Immunogenicity, reactogenicity, and IgE-mediated immune responses of a mixed whole-cell and acellular pertussis vaccine schedule in Australian infants: A randomised, double-blind, noninferiority trial.

BACKGROUND: In many countries, infant vaccination with acellular pertussis (aP) vaccines has replaced use of more reactogenic whole-cell pertussis (wP) vaccines. Based on immunological and epidemiological evidence, we hypothesised that substituting the first aP dose in the routine vaccination schedule with wP vaccine might protect against IgE-mediated food allergy. We aimed to compare reactogenicity, immunogenicity, and IgE-mediated responses of a mixed wP/aP primary schedule versus the standard aP-only schedule. METHODS AND FINDINGS: OPTIMUM is a Bayesian, 2-stage, double-blind, randomised trial. In stage one, infants were assigned (1:1) to either a first dose of a pentavalent wP combination vaccine (DTwP-Hib-HepB, Pentabio PT Bio Farma, Indonesia) or a hexavalent aP vaccine (DTaP-Hib-HepB-IPV, Infanrix hexa, GlaxoSmithKline, Australia) at approximately 6 weeks old. Subsequently, all infants received the hexavalent aP vaccine at 4 and 6 months old as well as an aP vaccine at 18 months old (DTaP-IPV, Infanrix-IPV, GlaxoSmithKline, Australia). Stage two is ongoing and follows the above randomisation strategy and vaccination schedule. Ahead of ascertainment of the primary clinical outcome of allergist-confirmed IgE-mediated food allergy by 12 months old, here we present the results of secondary immunogenicity, reactogenicity, tetanus toxoid IgE-mediated immune responses, and parental acceptability endpoints. Serum IgG responses to diphtheria, tetanus, and pertussis antigens were measured using a multiplex fluorescent bead-based immunoassay; total and specific IgE were measured in plasma by means of the ImmunoCAP assay (Thermo Fisher Scientific). The immunogenicity of the mixed schedule was defined as being noninferior to that of the aP-only schedule using a noninferiority margin of 2/3 on the ratio of the geometric mean concentrations (GMR) of pertussis toxin (PT)-IgG 1 month after the 6-month aP. Solicited adverse reactions were summarised by study arm and included all children who received the first dose of either wP or aP. Parental acceptance was assessed using a 5-point Likert scale. The primary analyses were based on intention-to-treat (ITT); secondary per-protocol (PP) analyses were also performed. The trial is registered with ANZCTR (ACTRN12617000065392p). Between March 7, 2018 and January 13, 2020, 150 infants were randomised (75 per arm). PT-IgG responses of the mixed schedule were noninferior to the aP-only schedule at approximately 1 month after the 6-month aP dose [GMR = 0·98, 95% credible interval (0·77 to 1·26); probability (GMR > 2/3) > 0·99; ITT analysis]. At 7 months old, the posterior median probability of quantitation for tetanus toxoid IgE was 0·22 (95% credible interval 0·12 to 0·34) in both the mixed schedule group and in the aP-only group. Despite exclusions, the results were consistent in the PP analysis. At 6 weeks old, irritability was the most common systemic solicited reaction reported in wP (65 [88%] of 74) versus aP (59 [82%] of 72) vaccinees. At the same age, severe systemic reactions were reported among 14 (19%) of 74 infants after wP and 8 (11%) of 72 infants after aP. There were 7 SAEs among 5 participants within the first 6 months of follow-up; on blinded assessment, none were deemed to be related to the study vaccines. Parental acceptance of mixed and aP-only schedules was high (71 [97%] of 73 versus 69 [96%] of 72 would agree to have the same schedule again). CONCLUSIONS: Compared to the aP-only schedule, the mixed schedule evoked noninferior PT-IgG responses, was associated with more severe reactions, but was well accepted by parents. Tetanus toxoid IgE responses did not differ across the study groups. TRIAL REGISTRATION: Trial registered at the Australian and New Zealand Clinical 207 Trial Registry (ACTRN12617000065392p).

Antibodies binding diverse pertactin epitopes protect mice from Bordetella pertussis infection.

