Innovations in cold chain equipment for immunization supply chains

BackgroundSince 2010, numerous new technologies have entered the immunization cold chain equipment market. The World Health Organization (WHO) Immunization Devices Programme—Performance, Quality and Safety (PQS)—has played a key role in bringing these to market. In this article, the authors explore the emergence of new cold chain equipment technologies from 2004 to 2016 and the role of PQS in this evolution.MethodsThis review focuses on three major vaccine cold chain technology innovations—solar direct-drive refrigerators, long-term passive cold boxes, and equipment with user-independent freeze prevention. For the review, we used online data from WHO PQS, a literature search, and unpublished research reports.ResultsTimelines with key milestones in the emergence of the three focus technologies show delays of between one and three years between earliest field trials and publication of WHO specifications; procurement builds after the WHO prequalification of initial devices.DiscussionThe timelines show the role of PQS as both gatekeeper and enabler for cold chain equipment technologies. The use of target product profiles by PQS has increased its ability to signal preferred attributes and to engage with manufacturers during the product-development stage. Procurement data show how demand for solar direct-drive refrigerators increased over time. Gavi, the Vaccine Alliance, is employing demand-generation strategies to try to drive procurement of technologies with favorable technical attributes.Conclusions

• •PQS plays an important role in early product development.
• •Target product profiles have proven to be a successful way to communicate desired attributes and focus developer research.
• •Field evaluations provide PQS with invaluable data to help refine specifications in line with actual performance in immunization settings.
• •Establishing more systematic post-market surveillance systems for cold chain equipment after large-scale deployment could have positive effects.
• •Efforts to communicate to countries and other immunization stakeholders about new technologies is needed to accelerate their uptake.

     

A report on the status of vaccination in Europe

Vaccine policy, decision processes and outcomes vary widely across Europe. The objective was to map these factors across 16 European countries by assessing (A) national vaccination strategy and implementation, (B) attributes of healthcare vaccination systems, and (C) outcomes of universal mass vaccination (UMV) as a measure of how successful the vaccination policy is.

• A.Eleven countries use standardised assessment frameworks to inform vaccine recommendations. Only Sweden horizon scans new technologies, uses standard assessments, systematic literature and health economic reviews, and publishes its decision rationale. Time from European marketing authorisation to UMV implementation varies despite these standard frameworks. Paediatric UMV recommendations (generally government-funded) are relatively comparable, however only influenza vaccine is widely recommended for adults.
• B.Fourteen countries aim to report annually on national vaccine coverage rates (VCRs), as well as have target VCRs per vaccine across different age groups. Ten countries use either electronic immunisation records or a centralised registry for childhood vaccinations, and seven for other age group vaccinations.
• C.National VCRs for infant (primary diphtheria tetanus pertussis (DTP)), adolescent (human papillomavirus (HPV)) and older adult (seasonal influenza) UMV programmes found ranges of: 89.1% to 98.2% for DTP-containing vaccines, 5% to 85.9% for HPV vaccination, and 4.3% to 71.6% for influenza vaccine. Regarding reported disease incidence, a wide range was found across countries for measles, mumps and rubella (in children), and hepatitis B and invasive pneumococcal disease (in all ages).

These findings reflect an individual approach to vaccination by country. High VCRs can be achieved, particularly for paediatric vaccinations, despite different approaches, targets and reporting systems; these are not replicated in vaccines for other age groups in the same country. Additional measures to improve VCRs across all age groups are needed and could benefit from greater harmonisation in target setting, vaccination data collection and sharing across EU countries.     

Immunogenicity,reactogenicity and safety of 2 doses of an adjuvanted herpes zoster subunit vaccine administered 2, 6 or 12 months apart in older adults: Results of a phase III,randomized, open-label,multicenter study

