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Discusses how the research efforts of Grace Eldering and Pearl Kendrick helped to treat and prevent whooping cough, a deadly disease that mostly affected children.

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. 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). 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 registered at the Australian and New Zealand Clinical 207 Trial Registry (ACTRN12617000065392p).

This phase 1 trial assessed the safety and immunogenicity of an investigational tetanus/diphtheria/acellular pertussis vaccine combined with CpG 1018 adjuvant 1500 μg (Tdap-1018 1500 μg) or 3000 μg (Tdap-1018 3000 μg) in adults and adolescents. In this randomized, active-controlled, multicenter, dose-escalation trial, healthy participants aged 10 to 22 years received 1 dose of Tdap-1018 1500 μg, Tdap-1018 3000 μg, or Boostrix. Geometric mean concentrations (GMCs) and booster response rates (BRRs) for antibodies against pertussis (pertussis toxin, filamentous hemagglutinin, pertactin), tetanus, and diphtheria antigens, and neutralizing antibodies against pertussis toxin were assessed 4 weeks after vaccination. Safety and tolerability were assessed for solicited post-injection reactions within 7 days after vaccination and unsolicited adverse events up to 12 weeks after vaccination. Of 117 enrolled participants, 80 adults (92%) and 30 adolescents (100%) completed the study. Both Tdap-1018 formulations were generally well tolerated, with no vaccine-related serious adverse events. Frequency and severity in post-injection reactions after Tdap-1018 administration were similar to Boostrix except for higher proportions of moderate pain for Tdap-1018. In adults at week 4, ratio of GMCs and BRRs for all antigens in the 3000-μg group were similar to or higher than Boostrix, with significantly higher GMC ratios for anti-pertussis toxin (2.1 [1.5–3.0]) and anti-tetanus (1.8 [1.1–2.9]) and significantly higher BRRs for anti-pertussis toxin (difference [95% CI]: 34.5% [13.4–54.6]), anti-pertactin (19.2% [4.4–38.1]), and anti-tetanus (30.0% [3.6–52.7]) antibodies. For adolescents, in the 3000-μg group, ratio of GMCs and BRRs were similar to or higher than Boostrix for all antigens. Both Tdap-1018 formulations showed acceptable safety and tolerability profiles. Tdap-1018 3000 μg induced similar or higher immune responses than Boostrix. ACTRN12620001177943 (Australian New Zealand Clinical Trials Registry; https://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=ACTRN12620001177943p). •Tdap-1018 was generally well tolerated in adults and adolescents.•Tdap-1018 3000 μg induced similar or higher immune responses than Boostrix.•The results support continued development of a Tdap booster adjuvanted with CpG 1018.

Both the quantity and quality of circulating anti-pertussis toxin antibodies are important for protection against severe pertussis. We compared the avidity of PT-IgG antibodies in pregnant women and their infants following vaccination during pregnancy with pertussis vaccines containing genetically-detoxified pertussis toxin (PT ) or chemically-detoxified PT (PT ). We analyzed serum samples collected earlier from pregnant women (at delivery) and their infants (at birth and 2 months of age) participating in a clinical trial where pregnant women had been vaccinated during pregnancy with recombinant acellular pertussis vaccine containing 1 µg PT (standalone, ap1 , [n=37], or combined to tetanus and diphtheria, Tdap1 [n=34]), 2 µg PT (Tdap2 , n=35), or 5 µg PT (TdaP5 , n=34), or acellular pertussis vaccine containing 8 µg PT (Tdap8 , n=35). Avidity was assessed by adding increasing concentrations (0.25, 0.5, 1, 1.5, 2, and 3 M) of NH SCN as a bond-breaking agent and measuring PT-IgG levels by ELISA. Compared with Tdap8 , TdaP5 vaccination was associated with significantly higher total absolute avidity (p<0.001) and medium-high to very-high avidity PT-IgG levels (p≤0.02) in mothers at delivery, infants at birth and infants at 2 months of age. Avidity was comparable to Tdap8 after vaccination with the low-dose PT formulations (ap1 , Tdap1 or Tdap2 ). There were no differences for vaccination during the 2 or 3 trimester of pregnancy. Compared with chemically detoxified vaccines, vaccination during pregnancy with recombinant genetically detoxified acellular pertussis vaccine at lower PT concentration provides infants with at least similar or higher quality PT-IgG antibodies. Consequently, recombinant pertussis vaccines may offer comparable or better protection against pertussis.

