Seroresponse Rates Research Articles

Safety and immunogenicity of the epicutaneous reactivation of pertussis toxin immunity in healthy adults: a phase I, randomized, double-blind, placebo-controlled trial

ObjectivesProtection induced by acellular vaccines can be short, requiring novel immunization strategies. Objectives of this study were to evaluate safety and capacity of a recombinant pertussis toxin (PTgen) -coated Viaskin® epicutaneous patch to recall memory responses in healthy adults. MethodsThis double-blind, placebo-controlled randomized trial (Phase I) assessed the safety and immunogenicity of PTgen administered on days 0 and 14 to healthy adults using Viaskin® patches applied directly or after epidermal laser-based skin preparation. Patch administration was followed by Boostrix®dTpa on day 42. Antibodies were assessed at days 0, 14, 28, 42 and 70. ResultsAmong 102 volunteers enrolled, 80 received Viaskin-PT (Viaskin-PT 25 μg (n = 25), Viaskin-PT 50 μg (n = 25), laser + Viaskin-PT 25 μg (n = 5), laser + Viaskin-PT 50 μg (n = 25)), Viaskin-placebo (n = 10) or laser + Viaskin-placebo (n = 2). Incidence of adverse events was similar across groups (any local event: 21/25 (84.0%), 24/25 (96.0%), 4/5 (80.0%), 24/25 (96.0%), 8/10 (80.0%), 10/12 (83.0%), respectively). Direct application induced no detectable response. On day 42, PT-IgG geometric mean concentrations were significantly higher following laser + Viaskin-PT 25 μg and 50 μg (139.87 (95% CI 87.30–224.10) and 121.76 (95% CI 95.04–156.00), respectively), than laser + Viaskin-placebo (59.49, 95% CI 39.37–89.90). Seroresponse rates were higher following laser + Viaskin-PT 25 μg (4/5 (80.0%), 95% CI 28.4–99.5) and 50 μg (22/25 (88.0%), 95% CI 68.8–97.5) than laser + Viaskin-placebo (0/12 (0.0%), 95% CI 0.0–26.5). ConclusionsViaskin-PT applied after laser-based epidermal skin preparation showed encouraging safety and immunogenicity results: anti-PT booster responses were not inferior to those elicited by Boostrix®dTpa. This study is registered at ClinicalTrials.gov (NCT 03035370) and was funded by DBV Technologies.

Randomized clinical trial of DTaP5-HB-IPV-Hib vaccine administered concomitantly with meningococcal serogroup C conjugate vaccines during the primary infant series

BackgroundConcomitant administration of vaccines simplifies delivery. DTaP5-HB-IPV-Hib is a fully liquid, combination vaccine against 6 diseases. This study evaluated the compatibility of DTaP5-HB-IPV-Hib with 2 different meningococcus group C conjugate (MCC) vaccines in infants. MethodsIn a phase 3, open-label study, 284 healthy infants from 11 UK centres received DTaP5-HB-IPV-Hib at age 2, 3, and 4 months; 13-valent pneumococcal conjugate vaccine (PCV13) at 2 and 4 months; a Haemophilus influenzae type b (Hib)-MCC vaccine and a measles/mumps/rubella vaccine at 12 months. Participants were randomised 1:1 to receive either an MCC-detoxified tetanus toxin vaccine (MCC-TT; n = 141) or an MCC-Corynebacterium diphtheriae CRM197 protein vaccine (MCC-CRM; n = 143) at 3 and 4 months. The primary outcome was seroprotection rate (SPR) to MCC (percent with rabbit complement serum bactericidal antibody titer ≥8). ResultsPer protocol analysis, MCC SPRs were 100 and 96.4 one month after the first dose, 100 and 99.1 after the second dose, and 100 and 97.3 after the third (booster) dose of MCC in the MCC-TT and MCC-CRM groups, respectively. One month after all 3 doses of DTaP5-HB-IPV-Hib, immunoglobulin G anti-polyribosylribitol phosphate SPRs (% ≥0.15 µg/mL) were 97.8 in the MCC-TT group and 100 in the MCC-CRM group; anti-hepatitis B antigen SPRs (% ≥10 mIU/mL) were 96.8 and 96.3 in the MCC-TT and MCC-CRM groups, respectively. All participants were seroprotected against diphtheria and tetanus (≥0.01 IU/mL) and poliovirus types 1, 2, and 3 (≥8 dilution), and seroresponse rates to all pertussis antigens were ≥90.4%. Two vaccine-related serious adverse events (transient severe abdominal pain and crying) occurred concomitantly in 1 participant in the MCC-CRM group. Adverse event rates were similar to other studies of DTaP5-HB-IPV-Hib, with pyrexia ≥38 °C in 10.9% of participants following any dose. ConclusionsDTaP5-HB-IPV-Hib can be effectively used in a 2-, 3-, and 4-month infant priming schedule when given with 2 doses of MCC.

