Geometric Mean Antibody Concentrations Research Articles

Non-typeable Haemophilus influenzae protein vaccine in adults with COPD: A phase 2 clinical trial

Loss of airway microbial diversity is associated with non-typeable Haemophilus influenzae (NTHi) infection and increased risk of exacerbation in chronic obstructive pulmonary disease (COPD). We assessed the safety and immunogenicity of an investigational vaccine containing NTHi antigens, recombinant protein D (PD) and combined protein E and Pilin A (PE-PilA), and AS01 adjuvant in adults with moderate/severe COPD and prior exacerbations.In this phase 2, observer-blind, controlled trial (NCT02075541), 145 COPD patients aged 40–80 years randomly (1:1) received two doses of NTHi vaccine or placebo 60 days apart, on top of standard care.Reactogenicity in the 7-day post-vaccination period was higher following NTHi vaccine than placebo. Most solicited adverse events (AEs) were mild/moderate. At least one unsolicited AE was reported during the 30-day post-vaccination period by 54.8% of NTHi vaccine and 51.4% of placebo recipients. One serious AE (placebo group) was assessed by the investigator as vaccine-related. Anti-PD, anti-PE and anti-PilA geometric mean antibody concentrations increased up to 30 days after each NTHi vaccine dose, waned thereafter, but remained higher than baseline (non-overlapping confidence intervals) up to 13 months post-dose 2. The frequency of specific CD4+ T cells increased following two doses of NTHi vaccine and remained higher than baseline. Exploratory analysis showed a statistically non-significant lower yearly rate of moderate/severe exacerbations in the NTHi vaccine group than following placebo (1.49 versus 1.73) in the one-year period post-dose 2, with estimated vaccine efficacy of 13.3% (95% confidence interval −24.2 to 39.5; p = 0.44).The NTHi vaccine had an acceptable safety and reactogenicity profile and good immunogenicity in adults with COPD.

Immunogenicity of pneumococcal conjugate vaccine formulations containing pneumococcal proteins, and immunogenicity and reactogenicity of co-administered routine vaccines – A phase II, randomised, observer-blind study in Gambian infants

BackgroundTwo conserved pneumococcal proteins, pneumolysin toxoid (dPly) and pneumococcal histidine triad protein D (PhtD), combined with 10 polysaccharide conjugates from the pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine (PHiD-CV) in two investigational pneumococcal vaccine (PHiD-CV/dPly/PhtD) formulations were immunogenic and well-tolerated when administered to Gambian children. Here, we report immunogenicity of the polysaccharide conjugates, and immunogenicity and reactogenicity of co-administered routine vaccines. MethodsIn this phase II, controlled, observer-blind, single-centre study, healthy infants aged 8–10 weeks were randomised (1:1:1:1:1:1) to six groups. Four groups received 3+0 schedule (2-3-4 months [M]) of PHiD-CV/dPly/PhtD (10 or 30 µg of each protein), PHiD-CV, or 13-valent pneumococcal conjugate vaccine; and two groups received 2+1 schedule (2-4-9 M) of PHiD-CV/dPly/PhtD (30 µg of each protein) or PHiD-CV. All infants received diphtheria-tetanus-whole cell pertussis-hepatitis B-Haemophilus influenzae type b (DTPw-HBV/Hib) and oral trivalent polio vaccines (OPV) at 2-3-4 M, and measles, yellow fever, and OPV vaccines at 9 M. We evaluated immune responses at 2-5-9-12 M; and reactogenicity 0–3 days post-vaccination. Results1200 infants were enrolled between June 2011 and May 2012; 1152 completed the study. 1 M post-primary vaccination, for each PHiD-CV serotype except 6B and 23F, ≥97.4% (3+0 schedule) and ≥96.4% (2+1 schedule) of infants had antibody concentrations ≥0.2 μg/mL. Immune responses were comparable between groups within the same vaccination schedules. Observed antibody geometric mean concentrations (GMCs) increased by 1 M post-primary vaccination compared to pre-vaccination. In the following months, GMCs and opsonophagocytic activity titres waned, with an increase post-booster for the 2+1 schedule. Immune responses to protein D and, DTPw-HBV/Hib, OPV, measles, and yellow fever vaccines were not altered by co-administration with pneumococcal proteins. Reactogenicity of co-administered vaccines was comparable between groups and did not raise concerns. ConclusionImmune responses to the 10 PHiD-CV polysaccharide conjugates and co-administered vaccines were not altered by addition of dPly and PhtD. ClinicalTrials.gov identifier NCT01262872.

