Infectious reactivation of cytomegalovirus explaining age- and sex-specific patterns of seroprevalence

Abstract

Human cytomegalovirus (CMV) is a herpes virus with poorly understood transmission dynamics. Person-to-person transmission is thought to occur primarily through transfer of saliva or urine, but no quantitative estimates are available for the contribution of different infection routes. Using data from a large population-based serological study (n = 5,179), we provide quantitative estimates of key epidemiological parameters, including the transmissibility of primary infection, reactivation, and re-infection. Mixture models are fitted to age- and sex-specific antibody response data from the Netherlands, showing that the data can be described by a model with three distributions of antibody measurements, i.e. uninfected, infected, and infected with increased antibody concentration. Estimates of seroprevalence increase gradually with age, such that at 80 years 73% (95%CrI: 64%-78%) of females and 62% (95%CrI: 55%-68%) of males are infected, while 57% (95%CrI: 47%-67%) of females and 37% (95%CrI: 28%-46%) of males have increased antibody concentration. Merging the statistical analyses with transmission models, we find that models with infectious reactivation (i.e. reactivation that can lead to the virus being transmitted to a novel host) fit the data significantly better than models without infectious reactivation. Estimated reactivation rates increase from low values in children to 2%-4% per year in women older than 50 years. The results advance a hypothesis in which transmission from adults after infectious reactivation is a key driver of transmission. We discuss the implications for control strategies aimed at reducing CMV infection in vulnerable groups.

Fig 1. Data and model fit.

Data (histograms) and model fit (lines) of IgG antibody measurements by age group and sex. Left- and right-hand panels show results for females (purple) and males (brown), respectively. The leftmost bars at -2.9 contain samples that are assumed uninfected, and the rightmost bars at 4.5 contain samples that are right-censored (with concentration >3.41 U/ml; Methods). Insets show the age group and number of samples.

Fig 2. Schematic of the transmission model.

Sⁱ(a) denotes the proportion of uninfected persons of age a and sex i (i ∈ {♀, ♂}), and Lⁱ(a) and Bⁱ(a) are the corresponding proportions of infected persons without and with increased antibodies, respectively. The infection and re-infection rates are given by λⁱ(a) and zλⁱ(a), and the reactivation rates are given by ρⁱ(a). We consider model scenarios with and without reactivation/re-infection in the B compartment (i.e. including or excluding the loop to the right of B).

Fig 3. Classification of samples.

Shown are the estimated components of the mixture distribution using the parameter posterior medians (left-hand panel; blue: susceptible; purple: infected; red: infected with increased antibody concentration), and receiver operating characteristic of binary classifications taking these estimates as ground truth (right-hand panel). The maximal Youden index for classification of uninfected versus infected persons is 0.97 at antibody concentration -0.70 U/ml, with sensitivity 0.99 and specificity 0.98. This value corresponds well with the threshold for infection of -0.8 U/ml provided by the supplier of the assay. The maximal Youden index for classification of persons with increased antibody concentration is 0.71 at antibody concentration 1.81 U/ml, with sensitivity 0.84 and specificity 0.87.

Fig 4. Estimation of age- and sex-specific prevalence.

Prevalence estimates are presented for females (top panel) and males (bottom panel), and for classes of low (susceptible, blue), intermediate (latently infected, purple), and high (latently infected with increased antibodies, red) antibody measurements. Shown are 1,000 samples from the posterior distribution (thin lines) with posterior medians (bold lines). Dots indicate the fraction of samples that would be classified as uninfected with the cut-off specified by the supplier of the assay. The number of samples per 1-year age group is approximately 35 (females) and 30 (males).

Fig 5. Parameter estimates.

Shown are kernel-smoothed posterior distributions of the relative susceptibility to re-infection (z), the transmissibility of primary infection (β₁) and reactivation/re-infection (β₂), and the reactivation rates in persons aged 0-20 years (ρ_[0,20), purple: females; brown: males), 20-50 years (ρ_[20,50)), and 50-80 years (ρ_{[50 − 80)}) of the transmission model with the possibility of multiple reactivations and re-infections (Model E in Table 1).

Fig 6. The force of infection and magnitude of reactivation relative to re-infection.

The top panel shows posterior estimates of the forces of infection in females and males in Model E (Table 1; purple: females; brown: males). The bottom panel shows the log₁₀ of the reactivation rates divided by the re-infection rates (ρⁱ(a)/zλⁱ(a) with i ∈ {♀, ♂}). Results are shown for 250 samples from the posterior distribution.