A Phase II, randomized, immunogenicity and safety study of a quadrivalent meningococcal conjugate vaccine, MenACYW-TT, in healthy adolescents in the United States

BackgroundMenACYW-TT is an investigational quadrivalent meningococcal conjugate vaccine intended for use in individuals ≥6 weeks of age. We evaluated the safety and immunogenicity of MenACYW-TT when compared to a licensed quadrivalent conjugate meningococcal vaccine (Menveo®; MCV4-CRM; GlaxoSmithKline, Italy), and when co-administered with tetanus, diphtheria, acellular pertussis (Tdap) and human papilloma virus (HPV4) vaccines in healthy meningococcal vaccine-naïve adolescents (10–17 years old) in the United States of America. MethodsIn this pivotal Phase II, open-label, multicenter study, 1715 participants were randomized to receive MenACYW-TT, MCV4-CRM, MenACYW-TT co-administered with Tdap and HPV4, or Tdap and HPV4 vaccines alone (NCT02199691).The primary objective was to evaluate whether antibody responses to MenACYW-TT antigens were non-inferior to antibody responses after MCV4-CRM administration. Meningococcal antibody titers were determined using human complement serum bactericidal assay (hSBA) with titers measured at baseline, and 30 days post vaccination (D30). A vaccine seroresponse was defined as baseline titers <1:8 with post-vaccination titers ≥1:8 or baseline titers ≥1:8 with a ≥4-fold increase at post-vaccination. Safety data were collected up to six months post-vaccination. ResultsNon-inferiority was demonstrated for MenACYW-TT vs MCV4-CRM (primary endpoint), and for MenACYW-TT co-administered with Tdap and HPV4 vs MenACYW-TT alone (secondary endpoint). The vaccine seroresponse rate was higher with MenACYW-TT than with MCV4-CRM, for each serogroup: A: 75.6% vs 66.4%; C: 97.2% vs 72.6%; W: 86.2% vs 66.6%; Y: 97.0% vs 80.8%. The safety profiles of MenACYW-TT, MCV4-CRM, and Tdap and HPV4 vaccines, administered with or without MenACYW-TT, were comparable. There were no vaccine-related serious adverse events. ConclusionsThe MenACYW-TT vaccine was well tolerated and generated an immune response that was non-inferior to the licensed MCV4-CRM vaccine. Immunogenicity and safety profiles were comparable when MenACYW-TT was administered with or without Tdap and HPV4 vaccines in meningococcal vaccine-naïve adolescents.

Adjuvanted recombinant HBV vaccine (HBV-AS04) is effective over extended follow-up in dialysis population. An open-label non randomized trial

Patients on regular dialysis show a poor response to hepatitis B vaccine due to uremia. A recombinant HB vaccine (containing an improved adjuvant system AS04, HBV-AS04) has been licensed but the evidence on its efficacy and safety in dialysis population over the long term is extremely limited. We have measured antibody (anti-HBs) persistence for up to 72months in a large cohort of patients on long-term dialysis (with susceptibility to HBV infection) who underwent vaccination with HBV-AS04 vaccine. Patients were prospectively recruited to receive four 20-mcg doses of HBV-AS04 by intramuscular route (deltoid muscle). Two vaccine schedules were adopted: 0,1,2, and 3month (n=217 patients) and 0,1,2, and 6 month (n=31patients). Anti-HBs antibody concentrations were tested at 1,2,3, 4, 7 and 12months and then every year up to 72months. Multivariate analysis was made to find the baseline parameters that were associated with the immune response to HBV-AS04 vaccine. Two hundred and seventy-two patients were included and 248completed the study. At completion of vaccine schedule, the frequency of responders (anti-HBs titers≥10mIU/mL) was 81.5% (202/248) (mean anti-HBs antibody titers, 384.9±391.9mIU/mL), according to per-protocol analysis. On the grounds of univariate analysis, age was lower in responder than non- responder patients to HBV AS04 even if no statistical significance was achieved (P=0.09). The sero-protection rate at month 72 was 77% (7/9) (anti-HBs antibody titers, 184.9±360.1mIU/mL, P=0.001). Multivariate analysis found a relationship between sero-response rate and age (P=0.04). No major side effects and no de novo HBV episodes were observed. Our open-label nonrandomized trial performed in a 'real-world' practice showed the persistence of anti-HBs antibody among responder patients over a very long follow-up. Studies with longer observation periods are under way.

Factors associated with hepatitis A virus infection among HIV-positive patients before and after implementation of a hepatitis A virus vaccination program at a medical centre in central Taiwan.

