a Center for American Indian and Alaskan Native Health, Department of International Health,
b Department of Biostatistics,
c Department of Health Policy and Management and
d Department of Pediatrics, The Johns Hopkins University Schools of Hygiene and Public Health and Medicine, Baltimore, Maryland, USA.
Reprint requests to: Dr Lawrence H Moulton, Department of International Health, 615 North Wolfe Street, Baltimore, MD 21205, USA. E-mail: lmoulton{at}jhsph.edu
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Abstract |
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Methods In a synthetic case-cohort study, we combined data from an efficacy trial, an immunization uptake records survey, and ongoing surveillance for Hib disease on the Navajo Nation from 1988 to 1992. Decline in the incidence of invasive Hib disease among children <2 years old was estimated via proportional hazards survival models as a function of individual immunization status and the proportion of immunized children in a community.
Results The predominant vaccine during the study period was Hib-OMPC (92% of immunizations). The effectiveness of receipt of at least one dose was 97.2%. Compared to communities with 020% coverage with at least one dose, residence in communities with 2040% and 4060% coverage was associated with risk reductions of 56.5% and 73.2%, respectively.
Conclusions The results indicate substantial indirect effects of Hib-OMPC immunization may occur even at relatively low levels of immunization coverage. Countries that implement Hib immunization programmes may receive greater benefits at the community level than those due to the direct protection conferred to the individual through vaccination.
Keywords Haemophilus influenzae, indirect effect, epidemiology, vaccine, biometry
Accepted 26 January 2000
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Introduction |
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Many researchers have documented that Hib conjugate vaccines reduce oropharyngeal (OP) carriage of the Hib organism in immunized infants35 and young children, as well as their unimmunized siblings.3 Such reductions are presumed to translate into decreased transmission of Hib among children.
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Prior Hib Vaccine Studies on the Navajo Nation |
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An important mechanism through which an indirect effect could result would be reduced oropharyngeal (OP) carriage of Hib. Takala et al.9 investigated Hib OP carriage in the Navajo and Apache populations. Of 1423 OP swabs obtained during well-child visits for children aged 4 months to 4 years, 40 were positive for Hib, with an adjusted odds ratio for carriage of 2.7 associated with not being age-appropriately immunized. This biological evidence of the potential for significant indirect effects was a strong factor in prompting us to use disease incidence rates to quantitatively assess the degree of protection indirectly conferred to non-immunized individuals relative to vaccine coverage on a population level.
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Subjects and Methods |
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Denominators were constructed for each SU by using US Census 1990 results and projecting for each year using IHS estimates of residents and catchment area user populations.
Written informed consent was obtained from parents or guardians of all infants enrolled in the Johns Hopkins University efficacy trial. The study protocols were approved by Institutional Review Boards of the Navajo Nation, the Johns Hopkins University, and the Indian Health Service.
Disease surveillance
Beginning with the efficacy trial in 1988, a Navajo Nation-wide practice was instituted to obtain a blood culture from any child under 2 years of age presenting to an IHS facility with a temperature of at least 103°F. This relatively high cut-off was chosen to help ensure uniformity of culture rates, and may have slightly lowered overall incidence rates, although not necessarily differentials in incidence rates. The blood cultures were taken to the in-house laboratories, and processed using standard bacteriology techniques. All laboratories with the NAIHS are Joint Commission on Accreditation of Healthcare Organization (JCAHO) accredited. Specimens that were positive for Hib were collected by Johns Hopkins University (JHU) staff and sent to the JHU laboratory in Whiteriver, AZ. The specimens were identified again using Haemophilus-Neisseria identification panels, and further serotyped using standard antisera methods (Microscan; Baxter Laboratories, West Sacramento, CA). During the efficacy trial, no suspected case (infant thought to have sepsis or meningitis) with a negative culture had a positive latex agglutination assay for H. influenzae capsular polysaccharide antigen.
