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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.

After pneumococcal disease and colonization have been controlled through vaccination campaigns, a reduced pneumococcal conjugate vaccine (PCV) schedule may be sufficient to sustain that control at reduced costs. We investigated whether a single primary dose and booster dose (1p+1) of the 10-valent PCV (PCV10) would be noninferior to alternative dose schedules in sustaining control of carriage of pneumococcal serotypes included in the vaccine. In Nha Trang, Vietnam, an area in which PCV had not been used previously, a PCV10 catch-up campaign was conducted in which the vaccine was offered to children younger than 3 years of age, after which a cluster-randomized trial was conducted in which children received PCV10 at 2, 3, and 4 months of age (3p+0 group); at 2, 4, and 12 months of age (2p+1 group); at 2 and 12 months of age (1p+1 group); or at 12 months of age (0p+1 group). Annual carriage surveys in infants (4 to 11 months of age) and toddlers (14 to 24 months of age) were conducted from 2016 through 2020. The primary end point was protection against carriage of vaccine serotypes, evaluated in a noninferiority analysis in the 1p+1 group as compared with the 2p+1 and 3p+0 groups, 3.5 years after vaccine introduction (noninferiority margin, 5 percentage points). Noninferiority of the 0p+1 schedule was also evaluated. In 2016, before the introduction of PCV10, vaccine-serotype carriage was found in 160 of 1363 infants (11.7%); in 2020, vaccine-serotype carriage was found in 6 of 333 (1.8%), 5 of 340 (1.5%), and 4 of 313 (1.3%) infants in the 1p+1, 2p+1, and 3p+0 groups, respectively, indicating noninferiority of 1p+1 to 2p+1 (difference, 0.3 percentage points; 95% confidence interval [CI], -1.6 to 2.2) and to 3p+0 (difference, 0.5 percentage points; 95% CI, -1.4 to 2.4). Similarly, 1p+1 was noninferior to 2p+1 and 3p+0 for protection against vaccine-serotype carriage among toddlers. In 2016, carriage of serotype 6A was found in 99 of 1363 infants (7.3%); in 2020, it was found in 12 of 333 (3.6%), 10 of 340 (2.9%), and 3 of 313 (1.0%) infants in the 1p+1, 2p+1, and 3p+0 groups, respectively. The 0p+1 schedule was also noninferior to the other three dose schedules among infants and toddlers, although cross-protection against serotype 6A was less common than with the other vaccination schedules. No PCV10-associated severe adverse effects were observed. A reduced vaccination schedule involving a single primary dose and booster dose of PCV10 was noninferior to alternative schedules in protecting against vaccine-serotype carriage in infants and toddlers. (Funded by the Bill and Melinda Gates Foundation and others; ClinicalTrials.gov number, NCT02961231.).

To better inform pneumococcal immunization policies, ongoing surveillance for pneumococcal community-acquired pneumonia (CAP) is crucial. To estimate the serotype-specific CAP burden of pneumococcal disease following the introduction of a new 15-valent pneumococcal conjugate vaccine (PCV), V114, a 15-plex serotype-specific urine antigen detection (SSUAD) assay was developed as a tool for surveillance of Streptococcuspneumoniae serotypes. V114–017 (NCT03547167; EudraCT 2017–004915-38) was a phase 3 randomized controlled trial in which participants (18–49 years) received V114 or 13-valent PCV (PCV13; as an active comparator), followed 6 months later by 23-valent pneumococcal polysaccharide vaccine (PPSV23). Here, we report findings from a prespecified sub-study nested within the phase 3 trial that descriptively assessed the impact of nasopharyngeal/oropharyngeal (NP/OP) carriage and pneumococcal vaccination on serotype detection with the SSUAD assay. In total, 301 individuals (all American Indian/Alaska Native) participated in the sub-study. NP/OP and urine samples were collected at 10 timepoints between baseline (prior to vaccination) and Month 7 (30 days following vaccination with PPSV23). NP/OP carriage was determined using qualitative polymerase chain reaction for pneumococcus detection and serotyping, and urine samples were tested in parallel with SSUAD. At any timepoint, NP/OP carriage was <2.0 % for 10 of the V114 serotypes; carriage was ∼2.6 % for serotype 1 and ranged between 4.0 % and 7.0 % for serotypes 4, 5, 9V, and 33F. At baseline, serotype-specific pneumococcal polysaccharide antigens were detected by SSUAD in only six study participants for serotypes 19A, 19F, and 1. SSUAD positivity for serotypes 4, 5, and 9V increased transiently following vaccination with V114/PCV13 and PPSV23, while SSUAD positivity lasted the longest for serotype 19A following PPSV23 vaccination. In general, SSUAD positivity appeared unrelated to NP/OP carriage. Our findings suggest SSUAD can support pneumococcal disease surveillance and vaccine effectiveness research, excluding individuals with recent pneumococcal vaccination to avoid false-positives.

