Functional immune responses to 11 non-PCV13 serotypes after immunization with a 23-valent pneumococcal polysaccharide vaccine in older adults

BackgroundThe 23-valent pneumococcal polysaccharide vaccine (PPSV23) has been recommended for adults aged ≥65 years. To evaluate functional immune response against the additional 11 serotypes that are included in PPSV23, but not the 13-valent pneumococcal conjugate vaccine (PCV13), serotype-specific anti-pneumococcal antibodies were examined using an opsonophagocytic assay (OPA).MethodsParticipants ≥65 years of age that were naïve to the pneumococcal vaccine were enrolled. They were divided into two groups according to their age: group 1 (N = 30; aged 65–74 years) and group 2 (N = 32; aged ≥75 years). The functional antibody response prior to and 4 weeks post-immunization with PPSV23 was determined, using a multiplexed OPA (MOPA) for 11 pneumococcal serotypes (2, 8, 9N, 10A, 11A, 12F, 15B, 17F, 20B, 22F, and 33F).ResultsGeometric mean OPA titers (GMTs) to 11 serotypes were significantly increased in both groups post-immunization compared to those prior to immunization. The GMTs for all serotypes were not significantly different between the two groups after immunization. The proportion of subjects with OPA titers post-immunization of ≥8 and ≥64 was 93–100% and 80–100% for the 11 serotypes, respectively, while subjects with a ≥4-fold increase in OPA titers ranged from 9 to 90% for the 11 serotypes.ConclusionsThis study revealed that PPSV23 vaccination induced significant functional immune responses to 11 non-PCV13 serotypes in older adults. The MOPA has been shown to be a useful tool for future application in evaluating new PCVs in older adults.The clinical trial registration number is KCT 0001963 (CRIS, https://cris.nih.go.kr/cris/en/).     

Immunogenicity and safety of a second administration of 13-valent pneumococcal conjugate vaccine 5 years after initial vaccination in adults 50 years and older

BackgroundVaccination effectively reduces invasive disease and pneumonia caused by Streptococcus pneumoniae. However, waning antibody titers and the ability of revaccination to boost titers in older adults have been concerns. A study to describe antibody persistence after vaccination with 13-valent pneumococcal conjugate vaccine (PCV13) and response to revaccination 5 years after the initial dose was conducted.MethodsPneumococcal vaccine–naive subjects aged 50–59 years were randomized and vaccinated with PCV13 plus trivalent inactivated influenza vaccine concomitantly or 1 month apart, then revaccinated with PCV13 five years later. Antipneumococcal polysaccharide opsonophagocytic activity (OPA) geometric mean titers (GMTs) and immunoglobulin G (IgG) geometric mean concentrations (GMCs) were determined before and approximately 1 month after each vaccination. Targeted local reactions and systemic events were collected for 14 days, adverse events (AEs) for 1 month, and serious AEs (SAEs) for 6 months after each vaccination.ResultsOf 1116 randomized subjects, 727 were revaccinated at year 5. Between the time of initial vaccination and revaccination, OPA GMTs and IgG GMCs declined but remained higher than levels before initial vaccination for 12 of the 13 vaccine serotypes. One month after revaccination, OPA GMTs and IgG GMCs were comparable with, or higher than, levels observed 1 month after initial vaccination for most vaccine serotypes. Local reactions were mostly mild. AEs were reported by <5% and SAEs by <1% of subjects at 1 and 6 months after revaccination, respectively. No SAEs were vaccine-related.ConclusionsRevaccination of adults ≥50 years with PCV13 five years after primary vaccination was safe and immunogenic. Additionally, antibody titers were maintained for at least 5 years after vaccination. The vaccine stimulated a memory response as shown by enhanced responses that were maintained or enhanced by revaccination.ClinicalTrials.gov registrationNCT00521586.     

Immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine in adults 18–49 years of age,naive to 23-valent pneumococcal polysaccharide vaccine

