Immunogenicity and safety of the 4CMenB and MenACWY-CRM meningococcal vaccines administered concomitantly in infants: A phase 3b,randomized controlled trial

BackgroundInvasive meningococcal disease has its highest incidence in infants. Co-administration of serogroup B (4CMenB) and quadrivalent conjugate (MenACWY-CRM) vaccines could protect against 5 clinically-relevant meningococcal serogroups.MethodsThis phase 3b, open, multicenter study (NCT02106390), conducted in Mexico and Argentina, enrolled and randomized (1:1:1) 750 healthy infants to receive either 4CMenB co-administered with MenACWY-CRM (4CMenB/MenACWY group), 4CMenB (4CMenB group), or MenACWY-CRM alone (MenACWY group) at ages 3, 5, 7 and 13 months. Non-inferiority of immune responses of co-administration to single administration of vaccines was assessed at 1 month post-booster dose (primary objective). Immunogenicity was evaluated pre- and 1 month post-primary and booster vaccinations using human serum bactericidal assay (hSBA). Safety was assessed.ResultsAt 1 month post-booster vaccination, between-group hSBA geometric mean titer (GMT) ratios ranged from 0.89 to 1.03 for serogroup B strains (group 4CMenB/MenACWY over 4CMenB), and from 1.05 to 2.48 for ACWY serogroups (group 4CMenB/MenACWY over MenACWY). The lower limit of the 2-sided 95% confidence intervals for all GMT ratios was >0.5; the primary objective was demonstrated. Across all groups and serogroup B strains, 68–100% and 87–100% of children had hSBA titers ≥5 at 1 month post-primary and booster vaccination, respectively. For serogroups ACWY, ≥96% (post-primary vaccination) and ≥98% (post-booster vaccination) of children in all groups had hSBA titers ≥4. Post-booster vaccination, GMTs increased ≥5.99-fold from pre-booster values for each strain/serogroup. Solicited adverse events (AEs) were more frequent in groups 4CMenB/MenACWY and 4CMenB than in MenACWY; incidence of all other AEs was similar between groups. Serious AEs were reported for 6, 13, and 11 participants in groups 4CMenB/MenACWY, 4CMenB, and MenACWY, respectively; 1 (group 4CMenB) was considered vaccine-related.ConclusionImmune responses elicited by co-administration of 4CMenB and MenACWY-CRM was non-inferior to single immunization. Co-administration of vaccines was immunogenic and well tolerated in infants.ClinicalTrials.gov: NCT02106390.An Audio Summary linked to this article that can be found on Figshare https://figshare.com/articles/Immunogenicity_and_safety_of_the_4CMenB_and_MenACWY-CRM_meningococcal_vaccines_administered_concomitantly_in_infants_-_A_phase_3b_randomized_controlled_trial/9945050.     

Immunogenicity and safety of concomitant administration of meningococcal serogroup B (4CMenB) and serogroup C (MenC-CRM) vaccines in infants: A phase 3b,randomized controlled trial

BackgroundAfter implementation of routine infant MenC vaccination, MenB remains a serious cause of meningococcal disease, yet to be targeted by vaccination programs in several countries. This study (NCT01339923) investigated the immunogenicity and safety of MenC CRM-conjugated vaccine (MenC-CRM) concomitantly administered with MenB vaccine (4CMenB).MethodsInfants (N = 251) were randomised 1:1 to receive 4CMenB and MenC-CRM (Group 1) or MenC-CRM alone (Group 2) at 3 and 5 months (M3, M5) and a booster at 12 months of age (M12), and pneumococcal vaccine at M3, M5, M7, M12. Antibody responses to meningococcal vaccines were measured at M3, M6, M12, and M13. Non-inferiority of MenC-CRM response in Group 1 vs Group 2 was demonstrated at M6 and M13, if the lower limit of the 95% confidence interval (LL95%CI) of the difference in percentage of infants with hSBA titres ≥1:8 was >−10%. Sufficiency of MenB response was achieved if LL95%CI of the percentage of infants with hSBA titres ≥1:4 against fHbp, NadA and PorA strains was ≥70% at M6 or ≥75% at M13. Adverse events (AEs) were collected for 7 days post-vaccination, and serious AEs (SAEs) and medically attended AEs throughout the study.ResultsNon-inferiority of MenC response in Group 1 vs Group 2 (LL95%CI −6.4% [M6]; −5.2% [M13]) and sufficiency of MenB response in Group 1 (LL95%CI 92%, 90%, 89% [M6]; 97%, 92%, 93% [M13] against fHbp, NadA, PorA, respectively) were demonstrated. Higher rates of mild to moderate solicited AEs were reported in Group 1. Unsolicited AEs and SAEs incidences were similar across groups.ConclusionsConcomitant administration of MenC-CRM and 4CMenB in infants was immunogenic, resulting in non-inferior responses against MenC compared to MenC-CRM alone and demonstration of sufficient immune response to MenB, after primary and booster vaccination. Reactogenicity was higher for concomitant vaccines administration, but no safety concerns were identified.     