A phase 1 randomized study assessing safety and immunogenicity of two 3-dose regimens of a Clostridium difficile vaccine in healthy older Japanese adults

BackgroundClostridium difficile infection (CDI) is a major global cause of nosocomial and community-acquired infections. Despite potentially severe or fatal complications and frequent recurrence, no preventive vaccine is currently available. This randomized, observer-blinded, placebo-controlled phase 1 study in older Japanese adults evaluated safety and immunogenicity of an investigational C difficile vaccine containing a mixture of genetically detoxified and chemically inactivated toxoids, A and B. MethodsHealthy Japanese adults aged 65 to 85 years were randomized in a 3:3:2 ratio to receive 100 or 200 μg of C difficile vaccine or placebo, respectively, at 0, 1, and 6 months (month regimen) or 1, 8, and 30 days (day regimen). The primary objective was safety evaluation. Vaccine immunogenicity, the secondary objective, was determined by assessing toxin A– and toxin B–specific neutralizing antibody levels in human sera. ResultsLocal reactions were reported by up to 33.3% of subjects per dose in the month regimen; percentages were generally higher in the 200-μg group. Such reactions were all mild or moderate in severity and generally transient. No adverse events in the month regimen led to subject withdrawal, and no serious adverse events were considered vaccine related. Further enrollment and dosing in the day regimen were discontinued after 3 subjects in the 100-μg group reported severe redness after dose 2. In the month regimen study arm, immune responses as measured by toxin-neutralizing antibody geometric mean concentrations, geometric mean fold rises, and proportions of subjects achieving prespecified fold rises were generally higher in the 200-μg group, peaked at month 7, and remained elevated at month 12. ConclusionsThe C difficile vaccine candidate was safe, well tolerated, and immunogenic when administered to healthy older Japanese adults at 0, 1, and 6 months. Results support continued development of the vaccine for the prevention of CDI.ClinicalTrials.gov identifier: NCT02725437.

The immunomodulatory effects of measles-mumps-rubella vaccination on persistence of heterologous vaccine responses.

It is proposed that measles-containing vaccines have immunomodulatory effects which include a reduction in all-cause childhood mortality. The antibody response to heterologous vaccines provides a means to explore these immunomodulatory effects. This is the first study to investigate the influence of measles-mumps-rubella (MMR) vaccine on the persistence of antibodies to a broad range of heterologous infant vaccinations given in the first year of life. In total, 319 children were included in the study. All infants received routine vaccinations at 6weeks, 4 and 6months of age. At 12months of age, 212 children were vaccinated with MMR and Haemophilus influenzae type b-meningococcus C (Hib-MenC) vaccines while the remaining 99 children had not yet received these vaccines. In the MMR/Hib-MenC-vaccinated group, blood was taken 28±14days after receiving these vaccines. Antibodies against diphtheria, tetanus, pertussis [pertussis toxin (PT), filamentous hemagglutinin, pertactin], poliomyelitis (type 1, 2, 3) and 13 pneumococcal serotypes were measured. Seroprotection rates and geometric mean antibody concentrations were compared between MMR/MenC-Hib-vaccinated and MMR/MenC-Hib-naïve participants. In the final analysis, 311 children were included. Seroprotection rates were lower in MMR/Hib-MenC-vaccinated children against PT and pneumococcal serotype 19A. After adjustment for prespecified factors, MMR/Hib-MenC-vaccinated infants had significantly higher antibody concentrations against tetanus (likely explained by a boosting effect of the carrier protein, a tetanus toxoid), while for the other vaccine antigens there was no difference in antibody concentrations between the two groups. MMR vaccination given at 12months of age in a developed country does not significantly influence antibody concentrations to heterologous vaccines received in the first year of life.

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.