BackgroundIn phase III trials, 2 doses of a herpes zoster (HZ) subunit vaccine (HZ/su; 50 µg varicella-zoster virus glycoprotein E [gE] and AS01_B Adjuvant System) administered 2-months apart in older adults (≥50 and ≥70 years) demonstrated >90% efficacy in preventing HZ and had a clinically acceptable safety profile. Here we report immunogenicity, reactogenicity and safety following administration of 2 HZ/su doses at intervals longer than 2 months.MethodsIn this Phase III, open-label trial conducted in the US and Estonia, 354 adults ≥50 years were randomized 1:1:1 to receive 2 HZ/su doses 2, 6, or 12 months apart. gE-specific humoral immune responses were evaluated at pre-vaccination, 1 and 12 months post-dose 2. Co-primary objectives were to compare immune responses to HZ/su 1 month post-dose 2 when given 6-months or 12-months apart to those administered 2-months apart. For each participant, safety information was collected from dose 1 to 12 months post-dose 2.Results346 participants completed the study and 343 were included in the according-to-protocol cohort for immunogenicity. One month post-dose 2, vaccine response rates were 96.5% (97.5% confidence interval [CI]: 90.4; 99.2) and 94.5% (97.5% CI: 87.6; 98.3) for the 0, 6- and 0, 12-month schedules, respectively, both schedules meeting the pre-defined criterion. Non-inferiority of anti-gE geometric mean concentrations was demonstrated for HZ/su administered on 0, 6-month compared to a 0, 2-month schedule; however, HZ/su administered on a 0, 12-month schedule did not meet the non-inferiority criterion. Injection site pain was the most commonly reported solicited adverse event (AE). 26 participants each reported at least 1 serious AE; none were assessed as related to vaccination.ConclusionsImmune responses to HZ/su administered at 0, 6-month were non-inferior to those elicited by a 0, 2-month schedule. HZ/su exhibited a clinically acceptable safety profile for all dosing intervals.Clinical Trials Registration: Clinicaltrials.gov (NCT01751165).     

Rescue of CD8+ T cell vaccine memory following sublethal γ irradiation

Sublethal γ irradiation eliminates CD8+ T cell mediated memory responses. In this work, we explored how these memory responses could be rescued in the aftermath of such exposure. We utilized two models of CD8+ T cell mediated immunity: a mouse model of Listeria monocytogenes (LM) infection in which CD8+ T cells specific for LM expressed antigens (Listeriolysin O, LLO) can be tracked, and a murine skin graft model in which CD8+ T cells mediate rejection across a MHC class I (D^d) disparity. In the LM immunized mice, LL0 specific CD8+ T memory cells were lost on irradiation, preserved with rapid revaccination with an attenuated strain 1–3 days post-irradiation (PI), and these mice survived a subsequent wild type LM challenge. A genetic “signature of rescue” identified a group of immune-associated mRNA maintained or upregulated following irradiation and rescue. A number of these factors, including IL-36γ, dectin-2 (Clec4n), and mir101c are upregulated rapidly after exposure of mice to sublethal γ radiation alone and are sustained by early, but not later rescue. Such factors will be evaluated as potential therapeutics to replace individual vaccines for global rescue of CD8+ T memory cell responses following sublethal γ irradiation. The skin allograft model mirrored that of the LM model in that the accelerated D^d skin allograft rejection response was lost in mice exposed to sublethal γ radiation, but infusion of allogeneic D^d expressing bone marrow cells 1–4 days PI preserved the CD8+ T memory mediated accelerated rejection response, further suggesting that innate immune responses may not always be essential to rescue of CD8+ memory T cells following γ irradiation.     

Regulated delayed attenuation enhances the immunogenicity and protection provided by recombinant Salmonella enterica serovar Typhimurium vaccines expressing serovar Choleraesuis O-polysaccharides

