Defining the vaccination window for respiratory syncytial virus (RSV) using age-seroprevalence data for children in Kilifi, Kenya

Abstract

Background: Respiratory syncytial virus (RSV) is an important cause of lower respiratory tract disease in early life and a target for vaccine prevention. Data on the age-prevalence of RSV specific antibodies will inform on optimizing vaccine delivery.

Methods: Archived plasma samples were randomly selected within age strata from 960 children less than 145 months of age admitted to Kilifi County Hospital pediatric wards between 2007 and 2010. Samples were tested for antibodies to RSV using crude virus IgG ELISA. Seroprevalence (and 95% confidence intervals) was estimated as the proportion of children with specific antibodies above a defined cut-off level. Nested catalytic models were used to explore different assumptions on antibody dynamics and estimate the rates of decay of RSV specific maternal antibody and acquisition of infection with age, and the average age of infection.

Results: RSV specific antibody prevalence was 100% at age 0-<1month, declining rapidly over the first 6 months of life, followed by an increase in the second half of the first year of life and beyond. Seroprevalence was lowest throughout the age range 5-11 months; all children were seropositive beyond 3 years of age. The best fit model to the data yielded estimates for the rate of infection of 0.78/person/year (95% CI 0.65-0.97) and 1.69/person/year (95% CI 1.27-2.04) for ages 0-<1 year and 1-<12 years, respectively. The rate of loss of maternal antibodies was estimated as 2.54/year (95% CI 2.30-2.90), i.e. mean duration 4.7 months. The mean age at primary infection was estimated at 15 months (95% CI 13-18).

Conclusions: The rate of decay of maternal antibody prevalence and subsequent age-acquisition of infection are rapid, and the average age at primary infection early. The vaccination window is narrow, and suggests optimal targeting of vaccine to infants 5 months and above to achieve high seroconversion.

Fig 1. Plots of RSV antibody titers.

Top row: Scatter plots of antibody titer level by age groups. Bottom row: Histograms of antibody titers by age groups. Red lines show the 1.5 cut-off used to define seropositivity.

Fig 2. The nested model structure for exploring age-prevalence data for RSV using catalytic infection models.

The compartments in the model represent the following states of the population: M = Individuals with maternally acquired antibodies (split into 2, M₁ and M₂ to allow for improved fit), S₀ = Seronegative after loss of maternally acquired antibodies, F₀ = Permanent seropositive status after infection, F₁ = Temporary seropositive status after primary infection, S₁ = Seronegative after loss of infection acquired antibodies. When p = 0, the model reduces to MSF, when p = 1 and only 1 rate of infection is estimated (λ₀ = λ₁) the model is MSFSF₁ and with p = 1 and 2 rates of infection estimated (λ₀ ≠ λ₁) the model is MSFSF₂.

Fig 3. Plot of the nested models output compared to the data.

The MSF model fit the data best with an AIC_C value of 634.6, the MSFSF₁ had an AIC_C of 635.6 while the MSFSF₂ had 637.9

Fig 4. Results of the MSF model fit and the confidence region.

Main: Of the three models in the nested model structure, the MSF model gave the best fit to the data and is shown by the blue line. The parameters were re-estimated to obtain the fits that gave the 95% confidence region by Bootstrapping method, grey lines. The red circles show the proportions seropositive by age group according to the data. Inset: A magnification for age range 0–3 years.

Fig 5. MSF Model predictions of the proportions seropositive and the force of infection acting on the different ages.

The dark blue bars show the proportion at different age groups that have maternally acquired antibodies while the pink bars show the proportion that have been infected and hence have infection acquired antibodies, as predicted by the MSF model. The dashed blue line shows the stepwise force of infection function.