From January 2016 to July 2017, we enrolled 658 HIV-positive male participants. Participants were stratified into anti-HAV-positive (n = 165) and anti-HAV-negative (n = 493) groups. A total of 364 anti-HAV-negative patients received vaccination against HAV and were followed up for 1.5 years. A Cox regression model was used to estimate the effects of factors predicting positive anti-HAV detection after vaccination. Patients with HIV had an anti-HAV-positive prevalence of 25.1% before vaccination. Of the 364 patients inoculated with the first dose of vaccine, 58.0% received the second dose. Seroresponse rates were 50.0% and 80.6%, respectively. Antibody production was 30.0% lower in patients with a CD4 T-cell count <200 cells/µL (adjusted relative risk (ARR) = 0.7; 95% confidence interval (CI) = 0.5-0.9) compared with those with 500 cells/µL. Hepatitis C co-infection reduced the production of antibodies by 50.0% (ARR = 0.5; 95% CI = 0.2-0.8). This study suggests that vaccination against hepatitis A be administered when the immunity of an HIV-positive patient is strong. The promotion of the current vaccination policy against hepatitis A in Taiwan has improved the vaccination rate; the response rate for receiving one dose of the vaccine doubled.

Safety and immunogenicity of a novel 10-valent pneumococcal conjugate vaccine candidate in adults, toddlers, and infants in The Gambia—Results of a phase 1/2 randomized, double-blinded, controlled trial

BackgroundA more affordable pneumococcal conjugate vaccine (PCV) that provides comparable protection to current PCVs is needed to ensure sustainable access in resource-limited settings. Serum Institute of India Pvt. Ltd.’s PCV candidate (SIIPL-PCV) has the potential to meet this need as manufacturing efficiency has been optimized and the vaccine targets the most prevalent disease-causing serotypes in Africa and Asia. We report SIIPL-PCV’s safety, tolerability, and immunogenicity in adults, toddlers, and infants in The Gambia. MethodsThis phase 1/2, randomized, double-blind trial sequentially enrolled 34 PCV-naive adults (18–40 years old), 112 PCV (Prevenar 13® [PCV13])-primed toddlers (12–15 months old), and 200 PCV-naive infants (6–8 weeks old), who were randomized (1:1) to receive SIIPL-PCV or a licensed comparator vaccine. Infants received three-doses of SIIPL-PCV or PCV13 at 6, 10, and 14 weeks of age co-administered with routine Expanded Program on Immunization (EPI) vaccines. Reactogenicity was solicited through seven-days post-vaccination; unsolicited adverse events (AEs) were assessed throughout the study. The safety and immunogenicity of a matching booster at 10–14 months of age were evaluated in a subset of 96 infants. Immune responses were evaluated post-primary and pre- and post-booster vaccinations. ResultsReactogenicity was primarily mild-to-moderate in severity. In infants, the most common solicited reactions were injection-site tenderness and fever, with no meaningful treatment-group differences. There were no serious or severe vaccine-related AEs and no meaningful trends in SAEs, vaccine-related AEs, or overall AEs. Infant post-primary seroresponse rates (IgG level ≥ 0.35 µg/mL) were ≥89% for all serotypes except 6A (79%) in the SIIPL-PCV group. IgG GMCs were >1 µg/mL for all serotypes in both SIIPL-PCV and PCV13 groups. Post-booster GMCs were comparable between groups. ConclusionSIIPL-PCV was well-tolerated, had an acceptable safety profile, and was immunogenic for all vaccine serotypes. Results support the evaluation of SIIPL-PCV in a phase 3 non-inferiority trial.Clinicaltrials.gov: NCT02308540.

Adjuvant effect of TLR7 agonist adsorbed on aluminum hydroxide (AS37): A phase I randomized, dose escalation study of an AS37-adjuvanted meningococcal C conjugated vaccine

An adjuvant system (AS37) has been developed containing a synthetic toll-like receptor agonist (TLR7a). We conducted a phase I randomized, observer-blind, dose-escalation study to assess the safety and immunogenicity of an investigational AS37-adjuvanted meningococcus C (MenC) conjugate vaccine in healthy adults (NCT02639351). A control group received a licensed MenC conjugate alum-adjuvanted vaccine. Eighty participants were randomized to receive one dose of control or investigational vaccine containing AS37 (TLR7a dose 12.5, 25, 50, 100 μg). All vaccines were well tolerated, apart from in the TLR7a 100 μg dose group, which had three reports (18.8%) of severe systemic adverse events. Four weeks after vaccination, human complement serum bactericidal assay seroresponse rates against MenC were 56–81% in all groups, and ELISA seroresponses were ≥81% for all AS37-adjuvanted vaccine groups (100% in 50 and 100 μg dose groups) and 88% in the control group. Antibody responses were maintained at six months after vaccination.

2725. Immunogenicity and Safety of a Booster Dose of a Quadrivalent Meningococcal Conjugate Vaccine (MenACYW-TT) in Adolescents and Adults