Factors related to vaccine uptake by young adult women in the catch-up phase of the National HPV Vaccination Program in Australia: Results from an observational study

BackgroundAustralia commenced a publically-funded, National Human Papillomavirus (HPV) Vaccination Program in 2007 with a two year catch-up phase for females aged 12–26 years.ObjectiveTo identify the factors associated with the uptake of the HPV vaccine (which has a recommended 3-dose schedule in Australia) by young adult women vaccinated by general practitioners and community-based programs within the catch-up phase.Methods1139 women who were eligible to receive the free HPV vaccine during the catch-up period were recruited in 2008–2009 (age 20–29 years at recruitment), in New South Wales, after having a normal (negative) cervical smear result recorded on the NSW Pap Test Register. Participants completed a self-administered questionnaire providing information on vaccination status, and sociodemographic and other factors.ResultsOverall, 880 (77%) women reported receiving ≥1 dose of the vaccine and 777 women (68%) reported receiving ≥2 doses. In multivariable analysis (adjusting for the period for which each woman was eligible for free HPV vaccination), uptake of ≥1 dose of the vaccine was significantly associated with being born in Australia (p < 0.01), being single (p = 0.02), being nulliparous (p < 0.01), living in a higher socioeconomic status area (p-trend = 0.03), living in more remote areas (p = 0.03), drinking alcohol (p < 0.01) and using hormonal contraceptives (p < 0.01). Although vaccinated women were more likely to have fewer sexual partners than unvaccinated women (p-trend = 0.02), they were also more likely to report a prior sexually transmitted infection (STI) (p = 0.03). Similar factors were associated with receiving ≥2 doses.ConclusionsIn this group, women living in higher socioeconomic status areas were more likely to be vaccinated against HPV in the catch-up phase of the national program. Although vaccinated women tended to have fewer sexual partners, they also reported prior STIs, which may be a marker of increased risk of prior exposure to HPV. The findings of this study reinforce the continuing need to prioritise equitable delivery of vaccination to various population subgroups.     

Immunogenicity and safety of one or two doses of the quadrivalent meningococcal vaccine MenACWY-TT given alone or with the 13-valent pneumococcal conjugate vaccine in toddlers: A phase III,open-label,randomised study

BackgroundWe evaluated the immunogenicity and safety of 1 and 2 doses of quadrivalent meningococcal serogroup A, C, W and Y tetanus toxoid-conjugate vaccine (MenACWY-TT) given alone or co-administered with 13-valent pneumococcal conjugate vaccine (PCV13) in toddlers.MethodsIn this phase III, open-label, controlled, multicentre study (NCT01939158), healthy toddlers aged 12–14 months were randomised into 4 groups to receive 1 dose of MenACWY-TT at month (M) 0 (ACWY_1), 2 doses of MenACWY-TT at M0 and M2 (ACWY_2), MenACWY-TT and PCV13 at M0 (Co-ad), or PCV13 at M0 and MenACWY-TT at M2 (PCV13/ACWY). Immune responses were assessed 1 month post-each vaccination. Solicited and unsolicited symptoms were recorded for 4 and 31 days post-each vaccination, respectively; serious adverse events (SAEs) and new onset of chronic illnesses (NOCIs) up to M9 from first vaccination.Results802 toddlers were vaccinated. Post-dose 1 of MenACWY-TT, ≥92.8% of toddlers had rSBA titres ≥1:8, and ≥62.5% had hSBA titres ≥1:4 for each meningococcal serogroup. Post-dose 2 of MenACWY-TT, rSBA titres ≥1:8 were observed in ≥98.0% and hSBA titres ≥1:4 in ≥95.3% of toddlers. Percentages of toddlers with hSBA titres ≥1:4 were higher after 2 doses versus 1 dose of MenACWY-TT for MenW (97.1% versus 62.5–68.9%) and MenY (95.3% versus 64.3–67.6%). Non-inferiority of immune responses to co-administered MenACWY-TT and PCV13 over their separate administration was demonstrated. AEs incidence was comparable among groups. SAEs were reported for 4.9%, 5.1%, 5.5% and 7.5%, and NOCIs for 2.0%, 3.0%, 0.5% and 3.5% of toddlers in the ACWY_1, ACWY_2, Co-ad and PCV13/ACWY groups, respectively; 4 SAEs reported in 3 toddlers were vaccine-related. Two fatal vaccine-unrelated SAEs were reported.ConclusionMenACWY-TT was immunogenic when administered as a single dose at 12–14 months of age. A second dose in toddlers increased hSBA responses against MenW and MenY. MenACWY-TT and PCV13 can be co-administered without impairing the immunogenicity or safety profile of either vaccine.     