Infection by the bacterium Bordetella pertussis continues to cause considerable morbidity and mortality worldwide. Many current acellular pertussis vaccines include the antigen pertactin, which has presumptive adhesive and immunomodulatory activities, but is rapidly lost from clinical isolates after the introduction of these vaccines. To better understand the contributions of pertactin antibodies to protection and pertactin's role in pathogenesis, we isolated and characterized recombinant antibodies binding four distinct epitopes on pertactin. We demonstrate that four of these antibodies bind epitopes that are conserved across all three classical Bordetella strains, and competition assays further showed that antibodies binding these epitopes are also elicited by B. pertussis infection of baboons. Surprisingly, we found that representative antibodies binding each epitope protected mice against experimental B. pertussis infection. A cocktail of antibodies from each epitope group protected mice against a subsequent lethal dose of B. pertussis and greatly reduced lung colonization levels after sublethal challenge. Each antibody reduced B. pertussis lung colonization levels up to 100-fold when administered individually, which was significantly reduced when antibody effector functions were impaired, with no antibody mediating antibody-dependent complement-induced lysis. These data suggest that antibodies binding multiple pertactin epitopes protect primarily by the same bactericidal mechanism, which overshadows contributions from blockade of other pertactin functions. These antibodies expand the available tools to further dissect pertactin's role in infection and understand the impact of antipertactin antibodies on bacterial fitness.

Assessing the In Vivo Effectiveness of Cationic Lipid Nanoparticles with a Triple Adjuvant for Intranasal Vaccination against the Respiratory Pathogen Bordetella pertussis.

Continuous outbreaks of pertussis around the world suggest inadequate immune protection in infants and weakened immune responses induced over time by the acellular pertussis vaccine. Vaccine adjuvants provide a means to improve vaccine immunogenicity and support long-term adaptive immunity against pertussis. An acellular pertussis vaccine was prepared with pertactin, pertussis toxin, and fimbriae 2/3 antigens combined with a triple-adjuvant system consisting of innate defense regulator peptide IDR 1002, a Toll-like receptor-3 agonist poly(I:C), and a polyphosphazene in a fixed combination. The vaccine was delivered intranasally in a cationic lipid nanoparticle formulation fabricated by simple admixture and two schema for addition of antigens (LT-A, antigens associated outside of L-TriAdj, and LAT, antigens associated inside of L-TriAdj) to optimize particle size and cationic surface charge. In the former, antigens were associated with the lipidic formulation of the triple adjuvant by electrostatic attraction. In the latter, the antigens resided in the interior of the lipid nanoparticle. Two dose levels of antigens were used with adjuvant comprised of the triple adjuvant with or without the lipid nanoparticle carrier. Formulation of vaccines with the triple adjuvant stimulated systemic and mucosal immune responses. The lipid nanoparticle vaccines favored a Th1 type of response with higher IgG2a and IgA serum antibody titers particularly for pertussis toxin and pertactin formulated at the 5 µg dose level in the admixed formulation. Additionally, the lipid nanoparticle vaccines resulted in high nasal SIgA antibodies and an early (4 weeks post vaccination) response after a single vaccination dose. The LT-A nanoparticles trended toward higher titers of serum antibodies compared to LAT. The cationic lipid-based vaccine nanoparticles formulated with a triple adjuvant showed encouraging results as a potential formulation for intranasally administered pertussis vaccines.

Overcoming Waning Immunity in Pertussis Vaccines: Workshop of the National Institute of Allergy and Infectious Diseases.

Despite high vaccine coverage in many parts of the world, pertussis is resurging in a number of areas in which acellular vaccines are the primary vaccine administered to infants and young children. This is attributed in part to the suboptimal and short-lived immunity elicited by acellular pertussis vaccines and to their inability to prevent nasal colonization and transmission of the etiologic agent Bordetella pertussis In response to this escalating public health concern, the National Institute of Allergy and Infectious Diseases held the workshop "Overcoming Waning Immunity in Pertussis Vaccines" in September 2019 to identify issues and possible solutions for the defects in immunity stimulated by acellular pertussis vaccines. Discussions covered aspects of the current problem, gaps in knowledge and possible paths forward. This review summarizes presentations and discussions of some of the key points that were raised by the workshop.

Pertussis (Whooping Cough).