2483. Twelve-Month Immunogenicity and Safety of an Adjuvanted Recombinant Zoster Vaccine in Immunosuppressed Adults Post Renal Transplant: a Phase III Randomized Clinical Trial

BackgroundThe efficacy of the non-live adjuvanted recombinant zoster vaccine (RZV, containing a truncated form of varicella-zoster glycoprotein E [gE] and Adjuvant System AS01B) is >90% in adults ≥50 years of age (YOA) (ZOE-50/70) and >68% in hematopoietic stem cell transplant recipients ≥18 YOA (ZOE-HSCT).1 This study (NCT02058589) evaluated immunogenicity and safety of RZV in renal transplant recipients ≥18 YOA receiving immunosuppressive therapy. Previously unreported reactogenicity and 12-month post-last dose safety and immune persistence data are presented.MethodsIn this phase III, 1:1 randomized, observer-blind, multicenter trial, patients received 2 doses of RZV or placebo. gE-specific immune responses were assessed at 1 (M2) and 12 (M13) months post-dose 2: humoral immunity by vaccine response rate (VRR) and geometric mean antibody concentration (GMC), and cell-mediated immunity (CMI) by VRR and CD4+ T-cell frequency. Solicited general and unsolicited adverse events (AEs) were collected 7 days pre-dose 1 as a within-participant control. Solicited and unsolicited AEs were also recorded for 7 and 30 days after each dose, respectively. Serious AEs (SAE) and potential immune-mediated diseases (pIMDs) were recorded up to study end (M13).ResultsHumoral and CMI in the RZV group persisted through M13 appearing higher in the RZV group vs. placebo (Table 1). The frequency of solicited local AEs and of general AEs myalgia and fever was higher in the RZV group vs. placebo and balanced between study groups for the other general AEs, pIMDs and SAEs (including allograft rejections) (Table 2, Figure 1). No concerns regarding renal function were reported. Suspected HZ cases were recorded among 2 RZV and 6 placebo recipients. In the RZV group, within-participant pre- and post-vaccination solicited general AEs were reported at similar rates for fatigue, gastrointestinal symptoms and headache, and higher rates post-vaccination for myalgia, shivering, and fever (Figure 1).ConclusionRZV was highly immunogenic, eliciting robust humoral and CMI that persisted up to 12 months in adult renal transplant recipients. No safety concerns were identified over a 1-year follow-up.Reference1. de la Serna, BMT Tandem Meeting 2018, abs LBA2. Funding: GlaxoSmithKline Biologicals SA Disclosures P. Vink, GSK group of companies: Employee and Shareholder, Salary and stock shares. S. J. Kim, GSK group of companies: Investigator, Research grant and Research support. M. Campins Marti, GSK group of companies: Consultant, Investigator, Scientific Advisor and Speaker’s Bureau, Consulting fee, Research grant and Speaker honorarium. D. Kumar, GSK group of companies: Scientific Advisor, Consulting fee. K. Doucette, GSK group of companies: Investigator, Research support. S. A. McNeil, GSK group of companies: Grant Investigator, Research grant and Research support. L. Campora, GSK group of companies: Employee and Shareholder, Salary. E. Di Paolo, GSK group of companies: Employee, Salary. M. El Idrissi, GSK group of companies: Employee, Salary. M. López-Fauqued, GSK group of companies: Employee, Salary. B. Salaun, GSK group of companies: Employee and Shareholder, Salary. T. Heineman, GSK group of companies: Consultant, Employee and Shareholder, Consulting fee and Salary. L. Oostvogels, GSK group of companies: Employee, Salary and stock and stock option.

Antibody persistence and safety and immunogenicity of a second booster dose nine years after a first booster vaccination with a reduced antigen diphtheria-tetanus-acellular pertussis vaccine (Tdap) in adults