Immunogenicity and safety of an AS03-adjuvanted H7N1 vaccine in adults 65 years of age and older: A phase II,observer-blind,randomized, controlled trial

BackgroundH7 influenza strains can cause severe and often fatal human infections, especially in the elderly. This phase II, observer-blind, randomized trial (www.ClinicalTrials.gov: NCT01949090) assessed the immunogenicity and safety of a novel AS03-adjuvanted H7N1 vaccine that may serve as a model H7-subtype vaccine.Methods360 adults ≥65 years of age in stable health received either 1 of 4 adjuvanted A/mallard/Netherlands/12/2000 split virion vaccine formulations (3.75 μg or 7.5 μg hemagglutinin adjuvanted with either AS03_A or AS03_B) or saline placebo, given as a 2-dose series. Immunogenicity was assessed using hemagglutination-inhibition (HI) and microneutralization (MN) assays for the per-protocol cohort, comprising 332 participants at 21 days post-each dose, 332 at month 6, and 309 at month 12 (HI assay only). Safety was assessed up to month 12 for all participants who had received ≥1 dose (360 participants).ResultsFor H7N1 HI antibody assessment at day 42 (21 days post-dose 2), seroprotection rates (SPR) in the vaccinated groups were 69.6%–88.7%, seroconversion rates (SCR) 69.6%–88.5%, mean geometric increase (MGI) 11.0–18.9, and HI geometric mean titers (GMTs) 55.0–104.8. These parameters declined by month 6 and month 12. Microneutralization GMTs were 46.2–74.7 in the vaccinated groups at day 42, while vaccine response rate (VRR; proportion with ≥4-fold increase in MN titer) was 46.4%–81.5%. For the cross-reactive H7N9 strain, at day 42, HI GMT were 64.3–201.3, SPR 78.6%–96.3%, SCR 79.3%–96.3%, and MGI 14.1–37.7; MN GMTs were 44.0–85.6, and VRR 46.4–85.2%.The most frequent solicited symptom was injection site pain (41.7%–65.0% of vaccine recipients). In total, 40 participants reported 67 serious adverse events; none were considered causally related to vaccination.ConclusionsIn adults aged ≥65 years, the adjuvanted H7N1 vaccine was immunogenic after 2 doses, and had an acceptable safety profile.www.ClinicalTrials.gov: NCT01949090.     

Cost-effectiveness analysis of catch-up hepatitis A vaccination among unvaccinated/partially-vaccinated children

BackgroundSince 2006, the US Centers for Disease Control and Prevention has recommended hepatitis A (HepA) vaccination routinely for children aged 12–23 months to prevent hepatitis A virus (HAV) infection. However, a substantial proportion of US children are unvaccinated and susceptible to infection. We present results of economic modeling to assess whether a one-time catch-up HepA vaccination recommendation would be cost-effective.MethodsWe developed a Markov model of HAV infection that followed a single cohort from birth through death (birth to age 95 years). The model compared the health and economic outcomes from catch-up vaccination interventions for children at target ages from two through 17 years vs. outcomes resulting from maintaining the current recommendation of routine vaccination at age one year with no catch-up intervention.ResultsOver the lifetime of the cohort, catch-up vaccination would reduce the total number of infections relative to the baseline by 741 while increasing doses of vaccine by 556,989. Catch-up vaccination would increase net costs by $10.2 million, or $2.38 per person. The incremental cost of HepA vaccine catch-up intervention at age 10 years, the midpoint of the ages modeled, was $452,239 per QALY gained. Across age-cohorts, the cost-effectiveness of catch-up vaccination is most favorable at age 12 years, resulting in an Incremental Cost-Effectiveness Ratio of $189,000 per QALY gained.ConclusionsGiven the low baseline of HAV disease incidence achieved by current vaccination recommendations, our economic model suggests that a catch-up vaccination recommendation would be less cost-effective than many other vaccine interventions, and that HepA catch-up vaccination would become cost effective at a threshold of $50,000 per QALY only when incidence of HAV rises about 5.0 cases per 100,000 population.     