Regulated delayed attenuation is a well-studied strategy for retaining the immunogenicity of Salmonella-vectored vaccines. In this study, this strategy was used to optimize two previously constructed recombinant Salmonella enterica serovar Typhimurium vaccines expressing S. Choleraesuis O-polysaccharides (OPS). The novel vaccine strains SLT31 (Δasd ΔrmlB-rfbP ΔP_crp::T araC P_BAD) and SLT33 (Δasd ΔrfbP ΔpagL::T araC P_BAD rfbP ΔP_crp::T araC P_BAD) were constructed by replacement of the native crp promoter with the arabinose-dependent araC P_BAD promoter. As controls, two vaccine strains with direct crp mutations were also constructed, namely, SLT30 (Δasd ΔrmlB-rfbP Δcrp) and SLT32 (Δasd ΔrfbP ΔpagL::T araC P_BAD rfbP Δcrp). Then, the ability to deliver the heterologous S. Choleraesuis OPS on the Asd⁺ plasmid pCZ1 to the mouse immune system was evaluated in the strains with or without regulated delayed attenuation. The SLT30 (pCZ1) and SLT31 (pCZ1) strains expressed only the heterologous OPS, while the SLT32 (pCZ1) and SLT33 (pCZ1) strains co-expressed the homologous and heterologous OPS. The strain SLT31 (pCZ1) or SLT33 (pCZ1), which exhibited regulated delayed attenuation, colonized mouse tissues significantly better and stimulated stronger antibody responses against S. Choleraesuis LPS post immunization than the SLT30 (pCZ1) or SLT32 (pCZ1) strain. Immunization with SLT31 (pCZ1) or SLT33 (pCZ1) resulted in a significant reduction in bacterial loads in mouse tissues and a greater degree of protection against a lethal S. Choleraesuis dose compared with the effects observed after SLT30 (pCZ1) or SLT32 (pCZ1) immunization (100% vs. 80% or 70% vs. 50%, respectively). In addition, all four vaccines conferred complete protection against S. Typhimurium challenge. Overall, our study demonstrates that regulated delayed attenuation via an araC P_BAD-regulated crp gene can enhance the cross-protection by Salmonella-vectored vaccines expressing heterologous OPS, and strain SLT31 (pCZ1) is a good candidate vaccine for preventing both S. Typhimurium and S. Choleraesuis infections.     

Safety of live vaccinations on immunosuppressive therapy in patients with immune-mediated inflammatory diseases,solid organ transplantation or after bone-marrow transplantation – A systematic review of randomized trials,observational studies and case reports

BackgroundLive vaccines are generally contraindicated on immunosuppressive therapy due to safety concerns. However, data are limited to corroborate this practice.ObjectivesTo estimate the safety of live vaccinations in patients with immune-mediated inflammatory diseases (IMID) or solid organ transplantation (SOT) on immunosuppressive treatment and in patients after bone-marrow transplantation (BMT).Data SourcesA search was conducted in electronic databases (Cochrane, Pubmed, Embase) and additional literature was identified by targeted searches.Eligibility criteriaRandomized trials, observational studies and case reports.PopulationPatients with IMID or SOT on immunosuppressive treatment and BMT patients <2 years after transplantation.Intervention/vaccinations looked atLive vaccinations: mumps, measles, rubella (MMR), yellow fever (YF), varicella vaccine (VV), herpes zoster (HZ), oral typhoid, oral polio, rotavirus, Bacillus Calmette–Guérin (BCG), smallpox.Data extractionOne author performed the data extraction using predefined data fields. It was cross-checked by two other authors.Results7305 articles were identified and 64 articles were included: 40 on IMID, 16 on SOT and 8 on BMT patients. In most studies, the administration of live vaccines was safe. However, some serious vaccine-related adverse events occurred. 32 participants developed an infection with the vaccine strain; in most cases the infection was mild. However, in two patients fatal infections were reported: a patient with RA/SLE overlap who started MTX/dexamethasone treatment four days after the YFV developed a yellow fever vaccine-associated viscerotropic disease (YEL-AVD) and died. The particular vaccine lot was found to be associated with a more than 20 times risk of YEL-AVD. One infant whose mother was under infliximab treatment during pregnancy received the BCG vaccine at the age of three months and developed disseminated BCG infection and died. An immunogenicity assessment was performed in 43 studies. In most cases the patients developed satisfactory seroprotection rates. In the IMID group, YFV and VV demonstrated high seroconversion rates. MTX and tumor necrosis factor inhibitory therapy appeared to reduce immune responses to VV and HZ vaccine, but not to MMR and YF-revaccination. Seroconversion in SOT and BMT patients showed mostly higher rates for rubella than for measles, mumps and varicella.LimitationsRisk of bias was high in the majority of studies since 39 of them were observational and 17 were case series/case reports. Only eight studies were randomized trials. BMT patient numbers included in this review were low.ConclusionsAlthough live vaccinations were safe and sufficiently immunogenic in most studies, some serious reactions and vaccine-related infections were reported in immunosuppressed IMID and SOT patients. Apart from mild vaccine-related infections MMR and VV vaccines were safe when administered less than two years after BMT.Implications of key findingsUntil further data are available, live vaccinations under most immunosuppressive treatments should only be administered after a careful risk benefit assessment of medications and dosages.FundingNone.     

