Characterization of the immune response induced by pertussis OMVs-based vaccine

For the development of a third generation of pertussis vaccine that could improve the control of the disease, it was proposed that the immune responses induced by the classic whole cell vaccine (wP) or after infection should be used as a reference point. We have recently identified a vaccine candidate based on outer membrane vesicles (OMVs) derived from the disease etiologic agent that have been shown to be safe and protective in mice model of infection. Here we characterized OMVs-mediated immunity and the safety of our new candidate. We also deepen the knowledge of the induced humoral response contribution in pertussis protection. Regarding the safety of the OMVs based vaccine (Tdap_OMVsBp,) the in vitro whole blood human assay here performed, showed that the low toxicity of OMVs-based vaccine previously detected in mice could be extended to human samples.Stimulation of splenocytes from immunized mice evidenced the presence of IFN-γ and IL-17-producing cells, indicated that OMVs induces both Th1 and Th17 response. Interestingly Tdap_OMVsBp-raised antibodies such as those induced by wP and commercial acellular vaccines (aP) which contribute to induce protection against Bordetella pertussis infection. As occurs with wP-induced antibodies, the TdapOMVsBp-induced serum antibodies efficiently opsonized B. pertussis. All the data here obtained shows that OMVs based vaccine is able to induce Th1/Th17 and Th2 mixed profile with robust humoral response involved in protection, positioning this candidate among the different possibilities to constitute the third generation of anti-pertussis vaccines.     

Outer membrane vesicles obtained from Bordetella pertussis Tohama expressing the lipid A deacylase PagL as a novel acellular vaccine candidate

In an effort to devise a safer and effective pertussis acelullar vaccine, outer membrane vesicles (OMVs) were engineered to decrease their endotoxicity. The pagL gene from Bordetella bronchiseptica, which encodes a lipid A 3-deacylase, was expressed in Bordetella pertussis strain Tohama I. The resulting OMVs, designated OMVs_BpPagL, contain tetra- instead of penta-acylated LOS, in addition to pertussis surface immunogens such as pertactin and pertussis toxin, as the wild type OMVs. The characterized pertussis OMVs_BpPagL were used in murine B. pertussis intranasal (i.n.) challenge model to examine their protective capacity when delivered by i.n. routes. Immunized BALB/c mice were challenged with sublethal doses of B. pertussis. Significant differences between immunized animals and the PBS treated group were observed (p < 0.001). Adequate elimination rates (p < 0.005) were observed in mice immunized either with OMVs_BpPagL and wild type OMVs. All OMV preparations tested were non toxic according to WHO criteria; however, OMVs_BpPagL displayed almost no weight loss at 3 days post administration, indicating less toxicity when compared with wild type OMVs. Induction of IL6- and IL1-expression in lung after i.n. delivery as well as neutrophil recruitment to airways showed coincident results, with a lower induction of the proinflammatory cytokines and lower recruitment in the case of OMVs_BpPagL compared to wild type OMVs.Given their lower endotoxic activity and retained protective capacity in the mouse model, OMVs_BpPagL obtained from B. pertussis seem as interesting candidates to be considered for the development of novel multi-antigen vaccine.     

CpG 1018® adjuvant enhances Tdap immune responses against Bordetella pertussis in mice

Bordetella pertussis is the causative agent of whooping cough (pertussis), a severe respiratory disease that can be fatal, particularly in infants. Despite high vaccine coverage, pertussis remains a problem because the currently used DTaP and Tdap vaccines do not completely prevent infection or transmission. It is well established that the alum adjuvant is a potential weakness of the acellular vaccines because the immunity provided by it is short-term. We aimed to evaluate the potential of CpG 1018® adjuvant to improve antibody responses and enhance protection against B. pertussis challenge in a murine model. A titrated range of Tdap vaccine doses were evaluated in order to best identify the adjuvant capability of CpG 1018. Antibody responses to pertussis toxin (PT), filamentous hemagglutinin (FHA), or the whole bacterium were increased due to the inclusion of CpG 1018. In B. pertussis intranasal challenge studies, we observed improved protection and bacterial clearance from the lower respiratory tract due to adding CpG 1018 to 1/20th the human dose of Tdap. Further, we determined that Tdap and Tdap + CpG 1018 were both capable of facilitating clearance of strains that do not express pertactin (PRN^-), which are rising in prevalence. Functional phenotyping of antibodies revealed that the inclusion of CpG 1018 induced more bacterial opsonization and antibodies of the Th1 phenotype (IgG2a and IgG2b). This study demonstrates the potential of adding CpG 1018 to Tdap to improve immunogenicity and protection against B. pertussis compared to the conventional, alum-only adjuvanted Tdap vaccine.     

