D. J. Nokes

Evaluating the cost-effectiveness of vaccination programmes: a dynamic perspective

Although there are many models which are used to calculate the health benefits (and thus the cost-effectiveness) of vaccination programmes, they can be divided into two groups: those which assume a constant force of infection, that is a constant per-susceptible rate of infection; and those which assume that the force of infection (at time t) is a function of the number of infectious individuals in the population at that time (dynamic models). In constant force of infection models the per-susceptible rate of infection is not altered, whereas in dynamic models mass immunization results in fewer infectious individuals in the community and thus a lower force of infection acting on those who were not immunized. We take an example of each of these types of model, examine their underlying assumptions and compare their predictions of the cost-effectiveness of a mass immunization programme against a hypothetical close contact infection, such as measles. We show that if cases of infection are the outcome of interest then the constant force of infection model will always underestimate the cost-effectiveness of the immunization programme except at the extremes when no one or everyone is immunized. However, unlike the constant force of infection model, the dynamic model predicts an increase in the average age at infection after immunization which could impact on the estimate of the cost-effectiveness of the programme if the risk of developing serious disease is a function of the age at infection (as, for instance, is the case for congenital rubella syndrome). Taking cases of infection as the outcome measure and using the dynamic model, the undiscounted cost-effectiveness ratio will tend to decline over time and approach a constant value, as the system moves from pre- to post-immunization equilibrium. We go on to show how the cost-effectiveness of a fixed-term immunization programme might change over time, and discuss why, under most circumstances, decision makers should not assume that elimination (permitting termination of mass immunization) will occur.

Epidemiological patterns of hepatitis B virus (HBV) in highly endemic areas

This paper uses meta-analysis of published data and a deterministic mathematical model of hepatitis B virus (HBV) transmission to describe the patterns of HBV infection in high endemicity areas. We describe the association between the prevalence of carriers and a simple measure of the rate of infection, the age at which half the population have been infected (A50), and assess the contribution of horizontal and perinatal transmission to this association. We found that the two main hyper-endemic areas of sub-Saharan Africa and east Asia have similar prevalences of carriers and values of A50, and that there is a negative nonlinear relationship between A50 and the prevalence of carriers in high endemicity areas (Spearmans Rank, P = 0.0086). We quantified the risk of perinatal transmission and the age-dependent of infection to allow a comparison between the main hyper-endemic areas. East Asia was found to have higher prevalences of HBeAg positive mothers and a greater risk of perinatal transmission from HBeAg positive mothers than sub-Saharan Africa, though the differences were not statistically significant. However, the two areas have similar magnitudes and age-dependent rates of horizontal transmission. Results of a simple compartmental model suggest that similar rates of horizontal transmission are sufficient to generate the similar patterns between A50 and the prevalences of carriers. Interrupting horizontal transmission by mass immunization is expected to have a significant, nonlinear impact on the rate of acquisition of new carriers.

Has oral fluid the potential to replace serum for the evaluation of population immunity levels?: a study of measles, rubella and hepatitis B in rural Ethiopia

OBJECTIVE To assess the suitability of using oral-fluid samples for determining the prevalence of immunity to vaccine-preventable infections. METHODS Paired blood and oral-fluid samples were obtained from 853 individuals of all ages from a rural Ethiopian community. Oral fluid around the gums was screened for measles- and rubella-specific antibodies using enhanced IgG antibody capture (GAC) enzyme-linked immunosorbent assays (ELISAs), and for anti-HBc antibodies using a prototype GACELISA. IgG antibodies in serum to measles, rubella and HBc were determined using commercial ELISAs. FINDINGS Relative to serum, oral fluid assay sensitivity and specificity were as follows: 98% and 87% for measles, 79% and 90% for rubella, and 43% and 87% for anti-HBc. These assay characteristics yielded population prevalence estimates from oral fluid with a precision equal to that of serum for measles (all ages) and rubella (ages < 20 years). CONCLUSION Our results suggest that oral fluid could have the potential to replace serum in IgG antibody prevalence surveys. Further progress requires assessment of variation in assay performance between populations as well as the availability of standardized, easy to use assays.

On the determinants of population structure in antigenically diverse pathogens

Many pathogens exhibit antigenic diversity and elicit strain–specific immune responses. This potential for cross–immunity structure in the host resource motivates the development of mathematical models, stressing competition for susceptible hosts in driving pathogen population dynamics and genetics. Here we establish that certain model formulations exhibit characteristics of prototype pattern–forming systems, with pathogen population structure emerging as three possible patterns: (i) incidence is steady and homogeneous; (ii) incidence is steady but heterogeneous; and (iii) incidence shows oscillatory dynamics, with travelling waves in strain–space. Results are robust to strain number, but sensitive to the mechanism of cumulative immunity.

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.

THE TRANSMISSION DYNAMICS AND CONTROL OF HEPATITIS B VIRUS IN THE GAMBIA

A deterministic, compartmental, mathematical model is used to describe the transmission dynamics of hepatitis B virus (HBV) in a high endemicity country. All three major transmission routes are included in the model, that is, perinatal, horizontal and sexual transmission. The model also reflects the demography of a typical developing country, and incorporates age-dependence in the rates of transmission and the probability of becoming a chronic carrier. Numerical simulations of the model are shown to capture the observed age-specific patterns of serological markers. The sensitivity of the model to age-specific heterogeneities and routes of transmission is investigated. The model is used in a preliminary study of the possible implications of mass infant immunization on HBV epidemiology, and the results suggest that eradication of HBV may be achieved by immunizing less than 70 per cent infants, which is relatively low compared to most childhood viral infections. This is due in part to the interaction between changes to the average age at infection under immunization, and the nature of age-dependence in the force of infection and the probability of becoming a carrier. However, numerical results also suggest that eradication may take many decades to be achieved, largely due to the presence of a pool of chronic carriers. Furthermore, there may be a significant lag between the implementation of mass infant immunization and a decline in the incidence of liver cancer.

