Dana J. T. Bruden

Using pneumococcal carriage data to monitor postvaccination changes in invasive disease.

Pneumococcal conjugate vaccines (PCVs) have been introduced worldwide. However, few developing countries have high-quality surveillance systems available for monitoring vaccine impact. We evaluated whether data from nasopharyngeal carriage studies can be used to accurately monitor post-PCV changes in the incidence of invasive pneumococcal disease (IPD) among children under 5 years of age. For various dates during 1991-2010, data on nasopharyngeal pneumococcal carriage and on IPD before and after administration of 7-valent PCV (PCV7) were available from England and Wales, the Netherlands, the Navajo and White Mountain Apache American Indian populations, and the US states of Massachusetts and Alaska. We estimated the change in carriage prevalence for each serotype in each study and then either calculated the average change (inverse variance-weighted) among vaccine and nonvaccine serotypes (model 1) or used mixed-effects models to estimate the change for each serotype individually, pooling serotype data within or between studies (models 2 and 3). We then multiplied these values by the proportion of IPD caused by each serotype during the pre-PCV7 period to obtain an estimate of post-PCV7 disease incidence. Model 1 accurately captured overall changes in IPD incidence following PCV7 introduction for most studies, while the more detailed models, models 2 and 3, were less accurate. Carriage data can be used in this simple model to estimate post-PCV changes in IPD incidence.

Effect of the 13-Valent Pneumococcal Conjugate Vaccine on Nasopharyngeal Colonization by Streptococcus pneumoniae—Alaska, 2008–2012

BACKGROUND In 2010, a 13-valent pneumococcal conjugate vaccine (PCV13) replaced a 7-valent vaccine (PCV7) that contained all PCV7 serotypes plus 6 additional serotypes (PCV6+). We conducted annual surveys from 2008 to 2012 to determine the effect of PCV13 on colonization by pneumococcal serotypes. METHODS We obtained nasopharyngeal swabs for pneumococcal identification and serotyping from residents of all ages at 8 rural villages and children age <60 months at 2 urban clinics. We conducted interviews/medical records review for all participants. RESULTS A total of 18 207 nasopharyngeal swabs (rural = 16 098; urban = 2109) were collected. From 2008 to 2012, 84% of rural and 90% of urban children age <5 years were age-appropriately vaccinated with a PCV. Overall pneumococcal colonization prevalence remained stable among rural (66%) and urban (35%) children age <5 years, and adults age ≥18 years (14%). Colonization by PCV6+ serotypes declined significantly among rural children age <5 years, urban children age <5, and adults age ≥18 over the course of the study (25%-5%, 22%-9%, 22%-6%, respectively). CONCLUSIONS PCV13 was rapidly introduced into the Alaska childhood immunization schedule and reduced colonization by PCV6+ serotypes among children. Unvaccinated adults also experienced comparable reductions in vaccine serotype colonization indicating substantial indirect protection from PCV13.

Haemophilus influenzae serotype a invasive disease, Alaska, USA, 1983-2011.

Before introduction of Haemophilus influenzae type b (Hib) vaccines, rates of Hib disease in Alaska’s indigenous people were among the highest in the world. Vaccination reduced rates dramatically; however, invasive H. influenzae type a (Hia) disease has emerged. Cases of invasive disease were identified through Alaska statewide surveillance during1983–2011. Of 866 isolates analyzed for serotype, 32 (4%) were Hia. No Hia disease was identified before 2002; 32 cases occurred during 2002–2011 (p<0.001). Median age of case-patients was 0.7 years; 3 infants died. Incidence of Hia infection (2002–2011) among children <5 years was 5.4/100,000; 27 cases occurred in Alaska Native children (18/100,000) versus 2 cases in non-Native children (0.5/100,000) (risk ratio = 36, p<0.001). From 12/2009 to 12/2011, 15 cases of Hia disease occurred in southwestern Alaska (in children <5 years, rate = 204/100,000). Since introduction of the Hib conjugate vaccine, Hia infection has become a major invasive bacterial disease in Alaska Native children.