Pertussis (whooping cough) is a respiratory infection caused by Bordetella pertussis. All ages are susceptible. In the prevaccine era, almost all children became infected. Pertussis is particularly dangerous in young infants, who account for practically all hospitalizations and deaths, but clinical disease is burdensome at any age. Widespread use of pertussis vaccines dramatically reduced cases, but concern over adverse reactions led to the replacement of standard whole-cell by acellular pertussis vaccines that contain only a few selected pertussis antigens and are far less reactogenic. Routine administration of acellular pertussis vaccines combined with diphtheria and tetanus toxoids is recommended in infancy with toddler and preschool boosters, at age 11, and during pregnancy. Boosting in the second half of every pregancy is critical to protection of the newborn. Waning of vaccine immunity over time has become an increasing concern, and several new pertussis vaccines are being evaluated to address this problem.

Intranasal Immunization with Acellular Pertussis Vaccines Results in Long-Term Immunity to Bordetella pertussis in Mice.

Bordetella pertussis colonizes the respiratory mucosa of humans, inducing an immune response seeded in the respiratory tract. An individual, once convalescent, exhibits long-term immunity to the pathogen. Current acellular pertussis (aP) vaccines do not induce the long-term immune response observed after natural infection in humans. In this study, we evaluated the durability of protection from intranasal (i.n.) pertussis vaccines in mice. Mice that convalesced from B. pertussis infection served as a control group. Mice were immunized with a mock vaccine (phosphate-buffered saline [PBS]), aP only, or an aP base vaccine combined with one of the following adjuvants: alum, curdlan, or purified whole glucan particles (IRI-1501). We utilized two study designs: short term (challenged 35 days after priming vaccination) and long term (challenged 6 months after boost). The short-term study demonstrated that immunization with i.n. vaccine candidates decreased the bacterial burden in the respiratory tract, reduced markers of inflammation, and induced significant serum and lung antibody titers. In the long-term study, protection from bacterial challenge mirrored the results observed in the short-term challenge study. Immunization with pertussis antigens alone was surprisingly protective in both models; however, the alum and IRI-1501 adjuvants induced significant B. pertussis-specific IgG antibodies in both the serum and lung and increased numbers of anti-B. pertussis IgG-secreting plasma cells in the bone marrow. Our data indicate that humoral responses induced by the i.n. vaccines correlated with protection, suggesting that long-term antibody responses can be protective.

Lack of evidence supporting a role of IFN-ß and TGF-ß in differential polarization of Bordetella pertussis specific-T cell responses.

Bordetella Pertussis (BP) vaccine-induced immunity is waning worldwide despite excellent vaccine coverage. Replacement of the whole-cell inactivated vaccine (wP) by an acellular subunit vaccine (aP) is thought to play a major role and to be associated with the recurrence of whooping cough. Previously, we detected that the polarization towards a Th2 and Th1/Th17 response in aP and wP vaccinees, respectively, persists upon aP boosting in adolescents and adults. Additionally, IL-9 and TGF-ß were found to be up-regulated in aP-primed donors and network analysis further identified IFN-ß as a potential upstream regulator of IL-17 and IL-9. Based on these findings, we hypothesized that IFN-ß produced following aP vaccination may lead to increased IL-9 and decreased IL-17 production. Also, due to the well characterized role of TGF-ß in both Th17 and Th9 differentiation, we put forth that TGF-ß addition to BP-stimulated CD4 + T cells might modulate IL-17 and IL-9 production. To test this hypothesis, we stimulated in vitro cultures of PBMC or isolated naive CD4 + T cells from aP vs wP donors with a pool of BP epitopes and assessed the effect of IFN-ß or TGF-ß in proliferative responses as well as in the cytokine secretion of IL-4, IL-9, IL-17, and IFN-γ. IFN-ß reduced BP-specific proliferation in PBMC as well as cytokine production but increased IL-9, IL-4, and IFN-γ cytokines in naïve CD4 + T cells. These effects were independent of the childhood vaccination received by the donors. Similarly, TGF-ß reduced BP-specific proliferation in PBMC but induced proliferation in naïve CD4 + T cells. However, stimulation was associated with a generalized inhibition of cytokine production regardless of the original aP or wP vaccination received by the donors. Our study suggests that key T cell functions such as cytokine secretion are under the control of antigen stimulation and environmental cues but molecular pathways different than the ones investigated here might underlie the long-lasting differential cytokine production associated with aP- vs wP-priming in childhood vaccination.

Effectiveness of experimental and commercial pertussis vaccines in the elimination of Bordetella pertussis isolates with different genetic profiles in murine model.