BackgroundBased on the success of vaccination with pneumococcal conjugate vaccines (PCVs) in children, recent studies have focused on PCVs in adults. Data from a randomized, double-blind study comparing the immunogenicity, tolerability, and safety of the 13-valent PCV (PCV13) and the 23-valent pneumococcal polysaccharide vaccine (PPSV23) in PPSV23-naive adults 60–64 years of age have been published. The same study also included a cohort of adults aged 18–49 years that received open-label PCV13. The purpose of this cohort was to examine the immunogenicity, safety, and tolerability of PCV13 in adult subjects 18–49 years of age compared with adults 60–64 years of age for whom PCV13 is approved.MethodsAdults naive to PPSV23 were grouped by age into 2 cohorts: 18–49 years (n = 899; further stratified by age into 3 subgroups 18–29, 30–39, and 40–49 years) and 60–64 years (n = 417). All subjects received 1 dose of PCV13. In both age groups, immunogenicity was assessed by antipneumococcal opsonophagocytic activity (OPA) geometric mean titers (GMTs) and IgG geometric mean concentrations (GMCs) 1 month after vaccination. Safety and tolerability were evaluated.ResultsIn adults aged 18–49 years, OPA GMTs and IgG GMCs were noninferior for all 13 serotypes and statistically significantly higher for all except 1 serotype (OPA GMT) and 5 serotypes (IgG GMCs) compared with adults 60–64 years. Immune responses were highest in the youngest age subgroup (18–29 years). Local reactions and systemic events were more common in adults 18–49 years compared with 60–64 years and were self-limited.ConclusionImmune responses to PCV13 are robust in adults ≥18 years of age, with highest responses observed in the youngest subgroup. Based on its safety and immunologic profile, PCV13 may serve an important therapeutic role in younger adults, particularly those with underlying medical conditions who have an increased risk of serious pneumococcal infections.     

Functional immune responses to twelve serotypes after immunization with a 23-valent pneumococcal polysaccharide vaccine in older adults

BackgroundThe 23-valent pneumococcal polysaccharide vaccine (PPSV23) was introduced as part of the national immunization program for the elderly (≥65 years of age) in Korea on 2013. To evaluate immune responses in this population, serotype-specific anti-pneumococcal antibodies were studied with opsonophagocytic assay (OPA).MethodsPneumococcal vaccine-naïve participants ≥65 years of age were enrolled. They were divided into two groups according to their age: 30 in (65–74 years) and 32 in group (≥75 years). The functional antibody response was determined by multiplexed OPA (MOPA) for 12 serotypes (1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F) before and 4 weeks after vaccination with PPSV23.ResultsGeometric mean titers (GMTs) to all tested serotypes significantly increased in both groups after vaccination compared to those before vaccination. There were no significant differences in either the fold rise (post-vaccination to pre-vaccination) or the percentage of participants with a ≥4-fold increase in OPA titers between two groups for any of the 12 serotypes. Following vaccination, GMT for serotype 9V was higher in group 1 than in group 2 (P = 0.011).ConclusionsPPSV23 induces functional immune response for 12 vaccine serotypes in both age groups. Further analysis is needed for the remaining 11 serotypes in the PPSV23, in order to develop a better understanding of the immune responses induced by PPV23 in older adults.     

Cost-effectiveness of a 23-valent pneumococcal polysaccharide vaccine immunization programme for the elderly in Shanghai,China

BackgroundTo evaluate the cost-effectiveness of adding 23-valent pneumococcal polysaccharide vaccine (PPSV23) to the immunization schedule for the elderly population (age > 60 years) in Shanghai, China.MethodsA decision-tree model, with data and assumptions adapted from the societal perspective of Shanghai City, was developed to project the health outcomes of PPSV23 vaccination (compared with no vaccination) over a lifetime course. Sensitivity analysis was used to test the model’s robustness. The clinical data, utility and treatment costs related to pneumococcal diseases were either cited from the literature or calculated from local sources.ResultsThe incremental cost-effectiveness ratio of PPSV23 vaccination compared with no vaccination was $16,699/quality-adjusted life years gained, which was lower than the per capita GDP of Shanghai ($16,840). Sensitivity analyses showed that the model’s outcome is robust.ConclusionsRoutine vaccination of the elderly population with PPSV23 is cost-effective in Shanghai, China.     

Immunogenicity and safety of concomitant MF59-adjuvanted influenza vaccine and 23-valent pneumococcal polysaccharide vaccine administration in older adults

BackgroundConcomitant administration of influenza and pneumococcal vaccines facilitates their uptake by older adults; however, data on immunogenicity and safety of concomitant administration of adjuvanted trivalent inactivated influenza vaccine (aIIV3) and 23-valent pneumococcal polysaccharide vaccine (PPSV23) have not been reported.MethodsSubjects aged ≥65 years (N = 224) were randomized 1:1:1:1 to receive MF59-aIIV3 alone, MF59-aIIV3 + PPSV23 in contralateral arms, MF59-aIIV3 + PPSV23 in the same arm or PPSV23 alone (Clinical Trial Number – NCT02225327). Hemagglutination inhibition assay and multiplex opsonophagocytic killing assay were used to compare immunogenicity after single or concomitant vaccination.ResultsAll groups met immunogenicity criteria for the influenza vaccine in older adults with similar seroconversion rates and geometric mean fold-increases, irrespective of concomitant vaccinations and injection site. For each pneumococcal serotype, opsonic index (OI) increased markedly after the PPSV23 vaccination, irrespective of the concomitant influenza vaccine. All subjects showed an OI ≥ 8 for serotypes 6B, 18C and 19A post-vaccination, with a suggestion that the ipsilateral concomitant vaccination might be associated with higher OIs for some antigens. Local and systemic adverse events were more common in subjects receiving PPSV23 compared to those receiving aIIV3 alone.ConclusionsNo interference was observed with antibody responses to influenza or pneumococcal antigens when aIIV3 and PPSV23 were administered concomitantly.     