A Longitudinal Hepatitis B Vaccine Cohort Demonstrates Long-lasting Hepatitis B Virus (HBV) Cellular Immunity Despite Loss of Antibody Against HBV Surface Antigen

BACKGROUND Long-lasting protection resulting from hepatitis B vaccine, despite loss of antibody against hepatitis B virus (HBV) surface antigen (anti-HBs), is undetermined. METHODS We recruited persons from a cohort vaccinated with plasma-derived hepatitis B vaccine in 1981 who have been followed periodically since. We performed serological testing for anti-HBs and microRNA-155 and assessed HBV-specific T-cell responses by enzyme-linked immunospot and cytometric bead array. Study subgroups were defined 32 years after vaccination as having an anti-HBs level of either ≥10 mIU/mL (group 1; n = 13) or <10 mIU/mL (group 2; n = 31). RESULTS All 44 participants, regardless of anti-HBs level, tested positive for tumor necrosis factor α, interleukin 10, or interleukin 6 production by HBV surface antigen-specific T cells. The frequency of natural killer T cells correlated with the level of anti-HBs (P = .008). The proportion of participants who demonstrated T-cell responses to HBV core antigen varied among the cytokines measured, suggesting some natural exposure to HBV in the study group. No participant had evidence of breakthrough HBV infection. CONCLUSIONS Evidence of long-lasting cellular immunity, regardless of anti-HBs level, suggests that protection afforded by primary immunization with plasma-derived hepatitis B vaccine during childhood and adulthood lasts at least 32 years.

Molecular Characterization of Streptococcus pneumoniae Serotype 12F Isolates Associated with Rural Community Outbreaks in Alaska

ABSTRACT Outbreaks of invasive pneumococcal disease (IPD) caused by Streptococcus pneumoniae serotype 12F were observed in two neighboring regions of rural Alaska in 2003 to 2006 and 2006 to 2008. IPD surveillance data from 1986 to 2009 and carriage survey data from 1998 to 2004 and 2008 to 2009 were reviewed to identify patterns of serotype 12F transmission. Pulsed-field gel electrophoresis was performed on all available isolates, and selected isolates were characterized by additional genetic subtyping methods. Serotype 12F IPD occurred in two waves in Alaska between 1986 and 2008. While cases of disease occurred nearly every year in Anchorage, in rural regions, 12F IPD occurred with rates 10- to 20-fold higher than those in Anchorage, often with many years between disease peaks and generally caused by a single predominant genetic clone. Carriage occurred predominantly in adults, except early in the rural outbreaks, when most carriage was in persons <18 years old. In rural regions, carriage of 12F disappeared completely after outbreaks. Different 12F clones appear to have been introduced episodically into rural populations, spread widely in young, immunologically naïve populations (leading to outbreaks of IPD lasting 1 to 3 years), and then disappeared rapidly from the population. Larger population centers might have been the reservoir for these clones. This epidemiologic pattern is consistent with a highly virulent, but immunogenic, form of pneumococcus.

Risk of End Stage Liver Disease, Hepatocellular Carcinoma and Liver-Related Death By Fibrosis Stage in the Hepatitis C Alaska Cohort

Long‐term prospective studies of the outcomes associated with hepatitis C virus (HCV) infection are rare and critical for assessing the potential impact of HCV treatment. Using liver biopsy as a starting point, we analyzed the development of end‐stage liver disease (ESLD), hepatocellular carcinoma (HCC), and liver‐related death (LRD) according to fibrosis stage among a cohort of American Indian/Alaska Native persons in Alaska. Persons were classified as having no/mild (Ishak = 0,1), moderate (Ishak = 2), or severe (Ishak = 3,4) fibrosis or cirrhosis (Ishak = 5,6). We examined time until development of ESLD, HCC, and LRD and report survival probabilities at 3, 5, 7, and 10 years. Of 407 persons, 39% (n = 150) had no/mild fibrosis, 32% (n = 131) had moderate fibrosis, 22% (n = 88) had severe fibrosis, and 9% (n = 38) had cirrhosis. The average time of follow‐up was 7.3 years. Within 5 years of biopsy, 1.7% (95% confidence interval [CI]: 0.4‐6.8) of persons with no/mild fibrosis developed ESLD compared with 7.9% (95% CI, 4.0‐15.2), 16.4% (95% CI, 9.6‐27.2), and 49.0% (95% CI, 33.0‐67.7) with moderate, severe fibrosis, and cirrhosis, respectively (P < 0.01). The 5‐year outcome of HCC was 1.0% (95% CI, 0.1‐7.0), 1.0% (95% CI, 0.1‐6.6), 1.1% (95% CI, 0.2‐7.7), and 13.4% (95% CI, 4.4‐36.7) among persons with no/mild fibrosis, moderate fibrosis, severe fibrosis, and cirrhosis, respectively (P < 0.01). Five years after biopsy, 0.0% (95% CI, 0.0‐14.8) of persons with no/mild fibrosis had suffered an LRD compared with 1.0% (95% CI, 0.2‐7.5) of persons with moderate fibrosis, 4.7% (95% CI, 1.5‐14.1) with severe fibrosis, and 16.3% (95% CI, 7.0‐35.1) with cirrhosis (P < 0.01). Conclusion: For prevention of HCC, LRD, and ESLD in the short term, HCV therapy should target individuals who have more than mild fibrosis. (Hepatology 2017;66:37–45).