The introduction of a 7-valent pneumococcal conjugate vaccine (PCV7) in 2000 dramatically reduced the incidence of invasive pneumococcal disease (IPD) caused by the seven serotypes covered by the vaccine. Following the introduction of PCV7, which contains a serotype 6B conjugate, some decrease in IPD due to serotype 6A was noted suggesting that the serotype 6B conjugate provided some partial cross-protection against serotype 6A. However, no effect on serotype 6C was observed. In 2010, a pneumococcal conjugate vaccine with expanded serotype coverage (PCV13) was introduced that expanded the serotype coverage to 13 serotypes including serotype 6A. To assess whether the 6A conjugate in PCV13 could potentially induce functional anti-6C antibody responses, an opsonophagocytic assay (OPA) for serotype 6C was developed. Randomly chosen subsets of immune sera collected from infants receiving three doses of PCV7 or PCV13 were tested in OPA assays for serotype 6A, 6B and 6C. PCV7 immune sera demonstrated strong OPA responses, defined as percentage of subjects having an OPA titer ≥1:8, to serotype 6B (100% responders), partial responses to serotype 6A (70% responders) but only minimal responses to serotype 6C (22% responders). In contrast, PCV13 immune sera showed strong OPA responses to serotypes 6A (100% responders), 6B (100% responders) and 6C (96% responders). Furthermore, during pre-clinical work it was observed that serotype 7F (included in PCV13) and serotype 7A (not included in PCV13) shared serogroup-specific epitopes. To determine whether such epitopes also may be eliciting cross-functional antibody, PCV13 immune sera were also tested in serotype 7A and 7F OPA assays. All PCV13 immune sera demonstrated OPA responses to both of these serotypes. Taken together these results suggest that immunization with PCV13 has the potential to induce cross-protective responses to related serotypes not directly covered by the vaccine.

Acute otitis media is one of the most commonly-diagnosed childhood infections. This study assessed the efficacy of a novel vaccine that contained polysaccharides from 11 different Streptococcus pneumoniae serotypes each conjugated to Haemophilus influenzae-derived protein D in prevention of acute otitis media. 4968 infants were randomly assigned to receive either pneumococcal protein D conjugate or hepatitis A vaccine at the ages of 3, 4, 5, and 12–15 months and were followed-up until the end of the second year of life. Middle-ear fluid was obtained for bacteriological culture and serotyping in children who presented with abnormal tympanic membrane or presence of middle-ear effusion, plus two predefined clinical symptoms. The primary endpoint was protective efficacy against the first episode of acute otitis media caused by vaccine pneumococcal serotypes. Analysis was per protocol. From 2 weeks after the third dose to 24–27 months of age, 333 clinical episodes of acute otitis media were recorded in the protein D conjugate group (n=2455) and 499 in the control group (n=2452), giving a significant (33·6% [95% CI 20·8–44·3]) reduction in the overall incidence of acute otitis media. Vaccine efficacy was shown for episodes of acute otitis media caused by pneumococcal vaccine serotypes (52·6% [35·0–65·5] for the first episode and 57·6% [41·4–69·3] for any episode). Efficacy was also shown against episodes of acute otitis media caused by non-typable H influenzae (35·3% [1·8–57·4]). The vaccine reduced frequency of infection from vaccine-related cross-reactive pneumococcal serotypes by 65·5%, but did not significantly change the number of episodes caused by other non-vaccine serotypes. These results confirm that using the H influenzae-derived protein D as a carrier protein for pneumococcal polysaccharides not only allowed protection against pneumococcal otitis, but also against acute otitis media due to non-typable H influenzae. Whether this approach would also allow improved protection against lower respiratory tract infections warrants further investigation.

Pneumococcal infection is an important cause of death and complications in adults with human immunodeficiency virus (HIV) infection, particularly in Africa. In this placebo-controlled, randomized trial involving 496 predominantly HIV-infected Malawian adults who had recently had an invasive pneumococcal infection, the 7-valent conjugated pneumococcal vaccine was found to have 74% efficacy in preventing subsequent invasive pneumococcal infection with a vaccine-associated serotype. In predominantly HIV-infected Malawian adults who had recently had an invasive pneumococcal infection, the 7-valent conjugated pneumococcal vaccine was found to have 74% efficacy in preventing subsequent invasive pneumococcal infection. Streptococcus pneumoniae is a leading cause of death and complications in adults with human immunodeficiency virus (HIV) infection, particularly in sub-Saharan Africa. 1 , 2 The risk of invasive pneumococcal disease is 30 to 100 times as high in patients with HIV infection as in age-matched controls without such infection. 3 , 4 Recurrent invasive pneumococcal disease is common, with up to 25% of patients having an additional episode, predominantly reinfection, in the subsequent 12 months. 1 , 5 Even among patients who have access to timely and effective care, the case fatality rate with invasive pneumococcal disease is at least 8% 6 and rises to 50% . . .

