Background. The 13-valent pneumococcal conjugate vaccine (PCV13) was licensed to replace the 7-valent pneumococcal conjugate vaccine (PCV7) based on serological noninferiority criteria. To date no ...randomized PCV13 pediatric trial has included clinical endpoints. Methods. This randomized double-blind trial compared the impact of PCV13 versus PCV7 on nasopharyngeal (NP) colonization and immunogenicity. Healthy infants were randomized (1:1) to receive PCV7 or PCV13 at ages 2, 4, 6, and 12 months; NP swabs were collected at 2, 4, 6, 7, 12, 13, 18, and 24 months, and blood was drawn at 7 and 13 months. Rates of NP acquisition and prevalence, and serotype-specific immunoglobulin G (IgG) concentrations were assessed. Results. The per protocol analysis population included 881 PCV13 and 873 PCV7 recipients. PCV13 significantly reduced NP acquisition of the additional PCV13 serotypes 1, 6A, 7F, and 19A; the cross-reacting serotype 6C; and the common PCV7 serotype 19F. For serotype 3, and the other PCV7 serotypes, there were no significant differences between the vaccine groups. There were too few serotype 5 events to draw inference. The impact on prevalence at predefined time points was similar to that observed with NP acquisition. PCV13 elicited significantly higher IgG responses for PCV13 additional serotypes and serotype 19F, and similar or lower responses for 6/7 PCV7 serotypes. Conclusions. PCV13 resulted in lower acquisition and prevalence of NP colonization than PCV7 did for 4 additional PCV13 serotypes, and serotypes 6C and 19F. It was comparable with PCV7 for all other common serotypes. These findings predict vaccine effectiveness through both direct and indirect protection. Clinical Trials Registration. NCT00508742.
Background. Life-threatening Streptococcus pneumoniae infections often occur after hematopoietic stem cell transplant (HSCT); vaccination is important for prevention. Methods. In an open-label study, ...patients (n = 251) 3–6 months after allogeneic HSCT received 3 doses of 13-valent pneumococcal conjugate vaccine (PCV13) at 1-month intervals, a fourth dose 6 months later, and 1 dose of 23-valent pneumococcal polysaccharide vaccine (PPSV23) 1 month later. Immunogenicity at prespecified time points and vaccine safety were assessed. Results. In the evaluable immunogenicity population (N = 216; mean age, 37.8 years), geometric mean fold rises (GMFRs) of immunoglobulin G geometric mean concentrations from baseline to postdose 3 showed significant increases in antibody levels across all PCV13 serotypes (GMFR range, 2.99–23.85; 95% confidence interval lower limit, >1); there were significant declines over the next 6 months, significant increases from predose 4 to postdose 4 (GMFR range, 3.00–6.97), and little change after PPSV23 (GMFR range, 0.86–1.12). Local and systemic reactions were more frequent after dose 4. Six patients experienced serious adverse events possibly related to PCV13 (facial diplegia, injection-site erythema and pyrexia, autoimmune hemolytic anemia, and suspected lack of vaccine efficacy after dose 3 leading to pneumococcal infection), PCV13 and PPSV23 (Guillain-Barré syndrome), or PPSV23 (cellulitis). There were 14 deaths, none related to study vaccines. Conclusions. A 3-dose PCV13 regimen followed by a booster dose may be required to protect against pneumococcal disease in HSCT recipients. Dose 4 was associated with increased local and systemic reactions, but the overall safety profile of a 4-dose regimen was considered acceptable. Clinical Trials Registration. NCT00980655.
Streptococcus pneumoniae is a major cause of severe disease worldwide, particularly in the elderly population. Due to increasing life expectancy in Japan and elsewhere, an effective vaccine which ...offers the possibility of prolonged protection is required. Protein conjugated pneumococcal vaccines, which have the ability to boost immunity (immunologic memory) on natural exposure or revaccination, may meet these requirements. An unconjugated 23-valent pneumococcal polysaccharide vaccine (PPSV23) has been available for decades; however data on protection against pneumonia are inconsistent. For the first time, a randomized, modified double-blind trial comparing the 13-valent pneumococcal conjugate vaccine (PCV13) with PPSV23 was conducted in PPSV23-naive adults ≥65 years of age in Japan. This study showed that statistically significantly greater functional antibody responses as measured by opsonophagocytic assays 1 month after vaccination were elicited in the PCV13 group (n = 366) compared with the PPSV23 group (n = 367) for 9 of the 12 serotypes in common with both vaccines and for serotype 6A, unique to PCV13. Local reactions collected within 14 days of vaccination were more frequent in the PCV13 (57.5%, 211/367) than PPSV23 (44.9%, 166/370) group, although severity was generally mild to moderate; systemic and adverse events were similar across groups. There were no treatment-related serious adverse events. Consistent with global studies comparing PCV13 with PPSV23, PCV13 use in Japanese subjects was safe and well-tolerated and elicited greater functional immune responses than PPSV23 for the majority of PCV13-serotypes. PCV13 has the potential to protect against pneumococcal disease in Japanese elderly adults.
