Robert Weatherholtz

Efficacy and safety of seven-valent conjugate pneumococcal vaccine in American Indian children: group randomised trial

BACKGROUND Streptococcus pneumoniae is the main cause of invasive bacterial disease in children aged younger than 2 years. Navajo and White Mountain Apache children have some of the highest rates of invasive pneumococcal disease documented in the world. We aimed to assess the safety and efficacy of a seven-valent polysaccharide protein conjugate pneumococcal vaccine (PnCRM7) against such disease. METHODS In a group-randomised study, we gave this vaccine to children younger than 2 years from the Navajo and White Mountain Apache Indian reservations; meningococcal type C conjugate vaccine (MnCC) served as the control vaccine. Vaccine schedules were determined by age at enrollment. We recorded episodes of invasive pneumococcal disease and serotyped isolates. Analyses were by intention to treat and per protocol. FINDINGS 8292 children enrolled in the trial. In the per protocol analysis of the primary efficacy group (children enrolled by 7 months of age) there were eight cases of vaccine serotype disease in the controls and two in the PnCRM7 group; in the intention-to-treat analysis we noted 11 cases of vaccine serotype disease in the MnCC control group and two in the PnCRM7 group. After group randomisation had been controlled for, the per protocol primary efficacy of PnCRM7 was 76.8% (95% CI -9.4% to 95.1%) and the intention-to-treat total primary efficacy was 82.6% (21.4% to 96.1%). INTERPRETATION PnCRM7 vaccine prevents vaccine serotype invasive pneumococcal disease even in a high risk population. Other regions with similar disease burden should consider including this vaccine in the routine childhood vaccine schedule.

Effect of pneumococcal conjugate vaccine on nasopharyngeal colonization among immunized and unimmunized children in a community-randomized trial

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.

Impact of More Than a Decade of Pneumococcal Conjugate Vaccine Use on Carriage and Invasive Potential in Native American Communities

BACKGROUND We assessed the impact of 12 years of pneumococcal conjugate vaccine (PCV7) use on pneumococcal nasopharyngeal carriage and serotype-specific invasive disease potential among Native Americans. METHODS Families were enrolled in a carriage study from 2006 to 2008; nasopharyngeal specimens and risk factor information were collected monthly for 7 visits. Pneumococcal carriage prevalence was compared with that before (1998-2000) and during (2001-2002) PCV7 introduction. We compared invasive disease incidence and carriage prevalence before and after PCV7 introduction to estimate changes in serotype-specific invasive potential. RESULTS We enrolled 1077 subjects from 302 households. There was an absolute reduction in carriage prevalence of 8.0% (95% confidence interval [CI], 4.5%-11.4%) in children aged <5 years and 3.1% (95% CI, 1.1%-5.1%) in adults. In children aged <5 years, vaccine-serotype carriage prevalence decreased by 22.8% (95% CI, 20.1%-25.3%), and nonvaccine serotype (NVT) increased by 15.9% (95% CI, 12.4%-19.3%). No significant change was detected in serotype-specific invasive potential after PCV7 introduction. CONCLUSIONS Pneumococcal carriage prevalence decreased in all ages since PCV7 introduction; vaccine-serotype carriage has been nearly eliminated, whereas the prevalence of NVT carriage has increased. The increase in the NVT invasive disease rate seems to be proportional to the increase in colonization prevalence.

Invasive Pneumococcal Disease a Decade after Pneumococcal Conjugate Vaccine Use in an American Indian Population at High Risk for Disease

BACKGROUND Before 7-valent pneumococcal conjugate vaccine (PCV7) introduction, invasive pneumococcal disease (IPD) rates among Navajo were several-fold those of the general US population. Only 50% of IPD cases in children involved PCV7 serotypes. METHODS We conducted active, population-based surveillance for IPD for the period 1995-2006. We documented case characteristics and serotyped the isolates. RESULTS Over 12-year period, we identified 1508 IPD cases, 447 of which occurred in children aged <5 years. Rates of IPD due to vaccine serotypes among children aged <1 year, 1 to <2 years, and 2 to <5 years decreased from 210, 263, and 51 cases per 100,000 population, respectively in 1995-1997 to 0 cases in 2004-2006 (P < .001). Among adults aged > or =65 years, rates of IPD due to vaccine serotypes decreased 81% (95% confidence interval, -98% to -9%; P = .02). Rates of nonvaccine serotype IPD were unchanged in all age strata except for persons aged 18 to <40 years, among whom the rate decreased by 35% from 27 to 18 cases per 100,000 population (95% confidence interval, -57% to -1%; P = .03). CONCLUSIONS Vaccine-serotype IPD has virtually been eliminated in the PCV7 era among Navajo of all ages. Overall rates of nonvaccine-serotype IPD have not increased, although increases have occurred for some individual types. Rates of all-serotype IPD among Navajo children remain 3-5-fold greater than in the general US population.

