Revealing Measles Outbreak Risk With a Nested Immunoglobulin G Serosurvey in Madagascar

Abstract

Madagascar reports few measles cases annually and high vaccination campaign coverage. However, the underlying age profile of immunity and risk of a measles outbreak is unknown. We conducted a nested serological survey, testing 1,005 serum samples (collected between November 2013 and December 2015 via Madagascar's febrile rash surveillance system) for measles immunoglobulin G antibody titers. We directly estimated the age profile of immunity and compared these estimates with indirect estimates based on a birth cohort model of vaccination coverage and natural infection. Combining these estimates of the age profile of immunity in the population with an age-structured model of transmission, we further predicted the risk of a measles outbreak and the impact of mitigation strategies designed around supplementary immunization activities. The direct and indirect estimates of age-specific seroprevalence show that current measles susceptibility is over 10%, and modeling suggests that Madagascar may be at risk of a major measles epidemic.

Figure 1.

Febrile-rash surveillance serological samples according to age and region, Madagascar, 2013–2015. A) The population and sample age structure in 5-year age groups. Sample age distribution is represented by the grey bars (n = 1,005), and the population age distribution (based on UNPD data (25)) is represented by the black-border bars. Younger persons (ages <15 years) are overrepresented in the sample. B) The sampling ratio of observed samples to expected samples (i.e., the proportion of samples from each region (n = 1,005) divided by the proportion of Madagascar’s population that resides in each region (44, 45)). The regions in red tints were oversampled. C) The vaccination ratio of observed to expected measles vaccination coverage (i.e., measles vaccination coverage by region divided by the national measles vaccination coverage, which is 0.69 (4, 46)). The central plateau and some eastern regions reported the highest vaccination coverage.

Figure 2.

Direct and indirect estimates of proportion measles seropositive by age, Madagascar, 2013–2015. The black dots represent the observed seroprevalence according to age in months based on the nested serological data (n = 1,005), where the size of the dots corresponds to the number of samples for each age in months. The blue solid and light blue shaded areas represent the mean and 95% confidence interval (CI) of the directly estimated proportion seropositive, based on the serological data, and show a general increase in seroprevalence with age, with the exception of a dip around age 13 years. The dashed green line represents the indirect estimates of proportion seropositive according to age, based on the birth cohort projection method. The 4 supplementary immunization activities (SIAs) conducted prior to 2015, including a 2004 SIA that targeted children ages 9 months through 14 years, had a large impact on indirectly inferred immunity (see Web Appendix 1 for history of SIAs). The indirect method estimated high immunity in children and adults up to age 25 years and a large pocket of susceptibility for those ages just outside the 2004 SIA targeted age group.

Figure 3.

The impact of supplementary immunization activity (SIA) on proportion susceptible, effective reproductive number (R_eff), campaign efficiency, and outbreak size, using data from Madagascar, 2013–2015. Using an age-structured model informed by the direct age-specific seroprevalence estimates, we simulated the impact of each SIA. We compared the proportion of the population susceptible (x-axis) to R_eff (y-axis) for assumed R₀ values of 10 (A), 15 (B), and 20 (C), 1 week following the implementation of measles SIA scenarios (age targets: lower age of 9 months through upper ages of 4, 9, 14, and 19 years). For reference, the black dashed lines indicate the thresholds of R_eff = 1 and susceptibility threshold (1 − p_c). We found that for all values of R₀, broader age ranges (i.e., up to ages 14 or 19 years) were necessary to achieve R_eff less than 1. If R₀ was 10 or 15, we found disagreement between the 2 evaluated elimination thresholds (proportion susceptible <(1 − p_c) and R_eff < 1) in their evaluation of the impact of SIA scenarios. We compared the estimated percent reduction in the number of measles cases over time (x-axis) and campaign efficiency (number of doses delivered to successfully vaccinate 1 susceptible individual; y-axis) for assumed R₀ values of 10 (D), 15 (E), and 20 (F), across measles SIA scenarios (age targets: lower age of 9 months through upper ages of 4, 9, 14, and 19 years). We found that a SIA campaign that targeted children of ages through 14 years to be the most efficient at deploying dosages to susceptible individuals while also reducing a large percentage of cases. Colors indicate the campaign age targets, including the condition in which no SIA was conducted. Thick lines indicate the expectation for the directly estimated mean age profile, and solid and dotted thin lines correspond to the upper and lower confidence bounds, respectively, of the directly estimated age profile. Lines span the range of outcomes for coverage rates of 70%–95% (right to left on the lines) for each SIA.