The aim of this study was to compare the elimination of Bordetella pertussis clinical isolates, representing different genotypes in relation to alleles encoding virulence factors (MLST-multi-locus antigen sequence typing), MLVA type (multi-locus variable-number tandem repeat analysis) and PFGE group (pulsed-field gel electrophoresis) from the lungs of naive mice or mice were immunised with the commercial whole-cell pertussis vaccine, the acellular pertussis vaccine and the experimental whole-cell pertussis vaccine. Molecular data indicate that the resurgence of pertussis in populations with high vaccine coverage is associated with genomic adaptation of B. pertussis, to vaccine selection pressure. Pertactin-negative B. pertussis isolates were suspected to contribute to the reduced vaccine effectiveness. It was shown that one of the isolates used is PRN deficient. The mice were intranasally challenged with bacterial suspension containing approximately 5 × 10 7 CFU/ml B. pertussis. The immunogenicity of the tested vaccines against PT (pertussis toxin), PRN (pertactin), FHA (filamentous haemagglutinin) and FIM (fimbriae types 2 and 3) was examined. The commercial whole-cell and acellular pertussis vaccines induced an immunity effective at eliminating the genetically different B. pertussis isolates from the lungs. However, the elimination of the PRN-deficient isolate from the lungs of mice vaccinated with commercial vaccines was delayed as compared to the PRN ( +) isolate, suggesting phenotypic differences with the circulating isolates and vaccine strains. The most effective vaccine was the experimental vaccine with the composition identical to that of the strains used for infection.

Early Protection against Pertussis Induced by Live Attenuated Bordetella pertussis BPZE1 Depends on TLR4.

Pertussis is a severe respiratory disease mainly caused by Bordetella pertussis Despite wide global vaccination coverage with efficacious pertussis vaccines, it remains one of the least well-controlled vaccine-preventable diseases, illustrating the shortcomings of the current vaccines. We have developed the live attenuated nasal pertussis vaccine BPZE1, currently undergoing clinical evaluation in human phase 2 trials. We have previously shown that in mice, BPZE1 provides strong and long-lasting protection against B. pertussis challenge by inducing potent Ab and T cell responses as well as secretory IgA and IL-17-producing resident memory T lymphocytes in the nasal cavity. In this study, we show that BPZE1 induces protection in mice against B. pertussis within days after vaccination, at a time when Ab and T cell responses were not detectable. Early protection was independent of T and B cell responses, as demonstrated by the use of SCID mice. Instead, it was due to TLR4-dependent signaling through the MyD88-dependent pathway of the innate immune response, as demonstrated in experiments with TLR4-deficient and MyD88-knockout mice. TLR2-dependent signaling did not play a major role in early protection. In addition, this study also shows that even at high doses, BPZE1 is safe in the severely immunocompromised MyD88-deficient mice, whereas virulent B. pertussis caused a severe pathological condition and death in these mice, even at a low dose. Finally, coadministration of virulent B. pertussis with BPZE1 did not cause exacerbated outgrowth of the virulent strain, thereby adding to the safety profile of this live vaccine candidate.

Does Bordetella pertussis vaccine offer any cross-protection against Bordetella bronchiseptica? Implications for pet owners with cystic fibrosis.

WHAT IS KNOWN AND OBJECTIVE: The Gram-negative bacterium, Bordetella bronchiseptica, causes lower airway respiratory disease in people with cystic fibrosis (CF), as well as in companion animals, especially dogs. Presently, there are several acellular vaccines available for B. pertussis but no vaccine available for B. bronchiseptica. However given the shared protein homology between these two closely related species, we wished to explore whether pertussis vaccines may offer some cross-protection against B. bronchiseptica. COMMENT: Bordetella pertussis and B. bronchiseptica are closely related phylogenetically, as well as sharing protein homology in several pertussis vaccine components, including (i) pertussis toxin (PT), (ii) filamentous haemagglutinin (FHA), (iii) pertactin and (iv) fimbriae (types 2 and 3). Given that pertussis vaccine contains cross-reactive antigens with B. bronchiseptica, licensed pertussis vaccines may therefore offer cross-protection against B. bronchiseptica. WHAT IS NEW AND CONCLUSION: Cystic fibrosis pet owners should ensure that they have an up-to-date vaccination record relating to their pertussis vaccine. Although no monovalent human pertussis vaccines are currently available, licensed non-live booster vaccines for B. pertussis are available for individuals in the age range >10 years old. People with CF should ensure that they are adequately and currently protected against pertussis, to avoid whooping cough, which may also offer some cross-protection against B. bronchiseptica and therefore help further mitigate the risk of zoonotic infection of this organism from pets to their owners.

