Seroepidemiology: an underused tool for designing and monitoring vaccination programmes in low- and middle-income countries.

Seroepidemiology, the use of data on the prevalence of bio-markers of infection or vaccination, is a potentially powerful tool to understand the epidemiology of infection before vaccination and to monitor the effectiveness of vaccination programmes. Global and national burden of disease estimates for hepatitis B and rubella are based almost exclusively on serological data. Seroepidemiology has helped in the design of measles, poliomyelitis and rubella elimination programmes, by informing estimates of the required population immunity thresholds for elimination. It contributes to monitoring of these programmes by identifying population immunity gaps and evaluating the effectiveness of vaccination campaigns. Seroepidemiological data have also helped to identify contributing factors to resurgences of diphtheria, Haemophilus Influenzae type B and pertussis. When there is no confounding by antibodies induced by natural infection (as is the case for tetanus and hepatitis B vaccines), seroprevalence data provide a composite picture of vaccination coverage and effectiveness, although they cannot reliably indicate the number of doses of vaccine received. Despite these potential uses, technological, time and cost constraints have limited the widespread application of this tool in low-income countries. The use of venous blood samples makes it difficult to obtain high participation rates in surveys, but the performance of assays based on less invasive samples such as dried blood spots or oral fluid has varied greatly. Waning antibody levels after vaccination may mean that seroprevalence underestimates immunity. This, together with variation in assay sensitivity and specificity and the common need to take account of antibody induced by natural infection, means that relatively sophisticated statistical analysis of data is required. Nonetheless, advances in assays on minimally invasive samples may enhance the feasibility of including serology in large survey programmes in low-income countries. In this paper, we review the potential uses of seroepidemiology to improve vaccination policymaking and programme monitoring and discuss what is needed to broaden the use of this tool in low- and middle-income countries

An economic analysis of a pneumococcal vaccine programme in people aged over 64 years in a developed country setting.

BACKGROUND: Polysaccharide pneumococcal vaccination for older adults is being introduced in developed country settings. Evidence of protection by this vaccine against pneumococcal pneumonia, or confirmation that illness and death from bacteraemia are prevented, is currently limited. Decisions are often made based on partial information. We examined the policy implications by exploring the potential economic benefit to society and the health sector of pneumococcal vaccination in older adults. METHODS: A model to estimate the potential cost savings and cost-effectiveness of a polysaccharide pneumococcal vaccine programme was based on costs collected from patients, the literature, and routine health-services data. The effect of a pneumococcal vaccine (compared with no vaccination) was examined in a hypothetical cohort aged over 64 years. The duration of protection was assumed to be 10 years, with or without a booster at 5 years. RESULTS: If it were effective against morbidity from pneumococcal pneumonia, the main burden from pneumococcal disease, the vaccine could be cost-neutral to society or the health sector at low efficacy (28 and 37.5%, respectively, without boosting and with 70% coverage). If it were effective against morbidity from bacteraemia only, the vaccine's efficacy would need to be 75 and 89%, respectively. If protection against both morbidity and mortality from pneumococcal bacteraemia was 50%, the net cost to society would be 2500 pounds per year of life saved ( 3365 pounds from the health-sector perspective). Results were sensitive to incidence, case-fatality rates, and costs of illness. CONCLUSIONS: A vaccine with moderate efficacy against bacteraemic illness and death would be cost-effective. If it also protected against pneumonia, it would be cost-effective even if its efficacy were low

Seroepidemiology of hepatitis B virus in Addis Ababa Ethiopia: transmission patterns and vaccine control

A community-based seroepidemiological survey of Addis Ababa, Ethiopia was conducted in 1994 to inform on the transmission dynamics and control of hepatitis B virus (HBV) infection. Venous blood from 4736 individuals under 50 years of age from 1262 households, selected using stratified cluster-sampling, was screened for HBV markers using commercial ELISAs. HBsAg prevalence was 7% (95% CI 6–8), higher in males (9%; 7–10) than females (5%; 4–6). HBeAg prevalence in HBsAg positives was 23% (18–29), and less than 1% of women of childbearing age were HBeAg positive. Overall HBV seroprevalence (any marker), rose steadily with age to over 70% in 40–49 year olds, indicating significant childhood and adult transmission. Estimated instantaneous incidence was 3–4/100 susceptibles/year, higher in males than females in 0–4 year olds, and peaking in early childhood and young adults. The age at which 50% had evidence of infection was around 20 years, and the herd immunity threshold is approximated at 63–77%. Addis Ababa is of intermediate-high HBV endemicity, with negligible perinatal transmission. Our main findings are the identification of a significant difference between males and females in the age-acquisition of HBV infection, and marked differences between age groups in HBV incidence rates. These results should target future research studies of underlying risk factors. Furthermore, we generate a crude estimate of the level of coverage of HBV vaccine that would be required to eliminate the virus from the study population

