aP Vaccines Research Articles

Acellular Pertussis Vaccine Components: Today and Tomorrow.

Pertussis is a highly communicable acute respiratory infection caused by Bordetella pertussis. Immunity is not lifelong after natural infection or vaccination. Pertussis outbreaks occur cyclically worldwide and effective vaccination strategies are needed to control disease. Whole-cell pertussis (wP) vaccines became available in the 1940s but have been replaced in many countries with acellular pertussis (aP) vaccines. This review summarizes disease epidemiology before and after the introduction of wP and aP vaccines, discusses the rationale and clinical implications for antigen inclusion in aP vaccines, and provides an overview of novel vaccine strategies aimed at better combating pertussis in the future.

ADVANCE system testing: Estimating the incidence of adverse events following pertussis vaccination in healthcare databases with incomplete exposure data

The Accelerated Development of VAccine beNefit-risk Collaboration in Europe (ADVANCE) is a public–private collaboration aiming to develop and test a system for rapid vaccine benefit-risk monitoring using existing European healthcare databases. Incidence rate (IR) estimates of vaccination-associated adverse events that are needed to model vaccination risks can be calculated from existing healthcare databases when vaccination (exposure) data are available. We assessed different methods to derive IRs in risk periods following vaccination when exposure data are missing in one database, using estimated IRs and IRRs from other databases for febrile seizures, fever and persistent crying. IRs were estimated for children aged 0–5 years in outcome-specific risk and non-risk periods following the first dose of acellular pertussis (aP) vaccination in four primary care databases and one hospital database. We compared derived and observed IRs in each database using three methods: 1) multiplication of non-risk period IR for database i by IR ratio (IRR) obtained from meta-analysis of IRRs estimated using the self-controlled case-series method, from databases other than i; 2) same method as 1, but multiplying with background IR; and 3) meta-analyses of observed IRs from databases other than i. IRs for febrile seizures were lower in primary care databases than the hospital database. The derived IR for febrile seizures using data from primary care databases was lower than that observed in the hospital database, and using data from the hospital database gave a higher derived IR than that observed in the primary care database. For fever and persistent crying the opposite was observed. We demonstrated that missing IRs for a post-vaccination period can be derived but that the type of database and the method of event data capture can have an impact on potential bias. We recommend IRs are derived using data from similar database types (hospital or primary care) with caution as even this can give heterogeneous results.

Development and Validation of a Bordetella pertussis Whole-Genome Screening Strategy.

The immune response elicited by the protective whole-cell pertussis (wP) versus the less-protective acellular pertussis (aP) vaccine has been well characterized; however, important clinical problems remain unsolved, as the inability of the currently administered aP vaccine is resulting in the reemergence of clinical disease (i.e., whooping cough). Strong evidence has shown that original, childhood aP and wP priming vaccines provide a long-lasting imprint on the CD4+ T cells that impacts protective immunity. However, aP vaccination might prevent disease but not infection, which might also affect the breadth of responses to Bordetella pertussis (BP) antigens. Thus, characterizing and defining novel targets associated with T cell reactivity are of considerable interest. Here, we compare the T cell reactivity of original aP and wP priming for different antigens contained or not contained in the aP vaccine and define the basis of a full-scale genomic map of memory T cell reactivity to BP antigens in humans. Our data show that the original priming after birth with aP vaccines has higher T cell reactivity than originally expected against a variety of BP antigens and that the genome-wide mapping of BP using an ex vivo screening methodology is feasible, unbiased, and reproducible. This could provide invaluable knowledge towards the direction of a new and improved pertussis vaccine design.

A novel method for the extraction of outer membrane vesicles (OMVs) from Bordetella pertussis Tohama strain

There are many pertussis outbreaks which is mainly due to the reduction in the immunity of acellular pertussis (aP) vaccines. Therefore, there is a crucial necessity to develop a new generation of pertussis vaccine. Preceding researches have shown that Bordetella pertussis outer membrane vesicles (OMVs) have appropriate specifications, making them a suitable vaccine candidate against pertussis. The OMVs were separated by a new serial ultra centrifugation technique. Transmission electron microscopy (TEM) examination, SDS-PAGE, Western blotting and ELISA assay were used to characterize the OMVs. TEM studies showed the size of the extracted OMVs at 40-200 nm. The presence of pertussis toxin, filamentous hemagglutinin, and pertactin was verified using Western blot and ELISA assay. The presented technique is a simple and effective way to obtain OMVs from Bordetella pertussis. So it can be utilized as an appropriate procedure in the development of an OMV-based vaccine against pertussis.

