PCV7 Recipients Research Articles

Association of Pneumococcal Conjugate Vaccination With Severe Acute Respiratory Syndrome Coronavirus 2 Infection Among Older Adult Recipients of Coronavirus Disease 2019 Vaccines: A Longitudinal Cohort Study.

Pneumococcal carriage is associated with increased acquisition and duration of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among adults. While pneumococcal conjugate vaccines (PCVs) prevent carriage of vaccine-serotype pneumococci, their potential impact on coronavirus disease 2019 (COVID-19)-related outcomes remains poorly understood in populations with prevalent immunity against SARS-CoV-2. We undertook a retrospective cohort study of adults aged ≥65 years in the Kaiser Permanente Southern California healthcare system who had received ≥2 COVID-19 vaccine doses, comparing risk of SARS-CoV-2 infection between 1 January 2021 and 31 December 2022 among recipients and nonrecipients of 13-valent PCV (PCV13) employing multiple strategies to mitigate bias from differential test-seeking behavior. The ajusted hazard ratio of confirmed SARS-CoV-2 infection comparing PCV13 recipients to nonrecipients was 0.92 (95% confidence interval [CI], .90-.95), corresponding to prevention of 3.9 (95% CI, 2.6-5.3) infections per 100 person-years. Following receipt of 2, 3, and ≥4 COVID-19 vaccine doses, aHRs (95% CI) were 0.85 (.81-.89), 0.94 (.90-.97), and 0.99 (.93-1.04), respectively. The aHR (95% CI) for persons who had not received COVID-19 vaccination in the preceding 6 months was 0.90 (.86-.93), versus 0.94 (.91-.98) within 6 months after COVID-19 vaccination. Similarly, aHRs (95% CI) were 0.92 (.89-.94) for persons without history of documented SARS-CoV-2 infection, versus 1.00 (.90-1.12) for persons with documented prior infection. Among older adults who had received ≥2 COVID-19 vaccine doses, PCV13 was associated with modest protection against SARS-CoV-2 infection. Protective effects of PCV13 were greater among individuals expected to have weaker immune protection against SARS-CoV-2 infection.

Pneumococcal carriage, serotype distribution, and antimicrobial susceptibility in Papua New Guinean children vaccinated with PCV10 or PCV13 in a head-to-head trial

BackgroundChildren in Papua New Guinea (PNG) are at high risk of pneumococcal infections. We investigated pneumococcal carriage rates, serotype distribution, and antimicrobial susceptibility in PNG children after vaccination with 10-valent or 13-valent pneumococcal conjugate vaccines (PCV10; PCV13). MethodsInfants (N = 262) were randomized to receive 3 doses of PCV10 or PCV13 at 1-2-3 months of age, followed by pneumococcal polysaccharide vaccination (PPV) or no PPV at 9 months of age. Nasopharyngeal swabs (NPS) collected at ages 1, 4, 9, 10, 23 and 24 months were cultured using standard bacteriological procedures. Morphologically distinct Streptococcus pneumoniae colonies were serotyped by the Quellung reaction. Antimicrobial susceptibility was determined by Kirby-Bauer disc diffusion and minimum inhibitory concentration (MIC). ResultsS. pneumoniae was isolated from 883/1063 NPS collected at 1–23 months of age, including 820 serotypeable (64 different serotypes) and 144 non-serotypeable isolates. At age 23 months, 93.6% (95%CI 86.6–97.6%) of PCV10 recipients and 88.6% (95%CI 80.1–94.4%) of PCV13 recipients were pneumococcal carriers, with higher carriage of PCV10 serotypes by PCV10 recipients (19.8%, 95%CI 12.2–29.5) than PCV13 recipients (9.3%, 95%CI 4.1–17.3) (p = 0.049). There were no other statistically significant differences between PCV10 and PCV13 recipients and children receiving PPV or no PPV. Nearly half (45.6%) of carried pneumococci were non-susceptible to penicillin based on the meningitis breakpoint (MIC ≥ 0.12 µg/mL), but resistance was rare (1.1%) using the non-meningitis cut-off (MIC ≥ 8 µg/mL). Non-susceptibility to trimethoprim-sulfamethoxazole (SXT) was common: 23.2% of isolates showed intermediate resistance (MIC 1/19–2/38 µg/mL) and 16.9% full resistance (MIC ≥ 4/76 µg/mL). PCV serotypes 14 and 19A were commonly non-susceptible to both penicillin (14, 97%; 19A, 70%) and SXT (14, 97%; 19A, 87%). ConclusionEven after PCV10 or PCV13 vaccination, children living in a high-risk setting such as PNG continue to experience high levels of pneumococcal colonization, including carriage of highly antimicrobial-resistant PCV serotypes.The study is registered with ClinicalTrials.gov (CTN NCT01619462).

