A Phase 3, Single-arm Trial to Evaluate the Safety and Immunogenicity of a 20-Valent Pneumococcal Conjugate Vaccine in Healthy Children 15 Months Through <18 Years of Age.

BACKGROUND: A 20-valent pneumococcal conjugate vaccine (PCV20), containing 13-valent PCV (PCV13) components and 7 additional polysaccharide conjugates, was developed to extend protection for pneumococcal disease. This phase 3 study assessed the safety and immunogenicity of PCV20 in children. METHODS: In this single-arm study, children (≥15 months-<18 years of age) received 1 dose of PCV20. Children <5 years of age had ≥3 prior doses of PCV13; children ≥5 years were recruited regardless of previous PCV receipt. Serotype-specific IgG concentrations and opsonophagocytic activity (OPA) titers were measured before and 1 month after PCV20. Local reactions and systemic events, adverse events (AEs), serious AEs, and newly diagnosed chronic medical conditions were collected. RESULTS: Of 839 enrolled participants, 831 (>99%) were vaccinated, and 819 (>97%) completed all study visits. Local reactions and systemic events were mostly mild to moderate in severity. No serious AEs were considered PCV20-related. IgG geometric mean fold rises (GMFRs) from before to 1 month after PCV20 ranged from 27.9-1847.7 (7 additional serotypes) and 2.9-44.9 (PCV13 serotypes) in children <5 years of age, and 10.5-187.7 (7 additional serotypes) and 4.3-127.9 (PCV13 serotypes) in children ≥5 years old. OPA GMFRs from before to 1 month after PCV20 ranged from 12.4-983.6 to 2.8-52.9 in children <5 years of age and from 11.5-499.0 to 5.3-147.9 in children ≥5 years of age. CONCLUSIONS: Among children ≥15 months through <18 years of age, PCV20 was well tolerated and induced robust responses to all 20 serotypes, supporting the use of PCV20 in children.

Evaluation of Clinical Case Definitions for Respiratory Syncytial Virus Lower Respiratory Tract Infection in Young Children.

BACKGROUND: Various case definitions of respiratory syncytial virus lower respiratory tract infection (RSV-LRTI) are currently proposed. We assessed the performance of 3 clinical case definitions against the World Health Organization definition recommended in 2015 (WHO 2015). METHODS: In this prospective cohort study conducted in 8 countries, 2401 children were followed up for 2 years from birth. Suspected LRTIs were detected via active and passive surveillance, followed by in-person clinical evaluation including single timepoint respiratory rate and oxygen saturation (by pulse oximetry) assessment, and nasopharyngeal sampling for RSV testing by polymerase chain reaction. Agreement between case definitions was evaluated using Cohen's κ statistics. RESULTS: Of 1652 suspected LRTIs, 227 met the WHO 2015 criteria for RSV-LRTI; 73 were classified as severe. All alternative definitions were highly concordant with the WHO 2015 definition for RSV-LRTI (κ: 0.95-1.00), but less concordant for severe RSV-LRTI (κ: 0.47-0.82). Tachypnea was present for 196/226 (86.7%) WHO 2015 RSV-LRTIs and 168/243 (69.1%) LRTI/bronchiolitis/pneumonia cases, clinically diagnosed by nonstudy physicians. Low oxygen saturation levels were observed in only 55/226 (24.3%) WHO 2015 RSV-LRTIs. CONCLUSIONS: Three case definitions for RSV-LRTI showed high concordance with the WHO 2015 definition, while agreement was lower for severe RSV-LRTI. In contrast to increased respiratory rate, low oxygen saturation was not a consistent finding in RSV-LRTIs and severe RSV-LRTIs. This study demonstrates that current definitions are highly concordant for RSV-LRTIs, but a standard definition is still needed for severe RSV-LRTI. CLINICAL TRIAL REGISTRATION: NCT01995175.

