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.     

Revaccination with 23-valent pneumococcal polysaccharide vaccine in the Japanese elderly is well tolerated and elicits immune responses

BackgroundFollowing primary vaccination of adults ⩾65 years of age with 23-valent pneumococcal polysaccharide vaccine (PPSV23), immune responses increase and thereafter appear to decrease over time. With increased life expectancy worldwide, revaccination with PPSV23 may be required for continued protection of the elderly population against pneumococcal disease. The present study evaluated the immunogenicity and safety of revaccination with PPSV23 in the Japanese elderly.MethodsDepending on prior history of PPSV23 vaccination, adults aged ⩾70 years were given a first dose (primary group; N = 81) or second dose (revaccination group; N = 161, at least 5 years after first dose) of PPSV23 intramuscularly. Subjects were matched for gender, age, and number and type of comorbidity across both groups. Blood samples were collected before and 4 weeks postvaccination to measure serotype-specific immunoglobulin G (IgG) concentrations and opsonophagocytic killing activity (OPA) antibody titers to serotypes included in the vaccine. Injection-site and systemic adverse events (AEs) were collected for 14 days postvaccination.ResultsBaseline serotype-specific IgG geometric mean concentrations (GMCs) and OPA geometric mean titers (GMTs) were generally higher in subjects with a prior history of PPSV23 vaccination than in PPSV23-naïve subjects. The levels of IgG GMCs and OPA GMTs after revaccination were generally comparable to those observed after primary vaccination. Incidences of systemic AEs were comparable between the 2 groups. Although incidences of injection-site AEs were higher following revaccination than primary vaccination, the difference was not clinically significant as most AEs were mild to moderate in intensity and resolved within 5 days after revaccination without treatment.ConclusionRevaccination with PPSV23 was well tolerated and associated with increases in serotype-specific IgG concentrations and OPA titers in the elderly who received a prior PPSV23 dose at least 5 years before. Revaccination with PPSV23 can be safely implemented in the elderly for continued prevention against pneumococcal disease.Clinical trial registry number: NCT02260882     

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.     

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 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.     

Pneumococcal vaccination in patients with systemic lupus erythematosus: A multicenter placebo-controlled randomized double-blind study

BackgroundInvasive pneumococcal disease and respiratory tract infections are both frequent and severe in patients with systemic lupus erythematosus (SLE). This study aimed to compare the immunological efficacy and safety of pneumococcal vaccination with the 23-valent polysaccharide (PPS) vaccine alone to a sequential immunization with the 7-valent pneumococcal conjugate (PnCj) vaccine followed by PPS in patients with SLE and stable diseaase.MethodsMulticenter randomized placebo-controlled double-blind trial: PPS vaccine alone (placebo-PPS group) or PnCj vaccine followed by PPS vaccine (PnCj-PPS group) 24 weeks later. The primary endpoint was the rate of responders at week 28 to at least 5 of the 7 serotypes (4, 6B, 9V, 14, 18C, 19F and 23F) shared by both PPS and PnCj. Pneumococcal IgG antibodies’ opsonophagocytic activity (OPA) were also assessed.ResultsTwenty-five patients in the placebo-PPS group and 17 in the PnCj-PPS group were included in a modified intention-to-treat analysis. The primary endpoint was reached in 72% (18/25) in the placebo-PPS and 76% (13/17) in the PnCj-PPS group (p = 0.75). There was no difference in the rates of responders with OPA. At week 52, 13/18 (72%) patients in the placebo-PPS group and 10/13 (77%) patients in the PnCj-PPS group (p = 0.77) that met the primary endpoint at week 28 were still responders to ≥5/7 serotypes shared by both PPS and PnCj vaccines. Nine SLE flares were reported in 6 patients (4 in the placebo-PPS and 2 in the PnCj-PPS groups respectively, p = 0.70).ConclusionSequential administration of PnCj vaccine followed by PPS vaccine is safe and shows short-term immunological efficacy in patients with SLE but was not superior to the PPS vaccine alone.Trial registration: www.clinicaltrials.gov, NCT NCT00611663     

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.     