Predicting vaccine effectiveness against invasive pneumococcal disease in children using immunogenicity data

The strength of the immune response, as measured by antibody concentrations, varies between pneumococcal conjugate vaccines (PCVs). Linking immunogenicity and effectiveness is necessary to assess whether changes in immune response from currently recommended PCVs to next-generation vaccines could impact effectiveness. Simulated reverse cumulative distribution curves were generated using published serotype-specific IgG concentrations with placebo or PCV7. This was combined with the published estimates of serotype-specific vaccine effectiveness of PCV7 against invasive pneumococcal disease to estimate the protective antibody concentration for each serotype in PCV7. Then, based on the published serotype-specific IgG concentrations in PCV13 recipients, reverse cumulative distribution curves were generated for the serotypes shared between PCV13 and PCV7. These estimated protective antibody concentration values were then used to predict the vaccine effectiveness of PCV13. The results were compared to published aggregate values for vaccine effectiveness. The aggregate median predicted vaccine effectiveness values were similar to previously reported observed values for the United Kingdom (93% versus 90%), Australia (71% versus 70%), and Germany (91% versus 90%). These results demonstrate that IgG concentrations of next-generation PCVs can be used to generate reliable estimates of vaccine effectiveness for serotypes shared with established PCVs.

Prevention of Coronavirus Disease 2019 Among Older Adults Receiving Pneumococcal Conjugate Vaccine Suggests Interactions Between Streptococcus pneumoniae and Severe Acute Respiratory Syndrome Coronavirus 2 in the Respiratory Tract.

BackgroundWhile secondary pneumococcal pneumonia occurs less commonly after coronavirus disease 2019 (COVID-19) than after other viral infections, it remains unclear whether other interactions occur between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Streptococcus pneumoniae.MethodsWe probed potential interactions between these pathogens among adults aged ≥65 years by measuring associations of COVID-19 outcomes with pneumococcal vaccination (13-valent conjugate vaccine [PCV13] and 23-valent pneumococcal polysaccharide vaccine [PPSV23]). We estimated adjusted hazard ratios (aHRs) using Cox proportional hazards models with doubly robust inverse-propensity weighting. We assessed effect modification by antibiotic exposure to further test the biologic plausibility of a causal role for pneumococci.ResultsAmong 531 033 adults, there were 3677 COVID-19 diagnoses, leading to 1075 hospitalizations and 334 fatalities, between 1 March and 22 July 2020. Estimated aHRs for COVID-19 diagnosis, hospitalization, and mortality associated with prior PCV13 receipt were 0.65 (95% confidence interval [CI], .59–.72), 0.68 (95% CI, .57–.83), and 0.68 (95% CI, .49–.95), respectively. Prior PPSV23 receipt was not associated with protection against the 3 outcomes. COVID-19 diagnosis was not associated with prior PCV13 within 90 days following antibiotic receipt, whereas aHR estimates were 0.65 (95% CI, .50–.84) and 0.62 (95% CI, .56–.70) during the risk periods 91–365 days and >365 days, respectively, following antibiotic receipt.ConclusionsReduced risk of COVID-19 among PCV13 recipients, transiently attenuated by antibiotic exposure, suggests that pneumococci may interact with SARS-CoV-2.

Kawasaki Disease following administration of 13-valent pneumococcal conjugate vaccine in young children

Kawasaki disease (KD) is a systemic vasculitis mainly affecting young children and the leading cause of acquired heart disease in developed countries. We performed a self-controlled case series analysis to investigate the association between PCV13 and KD. All hospitalized KD cases <2 y old from our hospital in Singapore from 2010 to 2014 were included. Complete KD cases were classified based on the definitions of the American Heart Association. During the study period, 288 KD cases were identified. A total of 21 KD cases (12 were classified as Complete KD) had date of onset within the risk interval of day 1 to day 28 post PCV13. The age-adjusted Relative Incidence (RI) for KD following PCV13 dose 1, dose 2 and dose 3 were 1.40 (95% CI, 0.72 to 2.71), 1.23 (95% CI, 0.62 to 2.44) and 0.34 (95% CI, 0.08 to 1.40) respectively. There were seven Complete KD cases with onset during the risk interval after dose 1 of PCV13 (age-adjusted RI 2.59, 95% confidence interval (CI), 1.16 to 5.81). We did not detect a significant increased risk for overall KD among PCV13 recipients.

