Long-term measles-induced immunomodulation increases overall childhood infectious disease mortality

Abstract

Immunosuppression after measles is known to predispose people to opportunistic infections for a period of several weeks to months. Using population-level data, we show that measles has a more prolonged effect on host resistance, extending over 2 to 3 years. We find that nonmeasles infectious disease mortality in high-income countries is tightly coupled to measles incidence at this lag, in both the pre- and post-vaccine eras. We conclude that long-term immunologic sequelae of measles drive interannual fluctuations in nonmeasles deaths. This is consistent with recent experimental work that attributes the immunosuppressive effects of measles to depletion of B and T lymphocytes. Our data provide an explanation for the long-term benefits of measles vaccination in preventing all-cause infectious disease. By preventing measles-associated immune memory loss, vaccination protects polymicrobial herd immunity.

Fig. 1. Measles incidence, nonmeasles infectious disease mortality, and measles-induced immunomodulation

Nonmeasles infectious disease mortality and measles incidence time series (A to C) and regressions (E to G) are shown for England and Wales, the United States, and Denmark. The vertical dashed lines in (A) to (C) indicate the year of introduction of the measles vaccine. (D) Measles-induced lymphopenia and subsequent measles-specific lymphocyte expansion in the weeks after MV infection, as described in (17, 23), are shown, and time is extended to depict hypothesized long-term immunomodulatory effects of MV infection and reconstitution of the immune response through individual exposures. Scatter plots and best-fit regression curves (plotted with 95% confidence bands) are shown for nonmeasles infectious disease mortality versus measles incidence for England and Wales (E), the United States (F), and Denmark (G).

Fig. 2. England and Wales: Measles-induced immunomodulation and nonmeasles infectious disease mortality (1952–1975)

Annual incidence of nonmeasles infectious disease mortality regressed against the prevalence of MV immunomodulation, given (A) no transform or (B) the best-fit gamma transform (that provides the best linear fit, R², to the data). Individual regression lines and 95% confidence intervals are plotted for regressions over the full data set (blue), the pre-vaccine era data only (green), and the post-vaccine era data only (red). R² is plotted against the mean duration of MV immunomodulation for the (C) gamma or (D) additive transformation for the full data set (blue lines) or the pre-vaccine data only (red lines). Inset graphs in (A) and (B) are the same as (C), and the location of the dots (color coded as per the regression lines) represent the duration of immunomodulation and the R² values associated with the scatter plot shown. In (E and F), the measured nonmeasles infectious disease mortality is plotted (broken line) along with the predicted annual mortalities (solid blue and red lines), predicted using the regression coefficients from the (H) untransformed or (I) best-fit transformed data. Predictions in (E) and (F) are either in sample and based on the full data set (blue line), or out of sample and based on the pre-vaccine data only (red line). In (F), for example, the in-sample mortality prediction is made from the regression coefficients (I) from the best-fit transformed data for the full data set (blue line), and mortality is also predicted entirely out of sample for the post-vaccine era by optimizing the gamma transformation and calculating regression coefficients using only data from the pre-vaccine era (red line; fig. S5C). (G) The best-fit gamma distribution (optimized against the full data set) is shown (dark red line), along with the distribution of under-5 bacterial invasive disease versus age after the depletion of maternal antibodies (broken gray line), and the relative risk of non-MV mortality after MV infection, described in (31), is also shown plotted against time since MV infection (blue points). (H) and (I) The regression coefficients for the best-fit lines shown in (A) and (B) are plotted with 95% confidence intervals in (H) and (I), respectively.

Fig. 3. USA: Measles-induced immunomodulation and nonmeasles infectious disease mortality (1943–1970)

(A to I) Plots are as described for England and Wales in Fig. 2.

Fig. 4. Denmark: Measles-induced immunomodulation and non-MV infectious disease mortality (1990–2010)

R² versus duration of measles-induced immunomodulation when measles data are transformed using (A) the additive transformation with yearly intervals or (B) the gamma transform with quarterly intervals, where yearly measles incidence was converted to quarterly incidence based on (33). The best-fit gamma transform (C), as well as the predicted nonmeasles mortality, predicted from the untransformed (D) or the best-fit gamma transform (E) MV immunomodulation data, are shown and are described for the respective figures in Figs. 2 and 3.