Ten-year follow-up on efficacy, immunogenicity and safety of two doses of a combined measles-mumps-rubella-varicella vaccine or one dose of monovalent varicella vaccine: Results from five East European countries.

BACKGROUND: We assessed the 10-year efficacy, immunogenicity and safety of two doses of a combined measles-mumps-rubella-varicella vaccine (MMRV) or one dose of a monovalent varicella vaccine (V) in children from Czech Republic, Lithuania, Poland, Romania and Slovakia. METHODS: This was a phase IIIB follow-up of an observer-blind, randomized, controlled trial (NCT00226499). In phase A, healthy children aged 12-22 months from 10 European countries were randomized in a 3:3:1 ratio to receive two doses of MMRV (MMRV group), one dose of MMR followed by one dose of V (MMR + V group), or two doses of MMR (MMR; control group), 42 days apart. Vaccine efficacy (VE) against varicella (confirmed by viral DNA detection or epidemiological link and clinical assessment) was calculated with 95% confidence intervals using Cox proportional hazards regression model. Immunogenicity was assessed as seropositivity rates and geometric mean concentrations (GMCs). Solicited and unsolicited adverse events (AEs) and serious AEs (SAEs) were recorded. RESULTS: A total of 3705 children were vaccinated (1590, MMRV group; 1586, MMR + V group; 529, MMR group). There were 663 confirmed varicella cases (47, MMRV group; 349, MMR + V group; 267, MMR group). VE ranged between 95.4% (Lithuania) and 97.4% (Slovakia) in the MMRV group and between 59.3% (Lithuania) and 74% (Slovakia) in the MMR + V group. At year 10, seropositivity rates were 99.5%-100% in the MMRV group, 98%-100% in the MMR + V group and 50%-100% in the MMR control group, and the anti-VZV antibody GMCs were comparable between MMRV and MMR + V groups. The occurrence of solicited and unsolicited AEs was similar across groups and no SAE was considered as vaccination-related. No new safety concerns were identified. CONCLUSIONS: Our results indicated that two doses of varicella zoster virus-containing vaccine provided better protection than one dose against varicella and induced antibody responses that persisted 10 years post-vaccination.

Quadrivalent Influenza Vaccine Prevents Illness and Reduces Healthcare Utilization Across Diverse Geographic Regions During Five Influenza Seasons: A Randomized Clinical Trial.

BACKGROUND: We evaluated an inactivated quadrivalent influenza vaccine (IIV4) in children 6-35 months of age in a phase III, observer-blind trial. METHODS: The aim of this analysis was to estimate vaccine efficacy (VE) in preventing laboratory-confirmed influenza in each of 5 independent seasonal cohorts (2011-2014), as well as vaccine impact on healthcare utilization in 3 study regions (Europe/Mediterranean, Asia-Pacific and Central America). Healthy children were randomized 1:1 to IIV4 or control vaccines. VE was estimated against influenza confirmed by reverse transcription polymerase chain reaction on nasal swabs. Cultured isolates were characterized as antigenically matched/mismatched to vaccine strains. RESULTS: The total vaccinated cohort included 12,018 children (N = 1777, 2526, 1564, 1501 and 4650 in cohorts 1-5, respectively). For reverse transcription polymerase chain reaction confirmed influenza of any severity (all strains combined), VE in cohorts 1-5 was 57.8%, 52.9%, 73.4%, 30.3% and 41.4%, respectively, with the lower limit of the 95% confidence interval >0 for all estimates. The proportion of vaccine match for all strains combined in each cohort was 0.9%, 79.3%, 72.5%, 24.1% and 28.6%, respectively. Antibiotic use associated with influenza illness was reduced with IIV4 by 71% in Europe, 36% in Asia Pacific and 59% in Central America. CONCLUSIONS: IIV4 prevented influenza in children 6-35 months of age in each of 5 separate influenza seasons in diverse geographical regions. A possible interaction between VE, degree of vaccine match and socioeconomic status was observed. The IIV4 attenuated the severity of breakthrough influenza illness and reduced healthcare utilization, particularly antibiotic use.

Clinical Presentation of Influenza in Children 6 to 35 Months of Age: Findings From a Randomized Clinical Trial of Inactivated Quadrivalent Influenza Vaccine.