Seroprevalence of pertussis in Madagascar and implications for vaccination.

Pertussis is a highly contagious infectious disease and remains an important cause of mortality and morbidity worldwide. Over the last decade, vaccination has greatly reduced the burden of pertussis. Yet, uncertainty in individual vaccination coverage and ineffective case surveillance systems make it difficult to estimate burden and the related quantity of population-level susceptibility, which determines population risk. These issues are more pronounced in low-income settings where coverage is often overestimated, and case numbers are under-reported. Serological data provide a direct characterisation of the landscape of susceptibility to infection; and can be combined with vaccination coverage and basic theory to estimate rates of exposure to natural infection. Here, we analysed cross-sectional data on seropositivity against pertussis to identify spatial and age patterns of susceptibility in children in Madagascar. A large proportion of individuals surveyed were seronegative; however, there were patterns suggestive of natural infection in all the regions analysed. Improvements in vaccination coverage are needed to help prevent additional burden of pertussis in the country.

Seasonal Bordetella pertussis pattern in the period from 2008 to 2018 in Germany.

BACKGROUND: After the introduction of a vaccine against B. pertussis the seasonal pattern with the highest number of infections in the spring to summer months changed. Recent studies from around the world suggest that B. pertussis infections again follow a seasonal pattern with increased incidence in summer.The aim of this study was to investigate whether respiratory infections caused by B. pertussis in the period from January 2008 to December 2018 also seasonally spread in Germany and if so, when the B. pertussis activity peaked. METHODS: We tested 19,031 samples, mainly from Southern Germany, collected in the period from January 2008 to December 2018 using a Multiplex PCR assay. We assessed the number and proportion of samples positive for B. pertussis, stratified by patient's age and month. The seasonal distribution was investigated by plotting the average proportion of positive samples for each month. RESULTS: We observed a B. pertussis seasonality with the highest number of positive samples in the months from June until September. In contrast, testing of samples for B. pertussis was requested most frequently in the period from October until March. The proportion of positive samples increased earlier in adolescents (age 10 to 19) than in other age groups. CONCLUSIONS: We found a seasonality of B. pertussis infections in Germany, which differs from the time when most samples are sent in for testing of B. pertussis. Our study suggests that clinicians should be more aware of B. pertussis infections in the months from June until September to prevent further transmission to vulnerable family members.

The global prevalence ptxP3 lineage of Bordetella pertussis was rare in young children with the co-purified aPV vaccination: a 5 years retrospective study.

BACKGROUND: The global prevalent ptxP3 strains varies from about 10% to about 50% of circulating B. pertussis population in different areas of China. METHODS: To investigate the difference of vaccination status between different genotypes in the circulating B. pertussis after 10 years of acellular pertussis vaccine (aPV) used in China. The nasopharyngeal swabs and isolates of B. pertussis from these patients were used to perform genotyping of antigen genes. We use antibiotic susceptibility test against erythromycin and sequencing methods for site 2047 of 23S rRNA to determine the resistance status. RESULTS: The ptxP1 allele with erythromycin resistant (ER) B. pertussis infection (total of 449 subjects) consisted of 84.70 to 96.70% from 2012 to 2016 in this study. Vaccinated with co-purified aPV was found in 133(133/403,33.0%), 1(1/9,11.1%) and 2(2/21,9.5%) in ptxP1/fhaB3-ER, ptxP1/fhaB2-ES and ptxP3/fhaB2-ES B. pertussis infected children each, which showed a significant difference (χ2 = 6.87, P = 0.032). CONCLUSIONS: The ptxP3-ES B. pertussis was rare while the ptxP1-ER B. pertussis was steadily increased in Xi'an, China from 2012 to 2016, where co-purified aPV was prevalent used. This pose a hypothesis that the co-purified aPV might protect against ptxP3 strains more efficient, which generated a rare chance for ptxP3 strains to be under the antibiotic pressure and further developed to be erythromycin resistance. A further cohort study and the mechanisms of the additional antigen proteins of co-purified aPV protected against B. pertussis should be consideration.

Evaluation of immunisation strategies for pertussis vaccines in Jinan, China - an interrupted time-series study.