Injection site reactions (ISRs; redness, swelling and pain) commonly occur within 1-2 days after vaccination. After administration of toxoid vaccines including diphtheria toxoid, a later onset of ...ISRs has also been observed. As the serotype capsular polysaccharides in the 13-valent pneumococcal conjugate vaccine (PCV13) are conjugated to cross-reactive material 197 (CRM
197
), a nontoxic variant of diphtheria toxin, the onset of ISRs over 14 days was explored in 8 adult studies with 19 cohorts. Subjects received PCV13 with aluminum phosphate (AlPO
4
, n = 5667) or without AlPO
4
(n = 304); 1097 subjects received 23-valent pneumococcal polysaccharide vaccine (PPSV23). Late ISRs with onset between days 6-14 were observed in 8/8 cohorts aged ≥65 years after PCV13 with AlPO
4
(incidence across cohorts for redness, 2.3%-19.6%; swelling, 0.9%-10.8%; pain, 1.6%-10.0%) and in 1/1 cohort after PCV13 without AlPO
4
(redness 10.5%; swelling 7.5%; pain 12.3%); and in 2/4 cohorts aged 50 to 64 years after PCV13 (redness 3.1%-4.8%; swelling 1.0%-3.2%; pain 3.7%-5%). Late ISRs were not generally observed in 1/1 cohort aged 18 to 49 years after PCV13; in 2/2 cohorts aged ≥53 years after PCV13 revaccination; and in 3/3 cohorts aged ≥60 years who received PPSV23, which does not contain CRM
197
. Post hoc analysis demonstrated numerically higher pneumococcal immune responses in subgroups with late ISRs versus those without. In conclusion, causality of late ISRs is likely multifactorial, with age and the PCV13 carrier protein CRM
197
potentially associated. AlPO
4
, a vaccine adjuvant, did not appear causally related. Observations do not affect the favorable risk-benefit profile of PCV13.
Streptococcus pneumoniae infection is a major global public health concern in older adults, especially as life expectancy continues to increase in most countries, including India. Recently, a ...13-valent pneumococcal conjugate vaccine (PCV13) with the ability to enhance immunity (immunologic memory) on natural exposure or revaccination has been shown to protect against community-acquired pneumonia and invasive pneumococcal disease in adults 65 years of age and older. An unconjugated 23-valent pneumococcal polysaccharide vaccine has been available for decades; however, data on protection against pneumonia are inconsistent. For the first time, a multicenter study has been conducted in India to assess the safety and immunogenicity of a single dose of PCV13 in adults aged 50 to 65 years. In this study, PCV13 elicited robust immune responses against all 13 pneumococcal serotypes as reflected by the magnitude of geometric mean fold rises (range, 6.6-102.7) in functional antibody levels from before to 1 month after vaccination. No serious adverse events occurred. These clinical trial findings support the safety and immunogenicity of PCV13 when administered to adults in India and indicate that a single dose of PCV13 has the potential to protect against vaccine-type pneumococcal disease in adults aged 50 to 65 years. ClinicalTrials.gov identifier: NCT02034877
Abstract
Background
Pneumococcal conjugate vaccines (PCVs) elicit lower immune response against serotypes carried before or at the time of vaccination (hyporesponsiveness) in infants. The limited ...studies conducted to date did not permit comprehensive insights regarding this phenomenon. This study, the largest ever conducted with both carriage and serologic endpoints, attempted to add insight on serotype-specific hyporesponsiveness in relation to the number of PCV doses administered before carriage acquisition.