Eighteen Years of Respiratory Syncytial Virus Surveillance: Changes in Seasonality and Hospitalization Rates in Southwestern Alaska Native Children.

Background: Alaska Native infants from the Yukon-Kuskokwim Delta (YKD) experienced respiratory syncytial virus (RSV) hospitalization rates 5 times higher and an RSV season twice as long as the general US infant population. We describe trends in hospitalization rates and seasonality during 18 years of continuous RSV surveillance in this population and explore contributions of climate and sociodemographic factors. Methods: We abstracted clinical and RSV test information from computerized medical records at YKD Regional Hospital and Alaska Native Medical Center from 1994 to 2012 to determine hospitalization rates and RSV season timing. Descriptive village and weather data were acquired through the US Census and Alaska Climate Research Center, University of Alaska, Fairbanks, respectively. Results: During 1994–2012, YKD infant RSV hospitalization rates declined nearly 3-fold, from 177 to 65 per 1000 infants/yr. RSV season onset shifted later, from mid October to late December, contributing to a significantly decreased season duration, from 30 to 11 weeks. In a multivariate analysis, children from villages with more crowded households and lacking plumbed water had higher rates of RSV hospitalizations (relative rate, 1.17; P = 0.0005 and relative rate, 1.45; P = 0.0003). No association of temperature or dew point was found with the timing or severity of RSV season. Conclusions: Although the RSV hospitalization rate decreased 3-fold, YKD infants still experience a hospitalization rate 3-fold higher than the general US infant population. Overcrowding and lack of plumbed water were associated with RSV hospitalization. Dramatic changes occurred in RSV seasonality, not explained by changes in climate.

The Economics of Strategies to Reduce Respiratory Syncytial Virus Hospitalizations in Alaska

BACKGROUND Alaska Native infants experience high rates of respiratory syncytial virus (RSV) hospitalizations. Through 2008, Alaska administered a 7-dose (maximum) palivizumab regime to high-risk infants from October to May. In 2009, the maximum was reduced to 3 doses for 32- to 34-week preterm babies and 6 doses for other groups. METHODS We used 11 years of data and regional Medicaid reimbursement rates to model the cost effectiveness of 4 palivizumab intervention strategies to reduce RSV hospitalizations among Alaskan infants including: current strategy, old strategy (1998-2008), and 2 hypothetical strategies using the current strategy plus 1 or 3 doses to all newborn infants during the RSV season. RESULTS The current strategy represents 5 hospitalizations averted per year for the palivizumab cohort (∼50-56 children) at ∼

Results of interferon-based treatments in Alaska Native and American Indian population with chronic hepatitis C

52 846 per hospitalization averted, compared with no intervention. Compared with the old strategy, the mean cost per hospitalization prevented for the current strategy was 63% lower, net program costs were 85% lower, and the mean hospitalizations prevented were 27% lower. Compared with current strategy only, the addition of 1 dose to all newborns during the RSV season could decrease the mean cost per hospitalization prevented by 23%, increase the number of hospitalizations prevented by 2.5-fold, and increase the net programmatic costs by 3.3-fold; administering up to 3 doses to infants further reduced hospitalizations and increased costs. CONCLUSIONS The current palivizumab strategy improved the cost-effectiveness ratio compared with the old strategy. Further improvement could be obtained by adding doses for Alaskan Native newborns during the RSV season; however, programmatic costs would increase.

Impact of the Pneumococcal Conjugate Vaccine and Antibiotic Use on Nasopharyngeal Colonization by Antibiotic Nonsusceptible Streptococcus pneumoniae, Alaska, 2000[FIGURE DASH]2010.

