Eugene Millar

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.

Revisiting Pneumococcal Carriage by Use of Broth Enrichment and PCR Techniques for Enhanced Detection of Carriage and Serotypes

ABSTRACT The measurement of pneumococcal carriage in the nasopharyngeal reservoir is subject to potential confounders that include low-density and multiple-strain colonization. To compare different methodologies, we picked a random sampling of 100 nasopharyngeal specimens recovered from infants less than 2 years of age who were previously assessed for pneumococcal carriage and serotypes by a conventional method that used direct plating from the transport/storage medium (50 specimens were culture negative and 50 specimens were culture positive for pneumococci). We used a broth enrichment approach and a conventional PCR approach (with and without broth enrichment) to determine pneumococcal carriage and serotypes, and the results were compared to the initial conventional culture-based results. Additionally, we used a lytA-targeted real-time PCR for pneumococcal detection. Broth enrichment for both the culture-based and the PCR-based methods enhanced the isolation of pneumococci and detection of serotype diversity, with the most effective serotype deduction method being one that used broth enrichment prior to sequential multiplex PCR. Similarly, we also found that broth enrichment followed by the lytA-specific real-time PCR was the most sensitive for the detection of apparent pneumococcal carriage. The broth enrichment, conventional multiplex PCR, and real-time PCR approaches used in this study were effective in detecting pneumococcal carriage in the 50 specimens that were negative by conventional direct plating from transport medium (range of numbers of positive specimens, 8/50 to 22/50 [16 to 44%]), and the three different serotyping approaches that used broth enrichment increased the number of serotype identifications from the 100 specimens (12 to 29 additional serotype identifications to be positive). A PCR-based approach that employed a broth enrichment step appeared to best enhance the detection of mixed serotypes and low-density pneumococcal carriage.

Indirect Effect of 7-Valent Pneumococcal Conjugate Vaccine on Pneumococcal Colonization among Unvaccinated Household Members

BACKGROUND Since the introduction of 7-valent pneumococcal conjugate vaccine (PCV7) in the United States, rates of invasive pneumococcal disease have decreased in both vaccinated and unvaccinated age groups. Reduction of invasive pneumococcal disease in unvaccinated groups has been attributed to reduced transmission of vaccine-type pneumococci in the community. Understanding the impact of PCV7 on carriage among vaccinated and unvaccinated community members is critical to interpreting, predicting, and understanding the impact of PCV7 on disease. METHODS A group-randomized, phase III efficacy trial of PCV7 was conducted among southwestern American Indian communities. Meningococcal conjugate vaccine against serogroup C was used as the control. After the trial was unblinded, we conducted a carriage study of participating communities to evaluate the impact of PCV7 on colonization among trial participants and their unvaccinated household members. RESULTS Adults and unvaccinated children aged <5 years living in households with a PCV7 vaccinee were less likely to be colonized with vaccine-type pneumococci (odds ratio [OR] for adults, 0.57; 95% confidence interval [CI], 0.33-0.99; OR for children, 0.57; 95% CI, 0.26-0.98) than were those living in a household with a control vaccinee. There was no difference for children aged 5-17 years. Decreases in vaccine-type carriage were offset by increases in carriage of nonvaccine types. Among adults living with a trial participant colonized with vaccine-type pneumococcus, those in the households randomized to receive PCV7 were less likely to be colonized with the same serotype than were those in the households randomized to receive the control vaccine (OR, 0.34; 95% CI, 0.11-0.99). CONCLUSIONS Vaccine-type pneumococcal carriage was lower among adults and unvaccinated children living with a PCV7 vaccinee. This is attributable to reduced exposure and reduced transmission when exposure occurs.

Effect of Community-Wide Conjugate Pneumococcal Vaccine Use in Infancy on Nasopharyngeal Carriage through 3 Years of Age: A Cross-Sectional Study in a High-Risk Population