BackgroundOver the last decades, pertussis showed periodic increases in its incidence among adults, despite being a vaccine-preventable disease. MethodsThis phase III, multicenter, extension study (NCT00489970) was conducted in adults from the United States, followed at Year (Y) 5 and Y9 post-vaccination with a dose of reduced-antigen-content tetanus-diphtheria-acellular pertussis vaccine containing either 3 (Tdap-B group) or 5 pertussis components (Tdap-A group). Willing participants in Tdap groups and newly-recruited participants (Control group) received one Tdap-B dose at Y9. Antibody persistence (at Y5 and Y9) and safety of Tdap-B at Y9 were assessed. Non-inferiority of immune response elicited by 2 Tdap doses was evaluated at Y9: (i) versus one Tdap-B dose for diphtheria and tetanus in terms of seroprotection rates; (ii) for all antigens in terms of booster response rates (Tdap-B and Tdap-A groups versus Control group); and (iii) for pertussis antigens in terms of geometric mean concentrations (GMCs) versus a 3-dose series of a combined diphtheria-tetanus-acellular pertussis vaccine (DTPa) administered during infancy. Results1257 participants were enrolled at Y5 and 809 participants were vaccinated at Y9. Seroprotection rates in both Tdap groups were ≥98.4% and ≥98.0% (Y5) and ≥98.3% and ≥98.1% (Y9) for diphtheria and tetanus, respectively. For pertussis antigens, antibody concentrations above assay cut-offs were observed for ≥76.6% (Y5) and ≥84.9% (Y9) of participants in Tdap groups. At Y9, one month post-Tdap vaccination, comparable seroprotection/seropositivity rates and antibody GMCs were observed among groups. Non-inferiority of immune responses in both Tdap groups was demonstrated when compared to the Control group for diphtheria and tetanus and to a 3-dose DTPa series for pertussis antigens. Non-inferiority criteria in terms of booster response were not met for all antigens. No safety concerns were raised. ConclusionA second dose of Tdap-B administered in adults, 9 years after initial Tdap vaccination, is immunogenic and well-tolerated.

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

BackgroundWe 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). MethodsIn 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. Results951 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. ConclusionAddition 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.

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.

Immunogenicity and safety of a second booster dose of an acellular pertussis vaccine combined with reduced antigen content diphtheria-tetanus toxoids 10 years after a first booster in adolescence: An open, phase III, non-randomized, multi-center study

ABSTRACTPertussis is a highly contagious disease, for which periodic peaks in incidence and an increasing number of outbreaks have been observed over the last decades. The reduced-antigen-content tetanus-diphtheria-acellular pertussis vaccine (Tdap) can be used to boost individuals aged ≥10 years, vaccinated in infancy with a diphtheria-tetanus-acellular pertussis vaccine (DTaP), to reduce pertussis morbidity and maintain protection against diphtheria and tetanus throughout adolescence and adulthood. This phase III, open-label, non-randomized, multicenter follow-up study (NCT01738477) enrolled 19–30-year-old participants from the United States who had received booster vaccination 10 years earlier with either Tdap (Tdap group) or Td (Td group). In total, 128 (Tdap group) and 37 (Td group) participants received Tdap vaccination. After administration of Tdap, all participants were seroprotected (antibody concentrations ≥0.1 international units [IU]/ml) against diphtheria and tetanus. Immune responses to a second Tdap dose in the Tdap group were shown to be non-inferior to responses elicited by a first Tdap dose in the Td group for diphtheria and tetanus and to a 3-dose DTaP vaccination during infancy for pertussis antigens (primary objectives). Post-booster vaccination, all participants in both groups had antibody concentrations above assay cut-offs and antibody geometric mean concentrations increased by 3.8–15.5-fold compared to pre-booster levels for all antigens. The incidence of adverse events was similar in the Td (80.6%) and Tdap (85.6%) groups (no serious adverse events reported). A Tdap dose administered after previous Td or Tdap vaccination was shown to be immunogenic and well-tolerated in young adults, supporting repeated vaccination with Tdap at 10-year intervals.

Persistence of immune response to an adjuvanted varicella-zoster virus subunit vaccine for up to year nine in older adults