Safety,tolerability, and immunogenicity of 7-valent pneumococcal conjugate vaccine in older infants and young children in China who are naive to pneumococcal vaccination: Results of a phase 4 open-label trial

BackgroundThis postlicensure study was conducted to assess immunogenicity and safety of PCV7 catch-up regimens in previously unvaccinated older infants and young children in China.MethodsHealthy children 121 days to <72 months were grouped by age and immunized with 1 of 4 PCV7 dosing regimens. Serotype-specific IgG geometric mean concentrations (GMCs) and percentage of subjects with IgG ≥ 0.35 μg/mL were assessed before vaccination and 1 and 12 months postvaccination. The incidence of clinically important adverse events (AEs) and serious AEs (SAEs), AEs leading to study withdrawal, and protocol-related AEs were assessed throughout the study.ResultsPrevaccination serotype-specific GMCs were generally low in subjects <24 months; the majority of children 24 to <72 months had IgG concentrations ≥0.35 μg/mL. One month postvaccination, GMCs were similar across groups for the 7 PCV serotypes, ranging from 3.95 to 13.02 μg/mL; the highest antibody levels were observed for serotype 14. Regardless of dosing regimen, >90% of subjects had IgG ≥ 0.35 μg/mL for each PCV serotype. At 12-month follow-up, IgG GMCs ranged from 0.65 to 5.19, and all remained above prevaccination IgG GMC; >70% of subjects had IgG ≥ 0.35 μg/mL. Older children generally had the most robust immune response both at 1 month postvaccination and during 12-month follow-up. PCV7 was well tolerated. Pyrexia, which was mild to moderate in severity, was the most common AE. Two subjects reported SAEs (n = 4), and there was 1 study withdrawal; none of these were considered treatment related.ConclusionIn China, PCV7 catch-up vaccinations given to older infants and young children naive to pneumococcal vaccines resulted in a robust immune response to all serotypes; this response persisted after 1 year. PCV7 was well tolerated in Chinese infants and children.     

Pneumococcal conjugate vaccine triggers a better immune response than pneumococcal polysaccharide vaccine in patients with chronic lymphocytic leukemia A randomized study by the Swedish CLL group

AimTo determine if patients with untreated chronic lymphocytic leukemia (CLL) benefit from vaccination with a 13-valent pneumococcal conjugated vaccine (PCV13), Prevenar13®, compared to a 23-valent pneumococcal polysaccharide vaccine (PPSV23), Pneumovax®, in terms of immune response.BackgroundStreptococcus pneumoniae causes substantial morbidity in patients with CLL, a group known to respond poorly to polysaccharide vaccines. Comparative studies with conjugated vaccines are lacking.Methods128 treatment naïve CLL patients from eight hematology clinics in Sweden were randomized to vaccination with PCV13 (n = 63) or PPSV23 (n = 65) after stratification by IgG level and CLL clinical stage (Rai). Blood samples for evaluation of immune response were obtained at baseline, and at one and six months after vaccination. Analyses for each of the 12 pneumococcal serotypes common for PCV13 and PPSV23 were performed by opsonophagocytic assay (OPA) and enzyme-linked immunosorbent assay (ELISA).ResultsPCV13 elicited a superior immune response than PPSV23 in 10/12 serotypes one month after vaccination and in 5/12 serotypes six months after vaccination, measured as OPA geometric mean titers (GMTs). Geometric mean concentrations of serotype-specific IgG antibodies elicited by PCV13 as measured by ELISA, were higher than those elicited by PPSV23 in half of the common serotypes, both after one and six months. PPSV23 did not trigger a better immune response than PCV13 for any of the serotypes, regardless of analysis method or time point of analysis. Negative predictive factors for vaccination response were hypogammaglobulinemia and long disease duration. Both vaccines were well tolerated.ConclusionsIn patients with previously untreated CLL, the efficacy of PCV13 in terms of immune response is superior to PPSV23 for most serotypes common for the two vaccines. We therefore propose that PCV13 should be included in vaccination programs against Streptococcus pneumoniae for CLL patients and administered as early as possible during the course of the disease.     

