Department of Epidemiology and Preventive Medicine, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia (current affiliation)

Understanding the potential for vaccination to change cytomegalovirus (CMV) epidemiology is important for developing CMV vaccines and designing clinical trials.

We constructed a deterministic, age-specific and time-dependent mathematical model of pathogen transmission, parameterized using CMV seroprevalence from the United States and Brazil, to predict the impact of vaccination on congenital CMV infection.

Concurrent vaccination of young children and adolescents would result in the greatest reductions in congenital CMV infections in populations with moderate and high baseline maternal seroprevalence. Such a vaccination strategy, assuming 70% vaccine efficacy, 90% coverage and 5-year duration of protection, could ultimately prevent 30%-50% of congenital CMV infections. At equilibrium, this strategy could result in a 30% reduction in congenital CMV infections due to primary maternal infection in the United States but a 3% increase in Brazil. The potential for an increase in congenital CMV infections due to primary maternal infections in Brazil was not predicted with use of a vaccine that confers protection for greater than 5 years.

Modeling suggests that vaccination strategies that include young children will result in greater declines in congenital CMV infection than those restricted to adolescents or women of reproductive age. Our study highlights the critical need for better understanding of the relative contribution of type of maternal infection to congenital CMV infection and disease, the main focus of vaccine prevention.

Congenital cytomegalovirus (cCMV) infection occurs when virus from the mother crosses the placenta and infects the immunologically immature fetus, as a result of primary maternal infection, reinfection or reactivation. The consequences of cCMV infection include fetal or infant death or neurological and sensory impairments [

Mathematical modeling has become increasingly useful for investigating the dynamics of infection and potential impact of vaccination and identifying critical knowledge gaps for study [

We constructed a deterministic, age-specific and time-dependent mathematical model of pathogen transmission, with six groups in our human population: susceptible, primarily infected, latently infected, reactivated/reinfected, susceptible vaccinated (before primary infection), and latently infected vaccinated (after primary infection) (

We defined

For disease transmission, we used different age group-specific contact mixing matrices (a quantitative description of the average number of contacts between individuals per day) to fit CMV seroprevalence data. The base-case scenario and estimates are based on the contact mixing matrix that best fit the seroprevalence data, a modified version of pattern III of Azevedo’s model [

Our models were parameterized using CMV seroprevalence [_{0}_{0} exactly for our specific model structure, while the latter is based only on seroprevalence data to deduce _{0} under the assumption that the force of infection is the same for all ages (

The number of cCMV infections by type of maternal infection in the pre- and post-vaccination equilibrium was estimated using age group-specific birth rates among women 15-49 years-old for each country (

We assessed the effect of age at vaccination, effectively vaccinated proportion (vaccine coverage

We conducted sensitivity analyses to evaluate the model-generated distribution of cCMV infections by type of maternal infection in the pre and post-vaccination equilibrium and the impact of vaccination. In these analyses, we assumed two different contact mixing matrices, pattern I from Azevedo’s study [

Using the NGM method, we estimated an _{0}

Assuming a vaccine with 70% efficacy, 90% coverage, and 5-year duration of protection, the greatest reduction in CMV seroprevalence from natural infection would be achieved by vaccination at age 0-12 months, potentially leading to CMV elimination both in the United States and in Brazil. This was predicted with shorter duration of vaccine protection (i.e. 2.5 years) as well, due to model assumptions of high infectiousness and contact rates among children ≤ 5 years of age. Considering vaccination of persons beginning at age ≥ 12 months, assuming the same vaccine parameters above, the greatest reduction of CMV seroprevalence would be achieved by a combined schedule of vaccination at ages 12-18 months and 15-19 years, followed by vaccination at age 12-18 months only, in both the United States and Brazil (

The greatest reduction in the overall number of cCMV infections would result from vaccination at age 0-12 months, potentially leading to elimination of cCMV infection both in the United States and in Brazil (