BackgroundThe MenACYW-TT conjugate vaccine is a quadrivalent meningococcal vaccine that contains tetanus toxoid as carrier protein. Vaccine is intended for global use in all age groups (i.e., individuals 6 weeks of age and older). This Phase III study evaluated the safety and immunogenicity of the vaccine when compared with a licensed quadrivalent meningococcal conjugate vaccine in individuals ≥ 15 years of age.MethodsA randomized, modified double-blind study (NCT02752906) was conducted in the United States and Puerto Rico. The study evaluated 810 participants primed with a licensed quadrivalent meningococcal conjugate vaccine (Menactra® [MenACWY-D] or MENVEO® [MenACWY-CRM]) in the 4 to 10 years prior to enrollment. Participants were randomly assigned to receive either a single booster dose of MenACYW-TT conjugate vaccine or MenACWY-D. Safety data were collected up to 6 months post-vaccination.ResultsNon-inferiority of immune response was demonstrated for MenACYW-TT vs. MenACWY-D based on percentages of participants achieving an serum bactericidal assay with human complement (hSBA) seroresponse for serogroups A, C, W, and Y at Day 30 post-vaccination. Post-vaccination hSBA geometric mean titers (GMTs) were higher following administration of MenACYW-TT compared with MenACWY-D for age subgroups ≥15 to < 18 years and ≥18 years. Relative to MenACWY-D, post-vaccination hSBA GMTs were higher for all 4 serogroups following administration of MenACYW-TT in participants who received the priming vaccine < 7 years prior to the booster; for participants who received priming vaccine ≥7 years prior to booster, post-vaccination GMTs were higher for serogroups C, W and Y, and comparable for serogroup A. In MenACWY-CRM-primed subjects, hSBA vaccine seroresponse rates were comparable for all 4 serogroups regardless of the booster vaccine administered. In MenACWY-D-primed subjects, hSBA seroresponse rates following MenACYW-TT booster administration were comparable for serogroups A and Y, and higher for serogroups C and W. Reactogenicity profiles were comparable across study groups.ConclusionMenACYW-TT conjugate vaccine was immunogenic and well tolerated when administered as a booster dose to individuals ≥15 years of age.Disclosures All authors: No reported disclosures.

Hepatitis B Vaccination and Waning Hepatitis B Immunity in Persons Living with HIV.

Persons with HIV are at a higher risk for acquiring HBV (hepatitis B virus) than the general population due to shared modes of transmission and are significantly more likely to develop and die from sequelae of chronic HBV infection. Early vaccination is key to achieving HBV protective immunity, but response rates are still much lower than in the general population, ranging from 35 to 70%. Individuals with HIV also experience more rapidly waning immunity than those without HIV. Strategies to augment initial response and improve long-term immunity in individuals with HIV include alterations in dose, frequency, and the use of immune adjuvants. Recent studies have focused on the use of different vaccine formulations, the use of vaccine adjuvants, increased number and strength of vaccine dosages, increased dose frequency, alternative routes of administration, dual vaccinations, and the use of booster vaccines. Although no consensus has been reached on the use of certain vaccination regimens, three and four double-dose vaccine schedules via the intramuscular route have demonstrated higher initial response rates. Early vaccination when CD4 cell counts are greater than 350/mm3 with low viral loads has been shown to improve initial response, along with completion of immunization series. Adjuvants such as TLR4 and TLR9 agonists appear to improve response to HBV vaccination, but further research is needed in individuals with HIV. Persons with HIV have significant lower initial and long-term seroresponse rates after HBV vaccination than immunocompetent individuals. Recent and ongoing studies continue to evaluate multiple strategies to improve these rates within a uniquely susceptible population.

Immunogenicity of the AIK-C measles vaccine in infants aged

Measles-associated deaths have been reported in infants <9 months during outbreaks. A cohort study was conducted on 210 infants aged 6–8 months to evaluate the immunogenicity and safety of the AIK-C measles vaccine containing 104.21 plaque-forming units (PFU)/0.5 mL produced in Vietnam. Paired serum samples were obtained from 196 subjects. Seropositivity was defined as ≥120 mIU/mL. The seroresponse rate was 173/196 (88.27%, 95% confidence interval (CI): 83.77–92.77%) with geometric mean titer (GMT) of 511 mIU/mL (95% CI: 688–880 mIU/mL), and no significant differences were observed by different age groups. Among 196 paired sera, they were categorized into four groups: 122 subjects <14 IU/mL, 28 subjects 14–<60 mIU/mL, 30 subjects 60–<120 mIU/mL, and 16 subjects ≥ 120 mIU/mL. The seroresponse rate was 112/122 (91.8%, 95% CI: 86.94–96.67%) with GMT (597 mIU/mL, 95% CI: 749–1002 mIU/mL) in the <14 mIU/L group. In the 14–<60 mIU/mL group, the seroresponse rate was 18/28 (64.29%) with 184 mIU/L of GMT and was significantly lower (p < 0.01) than that in the <14 mIU/mL group. In the 16 seropositive group, all subjects showed seroconversion (4-fold higher than before) with a higher GMT of 1078 mIU/mL. Local pain and itching at the injection site were observed in 8 subjects (3.8%) within 7 days of the vaccination. Regarding systemic adverse reactions, febrile illness ≥37.5 °C was observed in 14 subjects (6.7%). These results indicate that the AIK-C measles vaccine is effective and safe for infants aged 6–8 months and will contribute to reducing the number of measles-associated deaths in future outbreaks.