1972. Safety and Immunogenicity of 15-Valent Pneumococcal Conjugate Vaccine (PCV-15) Compared with PCV-13 in Healthy Older Adults Previously Vaccinated With 23-Valent Pneumococcal Polysaccharide Vaccine (PPV23)

BackgroundSafety and immunogenicity of a new formulation of PCV-15 (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19F, 19A, 22F*, 23F, 33F*) was evaluated in adults ≥65 years of age previously vaccinated with PPV23.MethodsStudy subjects who received PPV23 at least 1 year prior to study entry received a single dose of either PCV-15 or PCV-13 (125/arm) and were followed for safety for 14 days postvaccination. Serotype-specific Immunoglobulin G (IgG) geometric mean concentrations (GMCs) and opsonophagocytic activity (OPA) geometric mean titers (GMTs) were measured immediately prior and 30 days postvaccination. NCT02573081ResultsSafety profiles were comparable between PCV-15 and PCV-13 recipients. Following vaccination, serotype- specific antibody responses for the 13 shared serotypes were generally comparable between recipients of PCV- 15 and PCV-13 for IgG GMCs and geometric mean fold rises (GMFRs), OPA GMTs and GMFRs, and percentages of subjects with ≥4-fold-rise from baseline. Recipients of PCV-15 had numerically higher IgG GMCs and OPA GMTs than PCV-13 recipients for two serotypes unique to PCV-15 (22F, 33F).ConclusionPCV-15 was generally well tolerated when given as a single dose to adults ≥65 years of age previously vaccinated with PPV23. Following vaccination, serotype-specific IgG GMCs and OPA GMTs were comparable between recipients of PCV-15 and PCV-13 for 13 shared serotypes.*Not shared serotypes with PCV-13Disclosures U. Buchwald, Merck: Employee and Shareholder, Salary and stock options. J. Peterson, Merck: Investigator, Research grant. H. Stacey, Merckl: Investigator, Research grant. K. Julien, Merck: Investigator, Research grant. T. Sterling, Merck: Employee and Shareholder, Salary and stock options. M. Bruch, Merck: Employee and Shareholder, Salary and stock options. G. Tamms, Merck: Employee and Shareholder, Salary and stock options. J. Li, Merck: Employee and Shareholder, Salary and stock options. A. Pedley, Merck: Employee and Shareholder, Salary and stock options. K. Nolan, Merck: Employee and Shareholder, Salary and stock options. P. Benner, Merck: Employee and Shareholder, Salary and stock options. C. Abeygunawardana, Merck: Employee and Shareholder, Salary and stock options. M. Winters, Merck: Employee and Shareholder, Salary and stock options. M. Kosinski, Merck: Employee and Shareholder, Salary and stock options. J. Stek, Merck: Employee and Shareholder, Salary and stock options. L. Musey, Merck: Employee and Shareholder, Salary and stock options.

Safety and immunogenicity of 15-valent pneumococcal conjugate vaccine compared to 13-valent pneumococcal conjugate vaccine in adults ≥65 years of age previously vaccinated with 23-valent pneumococcal polysaccharide vaccine

ABSTRACTBackground: Pneumococcal disease remains a public health priority in adults. Previous studies have suggested that administration of pneumococcal polysaccharide vaccine or pneumococcal conjugate vaccine within three years following receipt of PPV23 was associated with increased reactogenicity and reduced antibody titers in comparison to longer intervals. Safety and immunogenicity of 15-valent pneumococcal conjugate vaccine (PCV15) was evaluated in adults ≥ 65 years of age with prior history of PPV23 vaccination (V114-007; NCT02573181).Methods: A total of 250 adults who received PPV23 at least 1 year prior to study entry received a single dose of either PCV15 or PCV13 (125/arm) and were followed for safety for 14 days postvaccination. Serotype-specific Immunoglobulin G (IgG) geometric mean concentrations (GMCs) and opsonophagocytic activity (OPA) geometric mean titers (GMTs) were measured immediately prior and 30 days postvaccination.Results: Safety profiles were comparable between PCV15 and PCV13 recipients. Following vaccination, serotype-specific antibody responses for the 13 shared serotypes were generally comparable between recipients of PCV15 and PCV13 for IgG GMCs, OPA GMTs, and geometric mean fold rises (GMFRs) and percentages of subjects with ≥ 4-fold-rise from baseline for both IgG and OPA. Recipients of PCV15 had numerically higher antibody responses than PCV13 for two serotypes unique to PCV15 (22F, 33F).Conclusion: PCV15 was generally well tolerated and induced high levels of IgG and OPA antibodies to all 15 serotypes included in the vaccine when given as a single dose to adults ≥ 65 years of age previously vaccinated with PPV23.