Primary and booster vaccination with an inactivated poliovirus vaccine (IPV) is immunogenic and well-tolerated in infants and toddlers in China

IntroductionReplacing live-attenuated oral poliovirus vaccines (OPV) with inactivated poliovirus vaccines (IPV) is part of the global strategy to eradicate poliomyelitis. China was declared polio-free in 2000 but continues to record cases of vaccine-associated-poliomyelitis and vaccine-derived-poliovirus outbreaks. Two pilot safety studies and two larger immunogenicity trials evaluated the non-inferiority of IPV (Poliorix™, GSK Vaccines, Belgium) versus OPV in infants and booster vaccination in toddlers primed with either IPV or OPV in China.MethodsIn pilot safety studies, 25 infants received 3-dose IPV primary vaccination (Study A, www.clinicaltrial.gov NCT00937404) and 25 received an IPV booster after priming with three OPV doses (Study B, NCT01021293). In the randomised, controlled immunogenicity and safety trial (Study C, NCT00920439), infants received 3-dose primary vaccination with IPV (N = 541) or OPV (N = 535) at 2,3,4 months of age, and a booster IPV dose at 18-24 months (N = 470, Study D, NCT01323647: extension of study C). Blood samples were collected before and one month post-dose-3 and booster. Reactogenicity was assessed using diary cards. Serious adverse events (SAEs) were captured throughout each study.ResultsStudy A and B showed that IPV priming and IPV boosting (after OPV) was safe. Study C: One month post-dose-3, all IPV and ≥98.3% OPV recipients had seroprotective antibody titres towards each poliovirus type. The immune response elicited by IPV was non-inferior to Chinese OPV. Seroprotective antibody titres persisted in ≥94.7% IPV and ≥96.1% OPV recipients at 18–24 months (Study D). IPV had a clinically acceptable safety profile in all studies. Grade 3 local and systemic reactions were uncommon. No SAEs were related to IPV administration.ConclusionTrivalent IPV is non-inferior to OPV in terms of seroprotection (in the Chinese vaccination schedule) in infant and toddlers, with a clinically acceptable safety profile.     

Immunogenicity,safety and reactogenicity of the pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) in 2–17-year-old children with asplenia or splenic dysfunction: A phase 3 study

BackgroundImmunization with pneumococcal vaccines is an important prophylactic strategy for children with asplenia or splenic dysfunction, who are at high risk of bacterial infections (including S. pneumoniae). This study aimed to assess immunogenicity and safety of pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV, GSK) in this at-risk population.MethodsThis phase III, multi-centre, open-label, controlled study, in which at-risk children with asplenia or splenic dysfunction were enrolled (age strata: 2–4, 5–10 and 11–17 years), was conducted in Poland and the Russian Federation. For the 2–4 years at-risk group, healthy age-matched children were enrolled as control. Unprimed children (not previously vaccinated with any pneumococcal vaccine) received 2 PHiD-CV doses (≥2 months apart) and pneumococcal vaccine-primed children received 1 dose. Immune responses were assessed pre-vaccination and one month post-each dose. Solicited and unsolicited adverse events (AEs) were recorded for 4 and 31 days post-vaccination, respectively, and serious AEs (SAEs) throughout the study.ResultsOf 52 vaccinated children (18 at-risk primed, 28 at-risk unprimed and 6 control unprimed), 45 (18, 23 and 4, respectively) were included in the according-to-protocol cohort for immunogenicity. Post-vaccination (post-dose 1 in primed and post-dose 2 in unprimed children), for each vaccine pneumococcal serotype and vaccine-related serotype 6A all at-risk children had antibody concentrations ≥0.2 µg/mL, and for vaccine-related serotype 19A at least 94.4%. Increases in antibody geometric mean concentrations were observed. For most serotypes, all at-risk children had post-vaccination opsonophagocytic activity (OPA) titers ≥8 and increases in OPA geometric mean titers were observed. No safety concerns were raised. One non-fatal SAE (respiratory tract infection, considered not vaccine-related) was reported by one at-risk unprimed child.ConclusionPHiD-CV was immunogenic and well tolerated in 2–17-year-old children with asplenia or splenic dysfunction.Clinical Trial Registry: www.clinicaltrials.gov, NCT01746108.     

Polyfunctional CD4 T-cells correlate with in vitro mycobacterial growth inhibition following Mycobacterium bovis BCG-vaccination of infants

BackgroundVaccination with Bacillus Calmette Guerin (BCG) protects infants against childhood tuberculosis however the immune mechanisms involved are not well understood. Further elucidation of the infant immune response to BCG will aid with the identification of immune correlates of protection against tuberculosis and with the design of new improved vaccines. The purpose of this study was to investigate BCG-induced CD4+ T-cell responses in blood samples from infants for cytokine secretion profiles thought to be important for protection against tuberculosis and compare these to PBMC-mediated in vitro mycobacterial growth inhibition.MethodsBlood from BCG-vaccinated or unvaccinated infants was stimulated overnight with Mycobacterium tuberculosis (M. tb) purified protein derivative (PPD) or controls and intracellular cytokine staining and flow cytometry used to measure CD4+ T-cell responses. PBMC cryopreserved at the time of sample collection were thawed and incubated with live BCG for four days following which inhibition of BCG growth was determined.ResultsPPD-specific IFNγ+TNFα+IL-2+CD4+ T-cells represented the dominant T-cell response at 4 months and 1 year after infant BCG. These responses were undetectable in age-matched unvaccinated infants. IL-17+ CD4+ T-cells were significantly more frequent in vaccinated infants at 4 months but not at 1-year post-BCG. PBMC-mediated inhibition of mycobacterial growth was significantly enhanced at 4 months post-BCG as compared to unvaccinated controls. In an analysis of all samples with both datasets available, mycobacterial growth inhibition correlated significantly with the frequency of polyfunctional (IFNγ+TNFα+IL-2+) CD4+ T-cells.ConclusionsThese data suggest that BCG vaccination of infants induces specific polyfunctional T-helper-1 and T-helper-17 responses and the ability, in the PBMC compartment, to inhibit the growth of mycobacteria in vitro. We also demonstrate that polyfunctional T-helper-1 cells may play a role in growth inhibition as evidenced by a significant correlation between the two.     