Immunogenicity of pentavalent rotavirus vaccine in Chinese infants

BackgroundA phase III, randomized, double-blind, placebo-controlled clinical study was conducted in China to assess the efficacy, safety, and immunogenicity of the pentavalent rotavirus vaccine (RotaTeqTM, RV5) among Chinese infants. The efficacy and safety data have been previously reported. This report presents the immunogenicity data of the study. Methods4,040 infants aged 6–12 weeks were randomly assigned in a 1:1 ratio to receive 3 oral doses of RV5 or placebo. Trivalent oral poliovirus vaccine (tOPV) and diphtheria, tetanus, and acellular pertussis vaccine (DTaP) were administered in a staggered-use (N = 3,240) or concomitant-use (N = 800) schedule. Immunogenicity of RV5 was evaluated in 800 participants (400 participants from each staggered- and concomitant-use immunogenicity subgroup). Geometric mean titers (GMTs) and seroresponse rates (≥3-fold rise from baseline to PD3) were measured for anti-rotavirus IgA in the staggered- and concomitant-use subgroups and measured for serum neutralizing antibodies (SNAs) to human rotavirus serotypes G1, G2, G3, G4, P1A[8] in the staggered-use subgroup. Immune responses to tOPV and DTaP co-administered with RV5 were also evaluated in the concomitant-use immunogenicity subgroup. (ClinicalTrials.gov registry: NCT02062385) ResultsThe PD3 GMT and seroresponse rate of anti-rotavirus IgA were higher in the RV5 group (82.42 units/mL, 89.4%) compared to the placebo group (0.33 units/mL, 10.1%). Rotavirus type-specific SNA responses were also higher in the RV5 group compared to the placebo group. In the concomitant-use subgroup, the seroprotection rates of anti-poliovirus type 1, 2, 3 in the participants who received RV5 were non-inferior to those who received placebo, and the antibody responses to DTaP antigens were comparable between the two vaccination groups. ConclusionsRV5 was immunogenic in Chinese infants. Immune responses induced by tOPV and DTaP were not affected by the concomitant use of RV5.

A second dose of a measles-mumps-rubella vaccine administered to healthy four-to-six-year-old children: a phase III, observer-blind, randomized, safety and immunogenicity study comparing GSK MMR and MMR II with and without DTaP-IPV and varicella vaccines co-administration

ABSTRACT In many countries, a second dose of a combined measles, mumps, and rubella (MMR) vaccine is recommended at 4–6 years of age – similarly to the booster of diphtheria, tetanus, acellular pertussis, and inactivated polio vaccine (DTaP-IPV) and the second dose of varicella vaccine (VV). Vaccine co-administration is generally encouraged if no interferences exist among the vaccines. This phase IIIa, randomized, controlled trial (NCT01621802) evaluated the immunogenicity and safety of MMR-RIT (Priorix, GSK) when given as a second dose with or without co-administration of DTaP-IPV and VV, using MMR II (M-M-R II, Merck & Co Inc.) as comparator. Antibody geometric mean concentrations or titers (GMCs/GMTs) and response rates to the components of all the administered vaccines were assessed. Solicited, unsolicited, and serious adverse events were recorded. Four thousand eleven children aged 4–6 years were enrolled. MMR-RIT elicited immune responses that were not inferior to those of MMR II in terms of GMCs and seroresponse rates when administered alone or when co-administered with DTaP-IPV and VV. The immune responses to the co-administered vaccines in MMR-RIT recipients were non-inferior to those in MMR II recipients. MMR-RIT and MMR II demonstrated similar reactogenicity profiles; the most frequent solicited adverse events across vaccine groups and sub-cohorts were local pain and fever. In conclusion, the immunogenicity and safety profiles of MMR-RIT administered with or without DTaP-IPV and VV were similar to those of MMR II.

2276. Immunogenicity of Takeda’s Bivalent Virus-Like Particle (VLP) Norovirus Vaccine (NoV) Candidate in Children From 6 Months up to 4 Years of Age