The Impact of the 13-Valent Pneumococcal Conjugate Vaccine on Pneumococcal Carriage in the Community Acquired Pneumonia Immunization Trial in Adults (CAPiTA) Study.

The impact of pneumococcal conjugate vaccination on the prevalence of nasopharyngeal carriage with pneumococci and other bacteria in adults is unknown. The direct effects of the 13-valent pneumococcal conjugate vaccine (PCV13) in community dwelling older adults was investigated as part of the randomized controlled Community Acquired Pneumonia immunization Trial in Adults (CAPiTA). We determined the carriage of Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, and Moraxella catarrhalis before and 6, 12, and 24 months after vaccination using polymerase chain reaction (PCR)-based methods and conventional cultures of nasopharyngeal and oropharyngeal swab samples in 1006 PCV13 recipients and 1005 controls. Serotyping of the 13 vaccine-type (VT) pneumococci was performed by PCR targeting capsular synthesis genes and Quellung reaction of isolates. Before randomization and based on PCR, 339 of 1891 subjects had nasopharyngeal carriage with any pneumococci (17.9%), and 114 of 1891 (6.0%) carried VT pneumococci. At 6 months after vaccination, VT pneumococcal carriage was significantly lower in PCV13 recipients than in the placebo group (relative risk, 0.53; 95% confidence interval, .35-.80; P = .04). There was no difference between the groups at 12 and 24 months after vaccination. Carriage of non-VT pneumococci, S. aureus, H. influenzae, and M. catarrhalis did not change between groups. In community-dwelling adults aged ≥65 years, a single dose of PCV13 seems to elicit a small and temporary reduction in VT carriage 6 months after vaccination. Neither replacement by non-VT serotypes nor impact on other nasopharyngeal bacteria was observed.

Playing "Whack-a-Mole" With Pneumococcal Serotype Eradication.

* Abbreviations: AOM — : acute otitis media IPD — : invasive pneumococcal disease PCV — : pneumococcal conjugate vaccine PCV7 — : 7-valent pneumococcal conjugate vaccine PCV13 — : 13-valent pneumococcal conjugate vaccine NP — : nasopharyngeal SPN — : Streptococcus pneumoniae In this issue of Pediatrics , Lee et al1 report surveillance data from Massachusetts communities regarding Streptococcus pneumoniae (SPN) colonization during the pneumococcal conjugate vaccine (PCV) era. Nasopharyngeal (NP) colonization is thought to precede SPN disease, so it is a reasonable measure of circulating (and potentially disease-producing) pneumococcal strains. Three aspects are notable: (1) shifting serotypes of known invasive pneumococcal disease (IPD) producers; (2) risk factors for colonization; and (3) evolving antibiotic resistance. Excluding HIV-associated pneumococcal deaths, global estimates attribute ∼11% of all deaths in children 1 to 59 months of age to SPN disease.2 SPN remains a concern for US practitioners, causing both IPD (eg, meningitis, pneumonia, and bacteremia) and noninvasive disease (eg, acute otitis media [AOM] and sinusitis). Practitioners likely see at least 1 child per week for whom SPN bacteremia, pneumonia, or meningitis is a concern. A preventive vaccine targeting the most common IPD strains seemed a reasonable strategy to reduce disease burden and ease providers’ fears of missing an impending severe IPD case. Introduced in 2000, 7-valent PCV (PCV7) markedly decreased IPD among PCV7 recipients,3–6 and also among non-PCV7 … Address correspondence to Douglas S. Swanson, MD, Infectious Diseases, Children’s Mercy Kansas City, 2401 Gillham Rd, Kanas City, MO 64108. E-mail: dswasnon{at}cmh.edu

Immunogenicity of the 13-Valent Pneumococcal Conjugate Vaccine in Older Adults With and Without Comorbidities in the Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA)

In the randomized controlled Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA), the efficacy of the 13-valent pneumococcal conjugate vaccine (PCV13) against first episodes of vaccine-type community-acquired pneumonia in adults aged ≥65 years was 46%. The long-term immunogenicity of PCV13 in pneumococcal vaccine-naive older adults was investigated as part of CAPiTA. We determined the immune responses to PCV13 before and at 1, 12, and 24 months after vaccination in 1006 PCV13 recipients and 1005 controls with 3 age-stratified study participant cohorts. PCV13 serotype-specific opsonophagocytic activity (OPA) titers and immunoglobulin G (IgG) concentrations were determined. Sample collection completeness was at least 93.4% at each time point. In all 3 age categories, a single dose of PCV13 elicited OPA titers and IgG concentrations for all 13 serotypes that were significantly higher than baseline and the corresponding responses in the placebo group at all time points. In the eldest subjects (≥80 years of age at vaccination), OPA titers and IgG concentrations remained above baseline and there was no apparent difference in OPA titers and IgG concentrations between those with self-reported comorbidities and healthy older adults. However, the study was not powered to determine statistical significance between different age and comorbidity groups, and thus these results are exploratory. In immunocompetent adults ≥65 years of age, PCV13 elicits significant increases in OPA titers and IgG concentrations that persist 2 years postvaccination for all 13 serotypes, regardless of age and comorbidity. NCT00744263.