Persistence of antibodies 3 years after booster vaccination of adults with combined acellular pertussis, diphtheria and tetanus toxoids vaccine

The duration of protection after vaccination with reduced antigen content diphtheria, tetanus and acellular pertussis vaccines (Tdap) is not known. Long-term post-vaccination serological data will help to improve understanding of the duration of humoral immunity and guide vaccination policy for the timing of repeat dose administration. The persistence of antibodies to Tdap antigens was measured 3 years after vaccination of adults 19-64 years of age with one of 2 Tdap vaccines (Boostrix^®, GlaxoSmithKline Biologicals; Tdap-B: or Adacel^®, Sanofi Pasteur; Tdap-A). In both groups, geometric mean concentrations for antibodies to diphtheria, tetanus, and pertussis vaccine antigens were decreased at year 3 relative to levels observed 1 month and 1 year following vaccination, but remained higher than pre-vaccination levels. Seroprotection rates for diphtheria and tetanus remained high for both Tdap vaccines (for diphtheria, 96.9% and 97.8% for the Tdap-B and Tdap-A groups, respectively; for tetanus, 98.1% and 99.6%, respectively).     

Vaccination of adults 65 years of age and older with tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine (Boostrix(®)): results of two randomized trials

Background

Pertussis can cause significant morbidity in elderly patients, who can also transmit this disease to infants and young children. There is little data available on the use of acellular pertussis vaccines in recipients ≥65 years of age.

Methods

Two studies examined the safety and immunogenicity of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine (Boostrix^®) in healthy ≥65 year olds. In Study A subjects received single doses of Tdap and seasonal influenza vaccine either co-administered or given one month apart. In Study B subjects received either Tdap or tetanus-diphtheria (Td) vaccine. Antibodies were measured before and one month after vaccination. Reactogenicity and safety were actively assessed using diary cards.

Results

A total of 1104 subjects 65 years of age and older received a Tdap vaccination in the two studies. In study A, no differences in immune responses to Tdap or influenza vaccine were observed between co-administered or sequentially administered vaccines. In study B, Tdap was non-inferior to Td with respect to diphtheria and tetanus seroprotection, and anti-pertussis GMCs were non-inferior to those observed in infants following a 3-dose diphtheria, tetanus and acellular pertussis (DTaP) primary vaccination series, in whom efficacy against pertussis was demonstrated. Reports of adverse events were similar between Tdap and Td groups.

Conclusions

Tdap was found to be immunogenic in subjects ≥65 years, with a safety profile comparable to US-licensed Td vaccine. Tdap and influenza vaccine may be co-administered without compromise of either the reactogenicity or immunogenicity profiles of the two vaccines.     

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.     

A phase 2 randomized controlled dose-ranging trial of recombinant pertussis booster vaccines containing genetically inactivated pertussis toxin in pregnant women

IntroductionDespite a decrease in infections caused by Bordetella pertussis due to COVID-19 pandemic, booster vaccination of pregnant women is still recommended to protect newborns. Highly immunogenic vaccines containing genetically inactivated pertussis toxin (PT_gen) and filamentous hemagglutinin (FHA) may generate comparable anti-PT antibody concentrations, even at lower doses, to chemically inactivated acellular pertussis vaccines (Tdap_chem) shown effective for maternal immunization.MethodsThis phase 2 randomized, observer-blind, active-controlled non-inferiority trial was conducted in healthy Thai pregnant women randomly assigned to receive one dose of low-dose recombinant pertussis-only vaccine containing 1 µg PT_gen and 1 µg FHA (ap1_gen), or tetanus, reduced-dose diphtheria combined with ap1_gen (Tdap1_gen), or combined with 2 µg PT_gen and 5 µg FHA (Tdap2_gen), or with 5 µg PT_gen and 5 µg FHA (TdaP5_gen, Boostagen®) or comparator containing 8 µg of chemically inactivated pertussis toxoid, 8 µg FHA, and 2.5 µg pertactin (Boostrix™, Tdap8_chem). Blood was collected at Day 0 and Day 28 post-vaccination. The non-inferiority of the study vaccines was assessed based on anti-PT IgG antibody levels on Day 28 pooled with results from a similarly structured previous trial in non-pregnant women.Results400 healthy pregnant women received one dose of vaccine. Combined with data from 250 non-pregnant women, all study vaccines containing PT_gen were non-inferior to comparator vaccine (Tdap8_chem). Both ap1_gen and TdaP5_gen vaccines could be considered to have superior immunogenicity to Tdap8_chem. Local and systemic solicited reactions were similar among all vaccine groups.ConclusionsVaccine formulations containing PT_gen were safe and immunogenic in pregnant women. The ap1_gen vaccine, with the lowest cost and reactogenicity, may be suitable for use in pregnant women when diphtheria and tetanus toxoids are not needed.This study is registered in the Thai Clinical Trial Registry (www.clinicaltrials.in.th), number TCTR20180725004.     