Opsonophagocytic activity against Streptococcus pneumoniae in Indigenous and non-Indigenous patients with severe chronic kidney disease immunized with 13-valent pneumococcal conjugate vaccine

Adults with chronic kidney disease (CKD) are at high risk of pneumococcal infections and recommended to receive pneumococcal immunization. Some studies suggest that previous immunization with 23-valent pneumococcal polysaccharide vaccine (PPV23) may decrease the immunogenicity of 13-valent pneumococcal conjugate vaccine (PCV13). Via quantitation of serum IgG, IgM, and IgA specific to 7 pneumococcal serotypes (3, 6B, 9V, 14, 19A, 19F, 23F), we recently found that the response to PCV13 in previously PPV23 immunized patients with severe CKD was inferior compared to PPV23 naïve patients. As a follow-up of the previous study, we assessed the titers of opsonizing antibodies specific to 13 vaccine serotypes in sera collected as per the original clinical trial protocol.Opsonophagocytic activity (OPA) titers were determined in 57 previously PPV23-immunized (Group 1) and 72 PPV23-naïve (Group 2) patients pre- and post-PCV13 immunization (days 28 and 365).Pre-immunization, the geometrical mean titers (GMT) for 3/13 serotype-specific antibodies were significantly higher in Group 1 than in Group 2. PCV13 induced a significant GMT rise in both groups; an increase in 5/13 serotype-specific GMTs in Group 1 and 12/13 GMTs in Group 2 was present at one year post-immunization. Fold increase in GMTs by day 28 ranged between 2.4 (serotype 1) and 24.6 (serotype 6A) in Group 1, and between 4.3 (serotype 3) and 67.0 (serotype 6A) in Group 2. The fold increase was significantly larger in Group 2 than in Group 1 for serotypes 1, 4, 7F, and 18C. Patients of Indigenous ethnic background had significantly higher GMT for serotypes 6B and 23F at baseline, and for serotypes 5, 6B, 14, 18C, 19A, 19F, and 23F at Day 28 post-immunization, compared to the non-Indigenous counterpart.Conclusions: Patients with severe CKD developed functionally active pneumococcal antibodies post-PCV13 immunization. Previously administered PPV23 had a negative impact on several serotype-specific OPA responses to PCV13 that lasted for at least one year post-immunization.ClinicalTrials.gov ID: NCT02370069.     

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.     

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.     

A trial to evaluate the safety and immunogenicity of a 20-valent pneumococcal conjugate vaccine in populations of adults ≥65 years of age with different prior pneumococcal vaccination

IntroductionA 20-valent pneumococcal conjugate vaccine, PCV20, was developed to expand protection against vaccine-preventable pneumococcal disease. PCV20 contains the components of the 13-valent pneumococcal conjugate vaccine, PCV13, and includes capsular polysaccharide conjugates for 7 additional serotypes. Thus, PCV20 may cover those additional serotypes in individuals previously vaccinated with PCV13 or provide benefits of immunization with a conjugate vaccine to individuals previously immunized with a pneumococcal polysaccharide vaccine. This study described the safety and immunogenicity of PCV20 in adults ≥65 years of age with prior pneumococcal vaccination.MethodsThis phase 3, multicenter, randomized, open-label study was conducted in the United States and Sweden. Adults ≥65 years of age were enrolled into 1 of 3 cohorts based on their prior pneumococcal vaccination history (23-valent pneumococcal polysaccharide vaccine [PPSV23], PCV13, or both PCV13 and PPSV23). Participants were randomized 2:1 within their cohort to receive a single dose of PCV20 or PCV13 in those with prior PPSV23 only, and PCV20 or PPSV23 in those with prior PCV13 only; all participants with prior PCV13 and PPSV23 received PCV20. Safety was assessed by prompted local reactions within 10 days, systemic events within 7 days, adverse events (AEs) within 1 month, and serious AEs (SAEs) and newly diagnosed chronic medical conditions (NDCMCs) within 6 months after vaccination. Immune responses 1 month after PCV20 were assessed.ResultsThe percentages of participants reporting local reactions, systemic events, and AEs after PCV20 administration were similar across cohorts and comparable with the PCV13 and PPSV23 control groups. SAE and NDCMC rates were low in all groups. Robust immune responses, including opsonophagocytic antibody responses, to the 20 vaccine serotypes were observed 1 month after PCV20 regardless of prior pneumococcal vaccination.ConclusionsPCV20 was well tolerated and immunogenic in adults ≥65 years of age previously vaccinated with different pneumococcal vaccine regimens.Clinicaltrials.gov NCT03835975.     