Safety and immunogenicity of a trivalent recombinant PcpA,PhtD, and PlyD1 pneumococcal protein vaccine in adults,toddlers, and infants: A phase I randomized controlled study

BackgroundPneumococcal protein vaccines (PPrVs) may provide improved protection over currently available polysaccharide and conjugated polysaccharide vaccines. Here, we examined the safety and immunogenicity of a trivalent recombinant PPrV containing PcpA, PhtD, and PlyD1.MethodsThis was a phase I, single-center, randomized, observer-blind study with safety review between cohorts. Adults (18–50 years; n = 30) and then toddlers (12–13 months; n = 30) were randomized 2:1 to receive aluminum-adjuvanted trivalent PPrV (PPrV + adj) containing 50 μg per antigen or placebo. Infants (42–49 days; n = 220) were next randomized to be injected at 6, 10, and 14 weeks of age with 10 μg PPrV + adj or placebo (n = 60; 2:1); 25 μg PPrV + adj, 25 μg unadjuvanted PPrV, or placebo (n = 100; 2:2:1); and 50 μg PPrV + adj or placebo (n = 60; 2:1). Solicited reactions were recorded for 7 days and unsolicited adverse events for 30 days after each vaccination. Concentrations of antibodies to the three vaccine antigens were measured by enzyme-linked immunosorbent assay.ResultsTenderness/pain was the most frequent injection-site reaction. Abnormal crying and irritability (infants), loss of appetite (toddlers), and headache, malaise, and myalgia (adults) were the most frequent systemic reactions. Reactions were mostly mild or moderate, resolved within 3 days, were not adjuvant- or dose-dependent, and were not increased by repeated vaccination. No immediate adverse events, hypersensitivity reactions, or treatment-related serious adverse events were reported. In all PPrV + adj cohorts, at least 75% of subjects had a ≥2-fold increase in all three antibody concentrations. In infants, antibody concentrations were higher with PPrV + adj than with unadjuvanted PPrV, higher with three than two vaccinations, and similar at the different vaccine doses.ConclusionsThe candidate trivalent PPrV was safe and immunogenic in adults, toddlers, and infants. Addition of aluminum adjuvant improved immunogenicity in infants without changing the safety profile.     

Immunogenicity and safety of a quadrivalent inactivated influenza vaccine compared with two trivalent inactivated influenza vaccines containing alternate B strains in adults: A phase 3, randomized noninferiority study

BackgroundVaccination is the most effective means of influenza prevention. Efficacy of trivalent vaccines may be enhanced by including both B strain lineages. This phase 3, double-blind study assessed the immunogenicity and safety/tolerability of a quadrivalent inactivated influenza vaccine (IIV4) versus the United States (US)-licensed 2014–2015 trivalent inactivated influenza vaccine (IIV3-Yamagata [IIV3-YAM]; Afluria) and IIV3 containing the alternate Victoria B strain (IIV3-VIC) in adults ≥18 years.MethodsParticipants (n = 3484) were randomized 2:1:1 and stratified by age to receive IIV4 (n = 1741), IIV3-YAM (n = 871), or IIV3-VIC (n = 872). The primary objective was to demonstrate noninferiority of the immunological response to IIV4 versus IIV3-YAM and IIV3-VIC. Noninferiority was assessed by hemagglutination inhibition geometric mean titer (GMT) ratio (IIV3/IIV4; upper bound of two-sided 95% confidence interval [CI] ≤ 1.5) and seroconversion rate (SCR) difference (IIV3 – IIV4; upper bound of two-sided 95% CI ≤ 10%) for vaccine strains. Solicited local and systemic adverse events (AEs) were assessed for 7 days postvaccination, AEs recorded for 28 days postvaccination, and serious AEs for 6 months postvaccination.ResultsIIV4 elicited a noninferior immune response for matched strains, and superior response for unmatched B strains not contained in IIV3 comparators. Adjusted GMT ratios (95% CI) for A/H1N1, A/H3N2, B/YAM, and B/VIC strains were 0.93 (0.88, 0.99), 0.93 (0.88, 0.98), 0.87 (IIV3-YAM; 0.82, 0.93), and 0.95 (IIV3-VIC; 0.88, 1.03), respectively. Corresponding values for SCR differences (95% CI) were −1.1 (−4.5, 2.3), −1.7 (−5.0, 1.7), −3.2 (IIV3-YAM; −7.4, 0.9), and −1.6 (IIV3-VIC; −5.8, 2.5). AEs were generally mild and experienced by 52.9% of participants. Serious AEs were reported with a slightly higher frequency with IIV4 (2.3%) versus IIV3-YAM (1.6%) and IIV3-VIC (1.5%).ConclusionsIIV4 demonstrated immunological noninferiority to the US-licensed IIV3, and superiority for unmatched B strains not contained in IIV3 comparators. Safety/tolerability profiles were similar across vaccine groups.Funding: Seqirus; Clinicaltrials.gov: NCT02214225.     