Incidence of Respiratory Syncytial Virus Lower Respiratory Tract Infections During the First 2 Years of Life: A Prospective Study Across Diverse Global Settings.

BACKGROUND: The true burden of lower respiratory tract infections (LRTIs) due to respiratory syncytial virus (RSV) remains unclear. This study aimed to provide more robust, multinational data on RSV-LRTI incidence and burden in the first 2 years of life. METHODS: This prospective, observational cohort study was conducted in Argentina, Bangladesh, Canada, Finland, Honduras, South Africa, Thailand, and United States. Children were followed for 24 months from birth. Suspected LRTIs were detected via active (through regular contacts) and passive surveillance. RSV and other viruses were detected from nasopharyngeal swabs using PCR-based methods. RESULTS: Of 2401 children, 206 (8.6%) had 227 episodes of RSV-LRTI. Incidence rates (IRs) of first episode of RSV-LRTI were 7.35 (95% confidence interval [CI], 5.88-9.08), 5.50 (95% CI, 4.21-7.07), and 2.87 (95% CI, 2.18-3.70) cases/100 person-years in children aged 0-5, 6-11, and 12-23 months. IRs for RSV-LRTI, severe RSV-LRTI, and RSV hospitalization tended to be higher among 0-5 month olds and in lower-income settings. RSV was detected for 40% of LRTIs in 0-2 month olds and for approximately 20% of LRTIs in older children. Other viruses were codetected in 29.2% of RSV-positive nasopharyngeal swabs. CONCLUSIONS: A substantial burden of RSV-LRTI was observed across diverse settings, impacting the youngest infants the most. Clinical Trials Registration. NCT01995175.

Concomitant administration of a liquid formulation of human rotavirus vaccine (porcine circovirus-free) with routine childhood vaccines in infants in the United States: Results from a phase 3, randomized trial.

BACKGROUND: In response to the detection of porcine circovirus type 1 (PCV-1) in the human rotavirus vaccine (HRV), a PCV-free HRV (no detection of PCV-1 and PCV-2 according to the detection limit of tests used) was developed. Liquid (Liq) PCV-free HRV previously showed immunogenicity and safety profiles comparable to lyophilized (Lyo) HRV. METHODS: This was a phase 3a, randomized, single-blind study (NCT03207750) conducted in the United States. Healthy infants aged 6-12 weeks received 2 doses (0, 2 months) of either Liq PCV-free HRV or Lyo HRV with routine vaccines (0, 2, 4 months): diphtheria-tetanus-acellular pertussis, hepatitis B and inactivated poliovirus combination vaccine (DTaP-HBV-IPV), monovalent tetanus toxoid-conjugated vaccine against Haemophilus influenzae type b (Hib-TT), and 13-valent pneumococcal conjugate vaccine. Co-primary objectives were: (i) to assess non-inferiority of immune responses to routine vaccine antigens 1 month post-dose 3 following co-administration with Liq PCV-free HRV compared to Lyo HRV; (ii) to rule out a 10% decrease in seroresponse to pertussis antigens after dose 3. Other objectives were to evaluate immunogenicity and safety of HRV vaccines. RESULTS: Of 1272 vaccinated infants, 990 (489 in Liq PCV-free HRV and 501 in Lyo HRV group) were included in the per-protocol set. All statistical criteria were met, thus co-primary objectives were demonstrated. Seroprotection/seropositivity rates in both groups were high: 100% for diphtheria/tetanus, ≥99.3% for HBV, ≥99.8% for polio, ≥99.8% for each pertussis antigen, ≥90.8% for all pneumococcal serotypes except serotype 3 (≥69.1%), and ≥ 97.4% for Hib. Most infants seroconverted for anti-RV antibodies (76.3% of Liq PCV-free HRV and 78.9% of Lyo HRV recipients). Geometric mean concentrations/titers were comparable between groups. Incidences of adverse events and serious adverse events were similar between groups. CONCLUSION: Routine pediatric vaccines co-administered with Liq PCV-free HRV showed non-inferior immune responses and similar safety profiles to those following co-administration with Lyo HRV.