Assessing the reactogenicity of Tdap vaccine administered during pregnancy and antibodies to Bordetella pertussis antigens in maternal and cord sera of Thai women

IntroductionPregnant Thai women have low antibody titers against B. pertussis antigens, which coincide with an increasing incidence of pertussis among Thai infants. Thus, there exists a potential benefit of a booster dose of tetanus- diphtheria-acellular pertussis (Tdap) vaccine administered during pregnancy. Here, we report the vaccine reactogenicity profile and birth outcomes in Tdap-vaccinated pregnant women who have or have not had prior immunization with tetanus vaccine, and the IgG levels to B. pertussis antigens in maternal and cord sera at delivery.Materials and methodsPregnant women (N = 370) aged 18–40 years were administered the Tdap vaccine (Boostrix®, GlaxoSmithKline, Rixensart, Belgium) at 26–36 weeks gestation. Adverse events following vaccination were identified by follow-up telephone call and medical record review. IgG against pertussis toxin (anti-PT), filamentous hemagglutinin (anti-FHA) and pertactin (anti-PRN) in both maternal and umbilical cord blood obtained at delivery were quantitatively evaluated using enzyme-linked immunosorbent assay (EUROIMMUN®, Lübeck, Germany).ResultsThere was no reported increase in the severity or duration of adverse events associated with the administration of an extra tetanus-containing vaccine within the previous five years (N = 181) or multiple doses of tetanus-containing vaccines during the current pregnancy (N = 98). Vaccination at least eight weeks prior to delivery resulted in high antibody titers to all B. pertussis antigens studied.ConclusionsThe reactogenicity of Tdap vaccine administered during pregnancy was not affected by prior tetanus toxoid immunization. High transplacental antibody against B. pertussis antigens in the cord blood provides evidence of antibody transfer and should thus help to protect newborns from pertussis during early life.     

Immunogenicity of a low-dose diphtheria,tetanus and acellular pertussis combination vaccine with either inactivated or oral polio vaccine compared to standard-dose diphtheria,tetanus, acellular pertussis when used as a pre-school booster in UK children: A 5-year follow-up of a randomised controlled study

This serological follow up study assessed the kinetics of antibody response in children who previously participated in a single centre, open-label, randomised controlled trial of low-dose compared to standard-dose diphtheria booster preschool vaccinations in the United Kingdom (UK). Children had previously been randomised to receive one of three combination vaccines: either a combined adsorbed tetanus, low-dose diphtheria, 5-component acellular pertussis and inactivated polio vaccine (IPV) (Tdap–IPV, Repevax^®; Sanofi Pasteur MSD); a combined adsorbed tetanus, low-dose diphtheria and 5-component acellular pertussis vaccine (Tdap, Covaxis^®; Sanofi Pasteur MSD) given concomitantly with oral polio vaccine (OPV); or a combined adsorbed standard-dose diphtheria, tetanus, 2-component acellular pertussis and IPV (DTap–IPV, Tetravac^®; Sanofi Pasteur MSD). Blood samples for the follow-up study were taken at 1, 3 and 5 years after participation in the original trial (median, 5.07 years of age at year 1), and antibody persistence to each vaccine antigen measured against defined serological thresholds of protection.All participants had evidence of immunity to diphtheria with antitoxin concentrations greater than 0.01 IU/mL five years after booster vaccination and 75%, 67% and 79% of children who received Tdap–IPV, Tdap + OPV and DTap–IPV, respectively, had protective antitoxin levels greater than 0.1 IU/mL. Long lasting protective immune responses to tetanus and polio antigens were also observed in all groups, though polio responses were lower in the sera of those who received OPV.Low-dose diphtheria vaccines provided comparable protection to the standard-dose vaccine and are suitable for use for pre-school booster vaccination.     