Lot-to-lot consistency,safety, tolerability,and immunogenicity of V114, a 15-valent pneumococcal conjugate vaccine,in healthy adults aged ≥50 years: A randomized phase 3 trial (PNEU-TRUE)

BackgroundOlder adults are at risk of pneumococcal disease and associated morbidity and mortality. This phase 3 study (V114-020) assessed lot-to-lot consistency across safety and immunogenicity outcomes for V114, a 15-valent pneumococcal conjugate vaccine (PCV), in healthy adults aged ≥ 50 years.MethodsAdults were randomized in a 3:3:3:1 ratio to receive a single dose of one of three lots of V114 or 13-valent PCV (PCV13), stratified by age (50–64 years, 65–74 years, and ≥ 75 years). Serotype-specific opsonophagocytic activity (OPA) and immunoglobulin G (IgG) antibodies were evaluated at baseline (Day 1) and 30 days post-vaccination. Non-serious and serious adverse events (AEs) were evaluated post-vaccination through 14 days and Month 6, respectively.ResultsOf 2340 participants enrolled, 2282 (97.5%) completed the study. Proportions of participants experiencing ≥ 1 AE were 81.0%, 77.4%, and 78.0% for V114 lots 1, 2, and 3, respectively. Comparison of V114 combined lots with PCV13 showed that proportions of participants experiencing AEs, solicited AEs, and serious AEs were comparable for both vaccines, with the exception of injection-site pain (more frequently reported with V114). OPA geometric mean titers (GMTs) and IgG geometric mean concentrations (GMCs) at 30 days post-vaccination were comparable across V114 lots, and all lots met predefined equivalence criteria for all 15 vaccine serotypes (lower and upper limits of the 95% confidence intervals of serotype-specific OPA GMT ratios for all possible pairwise comparisons across the three lots were within the equivalence margin of 0.5–2.0). Serotype-specific OPA GMTs and IgG GMCs were comparable in the V114 combined lots and PCV13 groups for the 13 shared serotypes and higher in the V114 group for serotypes unique to V114 (22F and 33F).ConclusionsV114 is well tolerated with a consistent safety profile and immune response across manufacturing lots.Clinical trials registration: NCT03950856 (www.clinicaltrials.gov); 2018-004266-33 (EudraCT).     

Pneumococcal polysaccharide vaccination administered early after neurotrauma or neurosurgery

ObjectivesPneumococcal vaccination is recommended to lower the risk of posttraumatic meningitis, and early vaccination may be of importance. After both trauma and central nervous system injury, immune-suppression may occur, which could affect T-cell function and the response to T-cell dependent vaccines. We therefore aimed to investigate the response to early vaccination with a T-cell independent pneumococcal polysaccharide vaccine (PPSV).MethodsThirty-three patients with basilar skull fracture and 23 patients undergoing transsphenoidal pituitary gland surgery were vaccinated with PPSV within 10 days after neurotrauma or neurosurgery. Twenty-nine neurosurgical patients vaccinated ⩾3 weeks after neurotrauma or neurosurgery served as controls. Serotype-specific anti-polysaccharide binding IgG antibody levels to serotypes 4, 6B, 9V, 14, 18C, 19F and 23F were determined by enzyme immunoassay.ResultsThe vaccination was safe and a highly significant antibody response was found against all serotypes in all groups (p < 0.001 for each of the serotypes). There were no differences between groups or in the group by time interaction in any of the serotypes. After early and late vaccination, protective levels were found in >80% for serotypes 9V, 14, 18C, 19F and 23F and in 70% and 50% for serotypes 6B and 4, respectively.ConclusionPatients vaccinated with PPSV within 10 days after neurotrauma or neurosurgery respond similarly to those vaccinated after ⩾3 weeks, indicating that PPSV can be administered early after neurotrauma or neurosurgery.Clinical Trials registration: NCT02806284.     