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.     

Influenza vaccine effectiveness to prevent influenza-related hospitalizations and serious outcomes in Canadian adults over the 2011/12 through 2013/14 influenza seasons: A pooled analysis from the Canadian Immunization Research Network (CIRN) Serious Outcomes Surveillance (SOS Network)

BackgroundOngoing assessment of influenza vaccine effectiveness (VE) is critical to inform public health policy. This study aimed to determine the VE of trivalent influenza vaccine (TIV) for preventing influenza-related hospitalizations and other serious outcomes over three consecutive influenza seasons.MethodsThe Serious Outcomes Surveillance (SOS) Network of the Canadian Immunization Research Network (CIRN) conducted active surveillance for influenza in adults ≥16 years (y) of age during the 2011/2012, 2012/2013 and 2013/2014 seasons in hospitals across Canada. A test-negative design was employed: cases were polymerase chain reaction (PCR)-positive for influenza; controls were PCR-negative for influenza and were matched to cases by date, admission site, and age (≥65 y or <65 y). All cases and controls had demographic and clinical characteristics (including influenza immunization status) obtained from the medical record. VE was estimated as 1-OR (odds ratio) in vaccinated vs. unvaccinated patients × 100%. The primary outcome was VE of TIV for preventing laboratory-confirmed influenza-related hospitalization; secondary outcomes included VE of TIV for preventing influenza-related intensive care unit (ICU) admission/mechanical ventilation, and influenza-related death.ResultsOverall, 3394 cases and 4560 controls were enrolled; 2078 (61.2%) cases and 2939 (64.5%) controls were ≥65 y. Overall matched, adjusted VE was 41.7% (95% Confidence Interval (CI): 34.4–48.3%); corresponding VE in adults ≥65 y was 39.3% (95% CI: 29.4–47.8%) and 48.0% (95% CI: 37.5–56.7%) in adults <65 y, respectively. VE for preventing influenza-related ICU admission/mechanical ventilation in all ages was 54.1% (95% CI: 39.8–65.0%); in adults ≥65 y, VE for preventing influenza-related death was 74.5% (95% CI: 44.0–88.4%).ConclusionsWhile effectiveness of TIV to prevent serious outcomes varies year to year, we demonstrate a statistically significant and clinically important TIV VE for preventing hospitalization and other serious outcomes over three seasons. Public health messaging should highlight the overall benefit of influenza vaccines over time while acknowledging year to year variability.ClinicalTrials.gov Identifier: NCT01517191.     

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 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.     

Modulation of the CD4+ T cell response after acellular pertussis vaccination in the presence of TLR4 ligation

Whole cell pertussis (wP) vaccines are gradually being replaced by aluminum salt-adjuvanted acellular pertussis (aP) vaccines. These promote CD4⁺ T cell responses with a non-protective Th2 component, while protective immune mechanisms to B. pertussis may rather involve long-lived Th1/Th17 type CD4⁺ T cells. Here we asked whether addition of a non-toxic meningococcal LPS derivative, LpxL1, as adjuvant can favorably modulate the aP-induced pertussis-specific CD4⁺ T cell response in mice. To assess the effect of TLR4 ligation, Th type, quantity, and memory potential of pertussis-specific CD4⁺ T cells were determined at the single-cell level after aP and aP+LpxL1 vaccination using intracellular cytokine staining and MHC class II tetramers. Adding LpxL1 to the aP vaccine weakened the Th2 component and strengthened the Th1/Th17 component of the specific CD4⁺ T cell response. Notably, LpxL1 addition also induced higher frequencies of tetramer positive CD4⁺ T cells in draining lymph nodes or blood, depending on the phase after vaccination. Moreover, there was a net profit in the number of CD4⁺ T cells with a central memory phenotype, preferred for long-term immunity. Thus, adding a TLR4 ligand as adjuvant to a current aP vaccine was associated with a more favorable pertussis-specific CD4⁺ T cell response.     