Whole-Cell Pertussis Vaccination and Decreased Risk of IgE-Mediated Food Allergy: A Nested Case-Control Study

Rates of food allergy have increased markedly in Australia and other high- income countries in recent years. On the basis of ecological observations, and the known immunologic characteristics of whole-cell pertussis (wP) compared with acellular pertussis (aP) vaccines, we hypothesized that wP vaccination in infancy protects against the development of food allergy. To determine whether infants who receive wP in infancy were less likely to develop IgE-mediated food allergy than those who received aP. Retrospective cohort-nested case-control study of Australian children born in the period 1997 to 1999, the period of transition from using wP-containing to aP-containing vaccines. Children diagnosed with IgE-mediated food allergy were individually matched to 10 controls by date of birth, socioeconomic decile, and jurisdiction of birth. The odds ratio of vaccination with wP versus aP among cases and matched controls was calculated using conditional logistic regression. The odds ratio of receiving the first dose as wP (rather than aP) among cases of food allergy compared with controls was 0.77 (95% CI, 0.62-0.95). The results of secondary analyses (any dose as wP vs aP-only, and wP-only vs aP-only) were broadly similar. Australian infants who received wP vaccines were less likely to be diagnosed with food allergy in childhood than contemporaneous children who received aP vaccines. If a protective effect is confirmed in a randomized controlled trial, wP or mixed wP and aP vaccination schedules could form part of an effective strategy for combating the rise in food allergies.

Pertussis vaccines: The first hundred years

Vaccines against pertussis have been used for more than a hundred years. This review describes the development of whole-cell (wP) and acellular pertussis (aP) vaccines, which, as DTP combination vaccines, have significantly reduced morbidity and mortality from pertussis, and which currently serve as the building blocks for a variety of vaccines used to immunize all infants worldwide. Two series of efficacy trials done in the 1950s for wP vaccines and in the 1990s for aP-vaccines have established standards for studying vaccine effectiveness. However, irrespective of their longtime use, critical aspects of pertussis vaccines remain unknown, including the exact mechanisms of protective immunity and a correlate of protection. Research to improve on the effectiveness and the duration of protection is ongoing, but although the vaccines are not perfect, only their continued use with a high coverage will ensure that infants and children are being protected from pertussis.

Rare Detection of Bordetella pertussis Pertactin-Deficient Strains in Argentina.

Pertussis resurgence had been attributed to waning vaccine immunity and Bordetella pertussis adaptation to escape vaccine-induced immunity. Circulating bacteria differ genotypically from strains used in production of pertussis vaccine. Pertactin-deficient strains are highly prevalent in countries that use acellular vaccine (aP), suggesting strong aP-imposed selection of circulating bacteria. To corroborate this hypothesis, systematic studies on pertactin prevalence of infection in countries using whole-cell vaccine are needed. We provide pertussis epidemiologic data and molecular characterization of B. pertussis isolates from Buenos Aires, Argentina, during 2000–2017. This area used primary vaccination with whole-cell vaccine. Since 2002, pertussis case incidences increased at regular 4-year outbreaks; most cases were in infants <1 year of age. Of the B. pertussis isolates analyzed, 90.6% (317/350) contained the ptxP3-ptxA1-prn2-fim3-2 allelic profile. Immunoblotting and sequencing techniques detected only the 2 pertactin-deficient isolates. The low prevalence of pertactin-deficient strains in Argentina suggests that loss of pertactin gene expression might be driven by aP vaccine.