BackgroundWith the introduction of routine childhood rotavirus vaccination, norovirus is now becoming the major cause of medically-attended gastroenteritis in children. Takeda is developing a norovirus vaccine (NoV) that contains genotypes GI.1 and GII.4 consensus (GII.4c) sequence VLPs. We report the immunogenicity data of NoV administered to children from 6 months up to 4 years of age.MethodsTwo age cohorts (1 to < 4 years, and 6 to < 12 months, n = 120 per cohort) were enrolled in this ongoing double-blind, randomized, phase 2 dose-finding study conducted in Colombia and Panama. Children received one or two intramuscular doses of NoV formulations containing 15/15, 15/50, 50/50 or 50/150 μg of GI.1/GII.4c VLPs adjuvanted with 0.5 mg Al(OH)3. Vaccinations were on Days 1 and 29, with saline placebo as dose two to maintain blinding in one dose groups. Antibody responses to each VLP were measured on days 1, 29 and 57 as functional histo-blood group binding antigen blocking antibodies (HBGA), expressed as seroresponse rates (SRR), the proportions displaying ≥ 4-fold increases over baseline, and geometric mean titres (GMT).ResultsEach formulation induced dosage-dependent HBGA responses after a single dose, with a further increase after a second dose. In 1- to <4 year-olds HBGA SRR against GI.1 and GII.4c after one dose were 55–62% and 67–82%, respectively. SRR increased to 93–100% and 83–100% after a second dose. In 6 to < 12 month-olds responses were lower after the first dose: SRRs were 10–61% and 17–65% for GI.1 and GII.4c, respectively, increasing to 83–100% and 80–92% after a second dose. GMTs reflected this pattern of responses with higher GMTs for GI.1 and GII.4c achieved with the 50/150 μg formulation than the other dosages after both vaccinations in both age cohorts.ConclusionIn 6–12 month-old infants and children up to 4 years of age, robust immune responses to the bivalent norovirus VLP vaccine candidates were observed; the highest HBGA responses in both age cohorts were observed after two doses of the 50/150 μg formulation. Further clinical evaluation of these formulations is underway in infants < 6 months of age. Clinical Trial Registration (NCT: 02153112, EudraCT: 2014-000778-20)Disclosures T. Masuda, Takeda Pharmaceuticals International AG: Employee, Salary. I. Lefevre, Takeda Pharmaceuticals International AG: Employee, Salary. P. Mendelman, Takeda Pharmaceuticals International AG: Employee, Salary. J. Sherwood, Takeda Pharmaceuticals International AG: Employee, Salary. S. Bizjajeva, Takeda Pharmaceuticals International AG: Employee, Salary. A. Borkowski, Takeda Pharmaceuticals International AG: Employee, Salary.

Neutralizing Antibody Responses to Homologous and Heterologous H1 and H3 Influenza A Strains After Vaccination With Inactivated Trivalent Influenza Vaccine Vary With Age and Prior-year Vaccination.

Prior influenza immunity influences the homologous neutralizing antibody responses elicited by inactivated influenza vaccines (IIV), but neutralizing antibody responses to heterologous strains have not been extensively characterized. We analyzed neutralizing antibody titers in individuals aged 1-88 who received the 2009-2010 season IIV before infection by or vaccination against the 2009 pandemic H1N1 virus. Neutralization titers to homologous and heterologous past, recent, and advanced H1 and H3 strains, as well as H2, H5, and H7 strains, were measured using influenza hemagglutinin pseudoviruses. We performed exploratory analyses based on age, prior-year IIV, and prevaccination titer, without controlling for Type I errors. IIV elicited neutralizing antibodies to past and advanced H1 and H3 strains, as well as to an H2 strain in individuals who were likely infected early in life. The neutralization of avian subtype viruses was rare, and there was no imprinting of neutralization responses to novel avian subtype viruses based on the influenza group. Compared to adults, children had higher seroresponse rates to homologous and heterologous strains, and their sera generated larger antigenic distances among strains. Seroresponse rates to homologous and heterologous strains were lower in subjects vaccinated with prior-year IIV, though postimmunization titers were generally high. IIV elicited neutralizing antibodies to heterologous H1 and H3 strains in all ages groups, but titers and seroresponse rates were usually higher in children. Prior-year vaccination with the same strains tended to blunt IIV neutralization responses to all strains in young and old age groups, yet postimmunization titers were high.

Immunogenicity and safety of measles-mumps-rubella vaccine at two different potency levels administered to healthy children aged 12–15 months: A phase III, randomized, non-inferiority trial

BackgroundThe potency of live viral vaccines decreases over time. We compared the immunogenicity and safety of GSK measles-mumps-rubella vaccine (MMR-RIT) formulations at two different potencies with that of the commercially-available MMR II formulation. MethodsIn this phase III observer-blind clinical study (NCT01681992), 4516 healthy children aged 12–15 months were randomized (1:1:1 ratio) to receive one dose of MMR-RIT at the minimum potency used for this study (MMR-RIT-Min) or MMR-RIT at the second lowest potency used for this study (MMR-RIT-Med), or control MMR II vaccine. A second dose (MMR-RIT or MMR II) was administered 42 days after the first. The study had 10 co-primary objectives to evaluate MMR-RIT versus MMR II immunogenicity via a hierarchical procedure. Anti-measles and anti-rubella antibodies were measured by ELISA and anti-mumps antibodies by ELISA and unenhanced plaque reduction neutralization test (PRNT). ResultsEach formulation induced immune responses to all vaccine antigens after each MMR dose. While the primary objectives for MMR-RIT-Min were not met, MMR-RIT-Med induced immune responses as measured by ELISA against the three vaccine antigens that met pre-specified non-inferiority criteria. The immune response following MMR-RIT-Med against mumps measured by PRNT failed the non-inferiority criterion for seroresponse rate: the 97.5% confidence interval lower limit (−10.94%) was beyond the pre-defined limit of −10%. Immune responses were comparable among groups post-dose 2. No safety concerns were identified, and MMR-RIT and MMR II vaccines had similar reactogenicity and safety profiles. ConclusionsOne dose of MMR-RIT formulation with lower potency (MMR-RIT-Med) induced a non-inferior immune response compared to commercial MMR II vaccine, measured by ELISA in one-year-old children. Non-inferiority was not demonstrated in terms of immune response against mumps virus measured by unenhanced PRNT, although the difference was of uncertain clinical relevance. After the second dose, immune responses were comparable among the MMR-RIT and MMR II groups.