Background There have been few reports of hepatitis C virus (HCV) treatment results with interferon-based regimens in indigenous populations. Objective To determine interferon-based treatment outcome among Alaska Native and American Indian (AN/AI) population. Design In an outcomes study of 1,379 AN/AI persons with chronic HCV infection from 1995 through 2013, we examined treatment results of 189 persons treated with standard interferon, interferon plus ribavirin, pegylated interferon plus ribavirin and triple therapy with a protease inhibitor. For individuals treated with pegylated interferon and ribavirin, the effect of patient characteristics on response was also examined. Results Sustained virologic response (SVR) with standard interferon was 16.7% (3/18) and with standard interferon and ribavirin was 29.7% (11/37). Of 119 persons treated with pegylated interferon and ribavirin, 61 achieved SVR (51.3%), including 10 of 46 with genotype 1 (21.7%), 38 of 51 with genotype 2 (74.5%) and 13 of 22 with genotype 3 (59.1%). By multivariate analysis, SVR in the pegylated interferon group was associated with female sex (p=0.002), estimated duration of infection (p=0.034) and HCV genotype (p<0.0001). There was a high discontinuation rate due to side effects in those treated with pegylated interferon and ribavirin for genotype 1 (52.2%). Seven of 15 genotype 1 patients treated with pegylated interferon, ribavirin and telaprevir or boceprevir achieved SVR (46.7%). Conclusions We had success with pegylated interferon-based treatment of AN/AI people with genotypes 2 and 3. However, there were low SVR and high discontinuation rates for those with genotype 1.Background There have been few reports of hepatitis C virus (HCV) treatment results with interferon-based regimens in indigenous populations. Objective To determine interferon-based treatment outcome among Alaska Native and American Indian (AN/AI) population. Design In an outcomes study of 1,379 AN/AI persons with chronic HCV infection from 1995 through 2013, we examined treatment results of 189 persons treated with standard interferon, interferon plus ribavirin, pegylated interferon plus ribavirin and triple therapy with a protease inhibitor. For individuals treated with pegylated interferon and ribavirin, the effect of patient characteristics on response was also examined. Results Sustained virologic response (SVR) with standard interferon was 16.7% (3/18) and with standard interferon and ribavirin was 29.7% (11/37). Of 119 persons treated with pegylated interferon and ribavirin, 61 achieved SVR (51.3%), including 10 of 46 with genotype 1 (21.7%), 38 of 51 with genotype 2 (74.5%) and 13 of 22 with genotype 3 (59.1%). By multivariate analysis, SVR in the pegylated interferon group was associated with female sex (p=0.002), estimated duration of infection (p=0.034) and HCV genotype (p<0.0001). There was a high discontinuation rate due to side effects in those treated with pegylated interferon and ribavirin for genotype 1 (52.2%). Seven of 15 genotype 1 patients treated with pegylated interferon, ribavirin and telaprevir or boceprevir achieved SVR (46.7%). Conclusions We had success with pegylated interferon-based treatment of AN/AI people with genotypes 2 and 3. However, there were low SVR and high discontinuation rates for those with genotype 1.Background There have been few reports of hepatitis C virus (HCV) treatment results with interferon-based regimens in indigenous populations. Objective To determine interferon-based treatment outcome among Alaska Native and American Indian (AN/AI) population. Design In an outcomes study of 1,379 AN/AI persons with chronic HCV infection from 1995 through 2013, we examined treatment results of 189 persons treated with standard interferon, interferon plus ribavirin, pegylated interferon plus ribavirin and triple therapy with a protease inhibitor. For individuals treated with pegylated interferon and ribavirin, the effect of patient characteristics on response was also examined. Results Sustained virologic response (SVR) with standard interferon was 16.7% (3/18) and with standard interferon and ribavirin was 29.7% (11/37). Of 119 persons treated with pegylated interferon and ribavirin, 61 achieved SVR (51.3%), including 10 of 46 with genotype 1 (21.7%), 38 of 51 with genotype 2 (74.5%) and 13 of 22 with genotype 3 (59.1%). By multivariate analysis, SVR in the pegylated interferon group was associated with female sex (p=0.002), estimated duration of infection (p=0.034) and HCV genotype (p<0.0001). There was a high discontinuation rate due to side effects in those treated with pegylated interferon and ribavirin for genotype 1 (52.2%). Seven of 15 genotype 1 patients treated with pegylated interferon, ribavirin and telaprevir or boceprevir achieved SVR (46.7%). Conclusions We had success with pegylated interferon-based treatment of AN/AI people with genotypes 2 and 3. However, there were low SVR and high discontinuation rates for those with genotype 1.