Studies in countries with high immunisation coverage suggest that the re-emergence of pertussis may be caused by a decreased duration of protection resulting from the replacement of whole-cell pertussis vaccine (WPV) with the acellular pertussis vaccine (APV). In China, WPV was introduced in 1978. The pertussis vaccination schedule advanced from an all-WPV schedule (1978-2007), to a mixed WPV/APV schedule (2008-2009), then to an all-APV schedule (2010-2016). Increases in the incidence of pertussis have been reported in recent years in Jinan and other cities in China. However, there have been few Chinese-population-based studies focused on the impact of schedule changes. We obtained annual pertussis incidences from 1956 to 2016 from the Jinan Notifiable Conditions Database. We used interrupted time series and segmented regression analyses to assess changes in pertussis incidence at the beginning of each year, and average annual changes during the intervention. Pertussis incidence decreased by 1.11 cases per 100 000 population (P = 0.743) immediately following WPV introduction in 1978 and declined significantly by 1.21 cases per 100 000 population per year (P < 0.0001) between 1978 and 2001. Immediately after APV replaced the fourth dose of WPV in 2008, the second and third doses in 2009, then replaced all four doses in 2010, pertussis incidence declined by 1.98, 1.98 and 1.08 cases per 100 000 population, respectively. However, the results were not statistically significant. There were significant increasing trends in pertussis incidence after APV replacements: 1.63, 1.77 and 1.78 cases/year in 2008-2016, 2009-2016 and 2010-2016, respectively. Our study shows that the impact of an all-WPV schedule may be less than the impacts of the sequential WPV/APV schedules. The short-term impact of APV was better than that of WPV; however, the duration of APV-induced protection was not ideal. The impact and duration of protective immunity resulting from APVs produced in China need further evaluation. Further research on the effectiveness of pertussis vaccination programme in Jinan, China is also necessary.

Chemical Synthesis and Immunological Evaluation of a Pentasaccharide Bearing Multiple Rare Sugars as a Potential Anti-pertussis Vaccine.

With the infection rate of Bordetella pertussis at a 60-year high, there is an urgent need for new anti-pertussis vaccines. The lipopolysaccharide (LPS) of B. pertussis is an attractive antigen for vaccine development. With the presence of multiple rare sugars and unusual glycosyl linkages, the B. pertussis LPS is a highly challenging synthetic target. In this work, aided by molecular dynamics simulation and modeling, a pertussis-LPS-like pentasaccharide was chemically synthesized for the first time. The pentasaccharide was conjugated with a powerful carrier, bacteriophage Qß, as a vaccine candidate. Immunization of mice with the conjugate induced robust anti-glycan IgG responses with IgG titers reaching several million enzyme-linked immunosorbent assay (ELISA) units. The antibodies generated were long lasting and boostable and could recognize multiple clinical strains of B. pertussis, highlighting the potential of Qß-glycan as a new anti-pertussis vaccine.

Boosting Teenagers With Acellular Pertussis Vaccines Containing Recombinant or Chemically Inactivated Pertussis Toxin: A Randomized Clinical Trial.

BACKGROUND: Protection induced by acellular pertussis (aP) vaccines is partial and short-lived, especially in teenagers, calling for novel immunization strategies. METHODS: We conducted an investigator-driven proof-of-concept randomized controlled trial in aP-primed adolescents in Geneva to assess the immunogenicity and reactogenicity of a novel recombinant aP (r-aP) vaccine including recombinant pertussis toxin (PT) and filamentous hemagglutinin (FHA) coadministered with tetanus-diphtheria toxoids (Td), compared to a licensed tetanus-diphtheria-aP vaccine containing chemically detoxified PT (cd/Tdap). The primary immunological endpoints were day 28/365 geometric mean concentrations (GMCs) of total and neutralizing anti-PT antibodies. Memory B cells were assessed. RESULTS: Sixty-two aP-primed adolescents were randomized and vaccinated with r-aP + Td or cd/Tdap. Reactogenicity, adverse events, and baseline GMCs were similar between the groups. Day 28 PT-neutralizing GMCs were low after cd/Tdap (73.91 [95% confidence interval {CI}, 49.88-109.52] IU/mL) and approximately 2-fold higher after r-aP + Td (127.68 [95% CI, 96.73-168.53] IU/mL; P = .0162). Anti-PT GMCs were also low after cd/Tdap (52.43 [95% CI, 36.41-75.50] IU/mL) and 2-fold higher after r-aP + Td (113.74 [95% CI, 88.31-146.50] IU/mL; P = .0006). Day 28 anti-FHA GMCs were similar in both groups. Day 365 anti-PT (but not PT-neutralizing) GMCs remained higher in r-aP + Td vaccinees. PT-specific memory B cells increased significantly after r-aP + Td but not cd/Tdap boosting. CONCLUSIONS: Boosting aP-primed adolescents with r-aP induced higher anti-PT and PT-neutralizing responses than cd/Tdap and increased PT-specific memory B cells. Despite this superior immunogenicity, r-aP may have to be given repeatedly, earlier, and/or with novel adjuvants to exert an optimal influence in aP-primed subjects. CLINICAL TRIALS REGISTRATION: NCT02946190.