Pertussis is an acute respiratory disease caused by . Due to its frequency and severity, prevention of pertussis has been considered an important public health issue for many years. The development of the whole-cell pertussis vaccine (wPV) and its introduction into the pediatric immunization schedule was associated with a marked reduction in pertussis cases in the vaccinated cohort. However, due to the frequency of local and systemic adverse events after immunization with wPV, work on a less reactive vaccine was undertaken based on isolated components that induced protective immune responses with fewer local and systemic reactions. These component vaccines were termed acellular vaccines and contained one or more pertussis antigens, including pertussis toxin (PT), filamentous haemagglutinin (FHA), pertactin (PRN), and fimbrial proteins 2 (FIM2) and 3 (FIM3). Preparations containing up to five components were developed, and several efficacy trials clearly demonstrated that the aPVs were able to confer comparable short-term protection than the most effective wPVs with fewer local and systemic reactions. There has been a resurgence of pertussis observed in recent years. This paper reports the results of a Consensus Conference organized by the World Association for Infectious Disease and Immunological Disorders (WAidid) on June 22, 2018, in Perugia, Italy, with the goal of evaluating the most important reasons for the pertussis resurgence and the role of different aPVs in this resurgence.

The immunogenicity of acellular pertussis vaccines and persistence of immunity after vaccination might be improved by using genetically inactivated pertussis toxin (PTgen) instead of chemically inactivated pertussis toxin (PTchem) because of the preservation of conformational epitopes. We assessed the safety and immunogenicity of two vaccines containing PTgen 1 year after vaccination. We did a phase 2/3 non-inferiority, randomised, controlled trial involving 450 adolescents (age 12–17 years) enrolled between July 6, 2015, and Aug 20, 2015. Participants were randomised 1:1:1 to receive one dose of vaccine containing PTgen and filamentous haemagglutinin (FHA) either in a monovalent formulation (aP[PTgen/FHA]) or in a combined formulation with tetanus and reduced-dose diphtheria toxoids (TdaP[PTgen/FHA]) or to receive a commercial vaccine containing reduced-dose PTchem (Tdap) as a comparator. We report a secondary trial outcome, namely antibody persistence 1 year after vaccination, assessed per protocol in 150 randomly preselected participants (50 per group). Seroconversion was defined as antibody titres at least four times greater than at baseline. Safety was assessed in all trial participants. This study is registered in the Thai Clinical Trial Registry, number TCTR20150703002. Between June 5, 2016, and Aug 9, 2016, 442 (98%) of 450 enrolled participants attended a 1-year follow-up visit. After 1 year, persistent seroconversion for pertussis toxin neutralising antibodies was seen in 38 (76%, 95% CI 64–88) participants in the aP(PTgen/FHA) group and 41 (81%, 70–92) in the TdaP(PTgen/FHA) group, but in only four (8%, 1–16) in the Tdap comparator group. Seroconversion rates for IgG antibodies against pertussis toxin and FHA were also greater in the aP(PTgen/FHA) group (82%, 95% CI 71–93 and 64%, 51–77, respectively) and TdaP(PTgen/FHA) group (75%, 63–87 and 56%, 42–70, respectively) than in the Tdap group (4%, 0–9, p<0·0001, and 28%, 16–41, p=0·0007, respectively). 13 serious adverse events were reported in 12 participants and all were judged to be unrelated to the study vaccines. Five pregnancies were reported during follow-up, none of which had any maternal or neonatal complications. A monovalent and a combined recombinant acellular pertussis vaccine containing PTgen induced antibody responses that were greater and sustained for longer than those achieved with the Tdap comparator vaccine. New recombinant pertussis vaccines containing PTgen might offer new opportunities to limit pertussis resurgence and can be widely used, including in pregnant women. BioNet-Asia.

Maternal tetanus, diphtheria, and acellular pertussis (Tdap) vaccination offers protection for neonates against clinical pertussis until primary vaccinations, but maternal antibodies also interfere with infants' immune responses to primary vaccinations. We investigated the effect of maternal Tdap vaccination on the pertussis antibody responses of infants starting primary vaccinations at age 3 months. In an open-label, parallel, randomised, controlled trial, pregnant women aged 18–40 years with a low risk of pregnancy complications were recruited through independent midwives at 36 midwife clinics in the Netherlands and received Tdap vaccination either at 30–32 weeks of pregnancy (maternal Tdap group) or within 48 h after delivery (control group). All term-born infants were vaccinated with the diphtheria, tetanus, and pertussis-inactivated poliomyelitis-Haemophilus influenzae type B-hepatitis B six-in-one vaccine and a ten-valent pneumococcal vaccine at 3 months, 5 months, and 11 months. Randomisation was done using a number generator in a 1:1 ratio and with sealed envelopes. Participants and clinical trial staff were not masked, but laboratory technicians were unaware of study group assignments. The primary endpoint was serum IgG pertussis toxin antibody concentrations at age 3 months. Cord blood and infant blood samples were collected at age 2 months, 3 months, 6 months, 11 months, and 12 months. Analysis was done by modified intention to treat with all randomly assigned participants in case a laboratory result was available. This trial is registered with ClinicaltTrialsRegister.eu (EudraCT 2012-004006-9) and trialregister.nl (NTR number NTR4314). The trial is now closed to new participants. Between Jan 16, 2014, and March 4, 2016, 118 pregnant women were enrolled into our study, with 58 in the maternal Tdap group and 60 in the control group. The geometric mean concentration (GMC) of pertussis toxin antibodies were higher in infants in the maternal Tdap group than in the control group infants at age 3 months (GMC ratio 16·6, 95% CI 10·9–25·2) and also significantly higher compared with control infants at age 2 months. After primary vaccinations, antibody concentrations for pertussis toxin, filamentous haemagglutinin, and pertactin were significantly lower at all timepoints in infants of the maternal Tdap group than in infants in the control group. No safety issues after maternal Tdap vaccination were encountered. In view of the high pertussis toxin antibody concentrations at age 3 months, maternal vaccination supports a delay of the first pertussis vaccination in infants until at least age 3 months. Maternal antibody interference affects antibody concentrations after primary and booster vaccinations. The clinical consequences of this interference remain to be established. The Dutch Ministry of Health, Welfare, and Sport.