Immunogenicity and safety of the 13-valent Pneumococcal Conjugate vaccine in 23-valent pneumococcal polysaccharide vaccine-naive and pre-immunized patients under treatment with chronic haemodialysis: a longitudinal quasi-experimental phase IV study

ObjectiveTo benchmark the immunogenicity of pneumococcal conjugated vaccine (PCV-13) versus pneumococcal polysaccharide vaccine (PPV-23) in haemodialysis patients pre-vaccinated or not with PPV-23. MethodsThe study is a longitudinal quasi-experimental phase IV study in chronic haemodialysis patients aged ≥50 years. Total (ELISA) and functional (opsonophagocytic assay) antibodies after pneumococcal vaccination were quantified at baseline, and after 28 and 365 days. Of 201 eligible patients, 155 were included. Patients were divided in four groups. PPV-23 naive patients were randomized to PPV-23 (40) or PCV-13 (40) vaccination. PPV-23-pre-vaccinated patients were categorized as being vaccinated more (40) or less (35) than 4 years before the study and all received PCV-13. ResultsPatients among the four groups had a significant ELISA antibody response for most serotypes that remained significant up to day 365 versus baseline. In PPV-23-naive patients, ELISA antibody titres were significantly higher among PCV-13 versus PPV-23 recipients for six serotypes (1.85–2.34-fold) after 28 days, and remained significantly higher for one serotype (6A, 1.57-fold) after 365 days. Following PCV-13 vaccination, increase in ELISA antibody titres was significantly higher among PPV-23-naive versus PPV-23-pre-vaccinated patients for 12 serotypes after 28 days (1.68–7.74-fold) and remained significantly higher in ten serotypes (1.44–3.29-fold) after 365 days. ConclusionImmune response after PPV-23 and PCV-13 remains significant for at least 1 year in non-PPV-23-pre-vaccinated patients. Among vaccine-naive haemodialysis patients PCV-13 seems more immunogenic than PPV-23. Immune response to PCV-13 is weaker in PPV-23-pre-vaccinated compared with vaccine-naive patients.

Exploratory efficacy endpoints in the Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA)

BackgroundThe Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA) assessed vaccine-type community-acquired pneumonia (VT-CAP) and vaccine-type invasive pneumococcal disease (VT-IPD) prevention with 13-valent pneumococcal conjugate vaccine (PCV13) in adults aged ⩾65years. We report vaccine efficacy (VE) of PCV13 for the remaining 23 exploratory endpoints and serotype distributions for pneumococcal CAP and IPD. MethodsThis was a parallel-group, randomised, placebo-controlled, double-blind trial comparing single-dose PCV13 with placebo. Exploratory CAP endpoints included first episode of confirmed non-VT (NVT) pneumococcal CAP; all confirmed episodes of NVT pneumococcal CAP, pneumococcal CAP, nonbacteraemic/noninvasive (NB/NI) VT pneumococcal CAP, and NB/NI pneumococcal CAP; and first and all episodes of culture-confirmed VT pneumococcal CAP, culture-confirmed pneumococcal CAP, culture-confirmed NVT pneumococcal CAP, probable VT pneumococcal CAP, probable NVT pneumococcal CAP, and probable and possible pneumococcal CAP. Exploratory IPD endpoints included all episodes of VT-IPD and IPD, and first and all episodes of NVT-IPD. The per-protocol and modified intent-to-treat (mITT) populations were evaluated. ResultsIn total, 84,496 participants were enrolled. Eight of 23 exploratory CAP and IPD endpoints were statistically significant in both populations. In the per-protocol population, these included VE of 29% for all episodes of confirmed pneumococcal CAP, 43% for all NB/NI episodes of VT pneumococcal CAP, 52% for all episodes of culture-confirmed pneumococcal CAP, and 53% for all episodes of IPD. Comparable VE estimates were observed in the mITT population. The most common VT serotypes were 1 (10 first episodes of confirmed pneumococcal CAP; 2 first episodes of IPD) and 7F (22; 7) among PCV13 and placebo recipients, respectively. ConclusionsThe results of this analysis yielded statistically significant PCV13 VE for all episodes of confirmed pneumococcal CAP (including NB/NI and culture-confirmed episodes) and for all episodes of IPD in adults aged ⩾65years. These findings are consistent with the primary efficacy analysis. ClinicalTrials.gov identifier: NCT00744263.

