Niche and neutral effects of acquired immunity permit coexistence of pneumococcal serotypes

Abstract

Over 90 capsular serotypes of Streptococcus pneumoniae, a common nasopharyngeal colonizer and major cause of pneumonia, bacteremia, and meningitis, are known. It is unclear why some serotypes can persist at all: They are more easily cleared from carriage and compete poorly in vivo. Serotype-specific immune responses, which could promote diversity in principle, are weak enough to allow repeated colonizations by the same type. We show that weak serotype-specific immunity and an acquired response not specific to the capsule can together reproduce observed diversity. Serotype-specific immunity stabilizes competition, and acquired immunity to noncapsular antigens reduces fitness differences. Our model can be used to explain the effects of pneumococcal vaccination and indicates general factors that regulate the diversity of pathogens.

Fig. 1

Serotype diversity is sensitive to the form of acquisition of nonspecific immunity and the strength of anticapsular immunity. (A) Diversity, measured by the Simpson Index, as a function of the strength of anticapsular immunity for different forms of acquired nonspecific immunity (durations that decay linearly to 0, ε_lin = 12.5 and ε_lin = 25; durations that decay exponentially to a nonzero value, ε = 0.10, ε = 0.25, and ε = 0.40; Section S4). The Simpson Index equals the probability of randomly picking two serotypes from the population with replacement; it was calculated as 1 - D, where D = Σp_i², and p_i denotes the frequency of the ith species. Measures were obtained by averaging annual estimates of the Simpson Index for each of the last 20 y of each simulation. The shaded area shows the range of diversity observed in carriage studies. (B) Observed rank-frequency distributions from carriage studies and the default model (ε = 0.25) without (σ = 0) and with (σ = 0.3) anticapsular immunity. The gray line shows the mean distribution from carriage studies, and the shading indicates the S.D. (Section S1). Error bars show S.D. based on ten simulations.

Fig. 2

The rate of acquisition of nonspecific immunity was modeled as a linear or exponential function, with the latter supported by observations. (A) The duration of carriage of four serotypes modeled as an exponential function of the number of times a host has previously cleared any serotype of pneumococcus (ε = 0.25). The durations of the different serotypes are shown as superimposed bars with the color indicating the serotype’s fitness (red, most fit; blue, least fit). (B) Observed mean durations of carriage of different serogroups (serotypes or groups of antigenically related serotypes) as a function of host age from (8).

Fig. 3

Vaccination causes at least short-term serotype replacement and can lower total carriage. (A, B) Sample dynamics involving vaccination assuming σ = 0.3. The prevalences (in children <5 y old) of individual serotypes, colored by their intrinsic fitness as in Fig. 2 are shown. The vaccine was given to all children six months old starting in year 400 (dashed line) and had a 60% efficacy against targeted serotypes: (A) Vaccination targeting the seven most intrinsically fit serotypes (ranks 1–7). (B) Vaccination targeting serotypes with ranks analogous to those included in the heptavalent pneumococcal conjugate vaccine (ranks 1–4, 8, 11, and 21; Section S7.1). (C) Simpson Index in children <5 y from the scenario in (B). (D) Total carriage prevalence (as a ratio of each year’s prevalence to the prevalence in year 399) over time in children <5 y and in individuals ≥5 y from the scenario in (B). (E) The ratio of each serotype’s post-vaccine prevalence (its mean prevalence in years 410–419) to its pre-vaccine prevalence (years 300–399) from the scenario in (B). Targeted serotypes are in red. In (C)-(E), shading or error bars show S.D. based on ten simulations. (F) As in (A), vaccination targeting the seven fittest serotypes but with natural immunity (σ = 0.7) stronger than vaccine-induced immunity.