Determinants of under-immunization and cumulative time spent under-immunized in a Quebec cohort

BackgroundUnder-immunization refers to a state of sub-optimal protection against vaccine preventable diseases. Vaccine coverage for age may not capture intentional or non-intentional spacing of vaccines in the recommended provincial immunization guidelines. We aimed to identify factors associated with coverage and under-immunization and to determine the number of days during which children were under-immunized during their first 24 months of life.MethodsSecondary analysis of children ≤3 years recruited through active surveillance for gastroenteritis from three Quebec pediatric emergency departments from 2012 to 2014. Vaccination status for children at least 24 months of age was determined using provincial immunization guidelines. Cumulative days under-immunized were calculated for DTaP-VPI-Hib, PCV, MMR, and Men-C-C. Factors associated with up-to-date (UTD) status at 24 months of life and for under-immunization ≥6 months were analyzed using logistic regression.ResultsOf 246 eligible children, 180 (73%) were UTD by 24 months of life. The mean cumulative days under-immunized for MMR was 107 days, for PCV 209 days, for Men-C-C 145 days, and for DTaP-VPI-Hib 227 days. Overall, 149 children (60%) experienced delay for at least 1 vaccine. Factors associated with both an UTD status at 24 months and concurrently associated with being under-immunization ≥6 months, included timely initiation of immunization (OR = 5.85; 95% CI: 2.80–12.22) and (OR = 0.13; 95% CI: 0.07–0.24), failure to co-administer 18-month vaccines (OR = 0.15; 95% CI: 0.10–0.21) and (OR = 3.29; 95% CI: 2.47–4.39), and having a household with ≥3 children under 18 years ((OR = 0.50; 0.28–0.86) and (OR = 2.99; 1.45–6.22), respectively.ConclusionPaired with an unexpected low level of coverage at 24 months of life, the majority of our cohort also experienced a state of under-immunization for a least one vaccine. Estimates of coverage do not capture intentional or non-intentional gaps in protection from vaccine preventable illnesses. Timely preventive care should be prioritized.     

Tetanus,diphtheria, and acellular pertussis vaccination during pregnancy and reduced risk of infant acute respiratory infections

BackgroundTo protect infants from pertussis infection, the Advisory Committee on Immunization Practices (ACIP) recommends women receive the tetanus toxoid, reduced diphtheria toxoid, acellular pertussis (Tdap) vaccine between 27 and 36 weeks of pregnancy. Here, we assessed the association between timing of maternal Tdap vaccination during pregnancy and acute respiratory infection (ARI) in infants <2 months of age.MethodsThis retrospective cohort study included 99,434 infants born to active duty military women in the Department of Defense Birth and Infant Health Registry from 2006 through 2013. Multivariable log-binomial regression was used to calculate relative risks (RRs) and 95% confidence intervals (CIs) for the association between maternal Tdap vaccination during pregnancy and infant ARI at <2 months of age.ResultsInfants of mothers who received Tdap vaccination during pregnancy vs those who did not were 9% less likely to be diagnosed with an ARI at <2 months of age (RR, 0.91; 95% CI, 0.84–0.99), and the risk was 17% lower if vaccination was received between 27 and 36 weeks of pregnancy (RR, 0.83; 95% CI, 0.74–0.93). Similar results were observed when comparing mothers who received Tdap vaccination prior to pregnancy in addition to Tdap vaccination between 27 and 36 weeks of pregnancy versus mothers who only received vaccination prior to pregnancy (RR, 0.85; 95% CI, 0.74–0.98).ConclusionsMaternal Tdap vaccination between 27 and 36 weeks of pregnancy was consistently protective against infant ARI in the first 2 months of life vs no vaccination during pregnancy, regardless of Tdap vaccination prior to pregnancy. Our findings strongly support current ACIP guidelines recommending Tdap vaccination in late pregnancy for every pregnancy.     