BACKGROUND A 7-valent pneumococcal conjugate vaccine (PnCRM7) has been shown to be highly effective in preventing invasive pneumococcal disease. Pneumococcal conjugate vaccines also protect against nasopharyngeal carriage of vaccine serotypes, but the duration of protection against nasopharyngeal carriage is not known. METHODS A group-randomized efficacy trial of PnCRM7 (vaccine serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F) was conducted on the Navajo and White Mountain Apache reservations from April 1997 to October 2000. A group C meningococcal conjugate vaccine was used as the control vaccine. Infants enrolled between 6 weeks and 7 months of age received 3 doses of vaccine 2 months apart and a fourth dose at 12-15 months of age. Vaccinees were enrolled in a nasopharyngeal carriage study from February 2001 to January 2002 to assess the duration of protection against pneumococcal carriage induced by PnCRM7. RESULTS We included 749 children in the analysis, including 468 children vaccinated with PnCRM7 and 281 children vaccinated with group C meningococcal conjugate vaccine. The median age was 3.3 years (range, 1-7 years), and the median time since last dose of study vaccine was 27 months (range, 12-48 months). Frequencies of overall pneumococcal carriage were similar among PnCRM7 and group C meningococcal conjugate vaccine recipients (63.9% vs. 60.5%, respectively). The absolute frequency of vaccine-type pneumococcal carriage was lower among PnCRM7 recipients (10.3%) than among controls (17.1%; P = .01). This reduction was offset by an increase of nonvaccine-type pneumococcal carriage among PnCRM7 recipients (39.2% vs. 29.8%; P = .01). CONCLUSION Community-wide PnCRM7 vaccination in infancy reduces the prevalence of vaccine-type carriage and increases the prevalence of nonvaccine-type carriage through at least 3 years of age.

Epidemiology of Invasive Haemophilus influenzae Type A Disease among Navajo and White Mountain Apache Children, 1988–2003

BACKGROUND Before the introduction of Haemophilus influenzae type b (Hib) conjugate vaccines, rates of H. influenzae disease among Navajo and White Mountain Apache (WMA) children were among the highest reported worldwide. Routine Hib vaccination has significantly reduced rates of Hib disease in these populations. As Hib disease rates decrease to very low levels, there are concerns that non-type b strains of H. influenzae may emerge as more prevalent causes of invasive disease in children. METHODS We reviewed population-based, active laboratory surveillance data from the period of 1988-2003 for invasive H. influenzae type a (Hia) disease among Navajo and WMA children aged <5 years. Clinical information on cases was collected by chart review. A sample of Hia isolates from Navajo children was typed by pulsed-field gel electrophoresis (PFGE). RESULTS During 1988-2003, a total of 76 reported cases of invasive Hia disease occurred among Navajo and WMA children. The overall annual incidence was 20.2 cases per 100,000 population aged <5 years. There was no increase in Hia disease rates after Hib vaccination was introduced. The median age of patients was 12 months. Meningitis (50% of cases) was the most common presentation, followed by pneumonia (27.6%). Two children with Hia disease died. PFGE analysis revealed a limited genetic diversity of Hia strains in this population. CONCLUSIONS Active surveillance data showed high rates of invasive Hia disease among Navajo and WMA children but no increase in the incidence after Hib vaccination was introduced. The presentation of Hia disease is similar to that of Hib disease in the prevaccine era.

Anticapsular Serum Antibody Concentration and Protection against Pneumococcal Colonization among Children Vaccinated with 7-Valent Pneumococcal Conjugate Vaccine

BACKGROUND Pneumococcal conjugate vaccines prevent invasive and noninvasive disease due to infection with vaccine serotypes. Pneumococcal conjugate vaccines also prevent nasopharyngeal acquisition of vaccine serotypes, although the mechanism is incompletely understood. METHODS An efficacy trial of a 7-valent pneumococcal conjugate vaccine was conducted on the Navajo and White Mountain Apache reservations, located in the Southwestern United States; group C meningococcal conjugate vaccine was the control vaccine. Infants were randomized to receive 7-valent pneumococcal conjugate vaccine or group C meningococcal conjugate vaccine at 2, 4, 6, and 12 months of age. Immunogenicity and nasopharyngeal colonization studies were nested in the efficacy trial. We analyzed the correlation between serotype-specific serum IgG concentration at 7 and 13 months of age and nasopharyngeal acquisition of disease at 12 and 18 months of age, respectively. We adjusted for potential confounders using multivariate logistic regression. RESULTS Among 203 subjects, we observed 60 acquisitions of vaccine-type pneumococci, including 19 acquisitions of serotype 19F (31.7%), and 17 acquisitions of serotype 23F (28.3%). Among recipients of 7-valent pneumococcal conjugate vaccine, increased serotype-specific serum IgG was associated with a reduction in nasopharyngeal acquisition of serotype 23F (relative risk, 0.53; 95% confidence interval, 0.31-0.93) but was not associated with a reduction in acquisition of serotype 19F (relative risk, 1.07; 95% confidence interval, 0.57-2.03). Among group C meningococcal conjugate vaccine recipients, serotype-specific serum IgG was not associated with a reduction in nasopharyngeal acquisition for either serotype. CONCLUSION An increase in serum antibody concentration was associated with reduced acquisition of serotype 23F pneumococcus (but not with reduced acquisition of serotype 19F pneumococcus) among recipients of 7-valent pneumococcal conjugate vaccine. Differences in antibody concentration, in the functional characteristics of antibody, or in antibody kinetics during infancy may account for differences in carriage protection.