A post hoc assessment of duration of protection in CAPiTA (Community Acquired Pneumonia immunization Trial in Adults)

BackgroundThe Community Acquired Pneumonia immunization Trial in Adults (CAPiTA) was conducted to evaluate 13-valent pneumococcal conjugate vaccine (PCV13) for the prevention of vaccine-type community-acquired pneumonia (VT-CAP) and vaccine-type invasive pneumococcal disease (VT-IPD) in adults aged ⩾65years. Plotting the cumulative number of episodes against time from vaccination demonstrated that efficacy was evident soon after vaccination and persisted throughout the duration of the study. This post hoc analysis was performed to quantify the persistence of vaccine efficacy (VE) of PCV13. MethodsThis was a parallel-group, randomized, placebo-controlled, double-blind trial. Subjects were enrolled between September 15, 2008 and January 30, 2010 at 101 sites in the Netherlands and randomized 1:1 to receive a single dose of PCV13 or placebo. The observed accumulation of episodes for VT-CAP, nonbacteremic/noninvasive VT-CAP (NB/NI-VT-CAP), and VT-IPD over the course of the study after vaccination was assessed. Post hoc time-to-event analyses of primary and secondary endpoints were performed. VE behavior over time was derived and effects of treatment, time, and time by treatment interactions were estimated. ResultsA total of 84,496 individuals were enrolled (PCV13, n=42,240; placebo, n=42,256). Cases of VT-CAP, NB/NI-VT-CAP, and VT-IPD were greater among placebo recipients compared with PCV13 recipients throughout the postvaccination observation period with a periodic rise in cases in the placebo group that was consistent with varied exposure and ensuing disease over time. There was a significant difference in disease-free survival among PCV13 recipients compared with placebo recipients for VT-CAP (log-rank test P=0.0005), NB/NI VT-CAP (P=0.0051), and VT-IPD (P=0.0004). VE ranged from 42.9% to 50.0% for VT-CAP, 36.2% to 48.5% for NB/NI-VT-CAP, and 66.7% to 75.0% for VT-IPD. ConclusionsThe results of this post hoc analysis of the persistence of PCV13 VE in adults ⩾65years, indicate that PCV13 was protective over the 5-year duration of the study, with no waning of efficacy observed. ClinicalTrials.gov identifierNCT00744263

Epidemiological Markers for Interactions Among Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus in Upper Respiratory Tract Carriage.

Cocolonization by Streptococcus pneumoniae and Haemophilus influenzae among children has been noted in numerous studies, as has an inverse relationship involving colonization with these species and Staphylococcus aureus. Interactions among these pathogens could mediate unanticipated outcomes of clinical interventions, including changes in H. influenzae and S. aureus disease incidence following pneumococcal vaccine introduction. However, it remains unclear whether cocolonization patterns represent true interspecies interactions or whether they result from confounding factors. We investigated polymicrobial carriage using longitudinal data from 369 Bedouin children and 400 Jewish children in Israel who were enrolled in a 7-valent pneumococcal conjugate vaccine (PCV7) trial. Children were swabbed 10 times between 2 and 30 months of age. The pathogens followed distinct age and seasonal distributions, but polymicrobial carriage associations persisted after controlling for these and other confounding factors. Receipt of PCV7 resulted in pneumococcal serotype replacement but did not influence total carriage of S. pneumoniae, H. influenzae, or S. aureus. The fact that S. pneumoniae, H. influenzae, and S. aureus polymicrobial carriage patterns do not result from confounding by age and season supports the idea of active interspecies interactions. However, pneumococcal serotype replacement may prevent changes in H. influenzae and S. aureus carriage among PCV7 recipients.

The Efficacy and Duration of Protection of Pneumococcal Conjugate Vaccines Against Nasopharyngeal Carriage: A Meta-regression Model.