Characterization of the key antigenic components of pertussis vaccine based on outer membrane vesicles

Pertussis has resurged during the last two decades in different countries. In particular in the 2010–2013 period large outbreaks were detected in US, Australia, UK and The Netherlands with significant mortality in infants. The epidemiological situation of pertussis points out the need to develop new vaccines and in this regard we previously developed a new vaccine based on outer membrane vesicles (OMVs) which have been shown to be safe and to induce protection in mice. Here we have further investigated the properties of OMVs vaccines; in particular we studied the contribution of pertussis toxin (PTx) and pertactin (Prn) in OMVs-mediated protection against pertussis. PTx-deficient OMVs and Prn-deficient OMVs were obtained from defective Bordetella pertussis mutants. The absence of PTx or Prn did compromise the protective capacity of the OMVs formulated as Tdap vaccine. Whereas the protective efficacy of the PTx-deficient OMVs in mice was comparable to Prn-deficient OMVs, the protective capacity of both of them was significantly impaired when it was compared with the wild type OMVs. Interestingly, using OMVs obtained from a B. pertussis strain which does not express any of the virulence factors but expresses the avirulent phenotype; we observed that the protective ability of such OMVs was lower than that of OMVs obtained from virulent B. pertussis phase. However, it was surprising that although the protective capacity of avirulent OMVs was lower, they were still protective in the used mice model. These results allow us to hypothesize that OMVs from avirulent phase shares protective components with all OMVs assayed. Using an immune proteomic strategy we identified some common components that could play an important role in protection against pertussis.     

DNA vaccine encoding type IV pilin of Actinobacillus pleuropneumoniae induces strong immune response but confers limited protective efficacy against serotype 2 challenge

Actinobacillus pleuropneumoniae is a gram-negative bacterial pathogen that causes swine pleuropneumonia, a highly contagious and often fatal disease that occurs worldwide. Our previous study showed that DNA vaccines encoding Apx exotoxin structural proteins ApxIA and/or ApxIIA, are a promising novel approach for immunization against the lethal challenge of A. pleuropneumoniae serotype 1. Vaccination against A. pleuropneumoniae is impeded by the lack of vaccines inducing reliable cross-serotype protection. Type IV fimbrial protein ApfA has been shown to be present and highly conserved in various serotypes of A. pleuropneumoniae. A novel DNA vaccine encoding ApfA (pcDNA-apfA) was constructed to evaluate the protective efficacy against infection with A. pleuropneumoniae serotype 2. A significant antibody response against pilin was generated following pcDNA-apfA immunization, suggesting that it was expressed in vivo. The IgG subclass (IgG1 and IgG2a) analysis indicates that the pcDNA-apfA vaccine induces both Th1 and Th2 immune responses. The IgA analysis shows that mucosal immunity could be enhanced by this DNA vaccine. Nevertheless, the strong antibody response induced by pcDNA-apfA vaccine only provided limited 30% protective efficacy against the serotype 2 challenge. These results in this study do not coincide with that the utility of type IV pilin is a good vaccine candidate against other infectious pathogens. It indicates that pilin should play a limited role in the development of a vaccine against A. pleuropneumoniae infection.     

Immunogenicity of reduced antigen content tetanus-diphtheria-acellular pertussis vaccine in adolescents as a sixth consecutive dose of acellular pertussis-containing vaccine

Three hundred and nineteen adolescents aged 10-12 years who had been previously vaccinated with five doses of acellular pertussis-containing vaccines received single doses of Tdap (reduced-antigen-content tetanus, diphtheria, acellular pertussis) and hepatitis A vaccines in a double-blind crossover trial. Long-term antibody persistence following vaccination with Tdap at pre-school age was similar to that following vaccination with DTaP (diphtheria-tetanus-acellular pertussis). After the sixth dose booster, Tdap induced a vigorous immune response, consistent with protection against diphtheria, tetanus and pertussis diseases.     