BACKGROUND: In an exploratory analysis of an inactivated quadrivalent influenza vaccine (IIV4) trial in children 6-35 months without risk factors for influenza, we evaluated clinical presentation of influenza illness and vaccine impact on health outcomes. METHODS: This phase III trial was conducted in 13 geographically diverse countries across 5 influenza seasons (2011-2014). Children were randomized 1:1 to IIV4 or control. Active surveillance was performed for influenza-like episodes (ILE); influenza was confirmed by reverse transcription polymerase chain reaction (RT-PCR). The total vaccinated cohort was evaluated (N = 12,018). RESULTS: 5702 children experienced ≥1 ILE; 356 (IIV4 group) and 693 (control group) children had RT-PCR-confirmed influenza. Prevalence of ILE was similar in RT-PCR-positive and RT-PCR-negative cases regardless of vaccination. Breakthrough influenza illness was attenuated in children vaccinated with IIV4; moderate-to-severe illness was 41% less likely to be reported in the IIV4 group than the control group [crude odds ratio: 0.59 (95% confidence intervals: 0.44-0.77)]. Furthermore, fever >39°C was 46% less frequent following vaccination with IIV4 than with control [crude odds ratio: 0.54 (95% confidence intervals: 0.39-0.75)] in children with breakthrough illness. Health outcome analysis showed that, each year, IIV4 would prevent 54 influenza cases per 1000 children and 19 children would need to be vaccinated to prevent 1 new influenza case. CONCLUSIONS: In addition to preventing influenza in 50% of participants, IIV4 attenuated illness severity and disease burden in children who had a breakthrough influenza episode despite vaccination.

Immunogenicity and safety of 11- and 12-valent pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccines (11vPHiD-CV, 12vPHiD-CV) in infants: Results from a phase II, randomised, multicentre study.

BACKGROUND: We assessed 2 investigational 11- and 12-valent vaccines, containing capsular polysaccharides of 10 serotypes as in the pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine (PHiD-CV) and CRM197-conjugated capsular polysaccharides of serotypes 19A (11-valent) or 19A and 6A (12-valent). METHODS: In this phase II, partially-blind, multicentre study (NCT01204658), healthy infants were randomised (1:1:1:1) to receive 11vPHiD-CV, 12vPHiD-CV, PHiD-CV, or 13-valent CRM197-conjugate pneumococcal vaccine (PCV13), at 2, 3, and 4 (primary series), and 12-15 months of age (booster dose), co-administered with DTPa-HBV-IPV/Hib. Confirmatory objectives assessed non-inferiority of investigational vaccines to comparators (PHiD-CV for common serotypes; PCV13 for 19A and 6A), in terms of percentage of infants with pneumococcal antibody concentrations ≥0.2 µg/mL and antibody geometric mean concentrations, post-primary vaccination. Reactogenicity and safety were assessed. RESULTS: 951 children received ≥1 primary dose, 919 a booster dose. Pre-defined immunological non-inferiority criteria were met simultaneously for 9/11 11vPHiD-CV serotypes (all except 23F and 19A) and 10/12 12vPHiD-CV serotypes (all except 19A and 6A); thus, non-inferiority objectives were reached. For each PHiD-CV serotype, percentages of children with antibody concentrations ≥0.2 µg/mL were ≥96.7% post-primary (except 6B [≥75.2%] and 23F [≥81.1%]), and ≥98.1% post-booster vaccination. For each PHiD-CV serotype except serotype 1, ≥81.0% and ≥93.9% of children had opsonophagocytic activity titres ≥8, post-primary and booster vaccination. AEs incidence was similar across all groups. SAEs were reported for 117 children (29 in the 11vPHiD-CV group, 26 in the 12vPHiD-CV group, 38 in the PHiD-CV group and 24 in the PCV13 group); 4 SAEs were considered vaccination-related. No fatal events were recorded. CONCLUSION: Addition of 19A and 6A CRM197-conjugates did not alter immunogenicity of the PHiD-CV conjugates; for both investigational vaccines post-booster immune responses to 10 common serotypes appeared similar to those elicited by PHiD-CV. Safety and reactogenicity profiles of the investigational vaccines were comparable to PHiD-CV. Clinical trial registry: NCT01204658.

Anamnestic Immune Response and Safety of an Inactivated Quadrivalent Influenza Vaccine in Primed Versus Vaccine-Naïve Children.