ABSTRACTBackground: In adults aged ≥60 years, two doses of the herpes zoster subunit vaccine (HZ/su; 50 µg varicella-zoster virus glycoprotein E [gE] and AS01B Adjuvant System) elicited humoral and cell-mediated immune responses persisting for at least six years. We assessed immunogenicity nine years post-initial vaccination.Methods: This open extension study (NCT02735915) followed 70 participants who received two HZ/su doses in the initial trial (NCT00434577). Blood samples to assess the cellular (intracellular cytokine staining) and humoral (ELISA) immunity were taken at year nine post-initial vaccination.Results: Participants' mean age at dose 1 was 72.3 years. The fold increases over pre-vaccination in the mean frequency of gE-specific CD4+ T-cells expressing ≥2 activation markers plateaued from year four post-dose 1 until year nine. Anti-gE antibody geometric mean concentrations plateaued and remained above pre-vaccination levels from year four onwards. Immunogenicity at year nine was similar across age strata (60–69, ≥70 years) and confirmed statistical prediction model results using data for up to year six. Further modeling using all data up to year nine predicted immune responses would remain above the pre-vaccination level up to year 15.Conclusion: In adults aged ≥60 years, HZ/su-induced immunogenicity remained above pre-vaccination levels for at least nine years post-initial vaccination.Summary: After vaccination with HZ/su, both cell mediated and humoral immunity remained above pre-vaccination levels up to year 9 regardless of age group. Immune responses are predicted to remain above baseline up to 15 years post initial vaccination.

Randomized Controlled Trial of the Safety and Immunogenicity of Revaccination With Tetanus-Diphtheria-Acellular Pertussis Vaccine (Tdap) in Adults 10 Years After a Previous Dose.

BackgroundReduced-antigen-content tetanus, diphtheria, and acellular pertussis (Tdap) vaccine is recommended in many countries for boosting immunity in adolescents and adults. Although immunity to these antigens wanes with time, currently available Tdap products are not labeled for repeat administration in the United States.MethodsWe performed an observer-blinded, randomized controlled trial in 1330 adults aged 18 to <65 years who received either the Tdap (n = 1002) or tetanus-diphtheria (Td) (n = 328) vaccine 8 to 12 years after a dose of Tdap vaccine administered previously. Solicited adverse events following immunization were documented for 7 days after vaccination, and serious adverse events and adverse events of medical significance were documented for 6 months after vaccination. Levels of antibodies against component vaccine antigens were measured before and 1 month after vaccination.ResultsA solicited adverse event was reported by 87.7% of Tdap and 88.0% of Td vaccine recipients. We found no significant differences in the rates of injection-site reactions, systemic reactions, or serious adverse events between the vaccine groups. A robust antibody response to each pertussis antigen in the Tdap-vaccinated group was found; postvaccination-to-prevaccination geometric mean antibody concentration ratios were 8:1 (pertussis toxoid), 5.9 (filamentous hemagglutinin), 6.4 (pertactin), and 5.2 (fimbriae 2 and 3). Postvaccination geometric mean concentrations of tetanus antibody (4.20 and 4.74 IU/mL, respectively) and diphtheria antibody (10.1 and 12.6 IU/mL, respectively) were similar in the Tdap and Td groups, and the rates of seroprotection against tetanus and diphtheria were >99% in both groups.ConclusionsA second dose of Tdap vaccine in adults approximately 10 years after a previous dose was well tolerated and immunogenic. These data might facilitate consideration of providing Tdap booster doses to adults.

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.

Immunogenicity and Safety of an Adjuvanted Herpes Zoster Subunit Vaccine in Older Adults Previously Vaccinated with a Live-Attenuated Herpes Zoster Vaccine: A Phase III, Group-Matched, Clinical Trial