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.     

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.     

Safety,tolerability, and immunogenicity of V114, a 15-valent pneumococcal conjugate vaccine,followed by sequential PPSV23 vaccination in healthy adults aged ≥50 years: A randomized phase III trial (PNEU-PATH)

BackgroundStreptococcus pneumoniae causes pneumococcal disease, and older adults are at an increased risk. Sequential vaccination of 13-valent pneumococcal conjugate vaccine (PCV13) followed by 23-valent pneumococcal polysaccharide vaccine (PPSV23) is recommended for broad protection against pneumococcal disease in some countries.MethodsThis phase III trial evaluated the safety, tolerability, and immunogenicity of sequential administration of either V114 (a 15-valent PCV containing serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, and 33F) or PCV13, followed 12 months later by PPSV23, in healthy adults aged ≥50 years (NCT03480763). A total of 652 participants were randomized 1:1 to receive either V114 or PCV13, followed by PPSV23.ResultsThe most common solicited adverse events (AEs) following PCV vaccination included injection-site pain and fatigue. Higher proportions of participants with these events were observed in the V114 group following PCV; however, these differences were not clinically significant. Following PPSV23 vaccination, the most common solicited AEs were injection-site pain and injection-site swelling; the proportions of participants with these events were comparable between both groups. Incidence of serious AEs was low in both groups following PCV and PPSV23, and none were related to study vaccines. No deaths occurred during the study. Serum opsonophagocytic activity geometric mean titers and immunoglobulin G geometric mean concentrations were comparable between both groups for all 15 serotypes in V114 following PPSV23. Immune responses elicited by V114 persisted for at least 12 months. Immune responses at 30 days and 12 months post-vaccination with PCV were comparable between both groups for the 13 shared serotypes and higher in the V114 group for the V114-unique serotypes (22F and 33F).ConclusionAdministration of V114 followed by PPSV23 was well tolerated and induced comparable antibody levels to PCV13 followed by PPSV23 in healthy adults aged ≥50 years.     

Immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine compared to a 23-valent pneumococcal polysaccharide vaccine in pneumococcal vaccine-naive adults

Background

Streptococcus pneumoniae is a major cause of morbidity and mortality among adults 50 years of age and older in the United States. Pneumococcal conjugate vaccines are efficacious against pneumococcal disease in children and may also offer advantages in adults.

Methods

We performed a randomized, modified double-blind trial that compared a single dose of 13-valent pneumococcal conjugate vaccine (PCV13) with 23-valent pneumococcal polysaccharide vaccine (PPSV23) in 831 pneumococcal vaccine naive adults 60–64 years of age. An additional group of 403 adults 50–59 years of age received open-label PCV13. Anti-pneumococcal opsonophagocytic activity (OPA) titers were measured at baseline, and at 1 month and 1 year after vaccination.

Results

In the randomized trial, the month 1 post-vaccination OPA geometric mean titers in the PCV13 group were statistically significantly higher than in the PPSV23 group for 8 of the 12 serotypes common to both vaccines and for serotype 6A, a serotype unique to PCV13, and were comparable for the other 4 common serotypes. The immune response to PCV13 was generally greater in adults 50–59 years of age compared to adults 60–64 years of age. OPA titers declined from 1 month to 1 year after PCV13 administration but remained higher than pre-vaccination baseline titers.

Conclusions

PCV13 induces a greater functional immune response than PPSV23 for the majority of serotypes covered by PCV13, suggesting that PCV13 could offer immunological advantages over PPSV23 for prevention of vaccine-type pneumococcal infection.     