Sero-epidemiology of rubella in the urban population of Addis Ababa Ethiopia

We conducted a community-based cluster sample survey of rubella sero-epidemiology in Addis Ababa, Ethiopia in 1994. Among 4666 individuals for whom complete data were available, rubella antibody prevalence was 91% (95% confidence interval: 90, 92). On multivariable analysis, seroprevalence was lower among individuals who were resident in Addis Ababa for 1 year or less. Approx. 50% seroprevalence was attained by age 4 years, and the estimated average age at infection was 5·2 years. The highest age-specific force of infection was estimated to occur in 5- to 9-year-olds. The early age at infection corresponded with a low estimated incidence of congenital rubella syndrome (CRS) of 0·3 per 1000 live births, equivalent to nine cases of CRS in 1994. The predicted critical level of immunity for elimination of rubella via vaccination was 85–91%, requiring 89–96% coverage with a vaccine of 95% effectiveness. Unless very high coverage of rubella vaccine could be guaranteed, the introduction of childhood vaccination could increase the incidence of CRS in Addis Ababa

A cohort study of the effectiveness of influenza vaccine in older people, performed using the United Kingdom general practice research database.

BACKGROUND: The effectiveness of influenza vaccination against hospitalization and death can only ethically be assessed in observational studies. A concern is that individuals who are vaccinated are healthier than individuals who are not vaccinated, potentially biasing estimates of effectiveness upward. METHODS: We conducted a historical cohort study of individuals >64 years of age, for whom there were data available in the General Practice Research Database for 1989 to 1999 in England and Wales. Rates of admissions for acute respiratory diseases and rates of death due to respiratory disease were compared over 692,819 person-years in vaccine recipients and 1,534,280 person-years in vaccine nonrecipients. RESULTS: The pooled effectiveness of vaccine against hospitalizations for acute respiratory disease was 21% (95% confidence interval [CI], 17%-26%). The rate reduction attributable to vaccination was 4.15 hospitalizations/100,000 person-weeks in the influenza season. Among vaccine recipients, no important reduction in the number of admissions to the hospital was seen outside influenza seasons. The pooled effectiveness of vaccine against deaths due to respiratory disease was 12% (95% CI, 8%-16%). A greater proportionate reduction was seen among people without medical disorders, but absolute rate reduction was higher in individuals with medical disorders, compared with individuals without such disorders (6.14 deaths due to respiratory disease/100,000 person-weeks vs. 3.12 deaths due to respiratory disease/100,000 person-weeks). Clear protection against death due to all causes was not seen. CONCLUSIONS: Influenza vaccination reduces the number of hospitalizations and deaths due to respiratory disease, after correction for confounding in individuals >64 years of age who had a high risk or a low risk for influenza. For elderly people, untargeted influenza vaccination is of confirmed benefit against serious outcomes

Impact on Epidemic Measles of Vaccination Campaigns Triggered by Disease Outbreaks or Serosurveys: A Modeling Study.

BACKGROUND: Routine vaccination supplemented by planned campaigns occurring at 2-5 y intervals is the core of current measles control and elimination efforts. Yet, large, unexpected outbreaks still occur, even when control measures appear effective. Supplementing these activities with mass vaccination campaigns triggered when low levels of measles immunity are observed in a sample of the population (i.e., serosurveys) or incident measles cases occur may provide a way to limit the size of outbreaks. METHODS AND FINDINGS: Measles incidence was simulated using stochastic age-structured epidemic models in settings conducive to high or low measles incidence, roughly reflecting demographic contexts and measles vaccination coverage of four heterogeneous countries: Nepal, Niger, Yemen, and Zambia. Uncertainty in underlying vaccination rates was modeled. Scenarios with case- or serosurvey-triggered campaigns reaching 20% of the susceptible population were compared to scenarios without triggered campaigns. The best performing of the tested case-triggered campaigns prevent an average of 28,613 (95% CI 25,722-31,505) cases over 15 y in our highest incidence setting and 599 (95% CI 464-735) cases in the lowest incidence setting. Serosurvey-triggered campaigns can prevent 89,173 (95% CI, 86,768-91,577) and 744 (612-876) cases, respectively, but are triggered yearly in high-incidence settings. Triggered campaigns reduce the highest cumulative incidence seen in simulations by up to 80%. While the scenarios considered in this strategic modeling exercise are reflective of real populations, the exact quantitative interpretation of the results is limited by the simplifications in country structure, vaccination policy, and surveillance system performance. Careful investigation into the cost-effectiveness in different contexts would be essential before moving forward with implementation. CONCLUSIONS: Serologically triggered campaigns could help prevent severe epidemics in the face of epidemiological and vaccination uncertainty. Hence, small-scale serology may serve as the basis for effective adaptive public health strategies, although, in high-incidence settings, case-triggered approaches are likely more efficient