BackgroundHerpes zoster (HZ), caused by reactivation of varicella-zoster virus (VZV), typically manifests as a dermatomal rash and can lead to postherpetic neuralgia (PHN). HZ and PHN risk increase with age. Efficacy against HZ induced by a live-attenuated zoster vaccine (ZVL; Merck) declines following vaccination (21% in years 5–12 post-vaccination). To ensure protection, revaccination can be considered. Therefore, we assessed immunogenicity and safety of HZ/su, a non-live candidate vaccine containing VZV glycoprotein E (gE) subunit and AS01B adjuvant system (GSK), in adults previously vaccinated with ZVL ≥5 years before, (HZ-PreVac) compared with adults not vaccinated with ZVL (HZ-NonVac).MethodsIn this phase III, group-matched, open, multicenter study (NCT02581410), 2 parallel groups of adults ≥65 years of age (YOA) received 2 HZ/su doses 2 months apart. A co-primary objective was to compare humoral immune responses 1 month post-dose 2 (M3) in the 2 groups (non-inferiority criterion: upper limit [UL] of the 95% confidence interval [CI] for HZ-NonVac/HZ-PreVac adjusted anti-gE antibody geometric mean concentration [GMC] ratio <1.5). Humoral and cellular immune responses were evaluated at various time points. Solicited and unsolicited adverse events (AEs) were recorded for 7 and 30 days post each dose, respectively. Serious AEs (SAEs), HZ cases and potential immune-mediated diseases (pIMDs) will be recorded until study end. Here, we present data up to M3, as the study is still ongoing.Results430 participants were vaccinated. M3 humoral immune responses in HZ-PreVac were non-inferior to those in HZ-NonVac and the co-primary objective was met as the UL of the 95% CI of the adjusted GMC ratio was 1.17 (Table 1). In addition, there were no apparent differences in CD4[2+] T-cell frequencies between groups (Figure 1). No clinically meaningful differences between frequencies of solicited AEs, unsolicited AEs or SAEs in the 2 groups were observed (Table 2). No SAEs considered vaccine-related by investigators, no suspected HZ cases and no pIMDs were reported up to M3.ConclusionHZ/su vaccination in adults ≥65 YOA who previously received ZVL stimulates strong immune responses and does not raise safety concerns.FundingGlaxoSmithKline Biologicals SADisclosures K. Grupping, GSK group of companies: Employee, Salary; L. Campora, GSK group of companies: Employee, Salary; M. Douha, GSK group of companies: Employee, Salary; T. C. Heineman, GSK group of companies: Consultant and Shareholder, Consulting fee; N. P. Klein, GSK group of companies: Investigator, Grant recipient sanofi pasteur: Investigator, Grant recipient; Merck & Co: Investigator, Grant recipient; MedImmune: Investigator, Grant recipient; Protein Science: Investigator, Grant recipient; Pfizer: Investigator, Grant recipient; H. Lal, Pfizer: Employee and Shareholder, Salary and Stock as part of compensation; GSK group of companies: Employee at the time of study and Shareholder, Salary and Stock as part of compensation; J. Peterson, GSK group of companies: Investigator, Principal investigator fees; L. Oostvogels, GSK group of companies: Employee and Shareholder, Salary and Shares

Persistence of Immune Response to an Adjuvanted Varicella-Zoster Virus Subunit Candidate Vaccine for up to Year 9 in Older Adults

BackgroundIn the ZOE-50 and ZOE-70 clinical trials, the candidate herpes-zoster subunit vaccine (HZ/su; 50µg varicella-zoster virus glycoprotein E [gE] and AS01B Adjuvant System) demonstrated high efficacy against HZ, with limited waning over 4 years and consistent efficacy across age cohorts. In adults ≥60 years of age, the immune responses elicited by 2 HZ/su doses administered 2 months apart persisted for at least 6 years.1 Here we report immunogenicity and safety 9 years post-initial vaccination.MethodsThis Phase IIIB, open, long-term extension study (NCT02735915) followed 70 participants who received 2 HZ/su doses in the initial trial (NCT00434577). Blood samples to evaluate the persistence of cellular (intracellular cytokine staining) and humoral (ELISA) immune responses were taken at 9 years post-initial vaccination. Limited safety follow-up was performed (1 visit).ResultsAll 70 participants (mean age at dose 1: 72.3 years; 61.4% female) were included in the according-to-protocol analysis. The fold increases over pre-vaccination in the frequency of gE-specific CD4+ T-cells expressing ≥2 activation markers plateaued after 4 years post-dose 1 (year 4: 3.4, year 5: 3.0, year 6: 3.4, year 9: 3.4). Anti-gE antibody geometric mean concentrations were also stable from year 4 onwards (Table 1) and remained above the pre-vaccination value of 1213.1mIU/mL. Cellular and humoral responses at year 9 were similar across age strata (60–69, ≥70 years). No vaccine-related serious adverse events nor suspected HZ episodes were reported.ConclusionIn adults ≥60 years of age, HZ/su-induced cellular and humoral immune responses remained above pre-vaccination levels for at least 9 years post-initial vaccination, confirming immune persistence predictions2 based on 6-year data.Table 1Pre-vaccination (95% CI)Year 4 (95% CI)Year 5 (95% CI)Year 6 (95% CI)Year 9 (95% CI) Anti-gE antibody GMC (mlU/mL) 1213.1 (983.8–1495.9)9643.5 (8309.7–11191.3)9124.1 (7805.1–10666.0)8490.5 (7292.1–9885.7)8931.2 (7625.7–10460.3)Disclosures S. Volpe, GSK: Employee, Salary; T. F. Schwarz, GSK: Investigator and Scientific Advisor, Consulting fee; J. Smetana, GSK: Investigator, personal fees; S. Ravault, GSK: Employee, GSK shares and Salary; M. P. David, GSK: Employee, Salary and stock; A. Bastidas, GSK: Employee, Salary; L. Oostvogels, GSK: Employee and Shareholder, Salary and shares