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.     

Impact of rotavirus vaccination on the burden of acute gastroenteritis in Nagoya city,Japan

BackgroundIn Nagoya city, Japan, rotavirus (RV) vaccination has been available since 2011 with estimated coverage reaching 92% by 2015 after the introduction of a public subsidy in 2012. This study assessed the impact of vaccination on the RV gastroenteritis (RVGE) burden in children aged <5 years old (y) by comparing RVGE hospitalizations and outpatient visits during pre-vaccination (2007–2011), transition (2011–2012) and subsidization (2012–2016) periods.MethodsAll hospitalizations and outpatient visits in children aged <5 y from 2 administrative districts of Nagoya city were identified from the hospital-based electronic databases of 4 hospitals. RVGE cases were identified by diagnostic code and/or positive results of diagnostic kits.ResultsCompared to the pre-vaccination period, there was a decrease in RVGE hospitalizations for children <5 y from 5.59 per 1000 person-year (kPY) to 3.65/kPY in the subsidization period (i.e. 34.69%). In children <1 y, the incidence of RVGE hospitalizations decreased continuously from 6.62/kPY in the pre-vaccination period to 1.84/kPY in the subsidization period (i.e. 72.19%). The highest decrease was observed in the subsidization season i.e. when high coverage was reached: 69% and 75.57% in the 2013/2014 season for 2–3 y and 3–4 y, and 74.03% in the 2014/2015 season for 4–5 y, respectively. Proportion of RVGE outpatient visits decreased by 87.44% for children <1 y and 57.05% for <5 y from the pre-vaccination to the subsidization period. This decrease started the first year of subsidization for children <1 y, 1–2 y and 2–3 y (78.89%, 18.86% and 5.80%) and the second year (2013/2014 season) for children 3–4 y and 4–5 y (87.73% and 51.78%).ConclusionsAlthough yearly fluctuations have been observed, the introduction of vaccination significantly decreased pediatric RVGE hospitalizations and outpatient visits, especially in the age group eligible for vaccination. During the second and third year of subsidization, we observed a herd protection effect on other age groups <5 y who were not eligible for vaccination.Clinicaltrial.gov.registered#:NCT01733862.     

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.     

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.     

Adenovirus type 35-vectored tuberculosis vaccine has an acceptable safety and tolerability profile in healthy,BCG-vaccinated,QuantiFERON®-TB Gold (+) Kenyan adults without evidence of tuberculosis

In a Phase 1 trial, we evaluated the safety of AERAS-402, an adenovirus 35-vectored TB vaccine candidate expressing 3 Mycobacterium tuberculosis (Mtb) immunodominant antigens, in subjects with and without latent Mtb infection. HIV-negative, BCG-vaccinated Kenyan adults without evidence of tuberculosis, 10 QuantiFERON^®-TB Gold In-Tube test (QFT-G)(−) and 10 QFT-G(+), were randomized 4:1 to receive AERAS-402 or placebo as two doses, on Days 0 and 56, with follow up to Day 182. There were no deaths, serious adverse events or withdrawals. For 1 AERAS-402 QFT-G(−) and 1 AERAS-402 QFT-G(+) subject, there were 3 self-limiting severe AEs of injection site pain: 1 after the first vaccination and 1 after each vaccination, respectively. Two additional severe AEs considered vaccine-related were reported after the first vaccination in AERAS-402 QFT-G(+) subjects: elevated blood creatine phosphokinase and neutropenia, the latter slowly improving but remaining abnormal until study end. AERAS-402 was not detected in urine or throat cultures for any subject. In intracellular cytokine staining studies, curtailed by technical issues, we saw modest CD4+ and CD8+ T cell responses to Mtb Ag85A/b peptide pools among both QFT-G(−) and (+) subjects, with trends in the CD4+ T cells suggestive of boosting after the second vaccine dose, slightly more so in QFT-G(+) subjects. CD4+ and CD8+ responses to Mtb antigen TB10.4 were minimal. Increases in Adenovirus 35 neutralizing antibodies from screening to end of study, seen in 50% of AERAS-402 recipients, were mostly minimal. This small study confirms acceptable safety and tolerability profiles for AERAS-402, in line with other Phase 1 studies of AERAS-402, now to include QFT-G(+) subjects.     