Heat shock protein complex vaccination induces protection against Helicobacter pylori without exogenous adjuvant

Background

The development of a vaccine against the human gastric pathogen Helicobacter pylori, the main causative agent of gastric adenocarcinoma, has been hampered by a number of issues, including the lack of a mucosal adjuvant for use in humans. Heat shock proteins (Hsp), highly conserved molecules expressed by both bacteria and mammalian species, possess a range of functions, including acting as chaperones for cellular proteins and the ability to activate innate immune receptors. Hsp complex (HspC) vaccines, containing Hsp derived from pathogenic bacteria, are immunostimulatory without addition of an exogenous adjuvant and can induce immunity against their chaperoned proteins. In this study we explored in mice the potential utility of a H. pylori HspC vaccine.

Results

Vaccination with H. pylori HspC, by either the subcutaneous or respiratory mucosal route, induced a strong antibody response, elevated gastric cytokine levels and significant protection against subsequent live challenge with this pathogen. The level of protection induced by non-adjuvanted HspC vaccine was equivalent to that which resulted from vaccination with adjuvanted vaccines. While protection induced by immunisation with adjuvanted vaccines was associated with the development of a moderate to severe atrophic gastritis, that induced by H. pylori HspC only resulted in a mild inflammatory response, despite an increase in pro-inflammatory gastric cytokines. This reduced gastritis correlated with an increase in IL-10 and IL-13 levels in the gastric tissues of HspC vaccinated, H. pylori challenged mice.

Conclusions

H. pylori HspC vaccines have the potential to overcome some of the issues preventing the development of a human vaccine against this pathogen: HspC induced protective immunity against H. pylori without addition of an adjuvant and without the induction of a severe inflammatory response. However, complete protection was not obtained so further optimisation of this technology is needed if a human vaccine is to become a reality.     

Randomized study of immune responses to two Tdap vaccines among adolescents primed with DTaP and comparison with results among adolescents primed with DTwP

BackgroundIt has been reported that persons primed with acellular (DTaP) pertussis vaccines have reduced duration of pertussis protection compared with those primed with whole-cell (DTwP) vaccines. However, due to the rapid transition to acellular vaccines, studies attempting directly to compare protection among DTaP-primed vs DTwP-primed individuals are subject to confounding by age and other limitations of ecological studies. Using validated assay results and stored sera from multiple Tdap studies, we evaluated two licensed Tdap vaccines among DTaP-primed adolescents to allow comparison with results obtained in the same laboratory from earlier studies involving DTwP-primed adolescents.MethodsParticipants 11–12 years of age who had received exactly 5 doses of DTaP vaccine prior to 7 years of age were randomly assigned in 2012 to receive one of two licensed Tdap vaccines. Serum specimens obtained pre- and post-vaccination were assayed for responses to the vaccines. Current results were then compared to results obtained in the same laboratory from prior randomized Tdap studies conducted among adolescents primed with DTwP or DTaP.ResultsBoth Tdap vaccines produced strong antibody responses to diphtheria and tetanus; responses to contained pertussis antigens were consistent with the differing levels of those antigens in each Tdap vaccine. However, postvaccination pertussis antibody responses were as much as 71% lower in these DTaP-primed adolescents compared with responses among DTwP-primed adolescents in a prior study of the same two Tdap vaccines. In contrast, results from the present study were similar to those seen in another study of Tdap among DTaP-primed adolescents.DiscussionTaken together, these results from randomized clinical trials provide direct evidence of reduced antibody responses to both licensed Tdap vaccines among adolescents primed with DTaP vaccine, compared with adolescents primed with DTwP vaccine.Clinical trial registry number: ClinicalTrials.gov, NCT01629589.     

Pertactin deficient Bordetella pertussis present a better fitness in mice immunized with an acellular pertussis vaccine

Bordetella pertussis is the etiologic agent of whooping cough and has been the target of vaccination for over fifty years. The latest strategies include the use of acellular pertussis vaccines that induce specific immunity against few virulence factors amongst which pertactin is included in three and five component acellular pertussis vaccines. Recently, it has been reported that B. pertussis clinical isolates loose the production of this adhesin in regions reaching high vaccine coverage with vaccines targeting this virulence factor. We here demonstrate that isolates not producing pertactin are capable of sustaining longer infection as compared to pertactin producing isolates in an in vivo model of acellular pertussis immunization. Loosing pertactin production might thus provide a selective advantage to these isolates in this background, which could account for the upraise in prevalence of these pertactin deficient isolates in the population.     