Safety and Immunogenicity of Measles Vaccination in HIV-Infected and HIV-Exposed Uninfected Children: A Systematic Review and Meta-Analysis

BackgroundHIV-infected and HIV-exposed uninfected (HEU) children have an increased risk of measles that may be due to altered immune responses or suboptimal timing of measles vaccination. We aimed to evaluate the safety and immunogenicity of measles vaccination in HIV-infected and HEU children. MethodsFor this systematic review and meta-analysis, we searched PubMed, Embase, Cochrane Library, CINAHL, Global Health Library and IndMED on May 9, 2018. Studies were included if they reported on safety or seroresponse (either seroprotection/seropositivity/seroconversion) after measles vaccination in HIV-infected or HEU children. We calculated pooled estimates to compare immunogenicity outcomes between HIV-infected, HEU and HIV-unexposed children, using risk ratios [RRs] (with 95%CIs). PROSPERO registration number: CRD42017057411. FindingsSeventy-one studies met the inclusion criteria (15,363 children). Twenty-eight studies reported on safety; vaccine-associated adverse events and deaths were uncommon. Sixty-two studies reported on immunogenicity, 27 were included in the meta-analysis. HIV-infected children had lower seroresponse rates after primary vaccination compared with HIV-unexposed (RR 0.74; 95%CI: 0.61–0.90, I2 = 85.9%) and HEU children (0.78; 0.69–0.88, I2 = 77.1%), which was mitigated by antiretroviral therapy and time interval between vaccination and serology. HEU and HIV-unexposed children had similar seroresponses. Vaccination at 6-months resulted in similar proportions of HIV-infected children having seroresponse compared with HIV-unexposed (0.96; 0.77–1.19) and HEU children (1.00; 0.73–1.37, I2 = 63.7%). InterpretationPrimary measles vaccination at 6-months of age may provide protection against measles during early infancy in settings with high prevalence of maternal HIV-infection, however, further studies are needed to evaluate this strategy in HEU children and HIV-infected children receiving antiretroviral therapy. FundingSouth African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation in Vaccine Preventable Diseases; Medical Research Council: Respiratory and Meningeal Pathogens Research Unit.

Immunogenicity and safety of a second dose of a measles-mumps-rubella vaccine administered to healthy participants 7 years of age or older: A phase III, randomized study

ABSTRACTThe introduction of vaccination programs against measles, mumps, and rubella (MMR) led to significant global reduction in morbidity and mortality from these diseases. The currently recommended MMR vaccination schedule in the United States of America comprises 2 vaccine doses typically administered at 12–15 months and 4–6 years, respectively. Considering recent outbreaks in the USA, catch-up vaccination with an additional dose of MMR vaccine could contribute to outbreak control and community protection. This phase III, observer-blind, randomized controlled trial (NCT02058563) assessed the immunogenicity and safety of a dose of the MMR-RIT vaccine (Priorix, GSK) compared to MMR II vaccine (control; M-M-R II, Merck&Co Inc.) in ≥7-year-olds who had received ≥1 previous dose of MMR vaccine. We assessed anti-measles, anti-mumps, and anti-rubella antibody geometric mean concentrations (GMCs; primary endpoint) and seroresponse rates (SRRs) at day 42 post-vaccination. Solicited, unsolicited, and serious adverse events (AEs) were recorded. The according-to-protocol cohort for immunogenicity included 869 participants (MMR-RIT: N = 433; MMR II: N = 436). We observed anti-measles, anti-mumps, and anti-rubella antibody GMCs of 1790.2 mIU/mL, 113.5 EU/mL, and 76.1 IU/mL, respectively, and SRRs of 98.8%, 98.4%, and 99.5%, respectively, after a dose of MMR-RIT; non-inferiority compared to MMR II was demonstrated. Both vaccines showed comparable reactogenicity profiles; the most common solicited AEs were injection site redness and pain, and fever (MMR-RIT: 12.2%, 11.8%, and 3.0%; MMR II: 11.7%, 11.5%, and 5.2%, respectively). The dose of MMR-RIT induced robust immune responses that were not inferior to those of MMR II, and was well tolerated.