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.

Toward elimination of Haemophilus influenzae type B carriage and disease among high-risk American Indian children.

OBJECTIVES This report describes the epidemiology of Haemophilus influenzae type b (Hib) invasive disease and oropharyngeal colonization among Navajo and White Mountain Apache children younger than 7 years in an era of widespread immunization. METHODS We conducted active surveillance for invasive H influenzae disease from 1992 to 1999 and an oropharyngeal carriage study from 1997 to 1999. The predominant vaccine used was PedvaxHib. RESULTS The average annual incidence of invasive Hib disease among children younger than 24 months was 22 cases per 100,000. Of 381 children younger than 7 years, only 1 (0.3%; 95% confidence interval = 0.0%, 1.3%) was colonized with Hib; 370 (97%) had received 2 or more doses of Hib conjugate vaccine. CONCLUSIONS Among Navajo and White Mountain Apache children, Hib conjugate vaccines have led to a sustained reduction in invasive Hib disease and a reduction in oropharyngeal Hib carriage. The disease incidence among children younger than 24 months remains 20 times higher than in the general US population. Hib elimination will require additional characterization of colonization and disease in these high-risk populations.

Nasopharyngeal carriage of Streptococcus pneumoniae in Navajo and White Mountain Apache children before the introduction of pneumococcal conjugate vaccine.

Background: Infants and children are frequently colonized with pneumococcus. Recent nasopharyngeal acquisition of pneumococcus is thought to precede disease episodes. The increased risk of pneumococcal disease among Navajo and White Mountain Apache populations has been documented. Little is known about the dynamics of pneumococcal carriage in these populations. Methods: A group randomized, controlled trial of 7-valent conjugate pneumococcal vaccine (PnCRM7, Wyeth) was conducted on the Navajo and Apache reservations. A nasopharyngeal (NP) carriage study was nested in the trial to evaluate the impact of PnCRM7 on carriage. Children <6 years of age had NP swabs collected at enrollment and at 6 and 12 months following enrollment. We analyzed carriage data from children in control vaccine randomized communities to describe the epidemiology of pneumococcal carriage. Results: Of the 410 participants enrolled, 92% were colonized with pneumococcus at least once during the course of the study. Sixty-three percent of NP specimens were positive for pneumococcus. The most common serotypes were 6A, 6B, nontypable, 23F, 14, 19F, 19A, and 9V. Thirty-eight percent of isolates were vaccine serotypes. Age <2 years, male sex, daycare attendance, and having a sibling colonized with pneumococcus were associated with an increased risk of carriage. Conclusions: The high carriage prevalence among Navajo and Apache children reflects an intense exposure to pneumococcus. The lack of modifiable risk factors for carriage highlights the importance of preventive strategies for disease control.

Pre- and Post-Conjugate Vaccine Epidemiology of Pneumococcal Serotype 6C Invasive Disease and Carriage within Navajo and White Mountain Apache Communities

BACKGROUND A second-generation 13-valent pneumococcal conjugate vaccine, PCV13, was recently licensed. Although PCV13 includes serotype 6A, the usefulness of that antigen may be limited by the emergence of a new serotype, 6C, which was identified among isolates initially characterized (Quellung reaction) as serotype 6A. The epidemiology of serotype 6C prior to and after 7-valent PCV (PCV7) introduction is incompletely understood. METHODS We analyzed conventionally serotyped 6A (CS6A) pneumococci from invasive disease case patients of all ages and carriage isolates from children and adults obtained in population-based studies among Navajo and White Mountain Apache communities during 1994-2009. Samples were tested by triplex polymerase chain reaction to resolve serotypes 6C and 6A. RESULTS A total of 74 invasive CS6A episodes occurred. All were retyped by polymerase chain reaction; 40 (54.1%) were serotype 6C. The mean annual incidence of serotype 6C invasive disease was 0.3 (95% confidence interval, 0.03-0.9), 0.7 (95% confidence interval, 0.2-1.3), and 1.5 (95% confidence interval, 1.0-2.1) cases per 100,000 population in the years prior to the PCV7 efficacy trial, during the time the PCV7 trial was conducted, and following PCV7 introduction and routine use, respectively (P = .01). In the routine vaccination era, 76% of invasive CS6As were serotype 6C; nearly all cases occurred in adults. The proportion of serotype 6C among CS6A carriage isolates increased from 42% to 61% to 94% in the prevaccine, early vaccine, and routine vaccination eras, respectively. CONCLUSION In the PCV7 routine use era, virtually all serogroup 6 invasive pneumococcal disease and carriage strains among Navajo and White Mountain Apache communities are 6C. Monitoring and evaluation of this and other emerging serotypes among invasive disease and carriage isolates is warranted.