ADVANCE system testing: Can safety studies be conducted using electronic healthcare data? An example using pertussis vaccination

IntroductionThe Accelerated Development of Vaccine benefit-risk Collaboration in Europe (ADVANCE) public-private collaboration, aimed to develop and test a system for rapid benefit-risk monitoring of vaccines using healthcare databases in Europe. The objective of this proof-of-concept (POC) study was to test the feasibility of the ADVANCE system to generate incidence rates (IRs) per 1000 person-years and incidence rate ratios (IRRs) for risks associated with whole cell- (wP) and acellular- (aP) pertussis vaccines, occurring in event-specific risk windows in children prior to their pre-school-entry booster. MethodsThe study population comprised almost 5.1 million children aged 1 month to <6 years vaccinated with wP or aP vaccines during the study period from 1 January 1990 to 31 December 2015. Data from two Danish hospital (H) databases (AUH and SSI) and five primary care (PC) databases from, UK (THIN and RCGP RSC), Spain (SIDIAP and BIFAP) and Italy (Pedianet) were analysed. Database-specific IRRs between risk vs. non-risk periods were estimated in a self-controlled case series study and pooled using random-effects meta-analyses. ResultsThe overall IRs were: fever, 58.2 (95% CI: 58.1; 58.3), 96.9 (96.7; 97.1) for PC DBs and 8.56 (8.5; 8.6) for H DBs; convulsions, 7.6 (95% CI: 7.6; 7.7), 3.55 (3.5; 3.6) for PC and 12.87 (12.8; 13) for H; persistent crying, 3.9 (95% CI: 3.8; 3.9) for PC, injection-site reactions, 2.2 (95% CI 2.1; 2.2) for PC, hypotonic hypo-responsive episode (HHE), 0.4 (95% CI: 0.4; 0.4), 0.6 (0.6; 0.6) for PC and 0.2 (0.2; 0.3) for H; and somnolence: 0.3 (95% CI: 0.3; 0.3) for PC. The pooled IRRs for persistent crying, fever, and ISR, adjusted for age and healthy vaccinee period were higher after wP vs. aP vaccination, and lower for convulsions, for all doses. The IRR for HHE was slightly lower for wP than aP, while wP was associated with somnolence only for dose 1 and dose 3 compared with aP. ConclusionsThe estimated IRs and IRRs were comparable with published data, therefore demonstrating that the ADVANCE system was able to combine several European healthcare databases to assess vaccine safety data for wP and aP vaccination.

Advance system testing: Vaccine benefit studies using multi-country electronic health data – The example of pertussis vaccination

The Accelerated Development of VAccine benefit-risk Collaboration in Europe (ADVANCE), a public-private consortium, implemented and tested a distributed network system for the generation of evidence on the benefits-risks of marketed vaccines in Europe. We tested the system by estimating the incidence rate (IR) of pertussis and pertussis-related complications in children vaccinated with acellular (aP) and whole-cell (wP) pertussis vaccine. Data from seven electronic databases from four countries (Denmark: AUH and SSI, Spain: SIDIAP and BIFAP, UK: THIN and RCGP RSC and Italy: Pedianet) were included in a retrospective cohort analysis. Exposure was defined as any pertussis vaccination (aP or wP). The follow-up time started 14 days after the first dose. Children who had received any pertussis vaccine from January 1990 to December 2015 were included (those who switched type, or had unknown type were excluded). The outcomes of interest were confirmed or suspected pertussis and pertussis-related pneumonia and generalised convulsions within one month of pertussis diagnosis and death within three months of pertussis diagnosis. The cohort comprised 2,886,367 children ≤5 years of age. Data on wP and aP vaccination were available in three and seven databases, respectively. The IRs (per 100,000 person-years) for pertussis varied largely and ranged between 0.15 (95% CI: 0.12; 0.19) and 1.15 (95% CI: 1.07; 1.23), and the trends over time was consistent with those observed from national surveillance databases for confirmed pertussis. The pertussis IRs decreased as the number of wP and aP vaccine doses increased. Pertussis-related complications were rare (89 pneumonia, 7 generalised convulsions and no deaths) and their relative risk (vs. non-pertussis) could not be reliably estimated. The study demonstrated the feasibility of the ADVANCE system to estimate the change in pertussis IRs following pertussis vaccination. Larger sample sizes would provide additional power to compare the risk for complications between children with and without pertussis. The feasibility of vaccine-type specific effectiveness studies may be considered in the future.

