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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).

Pertussis vaccination has been alleged to cause an encephalopathy that involves seizures and subsequent intellectual disability. In a previous retrospective study, 11 of 14 patients with so-called vaccine encephalopathy had Dravet syndrome that was associated with de-novo mutations of the sodium channel gene SCN1A. In this study, we aimed to establish whether the apparent association of Dravet syndrome with vaccination was caused by recall bias and, if not, whether vaccination affected the onset or outcome of the disorder. We retrospectively studied patients with Dravet syndrome who had mutations in SCN1A, whose first seizure was a convulsion, and for whom validated source data were available. We analysed medical and vaccination records to investigate whether there was an association between vaccination and onset of seizures in these patients. Patients were separated into two groups according to whether seizure onset occurred shortly after vaccination (vaccination-proximate group) or not (vaccination-distant group). We compared clinical features, intellectual outcome, and type of SCN1A mutation between the groups. Dates of vaccination and seizure onset were available from source records for 40 patients. We identified a peak in the number of patients who had seizure onset within 2 days after vaccination. Thus, patients who had seizure onset on the day of or the day after vaccination (n=12) were included in the vaccination-proximate group and those who had seizure onset 2 days or more after vaccination (n=25) or before vaccination (n=3) were included in the vaccination-distant group. Mean age at seizure onset was 18·4 weeks (SD 5·9) in the vaccination-proximate group and 26·2 weeks (8·1) in the vaccination-distant group (difference 7·8 weeks, 95% CI 2·6–13·1; p=0·004). There were no differences in intellectual outcome, subsequent seizure type, or mutation type between the two groups (all p values >0·3). Furthermore, in a post-hoc analysis, intellectual outcome did not differ between patients who received vaccinations after seizure onset and those who did not. Vaccination might trigger earlier onset of Dravet syndrome in children who, because of an SCN1A mutation, are destined to develop the disease. However, vaccination should not be withheld from children with SCN1A mutations because we found no evidence that vaccinations before or after disease onset affect outcome. Australian National Health and Medical Research Council.

To minimize Bordetella pertussis transmission, health care workers (HCW) should be regularly vaccinated against pertussis, e.g. every 10 years. Therefore, the previous 2012/2013 vaccination campaign in our hospital was repeated in 2023. Here we describe our findings of the campaign and a nested study on the reliability of recall of adverse events (AE) after 10 years. This was a prospective observational study including all HCW with patient contact. Those who had their last pertussis vaccination ≥10 years ago or with unknown date were offered a booster dose of Tdap (Adacel®) or Tdap-IPV (Adacel-Polio®) vaccine and were asked to report reactogenicity for seven days following vaccination. Those HCW who had participated in the 2012/2013 campaign were asked to report recall of vaccine tolerability back then. Of 916 eligible HCW, 705 (77.0 %) responded and 191 (27.1 %) of them were not up to date. Of these, 150 (78.5 %) plus 6 who were still up-to-date were vaccinated (Tdap-IPV: N = 91, 58.3 %, Tdap: N = 65; 41.7 %). After the vaccination campaign 684 (74.7 %) of all eligible HCW were up to date with their pertussis immunization status, including 63.4 % of nurses and 76.9 % of physicians. The most common adverse events in 133 (88.1 %) HCW were pain (66.7 %, day two), swelling (27.3 %, day two) and exhaustion (21.5 %, day two). Of 52 HCW who were vaccinated in both campaigns, 13 had ≥ 1 documented AE back in 2012/2013, of which only one remembered that the vaccination had not been well tolerated back then (Cohen's Kappa −0.04 for AE, −0.11 for swelling, −0.03 for redness and 0 for fever). We achieved an up-to date pertussis vaccination status in the majority of HCW. However, vaccinating all eligible HCW remains challenging in the absence of mandatory immunization. The recall of previous AE following immunization was poor.

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.

This randomized trial enrolled 442 infants in the Republic of Korea to assess the immunogenicity and safety of a combined diphtheria, tetanus, acellular pertussis, and inactivated poliovirus vaccine (DTaP–IPV; Tetraxim™) for primary vaccination at 2, 4 and 6 months of age compared with DTaP and IPV vaccines given separately. Immunogenicity was high in both groups; seroprotection and seroconversion rates of the combined vaccine (Group A) were non-inferior to the control vaccines (Group B). All subjects were seroprotected against poliovirus types 1, 2 and 3 (≥81/dil) and anti-diphtheria (≥0.01IU/mL); 99.0% were seroprotected against tetanus (≥0.1IU/mL). At least 93.6% had anti-diphtheria antibody titers ≥0.1IU/mL. Anti-pertussis toxoid (PT) and anti-filamentous haemagglutinin (FHA) seroconversion (≥4-fold increase in antibody titer) rates were 96.6% and 94.4% for Group A, 92.2% and 78.4% for Group B. Most solicited reactions occurred within 4 days of vaccination, resolved within 3 days and were mild. Severe solicited reactions occurred after ≤0.5% of doses in Group A and ≤0.9% in Group B. No withdrawals occurred because of adverse events. The DTaP–IPV combined vaccine given at 2, 4, and 6 months of age was well tolerated; immunogenicity was similar to the control vaccines.