Regarding vaccination of adolescents or adults, vaccination at age 20-29 years would result in reductions in the overall number of cCMV infections in the United States similar to those predicted for vaccination at age 12-18 months, particularly as the effectively vaccinated proportion approaches 100%, and greater than those predicted with vaccination of adolescents (

The changes in the distribution of cCMV infections by type of maternal infection throughout the decades-long period after vaccine introduction leading up to equilibrium are shown in

In Brazil, ten years after introduction of a combined schedule of vaccination at ages 12-18 months and 15-19 years, assuming 90% vaccination coverage, 70% vaccine efficacy and 5-year duration of protection, the overall number of cCMV infections would decrease by approximately 50%, with approximately 50%, 65% and 30% reductions in those due to maternal primary infection, reinfection and reactivation, respectively (

With increases in duration of vaccine protection, vaccination at ages 12-18 months or 15-19 years in the United States would lead to greater reductions in the number of cCMV infections, overall and due to any type of maternal infection (

In our sensitivity analyses, the predicted reductions in cCMV infections would not change substantially with the assumption of 5-year latency duration instead of 20 years (

Using a mathematical model of CMV epidemiology parameterized with data from the United States and Brazil, we assessed the potential impact of vaccination on CMV seroprevalence and cCMV infections. Concurrent vaccination at ages 12-18 months and 15-19 years would have the greatest impact on reducing the number of cCMV infections overall, both in populations with moderate and high baseline maternal seroprevalence. Our model suggests that such a vaccination strategy, assuming a vaccine with 70% efficacy, 90% coverage and 5-year duration of protection, could prevent nearly 30%-50% of cCMV infections during the 10-50 years after vaccine introduction. Better understanding the relative contribution of type of maternal infection to overall burden of cCMV infection and cCMV disease, the main focus of vaccine prevention [

Our analyses represent significant progress beyond the work of Griffiths [

The proportion of cCMV infections due to maternal reinfection vs. reactivation is not well understood, nor is the relative contribution of either of them to cCMV disease [

Our model relies on a number of key assumptions about CMV epidemiology for which data are lacking. Specifically, the susceptibility to reinfection and duration of latency and viral excretion following non-primary infections are unknown [

Although the focus of CMV vaccine trials for prevention of cCMV infection thus far has been mainly on prevention of primary infection in seronegative women of childbearing age [

Compartmental model of CMV infection with vaccination

Individuals enter susceptible compartment by birth (αN) and may also leave each compartment by death (µ(a)). The average time individuals in each age group (a) spend in that age group is proportional to the length of the age group (a) (not shown). λ(t,a) is the force of infection (primary infection) among susceptible individuals and ελ(t,a) is the force of infection (reinfection) among individuals with latent infection; γ and γ_{r} indicate the rate at which primarily infected develop latency and reactivated/reinfected individuals return to latently infected (1/time to recover from primary or non-primary infection), respectively; σ is the rate at which individuals reactivate a latent infection (1/time to reactivate CMV infection); ω is the effectively vaccinated proportion (vaccine coverage

Impact of vaccination on CMV seroprevalence from natural infection by age group at equilibrium, assuming different ages at vaccination, age-specific duration of infectiousness, 20 year duration of latency, and a vaccine with 70% efficacy, 90% coverage and 5-year duration of protection, United States and Brazil.

Black dots indicate available CMV serological data; U.S. data are from the 1999-2004 National Health and Nutrition Examination Survey [

Overall reduction in the annual number of cCMV infections at equilibrium by proportion of individuals effectively vaccinated by age at vaccination, assuming age-specific duration of infectiousness, 20 year duration of latency, and a vaccine with 5-year duration of protection, United States and Brazil.

Reduction in the annual number of cCMV infections, by type of maternal infection, at equilibrium by duration of vaccine protection, assuming age-specific duration of infectiousness, 20 year duration of latency, 90% vaccine coverage, 70% vaccine efficacy, and vaccination at 12-18 months or 15-19 years of age, United States and Brazil.

In figure 4c, black lines indicate impact of vaccination at 12-18 months of age only and gray lines indicate impact of combined schedule with vaccination at 12-18 months of age and 15-19 years of age.