Safety,tolerability, and immunogenicity of a 4-antigen Staphylococcus aureus vaccine (SA4Ag): Results from a first-in-human randomised,placebo-controlled phase 1/2 study

BackgroundA prophylactic Staphylococcus aureus four-antigen vaccine (SA4Ag) is under development for prevention of invasive S. aureus disease. A preliminary S. aureus three-antigen vaccine (SA3Ag) was reformulated to include a novel manganese transporter protein (MntC or rP305A). This study describes the first-in-human dose-finding, safety, and immunogenicity results for SA4Ag.MethodsIn this double-blind, sponsor-unblind, placebo-controlled, phase 1/2 study, 454 healthy adults aged 18–64 years were randomised to receive a single dose of one of three formulations of SA4Ag with escalating dose levels of rP305A or placebo. Functional immune responses were measured using opsonophagocytic activity (OPA) killing and fibrinogen-binding inhibition (FBI) assays; antigen-specific immunogenicity was assessed using a four-plex competitive Luminex® immunoassay (cLIA).ResultsA high proportion of SA4Ag recipients met the pre-defined antibody thresholds for each antigen at Day 29. A substantial and dose-level dependent immune response was observed for rP305A, with up to 18-fold rises in cLIA titres at Day 29. Robust functional responses were demonstrated, with >80-fold and >20-fold rises in OPA assay titres at Day 29 using S. aureus strains expressing capsular polysaccharide serotypes 5 and 8, respectively. Durable antibody responses were observed through month 12, gradually waning from peak levels achieved by days 11–15. SA4Ag was well tolerated, and no vaccine-related serious adverse events were reported.ConclusionsSingle-dose vaccination of SA4Ag in healthy adults aged 18–64 years safely induced rapid and robust functional immune responses that were durable through month 12, supporting further development of this vaccine. Trial registration number: NCT01364571     

Vaccine Adjuvant Systems containing monophosphoryl lipid A and QS-21 induce strong humoral and cellular immune responses against hepatitis B surface antigen which persist for at least 4 years after vaccination

BackgroundRecombinant hepatitis B surface antigen (HBsAg) was used as a model antigen to evaluate persistence of cellular and humoral immune responses when formulated with three different Adjuvant Systems containing 3-O-desacyl-4′-monophosphoryl lipid A (MPL) and QS-21, in an oil-in-water emulsion (AS02_B and AS02_V), or with liposomes (AS01_B).MethodsThis is an open, 4-year follow-up of a previous randomised, double-blind study. Healthy subjects aged 18–40 years received three vaccine doses on a month 0, 1, 10 schedule and were initially followed for 18 months. A total of 93 subjects (AS02_B: n = 30; AS02_V: n = 28; AS01_B: n = 35) were enrolled in this follow-up and had an additional blood sample taken at Year 4 (NCT02153320). The primary endpoint was the frequency of HBsAg-specific CD4⁺ and CD8⁺ T-cells expressing cytokines upon short-term in vitro stimulation of peripheral blood mononuclear cells with HBsAg-derived peptides. Secondary endpoints were anti-HBs antibody titres and frequency of HBsAg-specific memory B-cells.ResultsA strong and persistent specific CD4⁺ T-cell response was observed at Year 4 in all groups. HBsAg-specific CD4⁺ T-cells expressed mainly CD40L and IL-2, and to a lesser extent TNF-α and IFN-γ. HBsAg-specific CD8⁺ T-cells were not detected in any group. A high, persistent HBsAg-specific humoral immune response was observed in all groups, with all subjects seroprotected (antibody titre ≥10 mIU/mL) at Year 4. The geometric mean antibody titre at Year 4 was above 100,000 mIU/mL in all groups. A strong memory B-cell response was observed post-dose 2, which tended to increase post-dose 3 and persisted at Year 4 in all groups.ConclusionThe MPL/QS-21/HBsAg vaccine formulations induced persistent immune responses up to 4 years after first vaccination. These Adjuvant Systems offer potential for combination with recombinant, synthetic or highly purified subunit vaccines, particularly for vaccination against challenging diseases, or in specific populations, although additional studies are needed.     

Evaluating the effectiveness of the universal immunization program against varicella in Japanese children