Design of a group-randomized Streptococcus pneumoniae vaccine trial

A group-randomized, double-masked, phase III trial of a Streptococcus pneumoniae conjugate vaccine is being conducted in American Indian populations in the southwestern United States. Approximately 9000 infants will be enrolled in the primary efficacy cohort with vaccine allocation determined by community of residence. The trial is designed to continue until 48 cases of invasive pneumococcal disease due to vaccine serotypes have accumulated. Thirty-eight geographically and socially distinct areas were randomized within blocks formed by population size and geographic location. This design affords the opportunity to capture the effects of herd immunity (indirect effects) by estimating the impact of the vaccine intervention on nonimmunized infants. Group-randomized trials have challenging design and analysis features, many of which are discussed here in the context of the first such trial designed to lead to licensure of a drug or biologic in the United States.

Randomized, controlled trial efficacy of pneumococcal conjugate vaccine against otitis media among Navajo and White Mountain Apache infants.

We report the phase III trial efficacy of 7-valent pneumococcal conjugate vaccine against clinical and culture proven otitis media (OM) among Navajo and White Mountain Apache infants. Efficacy was −0.4% (95% CI: −19.4 to 15.6) for clinically-diagnosed OM, 5.1% (95% CI: −51.5 to 40.6) for severe OM, and 64% (95% CI: −34% to 90%) for vaccine serotype pneumococcal OM suggesting that this vaccine is efficacious for pneumococcal OM in this high risk population.

Seasonal drivers of pneumococcal disease incidence: impact of bacterial carriage and viral activity.

BACKGROUND Winter-seasonal epidemics of pneumococcal disease provide an opportunity to understand the drivers of incidence. We sought to determine whether seasonality of invasive pneumococcal disease is caused by increased nasopharyngeal transmission of the bacteria or increased susceptibility to invasive infections driven by cocirculating winter respiratory viruses. METHODS We analyzed pneumococcal carriage and invasive disease data collected from children <7 years old in the Navajo/White Mountain Apache populations between 1996 and 2012. Regression models were used to quantify seasonal variations in carriage prevalence, carriage density, and disease incidence. We also fit a multivariate model to determine the contribution of carriage prevalence and RSV activity to pneumococcal disease incidence while controlling for shared seasonal factors. RESULTS The seasonal patterns of invasive pneumococcal disease epidemics varied significantly by clinical presentation: bacteremic pneumococcal pneumonia incidence peaked in late winter, whereas invasive nonpneumonia pneumococcal incidence peaked in autumn. Pneumococcal carriage prevalence and density also varied seasonally, with peak prevalence occurring in late autumn. In a multivariate model, RSV activity was associated with significant increases in bacteremic pneumonia cases (attributable percentage, 15.5%; 95% confidence interval [CI], 1.8%-26.1%) but was not associated with invasive nonpneumonia infections (8.0%; 95% CI, -4.8% to 19.3%). In contrast, seasonal variations in carriage prevalence were associated with significant increases in invasive nonpneumonia infections (31.4%; 95% CI, 8.8%-51.4%) but not with bacteremic pneumonia. CONCLUSIONS The seasonality of invasive pneumococcal pneumonia could be due to increased susceptibility to invasive infection triggered by viral pathogens, whereas seasonality of other invasive pneumococcal infections might be primarily driven by increased nasopharyngeal transmission of the bacteria.

Comparative immunogenicity of 7 and 13-valent pneumococcal conjugate vaccines and the development of functional antibodies to cross-reactive serotypes.