Methods
In a double-blind randomized clinical trial (n = 1754 infants), 7-valent or 13-valent PCV was administered at ages 2, 4, 6, and 12 months. New acquisition was defined based on nasopharyngeal swabs at ages 2, 4, 6, 7, and 12 months. Serotype-specific immunoglobulin G levels were obtained 1 month after the infant series and 1 month after the toddler dose.
Results
A lower immune response after the infant series and the toddler dose was consistently observed for carriers of serotypes 6A, 6B, 18C, and 19F at predefined time points, with a similar trend observed in carriers of serotype 23F. In contrast, carriage of serotypes 9V, 14, and 19A did not generally affect immune responses. For some but not all serotypes, hyporesponsiveness was decreased with an increased number of vaccine doses received before acquisition. A complex interrelationship between carriage and immune response was observed between cross-reacting serotypes.
Conclusions
Carrier-induced hyporesponsiveness to PCVs is common, differs among serotypes, and depends on timing of carriage acquisition and prior number of administered PCV doses.
Clinical Trials Registration
NCT00508742.
Serotype-specific hyporesponsiveness of serological response to pneumococcal conjugate vaccines following acquisition of commonly carried pneumococcal serotypes in infants is complex and dependent on serotype and number of previous vaccine doses. This analysis showed no hyporesponsiveness following carriage of cross-reacting serotypes.
Background. Pediatrie respiratory infections caused by antibiotic-nonsusceptible Streptococcus pneumoniae (ANSP) continue to present an important challenge, even after introduction of 7-valent ...pneumococcal conjugate vaccine (PCV7). This randomized double-blind trial assessed the potential additional impact of PCV 13 over PCV7 on reducing ANSP carriage. Methods. Healthy infants were randomly assigned to receive PCV13 (n = 932) or PCV7 (n = 934) at ages 2,4,6, or 12 months. Eight nasopharyngeal specimens were collected by swabbing between ages 2 and 24 months. S. pneumoniae isolates were serotyped and tested for antimicrobial susceptibility by the disk-diffusion method and the Etest. Nasopharyngeal acquisition and prevalence of ANSP during ages 7-24 months were compared between the 2 vaccine groups. Results. In general, new acquisition of pneumococci nonsusceptible to penicillin, erythromycin, dindamycin, penicillin plus erythromycin, and multiple drugs (≥ 3 antibiotics) was significantly lower in the PCV 13 group compared with the PCV7 group; the main serotypes contributing to this significant decrease were serotype 19F, present in PCV13 and PCV7, and serotypes 6A and 19A, present in PCV13 only. Conclusions. PCV13 has a significant added benefit over PCV7 in reducing carriage of ANSP. Because carriage determines transmission, these results suggest that PCV 13 will provide protection against ANSP disease that exceeds protection provided by PCV7. Clinical Trials Registration. NCT00508742.
Highlights • High IgG levels after PCVs have a substantial effect on nasopharyngeal carriage. • Ethnicity did not influence this association despite differences in carriage rates. • These results may ...have important implications for herd protection. • IgG levels higher than defined by WHO for IPD are required to prevent carriage. • IgG levels required to protect against acquisition differ between serotypes.
•Some individuals have stronger immune responses against all serotypes in PCV.•Increasing time since vaccination was associated decreasing antibody levels.•Older participants tended to have higher ...antibody levels than younger participants.
The magnitude of an individual’s serotype-specific immunoglobulin G (IgG) response to a pneumococcal conjugate vaccine (PCV) has been associated with the vaccine’s protective efficacy against carriage of pneumococci of that serotype, though the relationship with other serotypes needs to be understood.
Using immunogenicity data collected during a trial comparing the 7-valent (PCV7) and 13-valent (PCV13) vaccines, we measured associations between serotype-specific IgG levels, and used multiple regressions to identify demographic predictors of response.
Vaccine-induced IgG levels were moderately positively correlated with one another, with pairwise correlation coefficients of 0.40–0.70. Principal component analysis of vaccine-serotype responses yielded one principal component indicating general immune responsiveness, and a second principal component mainly describing responses to serotype 14, which was the least correlated with the other responses. Overall, demographic variables explained only 17.0 and 20.4% of the geometric mean PCV7 and PCV13 responses, respectively. In both groups, older age at the first vaccine dose and shorter time from vaccination to antibody measurement were independently associated with stronger geometric mean responses.
Improved understanding of the nature and causes of variation in immune response may aid in optimizing vaccination schedules and identifying robust correlates of protection.
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