Safety and immunogenicity of a Vi-DT typhoid conjugate vaccine: Phase I trial in Healthy Filipino adults and children

BackgroundTyphoid fever remains a major public health problem in low- and middle-income countries where children aged 2–14 years bear the greatest burden. Vi polysaccharide is poorly immunogenic in children <2 years of age, and protection in adults is modest. The limitations of Vi polysaccharide vaccines can be overcome by conjugation of the Vi to a carrier protein. A typhoid conjugate vaccine composed of Vi polysaccharide conjugated to diphtheria toxoid (Vi-DT) has been developed. The Phase I study results are presented here. MethodsThis was a randomized, observer-blinded Phase I study to assess the safety and immunogenicity of Vi-DT compared to Vi polysaccharide vaccine, conducted in Manila, Philippines. Participants enrolled in an age de-escalation manner (18–45, 6–17 and 2–5 years) were randomized between Test (Vi-DT, 25 µg) administered at 0 and 4 weeks and Comparator (Vi polysaccharide, Typhim Vi® and Vaxigrip®, Sanofi Pasteur) vaccines. ResultsA total of 144 participants were enrolled (48 by age strata, 24 in Test and Comparator groups each). No serious adverse event was reported in either group. Solicited and unsolicited adverse events were mild or moderate in both groups with the exception of a 4-year old girl in Test group with grade 3 fever which resolved without sequelae. All participants in Test group seroconverted after first and second doses of Vi-DT while the proportions in the Comparator group were 97.1% and 97.2%, after first dose of Typhim Vi® and second dose of Vaxigrip®, respectively. Vi-DT showed 4-fold higher Geometric Mean Titers (GMT) compared to Typhim Vi® (adjusted for age strata, p < 0.001). No further increase of GMT was detected after the second dose of Vi-DT. Anti-DT IgG seroresponse rates were 81.2% and 84.5% post first and second Vi-DT doses, respectively. ConclusionsVi-DT vaccine was safe, well-tolerated and immunogenic in participants aged 2–45 years.ClinicalTrials.gov registration number: NCT02645032.

A randomized, open label trial to evaluate and compare the immunogenicity and safety of a novel liquid hexavalent DTwP-Hib/Hep B-IPV (EasySix™) to licensed combination vaccines in healthy infants

Immunogenicity and safety of a newly developed liquid DTwP-Hib/HepB-IPV hexavalent vaccine (EasySix™) was evaluated and compared with administration of commercially licensed Pentavac SD® (DTwP-HepB/Hib) and Imovax Polio® vaccine in an open-label, randomized multi-centric trial. 284 participants, aged 6–10weeks, randomized in a 1:1 allocation, received three doses of test or comparator vaccines, administered 4weeks apart. Immunogenicity of the vaccines was determined by measuring the baseline and post-vaccination antibody responses and comparing the proportions of subjects achieving seroprotection against the vaccine antigens; safety was evaluated in terms of solicited (local and systemic) and unsolicited incidences in the follow up phase. Post-vaccination, seroprotection was achieved against all six vaccine antigens in both vaccine groups. The seroresponse rate as well as geometric mean titers of antibody for all vaccine components were comparable between EasySix™ and Pentavac SD®-Imovax Polio® group. Both vaccines had similar reactogenicity profiles and were well tolerated; all adverse events resolved completely without any sequelae. Only one serious adverse event was reported that completely resolved; it was regarded unconnected to the vaccine administered. This study demonstrated that immunogenicity and safety profiles of EasySix™ vaccine, manufactured by Panacea Biotec Ltd, are non-inferior to the commercially available vaccines.Clinical trial registration: CTRI/2015/02/005578.

Four-year persistence of type-specific immunity after quadrivalent human papillomavirus vaccination in HIV-infected children: Effect of a fourth dose of vaccine

ObjectiveAlthough HIV-infected children are recommended to receive quadrivalent human papillomavirus vaccine (QHPV) there is limited information on their response to QHPV. This study in HIV-infected children, evaluated the magnitude and duration of immune responses to QHPV. This report describes type-specific serum antibody responses over a 4-to-5year period after either 3 or 4 doses of QHPV. Design/methodsHIV-infected children, ages 7-to-11years, received 3 doses of QHPV (n=96) or placebo (n=30). At 72weeks QHPV recipients received a fourth dose (n=84), while placebo recipients began the 3-dose QHPV schedule (n=27). HPV serotype-specific antibody was determined, by competitive Luminex immunoassay (cLIA) and IgG Luminex immunoassay, at 2, 3.5, and 4-to-5years after the last dose of QHPV in each treatment arm. ResultsAt 4-to-5years after the last dose of QHPV, antibody titers were significantly higher in 4-dose than in 3-dose group. However, the proportion of vaccinees with a seroresponse in the cLIA assay was not different between the two groups (86–93% for HPV types 6, 11, and 16, and 64% for HPV type 18). These results were very similar to the seroresponse rate in these HIV-infected children at 1month after completing vaccination. ConclusionsChildren with well-controlled HIV infection who receive 3 doses of the QHPV vaccine maintain seropositivity and antibody levels that are generally similar to children of the same age who are not HIV-infected. Antibody titer correlated strongly with low log HIV RNA, low CD8%, and high CD4%. Additionally, a fourth dose of vaccine in HIV-infected children produces a marked rise in antibody characteristic of an anamnestic response and persistence of high antibody levels.Study identification: IMPAACT P1085 (V501-021). CLINICALTRIALS.GOV identifier: NCT01206556.