Pneumococcal conjugate vaccines (PCVs) reduce disease largely through their impact on nasopharyngeal (NP) carriage acquisition of Streptococcus pneumoniae, a precondition for developing any form of pneumococcal disease. We aimed to estimate the vaccine efficacy (VEC) and duration of protection of PCVs against S. pneumoniae carriage acquisition through meta-regression models. We identified intervention studies providing NP carriage estimates among vaccinated and unvaccinated children at any time after completion of a full vaccination schedule. We calculated VEC for PCV7 serotypes, grouped as well as individually, and explored cross-protective efficacy against 6A. Efficacy estimates over time were obtained using a Bayesian meta-logistic regression approach, with time since completion of vaccination as a covariate. We used data from 22 carriage surveys (15 independent studies) from 5 to 64 months after the last PCV dose, including 14,298 children. The aggregate VEC for all PCV7 serotypes 6 months after completion of the vaccination schedule was 57% (95% credible interval: 50-65%), varying by serotype from 38% (19F) to 80%. Our model provides evidence of sustained protection of PCVs for several years, with an aggregate VEC of 42% (95% credible interval: 19-54%) at 5 years, although the waning differed between serotypes. We also found evidence of cross-protection against 6A, with a VEC of 39% 6 months after a complete schedule, decreasing to 0 within 5 years postvaccination. Our results suggest that PCVs confer reasonable protection against acquisition of pneumococcal carriage of the 7 studied serotypes, for several years after vaccination, albeit with differences across serotypes.

Safety, tolerability, and immunogenicity of 15-valent pneumococcal conjugate vaccine in healthy adults

BackgroundPneumococcal disease remains an important health priority despite successful implementation of pneumococcal conjugate vaccines (PCVs) in infant immunization programs, mainly due to the emergence of diseases caused by serotypes not included in licensed PCVs. A 15-valent pneumococcal conjugate vaccine (PCV-15) containing the 7 serotypes (4, 6B, 9V, 14, 18C, 19F, and 23F) included in licensed PCV-7 available at study initiation plus 8 additional serotypes (1, 3, 5, 6A, 7F, 19A, 22F, 33F) was developed and evaluated in healthy adults 18–45 years of age. MethodsSixty subjects received one dose of PCV-15 or PCV-7. Injection-site and systemic adverse events (AEs) were collected for 14-days postvaccination and serious AEs were collected for 30-days postvaccination. Safety laboratory tests (hematology, chemistry, and urinalysis) were evaluated prior to vaccination and 14-days postvaccination. Serotype-specific IgG and opsonophagocytic killing activity (OPA) responses to 15 serotypes included in PCV-15 were measured immediately prior to vaccination and 30-days postvaccination. ResultsAE incidences were comparable between vaccine groups although numerically higher frequencies of erythema (33.3% versus 13.3%), swelling (50.0% versus 23.3%), and myalgia (63.3% versus 36.7%) were reported among PCV-15 versus PCV-7 recipients. Majority of AEs, irrespective of vaccine received, were transient and of mild-to-moderate intensity. No clinically significant differences were observed when comparing AE duration and severity. No laboratory abnormalities, vaccine-related SAEs or discontinuations from the study due to AEs were reported. IgG concentrations for the shared serotypes substantially increased postvaccination at comparable levels between recipients of PCV-15 and PCV-7. Substantial increases in antibody (IgG and OPA) responses to 8 serotypes unique to PCV-15 were observed in PCV-15 recipients. Slight increases to 2 serotypes unique to PCV-15, serotypes 6A and 19A, were also noted in PCV-7 recipients. ConclusionPCV-15 displays an acceptable safety profile and induces IgG and OPA responses to all serotypes included in the vaccine.

Post hoc analysis of a randomized double-blind trial of the correlation of functional and binding antibody responses elicited by 13-valent and 7-valent pneumococcal conjugate vaccines and association with nasopharyngeal colonization.

In a randomized double-blind trial in healthy Israeli infants in Israel who received the 13-valent or 7-valent pneumococcal conjugate vaccine (PCV13 or PCV7, respectively) at 2, 4, 6, and 12 months, PCV13 significantly reduced nasopharyngeal (NP) colonization of serotypes 1, 6A, 7F, 19A, cross-reacting 6C, and the common PCV7 serotype 19F, from ages 7 to 24 months. No differences were observed between the vaccine groups for serotype 3 or for the remaining common PCV7 serotypes. For serotype 5, too few events were observed to draw an inference. Generally consistent with these findings, PCV13 elicited significantly higher enzyme-linked immunosorbent assay (ELISA) IgG-binding antibody responses than did PCV7 for the additional PCV13 serotypes 1, 3, 5, 6A, 7F, 19A, and for the common serotype 19F, with similar or lower responses for the remaining common serotypes. To further assess immunogenicity and colonization, we conducted a post hoc analysis of PCV13 functional antibody responses measured by opsonophagocytic activity (OPA) assays in a randomly selected subset of subjects. The pattern of functional antibody OPA responses elicited by PCV13 relative to PCV7 was similar to that of the ELISA anticapsular IgG-binding antibody responses described above. In addition, the OPA responses generally correlated positively with IgG responses for all 13 serotypes among the PCV13 recipients and for all 7 common serotypes and the additional serotype 6A but not for 19A or the other serotypes unique to PCV13 among the PCV7 recipients. This post hoc analysis supports an association between serum OPA functional and IgG-binding antibody levels, allowing for a transfer of inferred associations between IgG responses and NP colonization to OPA responses.