ADVANCE system testing: Benefit-risk analysis of a marketed vaccine using multi-criteria decision analysis and individual-level state transition modelling

BackgroundThe Accelerated Development of VAccine beNefit-risk Collaboration in Europe (ADVANCE) is a public-private collaboration aiming to develop and test a system for rapid benefit-risk (B/R) monitoring of vaccines using electronic health record (eHR) databases in Europe. Proof-of-concept studies were designed to assess the proposed processes and system for generating the required evidence to perform B/R assessment and near-real time monitoring of vaccines. We aimed to test B/R methodologies for vaccines, using the comparison of the B/R profiles of whole-cell (wP) and acellular pertussis (aP) vaccine formulations in children as an example. MethodsWe used multi-criteria decision analysis (MCDA) to structure the B/R assessment combined with individual-level state transition modelling to build the B/R effects table. In the state transition model, we simulated the number of events in two hypothetical cohorts of 1 million children followed from first pertussis dose till pre-school-entry booster (or six years of age, whichever occurred first), with one cohort receiving wP, and the other aP. The benefits were reductions in pertussis incidence and complications. The risks were increased incidences of febrile convulsions, fever, hypotonic-hyporesponsive episodes, injection-site reactions and persistent crying. Most model parameters were informed by estimates (coverage, background incidences, relative risks) from eHR databases from Denmark (SSI), Spain (BIFAP and SIDIAP), Italy (Pedianet) and the UK (RCGP-RSC and THIN). Preferences were elicited from clinical and epidemiological experts. ResultsUsing state transition modelling to build the B/R effects table facilitated the comparison of different vaccine effects (e.g. immediate vaccine risks vs long-term vaccine benefits). Estimates from eHR databases could be used to inform the simulation model. The model results could be easily combined with preference weights to obtain B/R scores. ConclusionExisting B/R methodology, modelling and estimates from eHR databases can be successfully used for B/R assessment of vaccines.

A nested case-control study measuring pertussis vaccine effectiveness and duration of protection in Manitoba, Canada, 1992–2015: A Canadian Immunization Research Network Study

BackgroundPertussis persists in Manitoba despite the universal availability of pertussis vaccines. Recent cases have included previously vaccinated individuals, raising concerns about declining vaccine effectiveness (VE). We measured pertussis VE and duration of protection using Manitoba’s provincial immunization and communicable disease registries. MethodsUsing a nested case-control design, individuals with laboratory-confirmed pertussis in Manitoba diagnosed between April 1, 1992, and March 31, 2015, were matched to up to five population-based controls on age, gender, geography, and case physician or number of physician visits. Conditional logistic regression was used to estimate VE against pertussis for both the whole-cell (wP) and acellular (aP) pertussis vaccines. Duration of protection was assessed using time since last dose. ResultsData on 534 eligible cases and 2614 controls were available for analysis. The adjusted VE estimate for aP-containing vaccines was 85% (95%CI: 74–91%); VE was 89% (66–96%) one to three years after the last vaccination. The adjusted VE of wP-containing vaccines was –15% (–91–31%) during a large outbreak in 1994 and 1995 compared to 35% (–26–66%) during non-outbreak years. ConclusionsOur estimates suggest that the aP vaccine was effective in preventing pertussis since its introduction in Manitoba. VE was lower during a large outbreak, highlighting the importance of separately analyzing outbreak periods when estimating pertussis VE over time.

Pertussis Toxin: A Key Component in Pertussis Vaccines?

B. pertussis is a human-specific pathogen and the causative agent of whooping cough. The ongoing resurgence in pertussis incidence in high income countries is likely due to faster waning of immunity and increased asymptomatic colonization in individuals vaccinated with acellular pertussis (aP) vaccine relative whole-cell pertussis (wP)-vaccinated individuals. This has renewed interest in developing more effective vaccines and treatments and, in support of these efforts, defining pertussis vaccine correlates of protection and the role of vaccine antigens and toxins in disease. Pertussis and its toxins have been investigated by scientists for over a century, yet we still do not have a clear understanding of how pertussis toxin (PT) contributes to disease symptomology or how anti-PT immune responses confer protection. This review covers PT’s role in disease and evidence for its protective role in vaccines. Clinical data suggest that PT is a defining and essential toxin for B. pertussis pathogenesis and, when formulated into a vaccine, can prevent disease. Additional studies are required to further elucidate the role of PT in disease and vaccine-mediated protection, to inform the development of more effective treatments and vaccines.