A double-blind, randomized, multicenter, controlled study to evaluate the immunogenicity, safety, and tolerability of varicella vaccine (VARIVAX™) passage extension 34 (PE34) process administered concomitantly with measles, mumps, and rubella vaccine (M-M-R™ II).

The varicella vaccine passage extension (VAR-PE) process was undertaken to extend the availability of varicella zoster virus (VZV)-containing vaccines. This study (V210-A03; NCT03239873) assessed the immunogenicity, safety, and tolerability of VAR-PE process in comparison with varicella vaccine commercial product 2016 (VAR) randomized 1:1 in 600 healthy children 12 to 23 months of age administered concomitantly with measles-mumps-rubella (MMR) vaccine. The VZV seroconversion rate at 6 weeks Postdose 1 in the PP population was 100% for both groups. VZV antibody response rates and GMTs of VZV antibodies to VAR-PE induced and were non-inferior to those induced by VAR 6 weeks Postdose 1. From Day 1 through Day 42, adverse events (AEs) were reported by 81.3% of participants Postdose 1 and 67.9% Postdose 2. From Day 1 through Day 42 Postdose 1, injection-site AEs related to varicella vaccine were reported by 31.1% and 29.7% of participants in VAR-PE and VAR, respectively, and Postdose 2, by 25.7% and 25.5% of participants in the VAR-PE and VAR groups, respectively. Systemic AEs were generally comparable for the 2 vaccination groups, with the exception of pyrexia and otitis media higher in VAR-PE, and diarrhea and teething higher in VAR. The incidence of systemic AEs was generally lower Postdose 2 compared with Postdose 1.

Immunogenicity and Safety of a Measles-Mumps-Rubella Vaccine Administered as a First Dose to Children Aged 12 to 15 Months: A Phase III, Randomized, Noninferiority, Lot-to-Lot Consistency Study.

BACKGROUND: MMR II (M-M-R II [Merck & Co, Inc.]) is currently the only measles, mumps, and rubella (MMR) vaccine licensed in the United States. A second MMR vaccine would mitigate the potential risk of vaccine supply shortage or delay. In this study, we assessed the immunogenicity and safety of another MMR vaccine (MMR-RIT [Priorix, GlaxoSmithKline]) compared with those of the MMR II in 12- to 15-month-old children who received it as a first dose. METHODS: In this phase III, observer-blinded, noninferiority, lot-to-lot consistency clinical trial (ClinicalTrials.gov identifier NCT01702428), 5003 healthy children were randomly assigned to receive 1 dose of MMR-RIT (1 of 3 production lots) or MMR II along with other age-recommended routine vaccines. We evaluated the immunogenicity of all vaccines in terms of antibody concentrations (by using an enzyme-linked immunosorbent assay or electrochemiluminescence assay) and/or seroresponse rates 43 days after vaccination. We also assessed the reactogenicity and safety of the vaccines. RESULTS: Immunoresponses after vaccination with MMR-RIT were robust and noninferior to those after vaccination with the MMR II. Immunogenicity of the 3 production lots of MMR-RIT was consistent; more than 97% of the children had a seroresponse to MMR components. The coadministered vaccines elicited similar immunoresponses in the MMR-RIT and MMR II groups. Both MMR vaccines resulted in comparable reactogenicity profiles, and no safety concerns were detected. CONCLUSIONS: If licensed, the MMR-RIT could provide a valid option for the prevention of measles, mumps, and rubella in children in the United States and would reduce potential risks of a vaccine shortage.

Lot-to-lot consistency, safety and immunogenicity of 3 lots of Haemophilus influenzae type b conjugate vaccine: results from a phase III randomized, multicenter study in infants.