BACKGROUND: It has not yet been demonstrated whether 2 doses of inactivated quadrivalent influenza vaccine (IIV4) prime a booster response in infants. We evaluated the anamnestic immune response to an IIV4 in children 17-48 months of age. METHODS: Children were randomized to 2 doses of IIV4 or control in the primary phase III study (NCT01439360). One year later, in an open-label revaccination extension study (NCT01702454), a subset of children who received IIV4 in the primary study (primed group) received 1 IIV4 dose and children who received control in the primary study (unprimed) received 2 IIV4 doses 28 days apart. The primary objective was to evaluate hemagglutination inhibition (HI) antibody titers 7 days after first IIV4 vaccination in the per-protocol cohort (N = 224 primed; N = 209 unprimed). Neutralizing and antineuraminidase antibodies were also measured. Safety was analyzed in the total vaccinated cohort (N = 241 primed; N = 229 unprimed). RESULTS: An anamnestic response was observed in primed children relative to unprimed controls, measured by age-adjusted geometric mean HI titer ratios against strains homologous (A/H1N1: 9.0; B/Victoria: 3.9) and heterologous (A/H3N2: 2.7; B/Yamagata: 6.7) to those in the primary vaccination series. The anamnestic response in primed children included increases in neutralizing antibodies (mean geometric increase: 5.0-10.6) and antineuraminidase antibodies (4.9-8.8). No serious adverse events related to vaccination were reported. CONCLUSIONS: In this study, 2-dose priming with IIV4 induced immune memory that was recalled with 1-dose IIV4 the following year to boost HI, antineuraminidase and neutralizing antibodies, even though the IIV4 strain composition partially changed.

Prevention of vaccine-matched and mismatched influenza in children aged 6-35 months: a multinational randomised trial across five influenza seasons.

BACKGROUND: Despite the importance of vaccinating children younger than 5 years, few studies evaluating vaccine prevention of influenza have been reported in this age group. We evaluated efficacy of an inactivated quadrivalent influenza vaccine (IIV4) in children aged 6-35 months. METHODS: In this phase 3, observer-blinded, multinational trial, healthy children from 13 countries in Europe, Central America, and Asia were recruited in five independent cohorts, each in a different influenza season. Participants were randomly assigned (1:1) to either IIV4 (15 µg haemagglutinin antigen per strain per 0·5 mL dose; a single dose on day 0 for vaccine-primed children, and two doses, on days 0 and 28, for vaccine-unprimed children) or to one or two doses of a non-influenza control vaccine. Primary endpoints were moderate-to-severe influenza or all influenza (irrespective of disease severity) confirmed by RT-PCR on nasal swabs. Cultured isolates were further characterised as antigenically matched or mismatched to vaccine strains. Efficacy was assessed in the per-protocol cohort and total vaccinated cohort (time-to-event analysis), and safety was assessed in the total vaccinated cohort. FINDINGS: Between Oct 1, 2011, and Dec 31, 2014, 12 018 children were recruited into the total vaccinated cohort (6006 children in the IIV4 group and 6012 children in the control group). 356 (6%) children in the IIV4 group and 693 (12%) children in the control group had at least one case of RT-PCR-confirmed influenza. Of these 1049 influenza strains, 138 (13%) were A/H1N1, 529 (50%) were A/H3N2, 69 (7%) were B/Victoria, and 316 (30%) were B/Yamagata. Overall, 539 (64%) of 848 antigenically characterised isolates were vaccine-mismatched (16 [15%] of 105 for A/H1N1; 368 [97%] of 378 for A/H3N2; 54 [86%] of 63 for B/Victoria; 101 [33%] of 302 for B/Yamagata). Vaccine efficacy was 63% (97·5% CI 52-72) against moderate-to-severe influenza and 50% (42-57) against all influenza in the per-protocol cohort, and 64% (53-73) against moderate-to-severe influenza and 50% (42-57) against all influenza in the total vaccinated cohort. There were no clinically meaningful safety differences between IIV4 and control. INTERPRETATION: IIV4 prevented influenza A and B in children aged 6-35 months despite high levels of vaccine mismatch. Vaccine efficacy was highest against moderate-to-severe disease, which is the most clinically important endpoint associated with greatest burden. FUNDING: GlaxoSmithKline Biologicals SA.

Growth of Czech breastfed infants in comparison with the World Health Organization standards.

Growth references are important for paediatric health monitoring. It is critical to understand differences in growth interpretation and potential consequences when using available growth references. This study compares the growth of Czech breastfed children with the current WHO growth standards 2006 and the Czech references 1991, 2001. A total of 960 infant/parent pairs in the Czech Republic were recruited through paediatric practices. Anthropometric data were collected during infants' first 12 months of life and parent questionnaires were gathered during a preventive visit at 18 months. Czech breastfed infants were longer with a greater head circumference at all percentiles compared to the WHO standards and were similar to the national references. The percentile weight-for-age and weight-for-length values of infants (: 6 months) were lower, and higher (6-12 months) compared to the WHO standards. The infant growth in the sample differed from both the WHO standards as well as the national references. Our findings indicate that the growth of Czech breastfed children differs from the current national references. These discrepancies were smaller compared to the WHO standards. The results of the study were used for new growth assessment guidelines to optimize feeding recommendations for Czech infants. The adoption of the WHO standards in the Czech Republic is not recommended.