Background Protection against disease or colonization from serotypes related to those in pneumococcal conjugate vaccines (i.e. cross-protection) vary by serotype; the basis for this variation is not understood. The 13-valent pneumococcal conjugate vaccine (PCV13) replaced 7-valent conjugate (PCV7) in the USA in 2010 allowing assessment of PCV7 and PCV13 immunogenicity and functional cross-protection in vitro. Methods Post-primary, pre-booster and post-booster sera from American Indian children receiving exclusively PCV7 or PCV13 were collected. IgG was measured by ELISA for 13 vaccine serotypes; functional antibody was assessed by opsonophagocytic killing assays for serotypes 6A/B/C and 19A/F. Results Post-primary IgG geometric mean concentrations (GMC) for serotypes 4 and 9V were lower in PCV13 recipients while 19F GMCs were higher. Only 19F differences persisted after receipt of the booster dose. Functional antibody activity was higher among PCV13 recipients for 6A, 6C, 19A and 19F (p<0.04), and among PCV7 recipients for 6B (p = 0.01). Following PCV7, functional antibodies to 6A but not 19A were observed. High levels of 6C functional activity were seen after PCV13 but not PCV7. Conclusions Functional antibody activity against 6A/B/C and 19A/F suggest that PCV13 is likely to control the 19A disease and 6C disease remaining despite widespread use of PCV7.

Predictors of Pneumococcal Conjugate Vaccine Immunogenicity among Infants and Toddlers in an American Indian PnCRM7 Efficacy Trial

BACKGROUND Pneumococcal conjugate vaccines are important for the prevention of serious illness and death among infants. Factors associated with pneumococcal conjugate vaccine immunogenicity have not been explored. METHODS Children <24 months of age received 2, 3, or 4 doses of 7-valent pneumococcal conjugate vaccine (PnCRM7) or control vaccine depending on age at enrollment. Serum samples were tested for serotype-specific antibodies by enzyme-linked immunosorbant assay. Multiple linear regression was used to determine predictors of immunogenicity. RESULTS Among 315 PnCRM7-vaccinated subjects and 295 control subjects enrolled at <7 months of age, geometric mean concentrations (GMCs) of antibodies were significantly higher after dose 3 than after dose 2 for all serotypes except type 4. The proportion of subjects with antibody concentrations > or =5.0 micro g/mL was higher for all serotypes, but the proportion with concentrations > or =0.35 micro g/mL was higher only for types 6B and 23F. Three-dose and 2-dose regimens for those 7-11 and 12-23 months of age, respectively, were highly immunogenic. Increased maternal antibody concentrations were associated with reduced responses to dose 1 and 3 but not to dose 4 of PnCRM7. CONCLUSIONS Maternal antibody is associated with a reduced infant response to PnCRM7 but does not interfere with immune memory. In infants, a third priming dose increases the antibody GMC and the proportion achieving an antibody concentration > or =5.0 micro g/mL but has little impact on the proportion achieving a concentration > or =0.35 micro g/mL.

Detection of G3P[3] and G3P[9] rotavirus strains in American Indian children with evidence of gene reassortment between human and animal rotaviruses

The distribution and evolution of human rotavirus strains is important for vaccine development and effectiveness. In settings where rotavirus vaccine coverage is high, vaccine pressure could select for replacement of common strains (similar to those included in rotavirus vaccines) with uncommon strains, some of which could be generated by reassortment between human and animal rotaviruses. Between 2002 and 2004, a phase‐III rotavirus vaccine clinical trial was conducted among American Indian children of the Navajo and White Mountain Apache tribes, which are known to be at high risk for rotavirus diarrhea. We evaluated the rotavirus strains collected from study participants who received placebo during the trial to determine the distribution of rotavirus genotypes and to detect emerging strains that contribute to disease and could influence rotavirus vaccine effectiveness. Three uncommon strains of human rotavirus, two G3P[3] and one G3P[9] strains were detected in stools of children aged 3 to 6 months of age. Segments of all 11 rotavirus genes were sequenced and genotyped by comparison of cognate gene fragments with reference strains. The G3P[3] strains had similar genotypes to each other and to reference dog and cat strains. The G3P[9] strain had similar genotypes to cow, cat and dog reference strains. Genetic analyses of these three strains support the known diversity generating mechanisms of rotavirus. J. Med. Virol. 83:1288–1299, 2011.