Quantity and Quality of Antibodies After Acellular Versus Whole-cell Pertussis Vaccines in Infants Born to Mothers Who Received Tetanus, Diphtheria, and Acellular Pertussis Vaccine During Pregnancy: A Randomized Trial.

The blunting effect of pertussis immunization during pregnancy on infant antibody responses induced by whole-cell pertussis (wP) vaccination is not well-defined. This randomized controlled trial (NCT02408926) followed term infants born to mothers vaccinated with tetanus, diphtheria, and acellular pertussis (Tdap) vaccine during pregnancy in Thailand. Infants received either acellular pertussis (aP)- or wP-containing vaccine at 2, 4, 6, and 18 months of age. A comparison group comprised wP-vaccinated children born to mothers not vaccinated during pregnancy. Antibodies against pertussis toxin (PT), filamentous hemagglutinin (FHA), and pertactin (PRN) were evaluated using commercial enzyme-linked immunosorbent assays. Functionality of antibodies against Bordetella pertussis was measured using Bordetella pertussis growth inhibition assay. After maternal Tdap vaccination, 158 infants vaccinated with aP-containing vaccines possessed higher antibody levels (P < .001) against all tested B. pertussis antigens postpriming compared to 157 infants receiving wP-containing vaccines. At 1 month postbooster, only anti-FHA and anti-PRN antibodies were still significantly higher (P < .001) in the aP group. Significantly higher anti-PT and anti-FHA (P < .001), but not anti-PRN immunoglobulin G, were observed among 69 wP-vaccinated infants born to control mothers compared with wP-vaccinated infants of Tdap-vaccinated mothers after primary and booster vaccination. The antibody functionality was higher in all wP-vaccinated infants at all times. Maternal Tdap vaccination inhibited more pertussis-specific responses in wP-vaccinated infants compared to aP-vaccinated infants, and the control group of unvaccinated women had highest PT-specific responses, persisting until after the booster dose. Antibody functionality was better in the wP groups. NCT02408926.Infant whole-cell pertussis (wP) vaccine responses are blunted after maternal Tdap vaccination. Pertussis antibody titers are higher in acellular pertussis (aP)- than wP-vaccinated infants of immunized mothers, yet quality of antibodies, measured as serum-mediated bacterial growth inhibition, is better after wP than aP vaccination.

Reactivating Immunity Primed by Acellular Pertussis Vaccines in the Absence of Circulating Antibodies: Enhanced Bacterial Control by TLR9 Rather Than TLR4 Agonist-Including Formulation.

Pertussis is still observed in many countries despite of high vaccine coverage. Acellular pertussis (aP) vaccination is widely implemented in many countries as primary series in infants and as boosters in school-entry/adolescents/adults (including pregnant women in some). One novel strategy to improve the reactivation of aP-vaccine primed immunity could be to include genetically- detoxified pertussis toxin and novel adjuvants in aP vaccine boosters. Their preclinical evaluation is not straightforward, as it requires mimicking the human situation where T and B memory cells may persist longer than vaccine-induced circulating antibodies. Toward this objective, we developed a novel murine model including two consecutive adoptive transfers of the memory cells induced by priming and boosting, respectively. Using this model, we assessed the capacity of three novel aP vaccine candidates including genetically-detoxified pertussis toxin, pertactin, filamentous hemagglutinin, and fimbriae adsorbed to aluminum hydroxide, supplemented—or not—with Toll-Like-Receptor 4 or 9 agonists (TLR4A, TLR9A), to reactivate aP vaccine-induced immune memory and protection, reflected by bacterial clearance. In the conventional murine immunization model, TLR4A- and TLR9A-containing aP formulations induced similar aP-specific IgG antibody responses and protection against bacterial lung colonization as current aP vaccines, despite IL-5 down-modulation by both TLR4A and TLR9A and IL-17 up-modulation by TLR4A. In the absence of serum antibodies at time of boosting or exposure, TLR4A- and TLR9A-containing formulations both enhanced vaccine antibody recall compared to current aP formulations. Unexpectedly, however, protection was only increased by the TLR9A-containing vaccine, through both earlier bacterial control and accelerated clearance. This suggests that TLR9A-containing aP vaccines may better reactivate aP vaccine-primed pertussis memory and enhance protection than current or TLR4A-adjuvanted aP vaccines.