BACKGROUND: Vaccination against Haemophilus influenzae type b (Hib) is included in routine pediatric immunization schedule in the United States. Previous vaccine shortages have created the need for additional options for Hib vaccination. METHODS: This phase III, randomized, multi-centered study (NCT01000974) evaluated the safety and immunogenicity of a monovalent tetanus toxoid-conjugate Hib vaccine (Hib-TT) compared to a monovalent (Hib-TT control) and a combination Hib-TT vaccine. We hierarchically assessed lot-to-lot consistency of 3 Hib-TT lots and non-inferiority of Hib-TT to Hib-TT control. We co-administered routine pediatric vaccines with Hib-TT vaccines at 2, 4, 6months (primary vaccination) and 15-18months of age (booster vaccination). We recorded adverse events (AEs) for 4 (solicited) and 31days (unsolicited) post-vaccination and serious AEs (SAEs) throughout the study. RESULTS: Of 4009 enrolled children, 3086 completed booster phase. Lot-to-lot consistency was not demonstrated. The study met statistical criteria for non-inferiority of Hib-TT to Hib-TT control in terms of immune responses to Hib and co-administered vaccines' antigens, but not in terms of participants achieving post-primary vaccination anti-PRP levels ≥1µg/mL. Because of the hierarchical nature of the objectives, non-inferiority could not be established. In all groups, 92.5-96.7% and 99.6-100% of participants achieved anti-PRP levels ≥0.15µg/mL, while 78.3-89.8% and 97.9-99.1% had anti-PRP levels ≥1µg/mL, post-primary and post-booster vaccination, respectively. Immune responses to co-administered vaccines and reported incidence of AEs were comparable among groups. We recorded SAEs for 107/2963 (3.6%), 24/520 (4.6%), and 21/520 (4.0%) children post-primary vaccination, and 29/2337 (1.2%), 4/435 (0.9%), and 2/400 (0.5%) children post-booster vaccination with Hib-TT, Hib-TT control and combination Hib-TT vaccine, respectively; 6/5330 (0.1%) SAEs in the Hib-TT groups were considered vaccine-related. CONCLUSION: Hib-TT induced seroprotective antibody concentrations in the majority of participants and was well-tolerated when co-administered with routine pediatric vaccines according to a 3+1 schedule.

Safety of a quadrivalent meningococcal serogroups A, C, W and Y conjugate vaccine (MenACWY-CRM) administered with routine infant vaccinations: results of an open-label, randomized, phase 3b controlled study in healthy infants.

BACKGROUND: The highest risk for invasive meningococcal disease (IMD) is in infants aged <1 year. Quadrivalent meningococcal conjugate vaccination has the potential to prevent IMD caused by serogroups A, C, W and Y. This phase 3b, multinational, open-label, randomized, parallel-group, multicenter study evaluated the safety of a 4-dose series of MenACWY-CRM, a quadrivalent meningococcal conjugate vaccine, concomitantly administered with routine vaccinations to healthy infants. METHODS: Two-month-old infants were randomized 3:1 to receive MenACWY-CRM with routine vaccines or routine vaccines alone at ages 2, 4, 6 and 12 months. Adverse events (AEs) that were medically attended and serious adverse events (SAEs) were collected from all subjects from enrollment through 18 months of age. In a subset, detailed safety data (local and systemic solicited reactions and all AEs) were collected for 7 days post vaccination. The primary objective was a non-inferiority comparison of the percentages of subjects with ≥1 severe systemic reaction during Days 1-7 after any vaccination of MenACWY-CRM plus routine vaccinations versus routine vaccinations alone (criterion: upper limit of 95% confidence interval [CI] of group difference <6%). RESULTS: A total of 7744 subjects were randomized with 1898 in the detailed safety arm. The percentage of subjects with severe systemic reactions was 16% after MenACWY-CRM plus routine vaccines and 13% after routine vaccines alone (group difference 3.0% (95% CI -0.8, 6.4%). Although the non-inferiority criterion was not met, post hoc analysis controlling for significant center and group-by-center differences revealed that MenACWY-CRM plus routine vaccinations was non-inferior to routine vaccinations alone (group difference -0.1% [95% CI -4.9%, 4.7%]). Rates of solicited AEs, medically attended AEs, and SAEs were similar across groups. CONCLUSION: In a large multinational safety study, a 4-dose series of MenACWY-CRM concomitantly administered with routine vaccines was clinically acceptable with a similar safety profile to routine vaccines given alone.