Background. Case reports have suggested that vaccines may trigger transverse myelitis (TM) or acute disseminated encephalomyelitis (ADEM), but the evidence for a causal association is inconclusive. We analyzed the association of immunization and subsequent development of TM or ADEM. Methods. We identified all cases of TM and ADEM in the Vaccine Safety Datalink population. Using a case-centered method, we compared vaccination of each case to vaccination of all matched persons in the study population, who received the same type of vaccine, with respect to whether or not their vaccination occurred during a predetermined exposure interval. We calculated a risk difference (excess risk) of TM and ADEM for each vaccine. Results. Following nearly 64 million vaccine doses, only 7 cases of TM and 8 cases of ADEM were vaccinated during the primary exposure window 5–28 days prior to onset. For TM, there was no statistically significant increased risk of immunization. For ADEM, there was no statistically significant increased risk following any vaccine except for Tdap (adolescent and adult tetanus, reduced diphtheria, acellular pertussis) vaccine. Based on 2 exposed cases, the odds ratio for Tdap exposure 5–28 days prior to ADEM onset was 15.8 (95% confidence interval [CI], 1.2–471.6; P = .04), and the estimated excess risk was 0.385 (95% CI, −.04 to 1.16) cases per million doses. Conclusions. We found no association between TM and prior immunization. There was a possible association of ADEM with Tdap vaccine, but the excess risk is not likely to be more than 1.16 cases of ADEM per million vaccines administered.

Two types of vaccines are currently licensed for use against pertussis: whole-cell (wP) and acellular pertussis (aP). There is evidence that wP confers more durable immunity than aP, however wP has been more frequently associated with adverse events following immunisation (AEFI). A comparison of the frequency of AEFI with the first doses of wP and aP has not yet been clearly documented. This must be done in light of recent considerations to move towards a wP prime-aP boost vaccination strategy in low and middle-income countries. To compare the frequency of AEFI associated with the first dose of the wP and aP vaccines. We also compared the frequency of AEFI associated with subsequent doses of wP. This systematic review was carried out in strict accordance with the published protocol. High heterogeneity amongst included one-armed studies did not allow for pooling of prevalence estimates. The prevalence estimates of AEFI at first vaccine dose of wP ranged from 0 to 75%, while the prevalence estimates of AEFI at first vaccine dose of aP ranges from 0 to 39%. The prevalence estimates of adverse events following second and third vaccine dose of wP ranged from 0 to 71% and 0 to 61%, respectively. Risk ratios among two-armed studies showed an increased risk of adverse events with first dose of wP compared to aP [local reaction RR 2.73 (2.33, 3.21), injection site pain RR 4.15 (3.24, 5.31), injection site swelling RR 4.38 (2.70, 7.12), fever over 38 °C RR 9.21 (5.39, 15.76), drowsiness RR 1.34 (1.18, 1.52) and vomiting RR 1.28 (0.91, 1.79)]. Our results confirm that, when comparing the first dose, wP is more reacotgenic than aP. The proposed wP prime followed by aP boost pertussis vaccine strategy should be approached with caution.

The frequency of long-lasting, intensely itching subcutaneous nodules at the injection site for aluminium (Al)-adsorbed vaccines (vaccination granulomas) was investigated in a prospective cohort study comprising 4,758 children who received either a diphtheria-tetanus-pertussis-polio- Haemophilus influenzae type b vaccine (Infanrix®, Pentavac®) alone or concomitant with a pneumococcal conjugate (Prevenar). Both vaccines were adsorbed to an Al adjuvant. Altogether 38 children (0.83 %) with itching granulomas were identified, epicutaneously tested for Al sensitisation and followed yearly. Contact allergy to Al was verified in 85 %. The median duration of symptoms was 22 months in those hitherto recovered. The frequency of granulomas induced by Infanrix® was > 0.66 % and by Prevenar > 0.35 %. The risk for granulomas increased from 0.63 to 1.18 % when a second Al-adsorbed vaccine was added to the schedule. Conclusion : Long-lasting itching vaccination granulomas are poorly understood but more frequent than previously known after infant vaccination with commonly used diphtheria-tetanus-pertussis-polio- Haemophilus influenzae type b and pneumococcal conjugate vaccines. The risk increases with the number of vaccines given. Most children with itching granulomas become contact allergic to aluminium. Itching vaccination granulomas are benign but may be troublesome and should be recognised early in primary health care to avoid unnecessary investigations, anxiety and mistrust.