Whole-cell or acellular pertussis vaccination in infancy determines IgG subclass profiles to DTaP booster vaccination

IntroductionDuration of protection against pertussis is shorter in adolescents who have been immunized with acellular pertussis (aP) in infancy compared with adolescents who received whole-cell pertussis (wP) vaccines in infancy, which is related to immune responses elicited by these priming vaccines. To better understand differences in vaccine induced immunity, we determined pertussis, diphtheria, and tetanus (DTaP) vaccine antigen-specific IgG subclass responses in wP- and aP-primed children before and after two successive DTaP booster vaccinations.MethodsBlood samples were collected in a cross-sectional study from wP- or aP-primed children before and 1 month after the pre-school DTaP booster vaccination at age 4 years. Blood samples were collected from two different wP- and aP-primed groups of children before, 1 month and 1 year after an additional pre-adolescent Tdap booster at age 9 years. IgG subclass levels against the antigens included in the DTaP vaccine have been determined with fluorescent-bead-based multiplex immunoassays.ResultsAt 4 years of age, the IgG4 proportion and concentration for pertussis, diphtheria and tetanus vaccine antigens were significantly higher in aP-primed children compared with wP-primed children. IgG4 concentrations further increased upon the two successive booster vaccinations at 4 and 9 years of age in both wP- and aP-primed children, but remained significantly higher in aP-primed children.ConclusionsThe pertussis vaccinations administered in the primary series at infancy determine the vaccine antigen-specific IgG subclass profiles, not only against the pertussis vaccine antigens, but also against the co-administered diphtheria and tetanus vaccine antigens. These profiles did not change after DTaP booster vaccinations later in childhood. The different immune response with high proportions of specific IgG4 in some aP-primed children may contribute to a reduced protection against pertussis.ISRCTN65428640; ISRCTN64117538; NTR4089.     

Acellular pertussis vaccine use in risk groups (adolescents, pregnant women, newborns and health care workers): a review of evidences and recommendations

Background

Pertussis is an acute infectious illness, caused by the bacteria Bordetella pertussis and commonly known as “whooping cough”. Waning immunity after vaccination or after natural infection contributes significantly to the increasing incidence rates in adolescents and adults. Prevention of pertussis in industrialized countries is mainly based on immunization with acellular vaccines in combination with other antigens. A booster dose with an adult-formulation tetanus-diphtheria toxoid and acellular pertussis vaccine (Tdap) is now recommended for all adolescents by several countries, and replacement of the decennial Td dose with a single or more doses of Tdap is recommended for adults.

Objective

Our review aims at describing the current knowledge on the impact of acellular pertussis vaccination in adolescents and adults, with particular focus on specific risk groups: adolescents, pregnant women and their newborns, and health care workers (HCWs), and secondly at suggesting possible immunization strategies.

Methods

Data were retrieved by searches of Pubmed, references, from relevant articles and open-access websites.

Results

In countries where an adolescent booster dose was adopted, a certain decrease of incidence rates was observed. No serologic correlate of protection after immunization exists, but subjects with high antibody levels against pertussis antigens are less likely to develop the disease. Tdap vaccine was demonstrated to induce antibodies to pertussis antigens exceeding those associated with efficacy in infants, in both adolescents and adults. Tdap use in pregnant women seems to be safe and might represent a useful tool in order to prevent pertussis cases in the first months of life. Neonatal immunization with monovalent acellular pertussis vaccine can efficiently prime T and B cells and act as a basis for future immune responses. Cocooning strategies involving all those surrounding newborns have started to be implemented. Their impact on infant pertussis cases will be evaluated in the coming years. Coverage in HCWs should be increased, given their important role in pertussis transmission in health care settings.

Conclusions

Despite the more recent position paper of WHO gives priority to infant and childhood vaccination against pertussis and leaves adolescent, adult and risk group immunization as an option for the future, data are quickly accumulating to support the need to consider pertussis vaccination as a crucial preventative intervention even in adolescents and special risk groups.     

