Predictions of the emergence of vaccine-resistant hepatitis B in The Gambia using a mathematical model

Vaccine escape variants of hepatitis B virus (HBV) have been identified world-wide. A mathematical model of HBV transmission is used to investigate the potential pattern of emergence of such variants. Attention is focused on The Gambia as a country with high quality epidemiological data, universal infant immunization and in which escape mutants after childhood infections have been observed. We predict that a variant cannot become dominant for at least 20 years from the start of vaccination, even when using a vaccine which affords no cross protection. The dominant factor responsible for this long time scale is the low rate of infectious contacts between infected and susceptible individuals (we estimate the basic reproduction number of hepatitis B in The Gambia to be 1·7). A variant strain that achieves high prevalence will also take many years to control, and it is questionable whether emergence will be identifiable by sero-surveillance until of high prevalence. The sensitivity of the model predictions to epidemiological and demographic factors is explored

Evaluation of a measles vaccine campaign by oral-fluid surveys in a rural Kenyan district: interpretation of antibody prevalence data using mixture models

We evaluated the effectiveness of a measles vaccine campaign in rural Kenya, based on oral-fluid surveys and mixture-modelling analysis. Specimens were collected from 886 children aged 9 months to 14 years pre-campaign and from a comparison sample of 598 children aged 6 months post-campaign. Quantitative measles-specific antibody data were obtained by commercial kit. The estimated proportions of measles-specific antibody negative in children aged 0–4, 5–9 and 10–14 years were 51%, 42% and 27%, respectively, pre- campaign and 18%, 14% and 6%, respectively, post-campaign. We estimate a reduction in the proportion susceptible of 65–78%, with ~85% of the population recorded to have received vaccine. The proportion of ‘weak’ positive individuals rose from 35% pre-campaign to 54% post-campaign. Our results confirm the effectiveness of the campaign in reducing susceptibility to measles and demonstrate the potential of oral-fluid studies to monitor the impact of measles vaccination campaigns

Improving sensitivity of oral fluid testing in IgG prevalence studies: application of mixture models to a rubella antibody survey

A method for the analysis of age-stratified antibody prevalence surveys is applied to a previously reported survey of antibody to rubella virus using oral fluid samples in which the sensitivity of the assay used was shown to be compromised. The age-specific distribution of the quantitative results of antibody tests using oral fluids is modelled as a mixture of strong positive, weak positive and negative components. This yields maximum likelihood estimates of the prevalence at each age and demonstrates that, when used in conjunction with mixture modelling techniques, the results of antibody prevalence studies using oral fluids accurately reflect those obtained using sera

Predictions of the emergence of vaccine-resistant hepatitis B in The Gambia using a mathematical model

Vaccine escape variants of hepatitis B virus (HBV) have been identified world-wide. A mathematical model of HBV transmission is used to investigate the potential pattern of emergence of such variants. Attention is focused on The Gambia as a country with high quality epidemiological data, universal infant immunization and in which escape mutants after childhood infections have been observed. We predict that a variant cannot become dominant for at least 20 years from the start of vaccination, even when using a vaccine which affords no cross protection. The dominant factor responsible for this long time scale is the low rate of infectious contacts between infected and susceptible individuals (we estimate the basic reproduction number of hepatitis B in The Gambia to be 1·7). A variant strain that achieves high prevalence will also take many years to control, and it is questionable whether emergence will be identifiable by sero-surveillance until of high prevalence. The sensitivity of the model predictions to epidemiological and demographic factors is explored

Kinetics of the neutralizing antibody response to respiratory syncytial virus infections in a birth cohort

The kinetics of respiratory syncytial virus (RSV) neutralizing antibodies following birth, primary and secondary infections are poorly defined. The aims of the study were to measure and compare neutralizing antibody responses at different time points in a birth cohort followed-up over three RSV epidemics. Rural Kenyan children, recruited at birth between 2002 and 2003, were monitored for RSV infection over three epidemic seasons. Cord and 3-monthly sera, and acute and convalescent sera following RSV infection, were assayed in 28 children by plaque reduction neutralization test (PRNT). Relative to the neutralizing antibody titers of pre-exposure control sera (1.8 log10 PRNT), antibody titers following primary infection were (i) no different in sera collected between 0 and 0.4 months post-infection (1.9 log10 PRNT, P = 0.146), (ii) higher in sera collected between 0.5 and 0.9 (2.8 log10 PRNT, P < 0.0001), 1.0–1.9 (2.5 log10 PRNT, P < 0.0001), and 2.0–2.9 (2.3 log10 PRNT, P < 0.001) months post-infection, and (iii) no different in sera collected at between 3.0 and 3.9 months post-infection (2.0 log10 PRNT, P = 0.052). The early serum neutralizing response to secondary infection (3.02 log10 PRNT) was significantly greater than the early primary response (1.9 log10 PRNT, P < 0.0001). Variation in population-level virus transmission corresponded with changes in the mean cohort-level neutralizing titers. It is concluded that following primary RSV infection the neutralizing antibody response declines to pre-infection levels rapidly (∼3 months) which may facilitate repeat infection. The kinetics of the aggregate levels of acquired antibody reflect seasonal RSV occurrence, age, and infection history