Adverse events following immunization (AEFI) requires special consideration in patients with primary immunodeficiency diseases (PID) because they may represent a “red flag” for the initial diagnosis and may cause disease complications. Therefore, the definition of appropriate vaccination schemes is a major issue in PID. The aim of this study is to describe the AEFI in a cohort of PID patients. Medical records from 379 PID patients were included. AEFI severity was classified according to the WHO 1999 guidelines. Causality was assessed using the Clinical Immunization Safety Assessment (CISA) 2009 criteria. Evidence of AEFI was found in 26 medical records and represented a total of 29 reactions. Most of the AEFI were observed in patients with idiopathic hypogammaglobulinemia (IHG), chronic granulomatous disease (CGD) and severe combined immunodeficiency (SCID), representing 10, 4 and 4 cases, respectively. A total of 21 reactions were associated with replicative vaccines, 7 of which were serious cases related to Bacille Calmette-Guérin (BCG). BCG was also the vaccine more often associated with definitive AEFI in PID. In addition to BCG-related complications, seizures were the most serious AEFI among PID patients. Our study included a large cohort of PID patients and confirmed an increased risk of serious AEFI in these populations. The design and implementation of neonatal screening strategies for the early detection of congenital lymphopenias and other PID are urgently needed to avoid serious complications of the BCG vaccine usually applied immediately after birth. Our findings also support the use of the acellular pertussis vaccine to minimize the appearance of seizures in PID patients vaccinated with diphtheria, pertussis and tetanus (DPT).

•10 years post-dTpa–IPV/dTpa+IPV/Td-IPV ≥73.5% seroprotected against D, T and polio.•10 years after dTpa–IPV/dTpa+IPV ≥78.7% seropositive against pertussis antigens.•One month post-decennial dTpa–IPV, ≥95.7% seroprotected against D, T and polio.•One month post-decennial dTpa–IPV, pertussis booster responses in ≥63.2% subjects.•Decennial dTpa–IPV booster was well tolerated and had an acceptable safety profile. Pertussis in adults and adolescents could be reduced by replacing traditional tetanus and diphtheria (Td) boosters with reduced-antigen-content diphtheria–tetanus–acellular pertussis (dTpa) vaccines. This study evaluated the administration of dTpa–IPV (dTpa–inactivated poliovirus) in adults ten years after they received a booster dose of either dTpa–IPV, dTpa+IPV or Td–IPV in trial NCT01277705. Open multicentre, phase IV study (www.clinicaltrials.gov NCT01323959) in which healthy adults, who had received a previous dose of dTpa–IPV, dTpa+IPV or Td–IPV ten years earlier, received a single decennial booster dose of dTpa–IPV (Boostrix™-polio, GlaxoSmithKline Vaccines). Blood samples were collected before and one month after booster vaccination. Antibody concentrations against all vaccine antigens were measured and reactogenicity and safety were assessed. A total of 211 subjects (mean age 50.3 years) received vaccination of whom 201 were included in the according-to-protocol cohort for immunogenicity. Before the decennial dTpa–IPV booster, ≥71.0% subjects were seroprotected/seropositive against all vaccine antigens. One month after the booster dose, all subjects were seroprotected against tetanus and poliovirus types 2 and 3; ≥95.7% subjects were seroprotected against diphtheria and ≥98.3% against poliovirus type 1. Anti-pertussis booster responses for the various antigens were observed in ≥76.5% (pertussis toxoid; PT), ≥85.1% (filamentous haemagglutinin; FHA) and ≥63.2% (pertactin; PRN) of subjects. During the 4-day follow-up, the overall incidence of local AEs was 71.6%, 75.0% and 72.2% in dTpa–IPV, dTpa+IPV and Td–IPV groups, respectively. Pain was the most frequent solicited local adverse event (AE; ≥62.7% subjects) and fatigue the most frequent solicited general AE (≥18.5%). No serious AEs were reported during the study. A booster dose of dTpa–IPV was immunogenic and well tolerated in adults who had received a booster dose of either dTpa–IPV, dTpa+IPV or Td–IPV, ten years previously and supports the repeated administration of dTpa–IPV.