Prenatal exposure to perfluroalkyl substances and children's IQ: The Taiwan maternal and infant cohort study

BackgroundPerfluoroalkyl substances (PFASs) are a group of fluorinated organic substances that are widely used in consumer products and are often detectable in human tissues. Human studies on prenatal exposure to PFASs and neurodevelopment in children are few and inconsistent.MethodsIn the Taiwan Maternal and Infant Cohort Study, we collected serum samples from pregnant women during the third trimester and measured concentrations of 9 PFASs using a high performance liquid chromatography system. A subsample of their children was assessed with full scale intelligence quotient (FSIQ), verbal IQ (VIQ) and performance IQ (PIQ) at both age 5 (n = 120) and 8 years (n = 120). We used multivariate linear regression models to examine prenatal PFAS exposure in relation to IQ scores at each age period.ResultsPrenatal perfluoroundecanoic acid (PFUnDA) concentrations were inversely associated with children's PIQ scores at age 5 years, with an adjusted coefficient (β) of −1.6 (95% confidence interval [CI]: (−3.0, −0.2). When children reached 8 years, most of the prenatal PFASs showed inverse association with children's FSIQ, VIQ and PIQ scores. Among them, prenatal perfluorononanoic acid (PFNA) reached significance. Children with higher prenatal PFNA levels had lower VIQ with an adjusted β of −2.1 (95% CI: −3.9, −0.2).ConclusionsWe found two prenatal PFAS exposure, both long-chain PFASs, in association with decreased IQ test scores in children. Our findings suggest more studies on long-chain PFASs and children's neurodevelopment.     

Immunologic non-inferiority and safety of the investigational pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine (PHiD-CV) 4-dose vial presentation compared to the licensed PHiD-CV 1-dose vial presentation in infants: A phase III randomized study

BackgroundTo support vaccination programs in developing countries, a 4-dose vial presentation of pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine (PHiD-CV) was developed. This study assessed immunologic non-inferiority and safety of the investigational PHiD-CV 4-dose versus licensed 1-dose vial presentation in infants.MethodsIn this phase III, mono-center, observer-blind study in Bangladesh, 6–10-week-old infants were randomized 1:1 to receive PHiD-CV primary vaccination (at ages 6, 10, 18 weeks) and a booster dose (at age 9 months) with a 4-dose vial (with preservative, 4DV group) or 1-dose vial (preservative-free, 1DV group). DTPw-HBV/Hib was (co)-administered per study protocol and polio, measles and rubella vaccines as part of the national immunization program. Non-inferiority of PHiD-CV 4-dose versus 1-dose vial for each vaccine pneumococcal serotype (VT) and vaccine-related serotype 19A in terms of antibody geometric mean concentration (GMC) was assessed (criterion: upper limit of 2-sided 95% confidence interval of antibody GMC ratios [1DV/4DV] <2-fold). Immune responses were measured. Solicited, unsolicited and serious adverse events (AEs) were evaluated.ResultsOf 320 infants (160 per group) vaccinated during the primary vaccination phase, 297 received a booster. Non-inferiority was demonstrated for each VT and 19A. One month post-primary vaccination, for most VT, ≥97.9% of infants in each group had antibody concentrations ≥0.2 μg/mL; for 19A ≥ 80.1% reached this threshold. Pneumococcal antibody responses and opsonophagocytic activity for each VT and 19A were within similar ranges between groups after primary and booster vaccination, as were anti-protein D responses. Booster immune responses were observed in both groups. Reported AEs were within similar ranges for both presentations.ConclusionImmunologic non-inferiority of PHiD-CV 4-dose vial (with preservative) versus PHiD-CV 1-dose vial (preservative-free) was demonstrated. Immune responses and reactogenicity following primary/booster vaccination were within similar ranges for both presentations. PHiD-CV 4-dose vial would help improve access and coverage in resource-limited countries.Clinical Trial Registry: NCT02447432.