Identification of group B respiratory syncytial viruses that lack the 60-nucleotide duplication after six consecutive epidemics of total BA dominance at coastal Kenya

Respiratory syncytial virus BA genotype has reportedly replaced other group B genotypes worldwide. We report the observation of three group B viruses, all identical in G sequence but lacking the BA duplication, at a coastal district hospital in Kenya in early 2012. This follows a period of six consecutive respiratory syncytial virus (RSV) epidemics with 100% BA dominance among group B isolates. The new strains appear only distantly related to BA variants and to previously circulating SAB1 viruses last seen in the district in 2005, suggesting that they were circulating elsewhere undetected. These results are of relevance to an understanding of RSV persistence

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 level and duration of RSV-specific maternal IgG in infants in Kilifi Kenya

Background Respiratory syncytial virus (RSV) is the major cause of lower respiratory tract infection in infants. The rate of decay of RSV-specific maternal antibodies (RSV-matAb), the factors affecting cord blood levels, and the relationship between these levels and protection from infection are poorly defined. Methods A birth cohort (n = 635) in rural Kenya, was studied intensively to monitor infections and describe age-related serological characteristics. RSV specific IgG antibody (Ab) in serum was measured by the enzyme linked immunosorbent assay (ELISA) in cord blood, consecutive samples taken 3 monthly, and in paired acute and convalescent samples. A linear regression model was used to calculate the rate of RSV-matAb decline. The effect of risk factors on cord blood titres was investigated. Results The half-life of matAb in the Kenyan cohort was calculated to be 79 days (95% confidence limits (CL): 76–81 days). Ninety seven percent of infants were born with RSV-matAb. Infants who subsequently experienced an infection in early life had significantly lower cord titres of anti-RSV Ab in comparison to infants who did not have any incident infection in the first 6 months (P = 0.011). RSV infections were shown to have no effect on the rate of decay of RSV-matAb. Conclusion Maternal-specific RSV Ab decline rapidly following birth. However, we provide evidence of protection against severe disease by RSV-matAb during the first 6–7 months. This suggests that boosting maternal-specific Ab by RSV vaccination may be a useful strategy to consider

Model evaluation of target product profiles of an infant vaccine against respiratory syncytial virus (RSV) in a developed country setting

Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract disease in children worldwide and is a significant cause of hospital admissions in young children in England. No RSV vaccine has been licensed but a number are under development. In this work, we present two structurally distinct mathematical models, parameterized using RSV data from the UK, which have been used to explore the effect of introducing an RSV paediatric vaccine to the National programme. We have explored different vaccine properties, and dosing regimens combined with a range of implementation strategies for RSV control. The results suggest that vaccine properties that confer indirect protection have the greatest effect in reducing the burden of disease in children under 5 years. The findings are reinforced by the concurrence of predictions from the two models with very different epidemiological structure. The approach described has general application in evaluating vaccine target product profiles

The incidence and clinical burden of respiratory syncytial virus disease identified through hospital outpatient presentations in Kenyan children

There is little information that describe the burden of respiratory syncytial virus (RSV) associated disease in the tropical African outpatient setting. Methods We studied a systematic sample of children aged <5 years presenting to a rural district hospital in Kenya with acute respiratory infection (ARI) between May 2002 and April 2004. We collected clinical data and screened nasal wash samples for RSV antigen by immunofluorescence. We used a linked demographic surveillance system to estimate disease incidence. Results Among 2143 children tested, 166 (8%) were RSV positive (6% among children with upper respiratory tract infection and 12% among children with lower respiratory tract infection (LRTI). RSV was more likely in LRTI than URTI (p<0.001). 51% of RSV cases were aged 1 year or over. RSV cases represented 3.4% of hospital outpatient presentations. Relative to RSV negative cases, RSV positive cases were more likely to have crackles (RR = 1.63; 95% CI 1.34–1.97), nasal flaring (RR = 2.66; 95% CI 1.40–5.04), in-drawing (RR = 2.24; 95% CI 1.47–3.40), fast breathing for age (RR = 1.34; 95% CI 1.03–1.75) and fever (RR = 1.54; 95% CI 1.33–1.80). The estimated incidence of RSV-ARI and RSV-LRTI, per 100,000 child years, among those aged <5 years was 767 and 283, respectively. Conclusion The burden of childhood RSV-associated URTI and LRTI presenting to outpatients in this setting is considerable. The clinical features of cases associated with an RSV infection were more severe than cases without an RSV diagnosis