Vaccinating women against pertussis in pregnancy protects young infants from severe disease and death. Vaccination-induced maternally derived antibodies, however, might subsequently modulate (and specifically blunt) the infant's serological response to their primary series of pertussis vaccinations. We examined the effect of pertussis immunisation in pregnancy on the immunogenicity of primary acellular or whole-cell pertussis vaccines in a west African cohort. GaPs was a randomised, controlled, double-blind, phase 4 trial conducted in The Gambia. We used a predefined block randomisation scheme to randomly assign healthy, HIV-negative, pregnant participants (1:1) to receive a pertussis-containing (tetanus-diphtheria-acellular pertussis-inactivated polio virus [Tdap-IPV]) or tetanus-toxoid only vaccine at 28–34 weeks' gestation. At the same time, their infants were randomly assigned (1:1) to receive diphtheria-tetanus-acellular pertussis (DTaP) or diphtheria-tetanus-whole-cell pertussis (DTwP) primary vaccine at 8, 12, and 16 weeks postnatally. Participants and trial staff were masked to the allocation of the maternal vaccine. The field team and participants became unmasked to the allocation of the infant vaccine at 16 weeks; laboratory staff and all other investigators remained masked to infant vaccine allocation until the end of the trial. The primary outcome was geometric mean concentration (GMC) of infant pertussis toxin-specific antibodies at 20 weeks and 9 months postnatally and was assessed in infants who received all three doses of the primary vaccine. Secondary outcomes included memory B-cell responses, and exploratory outcomes were total pertussis-specific antibody binding concentrations and functional antibody titres (pertussis toxin-specific neutralising activity [PTNA] and serum bactericidal activity [SBA]). Vaccine reactogenicity was assessed in mothers and infants for 3 days after each vaccine dose. Pregnant women had an extra safety visit 7 days after vaccination. The study is registered with ClinicalTrials.gov, NCT03606096. Between Feb 13, 2019, and May 17, 2021, we enrolled 343 maternal–infant pairs. 239 (77%) infants were included in the per-protocol immunogenicity analysis. Among infants of mothers receiving Tdap-IPV in pregnancy, at 20 weeks postnatally, the GMCs of anti-pertussis toxin IgG were more than three-fold lower in infants vaccinated with three doses of DTwP (n=64) than in infants vaccinated with three doses of DTaP (n=53; adjusted geometric mean ratio 0·28, 98·75% CI 0·16–0·50). This difference persisted up to 9 months (0·31, 0·17–0·55). Conversely, among infants born to tetanus toxoid-immunised mothers, post-vaccination GMCs of anti-pertussis toxin IgG at 9 months were higher in those vaccinated with DTwP (n=58) than in those vaccinated with DTaP (n=64; 2·02, 1·15–3·55). Tdap-IPV immunisation in pregnancy blunted anti-pertussis toxin IgG following primary vaccination in all infants but particularly in those receiving DTwP, with GMCs of anti-pertussis toxin IgG more than eight-fold lower in DTwP-vaccinated infants born to Tdap-IPV-vaccinated mothers than in DTwP-vaccinated infants born to tetanus toxoid-immunised mothers (0·12, 98·75% CI 0·07–0·22 at 20 weeks; 0·07, 0·03–0·17 at 9 months). Similarly, DTwP-vaccinated infants born to Tdap-IPV-vaccinated mothers also showed significant blunting of PTNA, SBA, total pertussis-specific antibody binding, and memory B-cell responses after primary immunisation, whereas minimal blunting was observed among DTaP-vaccinated infants. However, the absolute levels of these responses generated by DTwP-vaccinated infants remained similar to or, in many cases, were higher than those generated by DTaP-vaccinated infants. There was no difference in reactogenicity between the two maternal vaccines, with most reactions graded 0 or 1. There were no serious adverse events related to vaccination or trial participation. Vaccinating women with Tdap-IPV in pregnancy was safe and well tolerated in a sub-Saharan African setting and boosted the quantity and quality of pertussis-specific antibodies in infants in early life. Although Tdap-IPV was associated with relative blunting of the immune response to the DTwP primary vaccination series, pertussis-specific antibody quality and memory B-cell responses were nevertheless preserved, regardless of the vaccine given during pregnancy. GaPs was conducted as part of the Pertussis Correlates Of Protection Europe (PERISCOPE) consortium, which received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement 115910. This Joint Undertaking receives support from the EU's Horizon 2020 research and innovation programme, the European Federation of Pharmaceutical Industries and Associations, and the Bill & Melinda Gates Foundation.