A randomized clinical trial of the immunogenicity of 7-valent pneumococcal conjugate vaccine compared to 23-valent polysaccharide vaccine in frail, hospitalized elderly.

BackgroundElderly people do not mount strong immune responses to vaccines. We compared 23-valent capsular polysaccharide (23vPPV) alone versus 7-valent conjugate (PCV7) vaccine followed by 23vPPV 6 months later in hospitalized elderly.MethodsParticipants were randomized to receive 23vPPV or PCV7-23vPPV. Antibodies against serotypes 3, 4, 6A, 6B, 9V, 14, 18C, 19A, 19F, 23F were measured by enzyme-linked immunosorbent (ELISA) and opsonophagocytic (OPA) assays at baseline, 6 months and 12 months.ResultsOf 312 recruited, between 40% and 72% of subjects had undetectable OPA titres at baseline. After one dose, PCV7 recipients had significantly higher responses to serotypes 9V (both assays) and 23F (OPA only), and 23vPPV recipients had significantly higher responses to serotype 3 (ELISA), 19F and 19A (OPA only). In subjects with undetectable OPA titres at baseline, a proportionately greater rise in OPA titre (P<0.01) was seen for all serotypes after both vaccines. The GMT ratio of OPA was significantly higher at 12 months in the PCV7-23vPPV group for serotypes 6A, 9V, 18C and 23F. OPA titre levels for these serotypes increased moderately after 6 months, whereas immunity waned in the 23vPPV only arm.ConclusionWe did not show overwhelming benefit of one vaccine over the other. Low baseline immunity does not preclude a robust immune response, reiterating the importance of vaccinating the frail elderly. A schedule of PCV7-23vPPV prevents waning of antibody, suggesting that both vaccines could be useful in the elderly. Follow up studies are needed to determine persistence of immunity.Trial RegistrationThe Australian Clinical Trials Registry ACTRN12607000387426

Comparative Immunogenicity and Efficacy of 13-Valent and 7-Valent Pneumococcal Conjugate Vaccines in Reducing Nasopharyngeal Colonization: A Randomized Double-Blind Trial

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. 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. 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. 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. NCT00508742.

Immunogenicity and safety of pneumococcal conjugate polysaccharide and free polysaccharide vaccines alone or combined in HIV-infected adults in Brazil

BackgroundStreptococcus pneumoniae is a leading cause of hospitalization in HIV-infected adults therefore pneumococcal vaccine is recommended. The ideal antipneumococcal vaccine and effective vaccination regimen remain controversial and needs further evaluation. MethodsTo assess the efficacy of pneumococcal vaccines alone and combined, a randomized, blinded clinical trial was conducted in Brazil with 331 HIV-patients aged 18–60, with CD4-T cell count ≥200cells/mm3. Two interventions 60 days apart were done in three schedules: 23-valent pneumococcal polysaccharide vaccine (PPV23)/placebo; 7-valent pneumococcal conjugate vaccine (PCV7)/placebo; and PCV7 plus PPV23. Safety and reactogenicity were evaluated, and immunogenicity was assessed by an IgG enzyme-linked immunosorbent assay to S. pneumoniae serotypes 6B, 9V and 14, performed at baseline, 60 and 180 days after first intervention. Comparison of immunogenicity was based on geometric mean concentration (GMC), percentages of individuals with serotype-specific IgG≥0.35μg/mL and ≥1.0μg/mL and proportion of individuals with ≥4-fold increase in specific antibody concentrations for each serotype. ResultsDemographic and HIV conditions were similar, and both vaccines were well tolerated across vaccine groups. Significant increase in IgG-antibodies was observed to all serotypes evaluated. A greater proportion of PCV7 recipients reached and sustained IgG antibody concentrations at least four times as high as those at baseline, for serotypes 6B and 9V. A PPV23 dose after PCV7 did not enhance immunogenicity. ConclusionsIn this first trial conducted with HIV-infected immunologically stable adults in South America, both PPV23 and PCV7 were safe and immunogenic. Evidence suggesting PCV7 was more immunogenic than PPV23, as it elicited higher and persistent ≥4-fold increase of antibodies for 6B and 9V serotypes in a greater proportion of HIV-patients is noteworthy. Despite current recommendation of schedules combining PCV7 and PPV23, there is little evidence to support this practice and we did not observe benefits in this combination.