A randomized controlled study to evaluate the immunogenicity of a trivalent inactivated seasonal influenza vaccine at two dosages in children 6 to 35 months of age.

The trivalent inactivated influenza vaccine Fluarix™ is licensed in the US for adults and children from 3 years old. This randomized observer-blind study (NCT00764790) evaluated Fluarix™ at two doses; 0.25 ml (Flu-25) and 0.5 ml (Flu-50) in children aged 6-35 months. The primary objective was to demonstrate immunogenic non-inferiority vs. a control vaccine (Fluzone®; 0.25 ml). Children received Flu-25 (n = 1107), Flu-50 (n = 1106) or control vaccine (n = 1104) at Day 0 and for un-primed children, also on Day 28. Serum hemagglutination-inhibition titers were determined pre-vaccination and at Day 28 (primed) or Day 56 (un-primed). Non-inferiority was assessed by post-vaccination geometric mean titer (GMT) ratio, (upper 95% confidence interval [CI] ≤ 1.5) and difference in seroconversion rate (upper 95% CI ≤ 10%). Reactogenicity/safety was monitored. The immune response to Flu-50 met all regulatory criteria. Indicated by adjusted GMT ratios [with 95% CI], the criteria for non-inferiority of Flu-50 vs. control vaccine were reached for the B/Florida strain (1.13 [1.01-1.25]) but not for the A/Brisbane/H1N1 (1.74 [1.54-1.98]) or A/Uruguay/H3N2 (1.72 [1.57-1.89]) strains. In children aged 18-35 months similar immune responses were observed for Flu-50 and the control vaccine. Flu-50 induced a higher response than Flu-25 for all strains. Temperature (≥ 37.5°C) was reported in 6.2%, 6.4%, and 6.6% of the Flu-25, Flu-50, and control group, respectively. Reactogenicity/safety endpoints were within the same range for all vaccines. In children aged 6-35 months, immune responses with Flu-50 fulfilled regulatory criteria but did not meet the pre-defined criteria for non-inferiority vs. control. This appeared to be due to differences in immunogenicity in children aged<18 months.

Coadministration of RIX4414 oral human rotavirus vaccine does not impact the immune response to antigens contained in routine infant vaccines in the United States.

OBJECTIVE: This study was conducted to confirm the absence of immune interference of 2 doses of RIX4414 (Rotarix) on routine infant vaccinations in the United States. STUDY DESIGN: A total of 484 healthy infants aged 6 to 12 weeks were randomly assigned to 1 of 2 groups to receive 3 doses of Pediarix (combined diphtheria-tetanus-acellular pertussis-hepatitis B-poliovirus vaccine [DTaP-HBV-IPV]), Prevnar (7-valent pneumococcal conjugate vaccine [PCV7]), and ActHIB (Haemophilus influenzae type b conjugate vaccine [Hib]) at 2, 4, and 6 months of age with RIX4414 either coadministered at 2 and 4 months (Co-ad) or administered separately at 3 and 5 months (Sep-ad). Serum antibodies were measured 1 month after dose 3 of the DTaP-HBV-IPV, PCV7, and Hib vaccines. RESULTS: Antibody responses to all antigens were similar in infants in both the Co-ad and Sep-ad groups. Seroprotective antibody concentrations against diphtheria, tetanus, hepatitis B, and poliovirus types 1, 2, and 3 were achieved by >or=97.9% of the infants in both groups. Antipolyribosyl ribitol phosphate antibody levels of >or=1.0 microg/mL were achieved by 88.3% to 89.4% of infants in both groups. In both groups, >or=97.8% of the infants were seropositive for antipertussis antibodies and the 7 pneumococcal serotypes. Predefined criteria for noninferiority between groups were reached for all antigens. CONCLUSIONS: Two doses of RIX4414 coadministered with routine infant vaccines as recommended in the United States (DTaP-HBV-IPV, PCV7, and Hib) did not impair the immune response to any of the coadministered antigens.