Sequential administration of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine in pneumococcal vaccine–naïve adults 60–64 years of age

Background

Unlike free pneumococcal polysaccharide vaccines (PPSVs), pneumococcal conjugate vaccines (PCVs) induce a T–cell–dependent immune response. The study assessed potential influence of initial 13-valent PCV (PCV13) or 23-valent PPSV (PPSV23) on subsequent vaccine administrations.

Methods

We conducted a randomized, modified double-blind study in 720 pneumococcal vaccine–naïve adults 60–64 years of age. Subjects received either PCV13 at year 0 and PCV13 at year 1; PCV13 at year 0 and PPSV23 at year 1; or PPSV23 at year 0 and PCV13 at year 1. Antipneumococcal opsonophagocytic activity (OPA) titers were measured before and 1 month after each vaccination.

Results

OPA titers following PPSV23 given 1 year after PCV13 (PCV13/PPSV23) (a) were noninferior for the 12 common serotypes and significantly higher for 6 of 12 common serotypes than those following only an initial PPSV23; and (b) were significantly higher for 11 of 12 common serotypes compared with PPSV23 followed by PCV13 (PPSV23/PCV13). In addition, PPSV23 followed 1 year later by PCV13 (PPSV23/PCV13) elicited significantly lower OPA titers than after only an initial dose of PCV13 for all 13 serotypes. Responses after a second vaccination with either PCV13 (PCV13/PCV13) or PPSV23 (PCV13/PPSV23) were noninferior for 9 of 13 and 8 of 12 common serotypes compared with the initial PCV13 dose.

Conclusion

In pneumococcal vaccine–naïve adults 60–64 years of age, an initial PCV13 augmented the antipneumococcal response to subsequent administration of PPSV23 for many of the serotypes in common to both vaccines. In contrast, an initial PPSV23 resulted in a diminished response to subsequent administration of PCV13 for all serotypes. With a relatively short 1-year interval between doses, responses after a second vaccination with PCV13 (PCV13/PCV13) or PPSV23 (PCV13/PPSV23) were noninferior for a majority of serotypes compared with the initial PCV13 dose, probably reflecting the need for a longer interval between vaccine administrations.ClinicalTrials.gov Identifier: NCT00574548.     

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).     

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,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

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

Randomized clinical trial of a single versus a double dose of 13-valent pneumococcal conjugate vaccine in adults 55 through 74 years of age previously vaccinated with 23-valent pneumococcal polysaccharide vaccine

IntroductionIn older adults, prior administration of 23-valent pneumococcal polysaccharide vaccine (PPSV23) blunts the opsonophagocytic antibody (OPA) response to subsequent administration of 13-valent pneumococcal conjugate vaccine (PCV13). To determine whether a higher dose of PCV13 could mitigate this effect in adults 55 through 74 years of age, we compared OPA responses to a double dose of PCV13 in persons previously vaccinated with PPSV23 with responses to a single dose of PCV13 in previously vaccinated persons, and with a single dose in PPSV23 naïve persons.MethodsSubjects previously vaccinated with PPSV23 were randomly assigned to receive either a single injection or two concurrent injections of 0.5 mL PCV13. Naïve subjects received a single injection of 0.5 mL PCV13. Serotype-specific OPA responses to 12 of the PCV13 serotypes were assessed on samples collected on Day 29 and Day 181. Comparisons of the OPA titers between study groups were based on the lower bound of the 95% confidence interval of the log geometric mean ratio to define superiority (>1) and non-inferiority (>0.5).ResultsAt Day 29, the OPA responses to one dose in previously vaccinated (n = 284) versus one dose in naïve subjects (n = 311) achieved the threshold for non-inferiority for only 3 of the 12 serotypes. In previously vaccinated subjects, responses to a double dose (n = 288) versus a single dose met the threshold for superiority for 7 serotypes. The responses to a double dose in previously vaccinated subjects versus a single dose in naïve subjects met the threshold for non-inferiority for 9 serotypes.ConclusionsThere is a dose response to PCV13 in older adults and the higher response to a double dose in previously vaccinated adults is non-inferior to that of a single dose in naïve adults for 9 of the 12 PCV13 serotypes evaluated.