Suppression of human immunodeficiency virus replication during acute measles.

To determine the effect of measles virus coinfection on plasma human immunodeficiency virus (HIV) RNA levels, a prospective study of hospitalized children with measles was conducted between January 1998 and October 2000 in Lusaka, Zambia. Plasma HIV RNA levels were measured during acute measles and 1 month after hospital discharge. The median plasma HIV RNA level in 33 children with measles who were followed longitudinally was 5339 copies/mL at study entry, 60,121 copies/mL at hospital discharge, and 387,148 copies/mL at 1-month follow-up. The median plasma HIV RNA level in children without acute illness was 228,454 copies/mL. Plasma levels of immune activation markers were elevated during the period of reduced plasma HIV RNA. Plasma levels of several potential HIV suppressive factors also were elevated during acute measles. HIV replication is transiently suppressed during acute measles at a time of intense immune activation

Supplemental measles vaccine antibody response among HIV-infected and -uninfected children in Malawi after 1- and 2-dose primary measles vaccination schedules.

BACKGROUND: The long-term antibody response to measles vaccine (MV) administered at age 6 months with or without subsequent doses is not well documented. METHODS: Measles serum antibody responses were evaluated after a supplemental dose of measles vaccine (sMV) administered at a median age of 20 months among Malawian children who had previously received 2 doses of measles vaccine (MV) at ages 6 and 9 months (HIV-infected and random sample of HIV-uninfected) or 1 dose at age 9 months (random sample of HIV-uninfected). We compared measles antibody seropositivity between groups by enzyme linked immunoassay and seroprotection by plaque reduction neutralization geometric mean concentrations. RESULTS: Of 1756 children enrolled, 887 (50.5%) received a sMV dose following MV at 9 months of age and had specimens available after sMV receipt, including 401 HIV-uninfected children who received one MV dose at 9 months, 464 HIV-uninfected and 22 HIV-infected children who received two doses of MV at ages 6 and 9 months. Among HIV-uninfected children, protective levels of antibody were found post sMV in 90-99% through ages 24-36 months and were not affected by MV schedule. Geometric mean concentration levels of measles antibody were significantly increased post-sMV among those HIV-uninfected children previously non-responsive to vaccination. Among HIV-infected children, the proportion seroprotected increased initially but by 9 months post-sMV was no higher than pre-sMV. CONCLUSIONS: Our findings support early 2-dose MV to provide measles immunity for young infants without risk of interference with antibody responses to subsequent MV doses administered as part of SIAs

Monitoring vaccination coverage: Defining the role of surveys.

Vaccination coverage is a widely used indicator of programme performance, measured by registries, routine administrative reports or household surveys. Because the population denominator and the reported number of vaccinations used in administrative estimates are often inaccurate, survey data are often considered to be more reliable. Many countries obtain survey data on vaccination coverage every 3-5years from large-scale multi-purpose survey programs. Additional surveys may be needed to evaluate coverage in Supplemental Immunization Activities such as measles or polio campaigns, or after major changes have occurred in the vaccination programme or its context. When a coverage survey is undertaken, rigorous statistical principles and field protocols should be followed to avoid selection bias and information bias. This requires substantial time, expertise and resources hence the role of vaccination coverage surveys in programme monitoring needs to be carefully defined. At times, programmatic monitoring may be more appropriate and provides data to guide program improvement. Practical field methods such as health facility-based assessments can evaluate multiple aspects of service provision, costs, coverage (among clinic attendees) and data quality. Similarly, purposeful sampling or censuses of specific populations can help local health workers evaluate their own performance and understand community attitudes, without trying to claim that the results are representative of the entire population. Administrative reports enable programme managers to do real-time monitoring, investigate potential problems and take timely remedial action, thus improvement of administrative estimates is of high priority. Most importantly, investment in collecting data needs to be complemented by investment in acting on results to improve performance