A combination measles, mumps, rubella, and varicella vaccine (ProQuad) given to 4- to 6-year-old healthy children vaccinated previously with M-M-RII and Varivax.

BACKGROUND: In the United States, children receive primary doses of M-M-RII (Merck & Co, Inc, West Point, PA) and Varivax (Merck & Co, Inc) beginning at 12 months, often at the same health care visit. Currently a second dose of M-M-RII is given to 4- to 6-year-old children, to increase vaccination rates and to reduce the number of individuals without detectable antibodies. A second dose of a varicella-containing vaccine may result in similar benefits. OBJECTIVES: To demonstrate that ProQuad (measles, mumps, rubella, and varicella virus vaccine live; Merck & Co, Inc) may be given in place of a second dose of M-M-RII or second doses of M-M-RII and Varivax for 4- to 6-year-old children. METHODS: Four- to 6-year-old children who had been immunized previously with M-M-RII and Varivax were assigned randomly to receive either ProQuad and placebo (N = 399), M-M-RII and placebo (N = 195), or M-M-RII and Varivax (N = 205) and were then monitored for safety and immunogenicity. RESULTS: ProQuad was generally well tolerated. Similarity (noninferiority) was demonstrated in postvaccination antibody responses to measles, mumps, and rubella between recipients of ProQuad and all recipients of M-M-RII and in responses to varicella between recipients of ProQuad and recipients of Varivax. Postvaccination seropositivity rates for antibodies against all 4 viruses were nearly 100% in all 3 groups. Small fold increases were observed for measles, mumps, and rubella antibody titers. In contrast, substantial boosts in varicella antibody titers were observed among recipients of a second dose of varicella vaccine, administered as ProQuad or Varivax. CONCLUSIONS: ProQuad may be used in place of a second dose of M-M-RII or second doses of M-M-RII and Varivax for 4- to 6-year-old children.

Safety of cetirizine in infants 6 to 11 months of age: a randomized, double-blind, placebo-controlled study.

BACKGROUND: H(1)-antihistamines are widely used for symptom relief in allergic disorders in infants and children; however, there are few prospective, randomized, double-blind, controlled studies of these medications in young children, and to date, no such studies have been conducted in infants. OBJECTIVE: This prospective, randomized, parallel-group, double-blind, placebo-controlled study was designed to evaluate the safety of the H(1)-antihistamine cetirizine, particularly with regard to central nervous system and cardiac effects, in infants age 6 to 11 months, inclusive. METHODS: Infants who met the entry criteria for age and had a history of treatment with an H(1)-antihistamine for an allergic or other disorder were randomized to receive 0.25 mg/kg cetirizine orally or matching placebo twice daily orally for 1 week. RESULTS: The mean daily dose in cetirizine-treated infants was 4.5 +/- 0.7 mg (SD). No differences in all-cause or treatment-related adverse events were observed between the cetirizine- and placebo-treated groups. A trend was observed toward fewer adverse events and sleep-related disturbances in the cetirizine group compared with the placebo group. No prolongation in the linear corrected QT interval was observed in cetirizine-treated infants compared with either baseline values or with values in placebo-treated infants. CONCLUSIONS: We have documented the safety of cetirizine in this short-term investigation, the first randomized, double-blind, placebo-controlled study of any H(1)-antihistamine in infants. Additional prospective, randomized, double-blind, placebo-controlled, long-term studies of cetirizine and other H(1)-antihistamines are needed in this population.