Long-term antibody persistence study (3 years after last dose) of the 7-valent pneumococcal conjugate vaccine in young children in China

BackgroundIn a previous study, Chinese infants were vaccinated with 7-valent pneumococcal conjugate vaccine (PCV7) ⩾7 days before routine diphtheria, tetanus, and acellular pertussis vaccine (DTaP); PCV7 administered concomitantly with DTaP (PCV7 + DTaP); or DTaP alone. This study examined antibody persistence at a single time point 3 years after the last vaccination.MethodsChildren who participated in the prior PCV7 study were eligible to participate. A single blood sample was drawn at enrollment. Immunoglobulin G (IgG) geometric mean concentrations (GMCs) specific to the PCV7 serotypes and percentages of subjects with IgG ⩾0.35 μg/mL were compared for subjects receiving PCV7 versus PCV7 + DTaP (concomitant) and for PCV7 or PCV7 + DTaP (concomitant) versus DTaP alone. IgG concentrations at 3 years after the last vaccination were also compared with those after the infant series and toddler dose.ResultsThree years after the last vaccination with PCV7 or PCV7 + DTaP (concomitant), IgG GMCs for most PCV7 serotypes were lower than after the infant series or toddler dose but remained above prevaccination concentrations. IgG GMC were similar between the PCV7 and PCV7 + DTaP (concomitant) groups for 5 out of 7 serotypes but serotypes 4 and 19F were significantly lower in the PCV7 + DTaP (concomitant) recipients. Three years after the last vaccination, IgG GMCs were significantly higher for 6 of 7 PCV7 serotypes among those receiving PCV7 or PCV7 + DTaP (concomitant) compared with recipients of DTaP alone. Among subjects receiving DTaP alone, serotype-specific antibody concentrations were significantly higher for all serotypes 3 years after the last vaccination compared with after the infant series.ConclusionThree years after PCV7 vaccination, serotype-specific antibodies were lower than after the primary infant series but higher than prevaccination levels and higher among subjects who received PCV7 compared with those who did not. The immune response was comparable in children who received PCV7 with and without concomitant DTaP.Clinical Trial Registration: NCT01298544     

ELISA IgG concentrations and opsonophagocytic activity following pneumococcal protein D conjugate vaccination and relationship to efficacy against acute otitis media

We explored the relationship between efficacy against acute otitis media (AOM) and both ELISA anti-polysaccharide IgG geometric mean concentrations (GMCs) and opsonophagocytic (OPA) geometric mean titres (GMTs) following primary and booster vaccination with pneumococcal protein D (Haemophilus influenzae-derived) conjugate vaccine. It was possible to distinguish between the OPA GMTs of low and high efficacy serotypes, however no such distinction was evident for ELISA GMCs. Also, there was a trend towards lower ELISA and OPA serotype-specific responses in subjects who developed AOM compared to controls. We conclude that serotype-specific OPA GMTs are an important endpoint to consider for evaluation of pneumococcal conjugate vaccines with respect to the protective efficacy against AOM (Study ID: 347414/NCT00119743).     

Safety and immunogenicity of 15-valent pneumococcal conjugate vaccine in pneumococcal vaccine-naïve adults ≥50 years of age

BackgroundPneumococcal disease remains a public health priority in adults. Safety and immunogenicity of 15-valent pneumococcal conjugate vaccine (PCV15) containing 13 serotypes included in 13-valent pneumococcal conjugate vaccine (PCV13) plus 2 additional serotypes (22F and 33F) was evaluated in adults ≥50 years old (NCT01513551).Methods691 adults received one dose of PCV15, PCV13, or 23-valent pneumococcal polysaccharide vaccine (PPV23) and were followed 14 days for safety. Serotype-specific IgG geometric mean concentrations (GMCs) and opsonophagocytic activity (OPA) geometric mean titers (GMTs) were measured immediately prior and 1-month postvaccination.ResultsSafety profiles were comparable across vaccination groups. PCV15 induced comparable levels of IgG GMCs and OPA GMTs to PCV13 and PPV23 for shared serotypes. Serotype-specific antibodies were numerically higher among recipients of PCV15 than PCV13 and PPV23 for 7 and 12 shared serotypes, respectively; and lower for 4 and 1 serotype(s), respectively. PCV15 induced higher IgG and OPA antibodies than PCV13 or PPV23 for serotypes unique to PCV15 (22F and 33F not in PCV13; 6A not in PPV23).ConclusionsPCV15 displayed an acceptable safety profile and induced IgG and OPA to all 15 serotypes included in the vaccine, at levels comparable to PCV13 and PPV23 for shared serotypes with these vaccines.Study identification: V114-002.CLINICALTRIALS.GOV identifier: NCT01513551.© 2018 Merck & Co., Inc.     