Assessment of humoral and cell-mediated immune responses to pertussis vaccination: a systematic review protocol

IntroductionGlobally, some studies show a resurgence of pertussis. The risks and benefits of using whole-cell pertussis (wP) or acellular pertussis (aP) vaccines in the control of the disease have been...

National Outbreak of Pertussis in England, 2011-2012: A Case-control Study Comparing 3-Component and 5-Component Acellular Vaccines With Whole-cell Pertussis Vaccines.

In England, acellular pertussis (aP) vaccines replaced whole-cell pertussis (wP) vaccine in the primary immunization course in October 2004. Despite sustained high vaccine coverage, 10 454 cases were confirmed in England in 2011-2012, including 1648 (16%) in those aged 10-19 years. These individuals had been primed with either 3-component (aP3) or 5-component (aP5) aP vaccines or wP vaccine due to temporary supply shortages. We aimed to compare protection provided by different pertussis vaccines. We conducted a case-control study. Individuals born between 1997 and 2005, fully vaccinated in England, were included. Cases were laboratory confirmed between January 2011 and December 2012. Controls were identified from population vaccination registers, representing 20% of the population. We compared the odds of receiving different types of vaccines in cases and controls, adjusting for year of birth and time since last vaccine received. Odds ratios (ORs) were calculated with 95% confidence intervals (CIs). We analyzed 403 cases and 581 971 controls with 4 pertussis vaccines recorded. Compared to those who received 3 doses of wP for the primary course, cases had higher odds of receiving 3 doses of aP3 (OR, 3.86 [95% CI, 2.56-5.82]) but no significant association with receipt of 3 doses of aP5 (OR, 0.89 [95% CI, .29-2.73]). Previous studies have suggested that aP3 and aP5 vaccines provide shorter duration of protection than wP vaccine. Our findings suggest that a primary course with aP3 is associated with increased risk of confirmed pertussis compared with wP. Although follow-up was shorter for aP5 cohorts, their risk did not seem to differ from wP.

Differences in T cell responses to Bordetella Pertussis in adults as a function of whole cell versus acellular childhood vaccination

Abstract In the mid-1990s vaccine-related side effects prompted the replacement of the whole Pertussis (wP) by a new acellular Pertussis vaccine (aP). Unexpectedly, whooping cough cases have recently increased, and the switch to the aP vaccine suspected to underlie this rise in morbidity, despite the use of routine boosters. Here we compared the immune responses to aP boosters in children who received their initial doses with either wP or aP vaccines. The use of ex vivo AIM assays highlighted a Th2 vs Th1/Th17 differential polarization of PT-specific memory CD4+ T cells as a function of childhood vaccination. The nature of the differences was further investigated for memory subset composition, activation, exhaustion marker expression, and transcriptomic profiles. Remarkably, donors originally primed with aP were defective in their ex vivo capacity to expand memory cells following a booster aP immunization and less capable to proliferate in vitro in response to PT epitopes. By contrast antibody responses are boosted in both aP and wP cohorts following IgG subclass distribution. Most recently, we have assessed early immune responses followed aP boosting for the aP and wP cohorts using longitudinal transcriptomics data from PBMC. We have identified several modules of genes that are co-expressed; using cell frequency data from CyTOF we infer modules correlated with specific cell types. Furthermore, we identified certain modules that show differential expression profiles between the two cohorts and are mostly enriched in immune related functions. In conclusion, our data suggest that the original priming after birth with aP and wP vaccines induce different T cell phenotypes associated with long-term T cell polarization.

A Pertussis Outer Membrane Vesicle-Based Vaccine Induces Lung-Resident Memory CD4 T Cells and Protection Against Bordetella pertussis, Including Pertactin Deficient Strains.