Long-term immunity against pertussis induced by a single nasal administration of live attenuated B. pertussis BPZE1

Duration of vaccine-induced immunity plays a key role in the epidemiology and in the pattern of transmission of a vaccine-preventable disease. In the case of whooping cough, its re-emergence has been attributed, at least partly, to the waning of immunity conferred by current pertussis vaccines. We have recently developed a highly attenuated live vaccine, named BPZE1, which has been shown to be safe and to induce strong protective immunity against Bordetella pertussis infection in mice. In this study, we evaluated the long-term immunogenicity and protective efficacy induced by a single intranasal dose of BPZE1. Up to 1 year after immunization, BPZE1 showed significantly higher efficacy to protect adult and infant mice against B. pertussis infection than two administrations of an acellular pertussis vaccine (aPV). B. pertussis-specific antibodies were induced by live BPZE1 and by aPV, with increasing amounts during the first 6 months post-immunization before a progressive decline. Cell-mediated immunity was also measured 1 year after immunization and showed the presence of memory T cells in the spleen of BPZE1-immunized mice. Both cell-mediated and humoral immune responses were involved in the long-lasting protection induced by BPZE1, as demonstrated by adoptive transfer experiments to SCID mice. These data highlight the potential of the live attenuated BPZE1 candidate vaccine as part of a strategy to solve the problem of waning protective immunity against B. pertussis observed with the current aPV vaccines.     

A gold glyco-nanoparticle carrying a listeriolysin O peptide and formulated with Advax™ delta inulin adjuvant induces robust T-cell protection against listeria infection

In the search for an effective vaccine against the human pathogen, Listeria monocytogenes (Listeria), gold glyconanoparticles (GNP) loaded with a listeriolysin O peptide LLO_91–99 (GNP-LLO) were used to immunise mice, initially using a dendritic cell (DC) vaccine approach, but subsequently using a standard parenteral immunisation approach. To enhance vaccine immunogenicity a novel polysaccharide adjuvant based on delta inulin (Advax™) was also co-formulated with the GNP vaccine. Confirming previous results, DC loaded in vitro with GNP-LLO provided better protection against listeriosis than DC loaded in vitro using free LLO peptide. The immunogenicity of GNP-LLO loaded DC vaccines was further increased by addition of Advax™ adjuvant. However, as DC vaccines are expensive and impracticable for prophylactic use, we next asked whether the same GNP-LLO antigen could be used to directly target DC in vivo. Immunisation of mice with GNP-LLO plus Advax™ adjuvant induced LLO-specific T-cell immunity and protection against Listeria challenge. Protection correlated with an increased frequency of splenic CD4⁺ and CD8⁺ T cells, NK cells and CD8α⁺ DC, and Th1 cytokine production (IL-12, IFN-γ, TNF-α, and MCP-1), post-challenge. Enhanced T-cell epitope recruitment post-challenge was seen in the groups that received Advax™ adjuvant. Immunisation with GNP-LLO_91–99 plus Advax™ adjuvant provided equally robust Listeria protection as the best DC vaccine strategy but without the complexity and cost, making this a highly promising strategy for development of a prophylactic vaccine against listeriosis.     

Increasing FIM2/3 antigen-content improves efficacy of Bordetella pertussis vaccines in mice in vivo without altering vaccine-induced human reactogenicity biomarkers in vitro

Current acellular-pertussis (aP) vaccines appear inadequate for long-term pertussis control because of short-lived efficacy and the increasing prevalence of pertactin-negative isolates which may negatively impact vaccine efficacy. In this study, we added fimbriae (FIM)2 and FIM3 protein to licensed 2-, 3- or 5-component aP vaccines (Pentavac®, Boostrix®, Adacel®, respectively) to assess whether an aP vaccine with enhanced FIM content demonstrates enhanced efficacy. Vaccine-induced protection was assessed in an intranasal mouse challenge model. In addition, potential reactogenicity was measured by biomarkers in a human whole blood assay (WBA) in vitro and benchmarked the responses against licensed whole cell pertussis (wP) and aP vaccines including Easyfive®, Pentavac® and Pentacel®. The results show that commercial vaccines demonstrated reduced efficacy against pertactin-negative versus pertactin-positive strains. However, addition of higher amounts of FIM2/3 to aP vaccines reduced lung colonization and increased vaccine efficacy against a pertactin-negative strain in a dose-dependent manner. Improvements in efficacy were similar for FIM2 and FIM3-expressing strains. Increasing the amount of FIM2/3 proteins in aP formulations did not alter vaccine-induced biomarkers of potential reactogenicity including prostaglandin E₂, cytokines and chemokines in human newborn cord and adult peripheral blood tested in vitro. These results suggest that increasing the quantity of FIM proteins in current pertussis vaccine formulations may further enhance vaccine efficacy against B. pertussis infection without increasing the reactogenicity of the vaccine.