Acellular pertussis vaccines do not control pertussis. A new approach to offer protection to infants is necessary. BPZE1, a genetically modified Bordetella pertussis strain, was developed as a live attenuated nasal pertussis vaccine by genetically eliminating or detoxifying 3 toxins. We performed a double-blind, placebo-controlled, dose-escalating study of BPZE1 given intranasally for the first time to human volunteers, the first trial of a live attenuated bacterial vaccine specifically designed for the respiratory tract. 12 subjects per dose group received 10³, 10⁵ or 10⁷ colony-forming units as droplets with half of the dose in each nostril. 12 controls received the diluent. Local and systemic safety and immune responses were assessed during 6 months, and nasopharyngeal colonization with BPZE1 was determined with repeated cultures during the first 4 weeks after vaccination. Colonization was seen in one subject in the low dose, one in the medium dose and five in the high dose group. Significant increases in immune responses against pertussis antigens were seen in all colonized subjects. There was one serious adverse event not related to the vaccine. Other adverse events were trivial and occurred with similar frequency in the placebo and vaccine groups. BPZE1 is safe in healthy adults and able to transiently colonize the nasopharynx. It induces immune responses in all colonized individuals. BPZE1 can thus undergo further clinical development, including dose optimization and trials in younger age groups. ClinicalTrials.gov NCT01188512.

Long-term protection and herd immunity induced by existing pertussis vaccines are imperfect, and a need therefore exists to develop new pertussis vaccines. This study aimed to investigate the safety, colonisation, and immunogenicity of the new, live attenuated pertussis vaccine, BPZE1, when given intranasally. This phase 1b, double-blind, randomised, placebo-controlled, dose-escalation study was done at the phase 1 unit, Karolinska Trial Alliance, Karolinska University Hospital, Stockholm, Sweden. Healthy adults (18–32 years) were screened and included sequentially into three groups of increasing BPZE1 dose strength (107 colony-forming units [CFU], 108 CFU, and 109 CFU), and were randomly assigned (3:1 within each group) to receive vaccine or placebo. Vaccine and placebo were administered in phosphate-buffered saline contained 5% saccharose as 0·4 mL in each nostril. The primary outcome was solicited and unsolicited adverse events between day 0 and day 28. The analysis included all randomised participants who received a vaccine dose. Colonisation with BPZE1 was determined by repeatedly culturing nasopharyngeal aspirates at day 4, day 7, day 11, day 14, day 21, and day 28 after vaccination. Immunogenicity, as serum IgG and IgA responses were assessed at day 0, day 7, day 14, day 21, day 28, 6 months, and 12 months after vaccination. This trial is registered at Clinicaltrials.gov, NCT02453048. Between Sept 1, 2015, and Feb 3, 2016, 120 participants were assessed for eligibility, 48 of whom were enrolled and randomly assigned (3:1) to receive vaccine or placebo, with 12 participants each in a low-dose, medium-dose, and high-dose vaccine group. Adverse events between day 0 and day 28 were reported by one (8%, 95% CI 0–39) of 12 participants in both the placebo and low-dose groups, and two (17%; 2–48) of 12 participants in both the medium-dose and high-dose groups, including cough of grade 2 or more, oropharyngeal pain, and rhinorrhoea and nasal congestion. During this time, none of the participants experienced any spasmodic cough, difficulties in breathing, or adverse events following immunisation concerning vital signs. The tested doses of BPZE1 or placebo were well tolerated, with no apparent difference in solicited or unsolicited adverse events following immunisation between groups. Colonisation at least once after vaccination was observed in 29 (81%; 68–93) of 36 vaccinated participants. The tested vaccine doses were immunogenic, with increases in serum IgG and IgA titres against the four B pertussis antigens from baseline to 12 months. The tested vaccine was safe, induced a high colonisation rate in an adult population, and was immunogenic at all doses. These findings justify further clinical development of BPZE1 to ultimately be used as a priming vaccine for neonates or a booster vaccine for adolescents and adults, or both. ILiAD Biotechnologies.