•Conjugate pneumococcal polysaccharide vaccine allows for recall immune response.•This recall response occurs after follow-on use of conjugate or polysaccharide.•Polysaccharide vaccine results in diminished responses to subsequent conjugate.•When the use of both vaccines is considered, conjugate should be given first. 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. 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. 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. 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.

Background.Pneumococcal conjugate vaccines (PCVs) prevent vaccine serotype (VT) invasive disease; nonvaccine serotype (NVT) disease increases modestly. The impact of PCV on nasopharyngeal (NP) colonization is essential to understanding disease effects. Methods.We conducted a community-randomized controlled trial with catch-up vaccination through age 2 years investigating the effect of 7-valent PCV (PnCRM7) on NP colonization among American Indian infants and their unvaccinated contacts. Infants receiving blinded vaccine at 2, 4, 6, and 12–15 months of age had NP cultures obtained at age 7, 12, and 18 months. Serotype-specific colonization was detected by immunoblot. Results.We enrolled 566 vaccinated and 286 unvaccinated children from 511 households and collected 5157 specimens, of which 3525 (68.4%) had pneumococcus. PnCRM7 vaccinees were less likely to be colonized with VT (odds ratio [OR], 0.40 [95% confidence interval {CI}, 0.23–0.67]) but were more likely to be colonized with NVT pneumococci (OR, 1.67 [95% CI, 1.02–2.78]). PnCRM7 vaccinees were less densely colonized with VT strains than control vaccinees (OR, 0.61 [95% CI, 0.38–0.99]). Day care–attending unvaccinated children in PnCRM7 communities were less likely to have VT colonization than those in control communities (OR, 0.27 [95% CI, 0.07–1.07]). Conclusions.PnCRM7 reduces the risk of VT acquisition and colonization density but increases the risk of NVT acquisition among vaccinees and their household contacts.

This controlled trial involving 39,836 children evaluated the efficacy of a 9-valent pneumococcal conjugate vaccine in South Africa. Vaccination decreased the frequency of invasive pneumococcal disease among both HIV-negative and HIV-positive children and reduced the number of first episodes of radiologically confirmed pneumonia. In children a 9-valent conjugate vaccine prevents invasive disease. Acute respiratory tract infections are a major cause of death in children under the age of five years. 1 Streptococcus pneumoniae, the leading bacterial pathogen, 2 has become increasingly resistant to antibiotics. 3 , 4 Administration of a 7-valent vaccine conjugated to a noncatalytic cross-reacting mutant of diphtheria toxin (CRM197) reduced the incidence of invasive pneumococcal disease in children. 5 The formulation lacks serotypes 1 and 5, which are important causes of invasive pneumococcal disease throughout the world. 6 The efficacy of conjugate vaccine in the prevention of invasive pneumococcal disease among children infected with human immunodeficiency virus (HIV) is unknown. Therefore, we conducted a prospective, . . .

•Limited evidence suggests that PCVs impact vaccine-type carriage density.•This double-blind PCV study suggests no impact on vaccine-type carriage density.•PCV13 may affect carriage by reducing carrier number but not vaccine-type density.•Carriage density may not impact herd effects. In addition to reducing vaccine-type nasopharyngeal carriage rates, pneumococcal conjugate vaccines (PCVs) may decrease carriage density in vaccinated individuals still carrying vaccine serotypes. However, reduction of carriage density has not been systematically studied. This study compared the effect of PCV13 versus PCV7 on carriage density of the serotypes in PCV13 that are not included in PCV7. This randomized, double-blind study was conducted in southern Israel and included Jewish and Bedouin subjects. Per protocol, 881 and 873 infants received PCV13 and PCV7, respectively, at ages 2, 4, 6, and 12months. Nasopharyngeal cultures at ages 7, 12, 13, 18, and 24months were plated using the 4-quadrant semiquantitative method and graded 0 (negative) to 4 (growth in all plate quadrants). In this post hoc analysis, the least squares means of cumulative colonization densities per serotype and serotype combination of the total population and each ethnic subpopulation in each vaccine group were calculated, and differences between vaccine groups derived from a linear model. PCV13-vaccinated children still carrying the 6 additional PCV13 serotypes unique to PCV13 showed no significant differences in carriage density compared with the PCV7-vaccinated control group. No differences in carriage density were shown between Jewish and Bedouin subpopulations despite higher carriage rates among Bedouin subjects. Although PCV13 vaccination reduces vaccine-type carriage compared with PCV7 vaccination by reducing nasopharyngeal acquisition of the additional PCV13 serotypes as previously reported, the current study lacks evidence of a decrease in carriage density of these serotypes when acquired in vaccinated children. Despite the lack of effect on carriage density observed, surveillance data suggest a dramatic decrease in disease rates after PCV implementation. Thus, the current analysis suggests that PCV’s impact on carriage density has minimal or no impact on vaccine success. (www.ClinicalTrials.gov: NCT00508742)