The pertussis enigma: reconciling epidemiology, immunology and evolution.

Pertussis, a highly contagious respiratory infection, remains a public health priority despite the availability of vaccines for 70 years. Still a leading cause of mortality in developing countries, pertussis has re-emerged in several developed countries with high vaccination coverage. Resurgence of pertussis in these countries has routinely been attributed to increased awareness of the disease, imperfect vaccinal protection or high infection rates in adults. In this review, we first present 1980-2012 incidence data from 63 countries and show that pertussis resurgence is not universal. We further argue that the large geographical variation in trends probably precludes a simple explanation, such as the transition from whole-cell to acellular pertussis vaccines. Reviewing available evidence, we then propose that prevailing views on pertussis epidemiology are inconsistent with both historical and contemporary data. Indeed, we summarize epidemiological evidence showing that natural infection and vaccination both appear to provide long-term protection against transmission and disease, so that previously infected or vaccinated adults contribute little to overall transmission at a population level. Finally, we identify several promising avenues that may lead to a consistent explanation of global pertussis epidemiology and to more effective control strategies.

[Acellular vaccines (DTPa/dTpa) against whooping cough, protection duration]. / Vacunas acelulares (DTPa/dTpa) contra la tos ferina: duración de la protección.

INTRODUCTION: An increase in whooping cough in most of the developed countries has been detected in the last decade. OBJECTIVE: To determine whether the administration of dTpa vaccine instead of DTPa fifth dose is contributing to the appearance of these cases. METHODS: A descriptive study based on cases of whooping cough reported during an epidemic period in the city of Alicante in the first 5 months of 2014. Only pertussis cases confirmed by PCR were included in the study, and only those vaccinated with 5 doses were included in the analysis of the period of protection. RESULTS: A total of 104 cases of pertussis confirmed by PCR were reported, with 85 cases (82%) having had 5 doses of vaccine. The mean time and standard deviation (SD) of protection was 2.1±1.1 years with dTpa, and 5.1±1.5 years with DTPa (p<.001). In the protection, adjusted for age, it was observed that, after 3 years, only 47.6% of people vaccinated with dTpa were still protected, while people vaccinated with DTPa were 100% protected (P<.001). CONCLUSIONS: This study found that people who were properly vaccinated against pertussis and received their last re-vaccination dose with dTpa had a shorter period of protection than those who were vaccinated with DTPa.

Immune responses to pertussis vaccines and disease.

In this article we discuss the following: (1) acellular vaccines are immunogenic, but responses vary by vaccine; (2) pertussis antibody levels rapidly wane but promptly increase after vaccination; (3) whole-cell vaccines vary in immunogenicity and efficacy; (4) whole-cell vaccines and naturally occurring pertussis generate predominantly T-helper 1 (Th1) responses, whereas acellular vaccines generate mixed Th1/Th2 responses; (5) active transplacental transport of pertussis antibody is documented; (6) neonatal immunization with diphtheria toxoid, tetanus toxoid, and acellular pertussis vaccine has been associated with some suppression of pertussis antibody, but suppression has been seen less often with acellular vaccines; (7) memory B cells persist in both acellular vaccine- and whole cell vaccine-primed children; and (8) in acellular vaccine-primed children, T-cell responses remain elevated and do not increase with vaccine boosters, whereas in whole-cell vaccine-primed children, these responses can be increased by vaccine boosting and natural exposure. Despite these findings, challenges remain in understanding the immune response to pertussis vaccines.

Possible options for new pertussis vaccines.

Increasing evidence that the currently available acellular pertussis vaccines are not providing optimal control of pertussis in the United States and many other countries has stimulated interest in improvements of the current vaccines and in the development of new vaccines. A better understanding of the limitations of the current vaccines and the basis for the pertussis resurgence is needed to design improved vaccines. This article outlines several alternate approaches and summarizes the challenges related to the development of new or modified vaccines.

Clinical evaluation of pertussis vaccines: US Food and Drug Administration regulatory considerations.

The resurgence of pertussis in the United States has stimulated considerable public health interest in developing new vaccination strategies to improve control of pertussis. The purpose of this article is to review the US Food and Drug Administration's regulatory framework for the prelicensure clinical evaluation of preventive vaccines and the clinical approaches that have been used to demonstrate effectiveness of US-licensed vaccines containing an acellular pertussis component.

Report on the international workshop on alternatives to the murine histamine sensitization test (HIST) for acellular pertussis vaccines: state of the science and the path forward.

Regulatory authorities require safety and potency testing prior to the release of each production lot of acellular pertussis (aP)-containing vaccines. Currently, the murine histamine sensitization test (HIST) is used to evaluate the presence of residual pertussis toxin in aP containing vaccines. However, the testing requires the use of a significant number of mice and results in unrelieved pain and distress. NICEATM, ICCVAM, their partners in the International Cooperation on Alternative Test Methods, and the International Working Group for Alternatives to HIST organized a workshop to discuss recent developments in alternative assays to the HIST, review data from an international collaborative study on non-animal alternative tests that might replace the HIST, and address the path toward global acceptance of this type of method. Currently, there are three potential alternative methods to HIST. Participants agreed that no single in vitro method was sufficiently developed for harmonized validation studies at this time. It is unlikely that any single in vitro method would be applicable to all aP vaccines without modification, due to differences between vaccines. Workshop participants recommended further optimization of cell-based assays under development. Participants agreed that the next international collaborative studies should commence in 2013 based on discussions during this workshop.