Notation, definition and values of parameters in the mathematical model

Notation | Definition | Value |
---|---|---|

1/γ | Time to recover from primary infection | Age-specific: |

≤ 5 year-olds: 2 years | ||

6-19 year-olds: 1 year | ||

≥ 20 year-olds: 0.5 year | ||

1/γ_{r} | Time to recover from non-primary infection | (1/ γ)/2 |

1/σ | Time to reactivate CMV infection | 20 years or 5 years |

ω | Effectively vaccinated proportion (vaccine coverage | 0-100% |

1/ϕ | Time to lose vaccine protection | 2-50 years |

Change in the distribution and reductions in cCMV infection by type of maternal infection, 10, 20 and 50 years after introduction of vaccine, assuming mixing pattern III, age-specific duration of infectiousness, 20 year duration of latency, 90% vaccine coverage, 70% vaccine efficacy, 5-year duration of vaccine protection, and different ages at vaccination, United States and Brazil.

Setting | Age at | Type of | Distribution (%) of cCMV infections by | Reduction (%) in cCMV | |||||
---|---|---|---|---|---|---|---|---|---|

| |||||||||

Pre- | Years Post-Vaccination | Years Post-Vaccination | |||||||

| |||||||||

10 | 20 | 50 | 10 | 20 | 50 | ||||

United States | 12-18 | Primary | 16 | 12 | 14 | 20 | 39 | 35 | 21 |

Reinfection | 12 | 8 | 8 | 7 | 43 | 50 | 62 | ||

Reactivation | 72 | 80 | 79 | 72 | 4 | 13 | 35 | ||

Overall | 100 | 14 | 21 | 36 | |||||

| |||||||||

15-19 | Primary | 16 | 16 | 17 | 17 | 18 | 16 | 14 | |

Reinfection | 12 | 12 | 12 | 11 | 17 | 19 | 21 | ||

Reactivation | 72 | 72 | 72 | 71 | 15 | 17 | 19 | ||

Overall | 100 | 16 | 17 | 18 | |||||

| |||||||||

12-18 | Primary | 16 | 11 | 14 | 22 | 49 | 44 | 29 | |

Reinfection | 12 | 8 | 7 | 7 | 53 | 58 | 69 | ||

15-19 | Reactivation | 72 | 81 | 79 | 72 | 17 | 25 | 45 | |

Overall | 100 | 27 | 32 | 45 | |||||

| |||||||||

20-29 | Primary | 16 | 18 | 18 | 18 | 27 | 24 | 23 | |

Reinfection | 12 | 12 | 12 | 12 | 32 | 32 | 32 | ||

Reactivation | 72 | 71 | 70 | 70 | 32 | 32 | 32 | ||

Overall | 100 | 31 | 30 | 31 | |||||

| |||||||||

12-18 | Primary | 15 | 13 | 20 | 25 | 32 | 1 | −24 | |

Brazil | Reinfection | 38 | 28 | 27 | 27 | 46 | 49 | 48 | |

Reactivation | 47 | 59 | 53 | 48 | 5 | 17 | 24 | ||

Overall | 100 | 25 | 27 | 26 | |||||

| |||||||||

15-19 | Primary | 15 | 15 | 16 | 16 | 31 | 26 | 24 | |

Reinfection | 38 | 38 | 37 | 37 | 34 | 34 | 35 | ||

Reactivation | 47 | 48 | 47 | 47 | 30 | 32 | 32 | ||

Overall | 100 | 32 | 32 | 32 | |||||

| |||||||||

12-18 | Primary | 15 | 13 | 22 | 29 | 53 | 23 | −3 | |

Reinfection | 38 | 27 | 25 | 25 | 64 | 66 | 66 | ||

15-19 | Reactivation | 47 | 60 | 53 | 47 | 32 | 41 | 47 | |

Overall | 100 | 48 | 48 | 47 |

Footnote: Results for age at vaccination of 20-29 years not shown for Brazil because this scenario would lead to the least reduction in cCMV infections.