Effect of Tdap when administered before,with or after the 13-valent pneumococcal conjugate vaccine (coadministered with the quadrivalent meningococcal conjugate vaccine) in adults: A randomised controlled trial

Sequential or co-administration of vaccines has potential to alter the immune response to any of the antigens. Existing literature suggests that prior immunisation of tetanus/diphtheria-containing vaccines can either enhance or suppress immune response to conjugate pneumococcal or meningococcal vaccines. We examined this interaction among adult Australian travellers before attending the Hajj pilgrimage 2014. We also investigated tolerability of these vaccines separately and concomitantly. We randomly assigned each participant to one of three vaccination schedules. Group A received adult tetanus, diphtheria and acellular pertussis vaccine (Tdap) 3–4 weeks before receiving CRM197-conjugated 13-valent pneumococcal vaccine (PCV13) and CRM197-conjugated quadrivalent meningococcal vaccine (MCV4). Group B received all three vaccines on one day. Group C received PCV13 and MCV4 3–4 weeks before Tdap. Blood samples collected at baseline, each vaccination visit and 3–4 weeks after vaccination were tested using the pneumococcal opsonophagocytic assay (OPA) and by ELISA for diphtheria and tetanus antibodies. Funding for meningococcal serology was not available. Participants completed symptom diaries after each vaccination. A total of 111 participants aged 18–64 (median 40) years were recruited. No statistically significant difference was detected across the three groups in achieving OPA titre ⩾1:8 post vaccination. However, compared to other groups, Group A had a statistically significant lower number of subjects achieving ⩾4-fold rise in serotype 3, and also significantly lower geometric mean titres (GMTs) to six (of 13) pneumococcal serotypes (3, 5, 18C, 4, 19A and 9V). Group C (given prior PCV13 and MVC4) had statistically significant higher pre-Tdap geometric mean concentration (GMC) of anti-diphtheria IgG; however, there was no difference across the three groups following Tdap. Anti-tetanus IgG GMCs were similar across the groups before and after Tdap. No serious adverse events were reported. In conclusion, Tdap vaccination 3–4 weeks before concomitant administration of PCV13 and MCV4 significantly reduced the antibody response to six of the 13 pneumococcal serotypes in adults.The trial is registered at the Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12613000536763.     

Safety and immunogenicity of sequential administration of PCV13 followed by PPSV23 in pneumococcal vaccine-naïve adults aged ≥ 65 years: Comparison of booster effects based on intervals of 0.5 and 1.0 year

ObjectiveAn open-label study was conducted to compare the safety and immunogenicity of a sequential administration of 13-valent pneumococcal conjugate vaccine (PCV13) followed by 23-valent pneumococcal polysaccharide vaccine (PPSV23) between an interval of 0.5 (0.5-y) and 1 year (1.0-y) in adults aged ≥ 65 years.MethodsPneumococcal vaccine-naïve adults aged ≥ 65 years (n = 129) received a sequential administration with an interval of 0.5-y or 1.0-y or received a single administration of PPSV23 (single PPSV23). We evaluated the immunogenicity before and 1 month after each vaccination and at 0.5-y intervals for 2 years. The primary endpoint was the increase in geometric mean fold rises (GMFRs) of immunoglobulin G (IgG) or opsonophagocytic activity (OPA) for eight common serotypes one month after one dose of PPSV23. The secondary endpoint was the safety profile for one dose of PPSV23.ResultsOne month after administration of PPSV23, the GMFRs of IgG considerably increased for five of eight serotypes in the 1.0-y interval group, whereas the GMFRs of IgG considerably increased for two serotypes in the 0.5-y interval group. Furthermore, GMFRs of OPA markedly increased for all eight serotypes in the 1.0-y interval group, while GMFRs of OPA markedly increased for four serotypes in the 0.5-y interval group. At 2 years after initial vaccination, GMFRs of IgG or OPA were higher for all serotypes, except for serotype 3, than those in the single PPSV23 group irrespective of intervals. No significant difference was found in the frequencies of local reactions of all grades between the two intervals.ConclusionsThe 1.0-y interval provided better booster effects induced by PPSV23 than those of the 0.5-y interval in a sequential administration in pneumococcal vaccine-naïve adults aged ≥ 65 years. No difference was found in the safety profile between both intervals.     

Influence of initial vaccination with 13-valent pneumococcal conjugate vaccine or 23-valent pneumococcal polysaccharide vaccine on anti-pneumococcal responses following subsequent pneumococcal vaccination in adults 50 years and older

Background

Unlike free polysaccharide vaccines, pneumococcal polysaccharide conjugate vaccines (PCVs) induce a T cell-dependent immune response and have the potential to provide an extended duration of protection with repeated vaccinations.

Methods

This was an extension of a previous study in pneumococcal vaccine-naïve adults aged 50–64 years in which adults 60–64 years of age were given 13-valent PCV (PCV13) or 23-valent pneumococcal polysaccharide vaccine (PPSV23) and adults aged 50–59 were given PCV13. In this follow up study conducted about 4 years later, the 60–64 year olds initially given PCV13 received PCV13 or PPSV23, and those initially given PPSV23 received another PPSV23. All adults aged 50–59 years were re-vaccinated with PCV13. Anti-pneumococcal opsonophagocytic activity (OPA) titers were measured before and 1 month after vaccination.