ObjectiveMatched case control study was conducted to elucidate the effectiveness of the Oka/Biken vaccine immediately after implementation of the universal immunization program in Japan.MethodsCases were laboratory confirmed varicella patient under 15 years of age diagnosed at 14 designated pediatric clinics between September 2015 and September 2016. Controls were selected from patients who visited the same practice for different reasons as the varicella case within 2 weeks. Swab samples were collected from varicella suspected patients and molecular diagnostic assays were used to confirm varicella cases. Matched odds ratio were used to calculate vaccine effectiveness (VE).ResultsVaricella zoster virus DNA was detected in 183 (81.3%) of 225 suspected cases. One sample was excluded because it was positive for the Oka vaccine strain (182/225, 80.9%). Three hundred twenty-three control subjects were enrolled. The effectiveness of 1 dose of the Oka/Biken vaccine compared with no vaccine was 76.7% (95% confidence interval [CI]: 58.6–86.9%; P < 0.001). The effectiveness of 2 doses of the Oka/Biken vaccine was 94.2% (95% CI: 85.7–97.6%; P < 0.001). After adjusting for potential confounding effects, the adjusted VE of 1 and 2 doses of varicella vaccine were 76.9% (95% CI: 58.1–87.3%; P < 0.001) and 94.7% (95% CI: 86.0–98.0%; P < 0.001), respectively.ConclusionsVE of one dose of Oka/Biken varicella vaccine was insufficient to control varicella. Therefore, two doses of Oka/Biken varicella vaccine is significant for controlling varicella in Japan.     

A randomized clinical trial in adults and newborns in South Africa to compare the safety and immunogenicity of bacille Calmette-Guérin (BCG) vaccine administration via a disposable-syringe jet injector to conventional technique with needle and syringe

IntroductionIntradermal bacille Calmette-Guérin (BCG) vaccination by needle-free, disposable-syringe jet injectors (DSJI) is an alternative to the Mantoux method using needle and syringe (NS). We compared the safety and immunogenicity of BCG administration via the DSJI and NS techniques in adults and newborn infants at the South African Tuberculosis Vaccine Initiative (SATVI) research site in South Africa.MethodThirty adults and 66 newborn infants were randomized 1:1 to receive intradermal BCG vaccine (0.1 mL in adults; 0.05 mL in infants) via DSJI or NS. Wheal diameter (mm) and skin fluid deposition at the site of injection (SOI) were measured immediately post-vaccination. Adverse events and SOI reactogenicity data were collected 30 min and 1, 2, 4, and 12 weeks after vaccination for adults and at 30 min and 4, 10, and 14 weeks for infants. Blood was collected in infants at 10 and 14 weeks to assess BCG-specific T-cell immune responses.ResultsMore infant BCG vaccinations by DSJI deposited >5 μL fluid on the skin surface, compared to NS (49% versus 9%, p = 0.001). However, all 12 infant vaccinations that did not produce any SOI wheal occurred in the NS group (36%, p < 0.001). Median wheal diameter, in participants for which an SOI wheal formed, did not differ significantly between groups in infants (combined 3.0 mm IQR 2.0 to 4.0, p = 0.59) or in adults (combined 9.0 mm IQR 7.0 to 10.0, p = 0.13). Adverse events were similar between study arms. Proportion of participants with BCG scars after three months did not differ in adults (combined 97%, p = 0.67) or infants (combined 62%, p = 0.13). Frequencies of BCG-specific clusters of differentiation 4 (CD4) and clusters of differentiation 8 (CD8) T-cells co-expressing IFN-γ, TNF-α, IL-2, and/or IL-17 were not different in the DSJI and NS groups.ConclusionBCG vaccination of newborn infants via DSJI was more likely to deliver an appropriate intradermal wheal at the SOI as compared to NS, despite leaving more fluid on the surface of the skin. Safety, reactogenicity, and antigen-specific T-cell immune responses did not differ between DSJI and NS techniques.     

Immunogenicity and safety of a tetravalent E. coli O-antigen bioconjugate vaccine in animal models

BackgroundExtra-intestinal pathogenic Escherichia coli (ExPEC) are major human pathogens; however, no protective vaccine is currently available. We assessed in animal models the immunogenicity and safety of a 4-valent E. coli conjugate vaccine (ExPEC-4V, serotypes O1, O2, O6 and O25 conjugated to Exotoxin A from Pseudomonas aeruginosa (EPA)) produced using a novel in vivo bioconjugation method.MethodsThree doses of ExPEC-4V (with or without aluminum hydroxide) were administered to rabbits (2 μg or 20 μg per O-antigen, subcutaneously), mice (0.2 μg or 2 μg per O-antigen, subcutaneously) and rats (0.4 μg or 4 μg per O-antigen, intramuscularly). Antibody persistence and boostability were evaluated in rats using O6-EPA monovalent conjugate (0.4 μg O-antigen/dose, intramuscularly). Toxicity was assessed in rats (16 μg total polysaccharide, intramuscularly). Serum IgG and IgM antibodies were measured by ELISA.ResultsRobust antigen-specific IgG responses were observed in all animal models, with increased responses in rabbits when administered with adjuvant. O antigen-specific antibody responses persisted up to 168 days post-priming. Booster immunization induced a rapid recall response. Toxicity of ExPEC-4V when administered to rats was considered to be at the no observed adverse effect level.ConclusionsExPEC-4V conjugate vaccine showed good immunogenicity and tolerability in animal models supporting progression to clinical evaluation.