The Natural History of Respiratory Syncytial Virus in a Birth Cohort: The Influence of Age and Previous Infection on Reinfection and Disease

This study aimed to quantify the effect of age, time since last infection, and infection history on the rate of respiratory syncytial virus infection and the effect of age and infection history on the risk of respiratory syncytial virus disease. A birth cohort of 635 children in Kilifi, Kenya, was monitored for respiratory syncytial virus infections from January 31, 2002, to April 22, 2005. Predictors of infection were examined by Cox regression and disease risk by binomial regression. A total of 598 respiratory syncytial virus infections were identified (411 primary, 187 repeat), with 409 determined by antigen assay and 189 by antibody alone (using a “most pragmatic” serologic definition). The incidence decreased by 70% following a primary infection (adjusted hazard ratio = 0.30, 95% confidence interval: 0.21, 0.42; P < 0.001) and by 59% following a secondary infection (hazard ratio = 0.41, 95% confidence interval: 0.22, 0.73; P = 0.003), for a period lasting 6 months. Relative to the age group <6 months, all ages exhibited a higher incidence of infection. A lower risk of severe disease following infection was independently associated with increasing age (P < 0.001) but not reinfection. In conclusion, observed respiratory syncytial virus incidence was lowest in the first 6 months of life, immunity to reinfection was partial and short lived, and disease risk was age related.

The source of respiratory syncytial virus infection in infants : a household cohort study in rural Kenya

Background. Respiratory syncytial virus (RSV) vaccine development for direct protection of young infants faces substantial obstacles. Assessing the potential of indirect protection using different strategies, such as targeting older children or mothers, requires knowledge of the source of infection to the infants. Methods. We undertook a prospective study in rural Kenya. Households with a child born after the preceding RSV epidemic and ≥1 elder sibling were recruited. Nasopharyngeal swab samples were collected every 3–4 days irrespective of symptoms from all household members throughout the RSV season of 2009–2010 and tested for RSV using molecular techniques. Results. From 451 participants in 44 households a total of 15 396 nasopharyngeal swab samples were samples were collected, representing 86% of planned sampling. RSV was detected in 37 households (84%) and 173 participants (38%) and 28 study infants (64%). The infants acquired infection from within (15 infants; 54%) or outside (9 infants; 32%) the household; in 4 households the source of infant infection was inconclusive. Older children were index case patients for 11 (73%) of the within-household infant infections, and 10 of these 11 children were attending school. Conclusion. We demonstrate that school-going siblings frequently introduce RSV into households, leading to infection in infants.

An evaluation of oral-fluid collection devices for the determination of rubella antibody status in a rural Ethiopian community

We compared 3 different oral-fluid collection devices to assess their suitability for use in community studies of rubella antibody. Of 58 individuals enrolled from 13 households from a southern Ethiopian village, 38 provided a blood sample and oral fluids by the 3 devices: 2 proprietary, Omni-SAL and OraSure, and a third a polystyrene sponge swab (Sponge). The Sponge swab, used like a toothbrush, was most acceptable to survey staff and to participants of all ages, although it proved ill-adapted for fluid extraction. The other devices more often caused participant discomfort or anxiety, particularly in the young. Statistical comparison of rubella-specific immunoglobulin (Ig) G in oral fluid, measured by antibody-capture radioimmunoassay, and in serum, by indirect enzyme-linked immunosorbent assay, showed no clear differences between the devices in oral-fluid performance. Specificity range was 75-100% and sensitivity 73-85%, relative to serum. Specific-antibody levels declined with increasing age, with concomitant decreases in sensitivity, as previously documented. The relationship between specific IgG and total IgG in oral fluid differed by device. Specific IgG levels were highly correlated between paired samples using the Sponge device. We consider the Sponge device to be the most suitable for community survey work, although the extraction method requires improvement. Further work is needed to improve the sensitivity of antibody status determination in adults.

Molecular epidemiology of human rhinovirus infections in Kilifi, coastal Kenya†

This study reports pediatric surveillance over 3 years for human rhinovirus (HRV) at the District Hospital of Kilifi, coastal Kenya. Nasopharyngeal samples were collected from children presenting at outpatient clinic with no signs of acute respiratory infection, or with signs of upper respiratory tract infection, and from children admitted to the hospital with lower respiratory tract infection. Samples were screened by real‐time reverse transcriptase polymerase chain reaction (real‐time RT‐PCR) and classified further to species by nucleotide sequencing of the VP4/VP2 junction. Of 441 HRV positives by real‐time RT‐PCR, 332 were classified to species, with 47% (155) being HRV‐A, 5% (18) HRV‐B, and 48% (159) HRV‐C. There was no clear seasonal pattern of occurrence for any species. The species were present in similar proportions in the inpatient and outpatient sample sets, and no significant association between species distribution and the severity of lower respiratory tract infection in the inpatients could be determined. HRV sequence analysis revealed multiple but separate clusters in circulation particularly for HRV‐A and HRV‐C. Most HRV‐C clusters were distinct from reference sequences downloaded from GenBank. In contrast, most HRV‐A and HRV‐B sequences clustered with either known serotypes or strains from elsewhere within Africa and other regions of the world. This first molecular epidemiological study of HRV in the region defines species distribution in accord with reports from elsewhere in the world, shows considerable strain diversity and does not identify an association between any species and disease severity. J. Med. Virol. 84:823–831, 2012.