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.

Pertactin-Negative and Filamentous Hemagglutinin-Negative Bordetella pertussis, Australia, 2013-2017.

During the 2008-2012 pertussis epidemic in Australia, pertactin (Prn)-negative Bordetella pertussis emerged. We analyzed 78 isolates from the 2013-2017 epidemic and documented continued expansion of Prn-negative ptxP3 B. pertussis strains. We also detected a filamentous hemagglutinin-negative and Prn-negative B. pertussis isolate.

Antibody responses to Bordetella pertussis and other childhood vaccines in infants born to mothers who received pertussis vaccine in pregnancy - a prospective, observational cohort study from the United Kingdom.

The maternal Tdap (tetanus, diphtheria and acellular pertussis) vaccination programme in the United Kingdom has successfully reduced cases of pertussis in young infants. In addition to prevention of pertussis cases, it is also important to investigate the persistence of maternal antibodies during infancy and the possible interference of maternal antibodies with infant responses to vaccines. We recruited mother-infant pairs from vaccinated and unvaccinated pregnancies and measured concentrations of immunoglobulin (Ig)G against pertussis toxin (PTx), filamentous haemagglutinin (FHA), pertactin (Prn), diphtheria toxin (DTx), tetanus toxoid (TTx) Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae in mothers and infants at birth, and in infants at 7 weeks and at 5 months. Thirty-one mother-infant pairs were tested. Tdap-vaccinated women had significantly higher antibody against Tdap antigens, compared to unvaccinated women (DTx, P = 0·01; PTx, FHA, Prn and TTx, P < 0·001). All antibodies were actively transferred to the infants (transfer ratio  > 1) with higher transfer of DTx (P = 0·04) and TTx (P = 0·02) antibody in Tdap-vaccinated pregnancies compared to unvaccinated pregnancies. Infants from Tdap-vaccinated pregnancies had significantly elevated antibodies to all antigens at birth (P < 0.001) and at 7 weeks (FHA, Prn, TTx, P < 0·001; DTx, P = 0.01; PTx, P = 0·004) compared to infants from unvaccinated pregnancies. Infants from Tdap-vaccinated and -unvaccinated pregnancies had comparable antibody concentrations following primary pertussis immunization (PTx, P = 0·77; FHA, P = 0·58; Prn, P = 0·60; DTx, P = 0·09; TTx, P = 0·88). These results support maternal immunization as a method of protecting vulnerable infants during their first weeks of life.

Immunogenicity and protective potential of Bordetella pertussis biofilm and its associated antigens in a murine model.

The resurgence of whooping cough reflects novel genetic variants of Bordetella pertussis and inadequate protection conferred by current acellular vaccines (aP). Biofilm is a source of novel vaccine candidates, including membrane protein assembly factor (BamB) and lipopolysaccharide assembly protein (LptD). Responses of BALB/c mice to candidate vaccines included IFN-γ and IL-17a production by spleen and lymph node cells, and serum IgG1 and IgG2a reactive with whole bacteria or aP. Protection was determined using bacterial cultured from lungs of vaccinated mice challenged with virulent B. pertussis. Mice vaccinated with biofilm produced efficient IFN-γ responses and more IL-17a and IgG2a than mice vaccinated with planktonic cells, aP or adjuvant alone. Vaccination with aP produced abundant IgG1 with little IgG2a. Mice vaccinated with aP plus BamB and LptD retained lower bacterial loads than mice vaccinated with aP alone. Whooping cough vaccines formulated with biofilm antigens, including BamB and LptD, may have clinical value.