Pertussis is a respiratory infectious disease that has been resurged during the last decades. The change from the traditional multi-antigen whole-cell pertussis (wP) vaccines to acellular pertussis (aP) vaccines that consist of a few antigens formulated with alum, appears to be a key factor in the resurgence of pertussis in many countries. Though current aP vaccines have helped to reduce the morbidity and mortality associated with pertussis, they do not provide durable immunity or adequate protection against the disease caused by the current circulating strains of Bordetella pertussis, which have evolved in the face of the selection pressure induced by the vaccines. Based on the hypothesis that a new vaccine containing multiple antigens could overcome deficiencies in the current aP vaccines, we have designed and characterized a vaccine candidate based on outer membrane vesicle (OMVs). Here we show that the OMVs vaccine, but not an aP vaccine, protected mice against lung infection with a circulating pertactin (PRN)-deficient isolate. Using isogenic bacteria that in principle only differ in PRN expression, we found that deficiency in PRN appears to be largely responsible for the failure of the aP vaccine to protect against this circulating clinical isolates. Regarding the durability of induced immunity, we have already reported that the OMV vaccine is able to induce long-lasting immune responses that effectively prevent infection with B. pertussis. Consistent with this, here we found that CD4 T cells with a tissue-resident memory (TRM) cell phenotype (CD44+CD62LlowCD69+ and/or CD103+) accumulated in the lungs of mice 14 days after immunization with 2 doses of the OMVs vaccine. CD4 TRM cells, which have previously been shown to play a critical role sustained protective immunity against B. pertussis, were also detected in mice immunized with wP vaccine, but not in the animals immunized with a commercial aP vaccine. The CD4 TRM cells secreted IFN-γ and IL-17 and were significantly expanded through local proliferation following respiratory challenge of mice with B. pertussis. Our findings that the OMVs vaccine induce respiratory CD4 TRM cells may explain the ability of this vaccine to induce long-term protection and is therefore an ideal candidate for a third generation vaccine against B. pertussis.

Immunization with whole cell but not acellular pertussis vaccines primes CD4 TRM cells that sustain protective immunity against nasal colonization with Bordetella pertussis

ABSTRACT Protective immunity wanes rapidly after immunization of children with acellular pertussis (aP) vaccines and these vaccines do not prevent nasal colonization or transmission of Bordetella pertussis in baboons. In this study, we examined the role of tissue-resident memory T (TRM) cells in persistent protective immunity induced by infection or immunization with aP and whole-cell pertussis (wP) vaccines in mice. Immunization of mice with a wP vaccine protected against lung and nasal colonization, whereas an aP vaccine failed to protect in the nose. IL-17 and IFN-γ-secreting CD69+CD4+ TRM cells were expanded in the lung and nasal tissue after B. pertussis challenge of mice immunized with wP, but not aP vaccines. However, previous infection induced the most persistent protection against nasal colonization and this correlated with potent induction of nasal tissue TRM cells, especially IL-17-secreting TRM cells. Blocking T cell migration to respiratory tissue during immunization with a wP vaccine impaired bacterial clearance, whereas transfer of TRM cells from convalescent or wP-immunized mice conferred protection to naïve mice. Our findings reveal that previous infection or wP vaccination are significantly more effective than aP vaccination in conferring persistent protective immunity against B. pertussis and that this is mediated by respiratory TRM cells.

New Pertussis Vaccines: A Need and a Challenge.

Effective diphtheria, tetanus toxoids, whole-cell pertussis (wP) vaccines were used for massive immunization in the 1950s. The broad use of these vaccines significantly reduced the morbidity and mortality associated with pertussis. Because of reports on the induction of adverse reactions, less-reactogenic acellular vaccines (aP) were later developed and in many countries, especially the industrialized ones, the use of wP was changed to aP. For many years, the situation of pertussis seemed to be controlled with the use of these vaccines, however in the last decades the number of pertussis cases increased in several countries. The loss of the immunity conferred by the vaccines, which is faster in the individuals vaccinated with the acellular vaccines, and the evolution of the pathogen towards geno/phenotypes that escape more easily the immunity conferred by the vaccines were proposed as the main causes of the disease resurgence. According to their composition of few immunogens, the aP vaccines seem to be exerting a greater selection pressure on the circulating bacterial population causing the prevalence of bacterial isolates defective in the expression of vaccine antigens. Under this context, it is clear that new vaccines against pertussis should be developed. Several vaccine candidates are in preclinical development and few others have recently completed phaseI/phaseII trials. Vaccine candidate based on OMVs is a promising candidate since appeared overcoming the major weaknesses of current aP-vaccines. The most advanced development is the live attenuated-vaccine BPZE1 which has successfully completed a first-in-man clinical trial.