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

Immunization 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. This 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 11-17years), was conducted in Poland and the Russian Federation. For the 2-4years 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 (≥2months 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 31days post-vaccination, respectively, and serious AEs (SAEs) throughout the study. Of 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 ≥0.2µg/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. PHiD-CV was immunogenic and well tolerated in 2-17-year-old children with asplenia or splenic dysfunction. Clinical Trial Registry: www.clinicaltrials.gov, NCT01746108.

Immunogenicity of 13-valent pneumococcal conjugate vaccine among children with underlying medical conditions.

Streptococcus pneumoniae is a leading cause of vaccine-preventable disease in children under 5years. Immunocompromised children and those with underlying diseases are at increased risk of severe complications from vaccine-preventable infections. We studied the humoral immune response to the 13-valent pneumococcal conjugate vaccine (PCV13) in children with HIV-infection, kidney or lung disease and compared this to the response in healthy control children. Children aged 12-71months with underlying conditions including HIV-infection and those with kidney and lung diseases (at-risk children), and a healthy control group were vaccinated with PCV13. The at-risk children received two doses of PCV13 and the controls received one dose. Serotype-specific antibodies for all PCV13 serotypes were measured by a luminex-based enzyme immunoassay at baseline and post-vaccination. After the first PCV13 dose, the fold-increase in serotype-specific antibody geometric mean concentrations (GMCs) from baseline and the percentage of participants with ≥4-fold-increase in antibody concentrations was similar between the control and at-risk children. GMCs were, however, lower for three of the 13 serotypes in HIV-infected children, higher for serotype 6B in children with kidney disease and higher for serotypes 6B and 14 in children with lung disease. After second vaccine dose HIV-infected children had an increase in GMCs from post-first dose for nine serotypes but the percentage of participants with ≥4-fold-increase from baseline was similar post-second dose compared to post-first dose except for serotypes 6A and 19F. In children with kidney or lung diseases the immune responses after second vaccine dose were similar to post-first dose. Attenuated responses were observed for serotypes 3 and 19A in all study-groups, which was especially pronounced in the at-risk groups. All study-groups mounted an immune response to PCV13, with the at-risk groups having responses that were mostly similar to the control children.

A case series evaluating the serological response of adult asthma patients to the 23-valent pneumococcal polysaccharide vaccine

BackgroundAsthma is an independent risk factor for invasive pneumococcal disease; however, the immune response of adult asthma patients to pneumococcal vaccination is unknown. We explore the serologic response of patients with moderate to severe asthma to the 23-valent pneumococcal polysaccharide vaccine (PPSV23).MethodsSeventeen moderate to severe adult asthma patients that had not been vaccinated against pneumococcus over the 5 previous years were prospectively recruited from a tertiary care asthma clinic. Serum was analyzed for the presence of antibodies to five capsular polysaccharide (CP) antigens (6B, 9V, 19A, 19F, 23F) before and 4 weeks after PPSV23 vaccination.ResultsThere was a wide variability in baseline anti-CP antibody concentrations. Other than for serotype 19A, our patients frequently have baseline anti-CP antibody concentrations below 1 µg/mL (35% for serotype 19F, 41% for serotypes 9V and 23F, and 59% for serotype 6B). All post-vaccination geometric mean antibody concentrations were significantly higher than baseline. In the 31 tests where the baseline antibody concentration was <1 µg/mL, 77.4% had at least a twofold increase post-vaccination. Despite this, a large proportion of post-vaccination anti-CP antibody concentrations remained <1 µg/mL (51.6% of tests). Nine patients had at least one anti-CP antibody concentration <1 µg/mL post-vaccination. There was no difference between these patients and the remaining eight patients in demographic or clinical variables.ConclusionsPatients with moderate to severe asthma have variable baseline and low post-vaccination antibody concentrations to common CP antigens included in the PPSV23 vaccine. The clinical relevance of these observations remains to be determined since the threshold concentration in adults required for clinical protection from invasive pneumococcal disease is uncertain.