Results

A second PCV13 given about 4 years after a first vaccination induced OPA titers that were significantly higher than those following the initial vaccination for 7 of 13 serotypes in the older group, and 6 of 13 serotypes in the younger group, and responses to the remaining serotypes were largely non-inferior. In contrast, OPA titers following revaccination with PPSV23 were statistically significantly lower for 9 of the 13 serotypes, and non-inferior for the remaining serotypes, when compared to the responses to the first PPSV23. OPA titers in the older adults who received PPSV23 after initial PCV13 were significantly higher than those following a first PPSV23 for 10 of the 13 serotypes.

Conclusion

In adults 50 to 64 years of age, initial vaccination with PCV13 establishes an immune state that results in recall anti-pneumococcal responses upon subsequent vaccination with either conjugated or free polysaccharide vaccine. In contrast, initial vaccination with PPSV23 results in an immune state in which subsequent PPSV23 administration yields generally lower responses compared with the initial responses.     

Methotrexate reduces vaccine-specific immunoglobulin levels but not numbers of circulating antibody-producing B cells in rheumatoid arthritis after vaccination with a conjugate pneumococcal vaccine

BackgroundTreatment with methotrexate (MTX) in patients with rheumatoid arthritis (RA) leads to decreased total immunoglobulin (Ig) levels and impairs vaccine-specific IgG antibody levels following pneumococcal vaccination. The mechanisms by which MTX exerts these effects in RA are unknown. We aimed to evaluate whether MTX reduces vaccine-specific serum Ig levels and their functionality in RA patients following vaccination with pneumococcal conjugate vaccine, and if numbers of antigen-specific circulating plasmablasts are affected.MethodsTen patients with RA on MTX and 10 RA patients without disease modifying anti-rheumatic drug (DMARD) were immunized with a dose 13-valent pneumococcal conjugate vaccine (Prevenar13). Circulating plasmablasts producing total IgG and IgA as well as specific IgG and IgA against two pneumococcal capsular serotypes (6B and 23F) were enumerated using ELISPOT 6 days after vaccination. IgG levels against both these serotypes were determined with ELISA before and 4–6 weeks after vaccination. Positive antibody response was defined as ⩾2-fold increase of pre-vaccination antibody levels. The functionality of vaccine specific antibodies to serotype 23F was evaluated by measuring their ability to opsonize bacteria using opsonophagocytic assay (OPA) in 4 randomly chosen RA patients on MTX and 4 RA patients without DMARD.ResultsAfter vaccination, RA patients on MTX showed significant increase in pre- to postvaccination antibody levels for 6B (p < 0.05), while patients without DMARD had significant increases for both 6B and 23F (p < 0.05 and p < 0.01, respectively). Only 10% of RA on MTX and 40% of RA patients without DMARD showed positive post-vaccination antibody responses for both serotypes. Increased opsonizing ability after vaccination was detected in 1 of 4 RA patients on MTX and 3 of 4 patients on RA without DMARD. However, numbers of circulating total and vaccine-specific IgG- or IgA-producing plasmablasts did not differ between RA patients with or without MTX.ConclusionsMTX treatment in RA leads to reduced vaccine-specific antibody responses and their functionality compared to untreated RA following pneumococcal vaccination using polysaccharide-protein conjugate vaccine. However, since there was no reduction in numbers of circulating total or vaccine-specific antibody-producing plasmablasts after vaccination this effect is probably not due to reduced activation of B cells in lymphoid tissue.Clinical trial registration: NCT02240888.     

Immunogenicity and safety of 13-valent pneumococcal conjugate vaccine (PCV13) formulated with 2-phenoxyethanol in multidose vials given with routine vaccination in healthy infants: An open-label randomized controlled trial