Immunization status
Information on vaccine utilization among approximately 18 000 Navajo infants born from April 1988 through June 1992 was obtained from an immunization coverage study conducted by Johns Hopkins personnel. This period was divided into calendar quarters, within each of which one in every 17 live births was sampled from sequential entries in logbooks kept in each Indian Health Service geographical area (SU). Chart reviews of the 894 sampled children were performed to yield basic immunization information up to 24 months of age.
Greater accuracy was gained by combining these coverage study data with data on the 5190 infants enrolled in the efficacy trial from 1988 to 1990, forming a synthetic cohort through use of sampling fractions. From 1988 to August 1990, only efficacy trial participants were receiving Hib vaccine, and thus they perfectly reflect Hib vaccine uptake during that time. After that, the participants continue to represent themselves, while the sampled chart data were used to estimate vaccine coverage among non-participants. Duplicates were eliminated through the use of chart information on participation in the efficacy trial, and by matching on the IHS Medical Registration Number. For each date of a positive Hib culture, a pass was made through the synthetic cohort data to calculate the proportion of children who were <24 months of age as of that date who had received at least one dose with a Hib conjugate vaccine.
Statistical methods
The analytical approach was that of a case-cohort study. All Navajo infants born between 1 May 1988 and 30 June 1992 constituted the full cohort. All infants who were either enrolled in the efficacy study or were sampled in the immunization coverage study were considered to be in the subcohort for which complete immunization status was known.
Cox proportional hazards regression models were fit to examine the relationship of the proportions of children in a SU immunized with Hib conjugate vaccine to risk of invasive Hib disease. A calendar time line with staggered entry was employed to adjust for seasonality.10 Infants in the subcohort entered the risk set on their dates of birth and then were censored on the date of positive Hib culture, the date they reached 24 months of age, or 30 June 1992, whichever came first. Those who became invasive Hib disease cases in the designated calendar and age frame but were not in the subcohort entered the risk set on the dates of their positive Hib cultures.
We closely controlled for age through use of a spline function. A dichotomous, time-varying covariate indicated receipt of first Hib conjugate vaccine: 0 until vaccination, then 1. The focus of the investigation was a set of four time-varying dummy terms for the percentage of children <24 months of age in the index (case) child's SU of residence who had received at least one Hib immunization, representing: 019% (reference category), 2039%, 4059%, 6079%, and 8099%.
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Results |
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Discussion |
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Indirect effect of Hib immunization was not seen in a nationwide study in the Netherlands,14 but the statistical methods used were imprecise, and the immunization uptake of 97% was too high to see effects within age cohorts. In a recent study of Alaskan Native children, high levels of immunization with Hib-OMPC failed to reduce oropharyngeal carriage rates below 615% in children <6 years of age,15 and there was a concomitant rise in incidence of invasive Hib disease among young Hib-OC recipients. Takala et al.9 showed that in a 1991 sample of children on the Navajo Nation, 1.6% of children <15 months of age who had received at least one Hib-OMPC immunization were positive for Hib OP carriage, compared to 4.7% among those who were unimmunized. Although carriage was not eliminated, our data suggest that this magnitude of reduction in colonization may be sufficient to interrupt transmission to a significant degree in children <2 years of age. One feature of the Hib-OMPC vaccine that may be important in this regard is the high antibody response following a single injection at 2 months old (90% of infants >0.15µg).6
By following cohorts and sampled cohorts of children over time, and utilizing information on the varying immunization uptake of their communities of residence, we were able to quantify the degree to which a given level of vaccine coverage corresponds to risk reduction. The opportunity to further quantify the degree of indirect effects still exists in countries where Hib immunization is not routine. Geographically phased-in immunization programmes coupled with surveillance activities could further add to our knowledge of these effects.
The results of our investigation may provide some guidance as to the degree of effect a less industrialized country might realize even with limited coverage levels in a Hib immunization programme. Data on indirect effects provided here could be incorporated into cost-benefit analyses of the introduction of such programmes.
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Acknowledgments |
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Notes |
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References |
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