Will Infant Hepatitis B Vaccination Protect Into Adulthood?: Extended Canadian Experience After a 2-, 4- and 6-month Immunization Schedule.

Hepatitis B virus (HBV) vaccination programs generally target infants to prevent chronic HBV infection and/or preadolescents to reduce transmission in adulthood. To assess whether infant HBV immunization can potentially accomplish both objectives, we measured residual immunity 10-16 years after vaccination in Canadian children. A prospective, parallel group, single center study enrolled adolescents given HBV vaccine at 2, 4 and 6 months of age. Exclusion criteria included prior HBV infection and additional vaccinations. At follow-up anti-HBs testing, participants were 10-11 or 15-16 years old; those with <12 mIU/mL anti-HBs by the assay used were challenged with HBV vaccine to assess immune memory-based responsiveness. A total of 137 tested participants were 10-11 and 213 were 15-16 years old, respectively; none had evidence of prior HBV infection. At baseline, 78% of younger and 64% of older participants had <12 mIU/mL anti-HBs (P = 0.006) and were challenged with vaccine: 103/106 (97.2%) younger and 123/135 (91.1%) older participants developed ≥12 mIU/mL anti-HBs (P = 0.06), with geometric mean antibody concentration of 590 (95% confidence interval: 473-737) and 319 mIU/mL (95% confidence interval: 229-445; P = 0.004), respectively. Immune memory loss may have occurred in 3 younger (2.2%) and 12 older children (5.6%; P = 0.06) who were nonresponsive to first but not second vaccine challenge. After HBV vaccination at 2, 4 and 6 months of age, most adolescents had little or no residual antibody but nearly all responded to HBV challenge, confirming immune memory persistence. However, anamnestic responses were weaker in 15- to 16-year olds and lost in some. Booster responses in 10- to 11-year olds were vigorous in comparison. Extended evaluation of protection is warranted.

Comparison of the immunogenicity and safety of the purified chick embryo cell rabies vaccine manufactured in India and Germany: A randomized, single blind, multicentre, phase IV clinical study

ABSTRACTThis phase IV, single blind study assessed the immunogenicity and safety of India-manufactured purified chick embryo cell rabies vaccine (PCECV), compared with a German-manufactured batch obtained by the same production process. A total of 340 participants enrolled at 2 study sites in India were randomized (1:1:1:1) in 4 groups to receive a 5-dose Essen regimen with either 1 of the 3 Indian batches (PCECV-I) or the German batch (PCECV-G), administered on Days (D) 0, 3, 7, 14 and 30. The lot-to-lot consistency of PCECV-I batches in terms of induced immune response at D14 was demonstrated. The immune response elicited by PCECV-I was shown to be non-inferior to that induced by PCECV-G, as the lower limit of the 95% confidence interval for the ratio (PCECV-I/PCECV-G) of rabies virus neutralising antibody (RVNA) geometric mean concentrations was higher than 0.5 at D14. At least 96% of participants developed adequate RVNA concentrations (≥ 0.5 IU/mL) by D14 and all achieved RVNA concentrations ≥ 0.5 IU/mL by D90. RVNA levels were comparable across all groups throughout the entire study. Solicited local and general symptoms had a similar incidence in all groups. Unsolicited adverse events (AEs) were reported by 11% of participants. Only 1 serious AE (leg fracture) was reported and was not related to vaccination. No deaths and no rabies cases were recorded during the 90 days of observation. The study showed that the 3 PCECV-I and the PCECV-G batches induced a similar immune response and had a comparable safety profile when administered according to a 5-dose schedule.