BackgroundThis open-label randomized controlled trial in infants compared safety, tolerability, and immunogenicity of the 13-valent pneumococcal conjugate vaccine (PCV13) formulated with the preservative 2-phenoxyethanol (2-PE) in a multidose vial (MDV) to the current PCV13 without 2-PE in a single-dose syringe (SDS).MethodsGambian infants were randomized 1:1 to receive PCV13 as either MDV or SDS at ages 2, 3, and 4 months. Serotype-specific antipneumococcal antibody responses and opsonophagocytic activity ([OPA]; subset) were measured at age 5 months. Noninferiority was declared if the lower bound of the 97.5% CI for the difference (MDV-SDS) in proportions of subjects achieving IgG concentrations ≥0.35 μg/mL (primary endpoint) was greater than −10%. IgG geometric mean concentrations (GMCs) were noninferior if the lower limit of the two-sided 97.5% CI of the geometric mean ratio (MDV vs SDS) was greater than 0.5. Reactogenicity and other adverse events were collected.Results500 participants were randomized and vaccinated; 489 (MDV: n = 245; SDS: n = 244) completed the trial. Noninferiority of MDV was demonstrated for all serotypes as measured by percentage of subjects achieving antibody responses above ≥0.35 μg/mL. IgG GMCs (coprimary endpoint) also demonstrated noninferiority of MDV; OPA results supported these findings. Safety and tolerability were comparable between groups.ConclusionsPCV13 in MDV was safe and immunogenic when administered according to the routine schedule to infants. MDV was noninferior to SDS for all 13 pneumococcal serotypes. Comparable immunogenicity and safety profiles of PCV13 MDV and SDS suggest PCV13 MDV can help optimize vaccination in resource-limited settings. ClinicalTrials.gov NCT01964716 https://clinicaltrials.gov/ct2/show/NCT01964716.     

A randomized study of fever prophylaxis and the immunogenicity of routine pediatric vaccinations

ObjectiveProphylactic antipyretic use during pediatric vaccination is common. This study assessed whether paracetamol or ibuprofen prophylaxis interfere with immune responses to the 13-valent pneumococcal conjugate vaccine (PCV13) given concomitantly with the combined DTaP/HBV/IPV/Hib vaccine.MethodsSubjects received prophylactic paracetamol or ibuprofen at 0, 6–8, and 12–16 h after vaccination, or 6–8 and 12–16 h after vaccination at 2, 3, 4, and 12 months of age. At 5 and 13 months, immune responses were evaluated versus responses in controls who received no prophylaxis.ResultsAfter the infant series, paracetamol recipients had lower levels of circulating serotype-specific pneumococcal anticapsular immunoglobulin G than controls, reaching significance (P < 0.0125) for 5 serotypes (serotypes 3, 4, 5, 6B, and 23F) when paracetamol was started at vaccination. Opsonophagocytic activity assay (OPA) results were similar between groups. Ibuprofen did not affect pneumococcal responses, but significantly (P < 0.0125) reduced antibody responses to pertussis filamentous hemagglutinin and tetanus antigens after the infant series when started at vaccination. No differences were observed for any group after the toddler dose.ConclusionsProphylactic antipyretics affect immune responses to vaccines; these effects vary depending on the vaccine, antipyretic agent, and time of administration. In infants, paracetamol may interfere with immune responses to pneumococcal antigens, and ibuprofen may reduce responses to pertussis and tetanus antigens. The use of antipyretics for fever prophylaxis during infant vaccination merits careful consideration.ClinicalTrials.gov identifier: NCT01392378 https://clinicaltrials.gov/ct2/show/NCT01392378?term=NCT01392378&rank=1     

Immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine and an MF59-adjuvanted influenza vaccine after concomitant vaccination in ⩾60-year-old adults

BackgroundConcomitant administration of influenza and pneumococcal vaccines could be an efficient strategy to increase vaccine uptake among older adults. Nevertheless, immune interference and safety issues have been a concern when more than one vaccines are administered at the same time.MethodsSubjects aged ⩾60 years were randomized in a 1:1:1 ratio to receive MF59-adjuvanted trivalent inactivated influenza vaccine (MF59-aTIV) + 13-valent pneumococcal conjugate vaccine (PCV13) (Group 1), PCV13 alone (Group 2), or MF59-aTIV alone (Group 3). Hemagglutination inhibition (HI) and opsonophagocytic activity (OPA) assays were used to compare immunogenicity after single or concomitant vaccination.ResultsA total of 1149 subjects (Group 1, N = 373; Group 2, N = 394; Group 3, N = 382) were available for the assessment of immunogenicity and safety. All groups met immunogenicity criteria for the influenza vaccine in older adults with similar seroprotection rates, seroconversion rates, and geometric mean titer (GMT) fold-increases, irrespective of concomitant vaccination. For each pneumococcal serotype, OPA titers increased markedly after the PCV13 vaccination, irrespective of the concomitant influenza vaccination. After concomitant administration, the non-inferiority criteria of GMT ratios were met for all three influenza subtypes and 13 pneumococcal serotypes. No vaccine-related serious adverse events occurred.ConclusionsConcomitant MF59-aTIV and PCV13 administration showed no interference with antibody response and showed good safety profiles.(Clinical Trial Number – NCT02215863).