Evaluating Vaccination Strategies for Zika Virus in the Americas

Since the Zika flavivirus was introduced into Brazil, it has spread across Central and South America and the Caribbean, fueled by widespread distribution of the Aedes aegypti vector and a susceptible human population (1). Zika virus infection has been associated with GuillainBarr syndrome in adults, congenital birth defects (including microcephaly, vision-threatening ocular lesions, and central nervous system lesions), and fetal death (25). Despite the vector-control measures already implemented in many affected countries to combat dengue and yellow fever, Zika continued to spread throughout 2016 and into 2017 (6). Sustained reduction of risk for future outbreaks will likely require a combination of vector control and vaccination, as is necessary for yellow fever, another flavivirus (7). Zika vaccine development has progressed quickly, benefiting from existing technologies underlying other flavivirus vaccines (8). A viable vaccine is expected to be available in the next several years (9). A vaccine's effectiveness in preventing infections depends not only on its efficacy but also on demographic and fertility patterns, local Zika attack rates, and the proportion of the population still susceptible when it becomes available. Supplies may initially be insufficient to cover the entire population. In this case, vaccine supply should be allocated to minimize infections in pregnant women because perinatal transmission to infants has the gravest consequences. The World Health Organization (WHO) has proposed prioritizing females aged 9 to 49 years, followed by males aged 9 to 49 years, for receipt of Zika vaccine (10, 11). Although women in the peak of their fertility years are a clear priority during an outbreak, how to extend vaccination to other women and to men is less clear. This is particularly challenging when the likely timing of an outbreak is uncertain. Previous models have projected that up to 93.4 million people, including 1.65 million pregnant women, would be infected during the first epidemic wave in the Americas (12). A predictive model has suggested that herd immunity from the first epidemic wave could provide up to a decade of protection against future epidemics (13). Other forecasts have warned that Zika could become sylvatic in parts of the Americas, including Brazil, which would pose a continual reintroduction threat (14). These studies also warned that Zika outbreaks could be exacerbated by cross-interaction with dengue vaccination (15). To evaluate the potential for vaccination to reduce future transmission of Zika virus, we developed an age-stratified model applied in each of 34 affected countries and territories. By accounting for country-specific demographics, vector abundance, and potential sexual transmission, we evaluated the effectiveness of Zika vaccination for averting prenatal infections. Methods Model Overview We developed a compartmental model of Zika transmission, incorporating both vector-borne and sexual transmission. Susceptible men and women are at risk for becoming asymptomatically exposed to Zika by vector-borne or sexual routes, from which they become infectious. Infectiousness to mosquitoes lasts between 4 and 7 days (16). After this phase, women recover but men remain infectious to their female partners for an additional 15 to 180 days (17). Immunologic protection is conferred on recovery or via vaccination and is assumed to be robust, consistent with other flaviviruses (18, 19). Each of these clinical and epidemiologic states (susceptible, exposed, infected, recovered, or vaccinated) is stratified by age and sex. We accounted for age-specific fertility, which is fundamental to accurately estimating prenatal infection risk, and background age-specific mortality. Mosquito vectors are susceptible to Zika infection, are latently infected, or are infectious to humans. As our primary outcome, we quantified the burden of an epidemic as the predicted prenatal Zika incidence, measured as infections per 1000 pregnancies over 5 years. A model flow chart and equations describing the system are in Part 1 of the Supplement. Supplement. Supplemental Methods and Results Transmission We assumed that symptomatic and asymptomatic infection are equally infectious. We also assumed frequency-dependent, homogeneous transmission between humans and mosquitoes and no waning of natural immunity, consistent with other flaviviruses (18, 19). We modeled sexual transmission by incorporating age- and sex-specific rates of partnership formation and mixing matrixes, which define the probability of sexual contact between men and women for every age combination (Supplement Tables 1 and 2) (2022). Immune persons will neither acquire nor transmit infections even if exposed in the future, thereby reducing the overall transmission rate and indirectly protecting susceptible persons through herd immunity. Vaccination We simulated vaccination by calculating the number of persons who would be vaccinated within each age and sex group (as determined by the planned coverage for that group) and moving these persons from the susceptible to the vaccinated group before the epidemic (Supplement Figure 1). We analyzed vaccination strategies in the following 5 groups: females aged 9 to 49 years (the WHO target product profile), both sexes aged 9 to 49 years, single 5-year age cohorts of females between ages 10 and 49 years, only males aged 9 to 49 years, and scale-up beginning with the 5-year age cohorts in the third strategy and expanding in 5-year age increments. Vaccination of Females Aged 9 to 49 Years To quantify the effect of vaccination according to the WHO target product profile on prenatal infections (11), we modeled coverage ranging from 0% to 90% of females aged 9 to 49 years. Vaccination of Population Aged 9 to 49 Years As a secondary strategy, we extended coverage to include 0% to 90% of both males and females aged 9 to 49 years. Age-Specific Vaccination Effect To quantify the effect of age-specific vaccination, we compared vaccination of women in each 5-year age group between ages 15 and 49 years. For each country, we also tested the correlation between the age-specific fertility rate and prenatal infections averted per dose using a simple linear regression. Indirect Protection To quantify the indirect protection conferred by vaccinating the nonchildbearing population, we simulated the reduction in prenatal infections achieved by vaccinating only males aged 9 to 49 years. Vaccination Scale-up To determine how a limited supply of vaccines should be allocated, we modeled the effect of vaccinating each possible contiguous age group, constrained by age breaks at 5-year intervals (ages 10 to 14 years, 10 to 19 years, and so on up to 10 to 49 years, followed by 15 to 19 years, 15 to 24 years, and so forth). We then plotted the prenatal infections averted and vaccines administered under each scenario and determined the age groups for which targeted vaccination dominates (that is, averts at least as many infections as all other strategies that use as many or more vaccine doses). From this set of dominant strategies, we first identified the 5-year age group with the optimal vaccination effect per dose. We then identified the next 3 age groups expanding on this optimal age group. Countries and Territories We modeled Puerto Rico, the U.S. Virgin Islands, and the following 32 countries: Aruba, Barbados, Belize, Bolivia, Bonaire, Brazil, Colombia, Costa Rica, Cuba, Curacao, Dominica, Dominican Republic, Ecuador, El Salvador, French Guiana, Guadeloupe, Guatemala, Guyana, Haiti, Honduras, Jamaica, Martinique, Mexico, Nicaragua, Panama, Paraguay, Saint Lucia, Saint Martin, Saint Vincent and the Grenadines, Suriname, Trinidad and Tobago, and Venezuela (23). Human Demographics For each country, we constructed annual age groups from birth to 100 years among males and females, initialized the population distribution, and parametrized region- and age-specific fertility and mortality rates from United Nations data (Supplement Tables 3 to 6). Mosquito Population For each region, we calibrated the mosquito birth rate to align the model equilibrium mosquito prevalence with empirical estimates (Supplement Table 7) and incorporated seasonal fluctuations in mosquito abundance (24). For countries in which mosquito prevalence indexes were unavailable, we substituted estimates from geographically proximate countries. Because we did not evaluate vector control, we did not include A aegypti pupal or larval development in the model. Vaccine Efficacy We assumed a base-case vaccine efficacy of 75% as a midpoint within the recommended minimal and preferred vaccine efficacies of 70% and 80%, respectively, designated in the WHO target product profile for Zika vaccine (25). Parameter Calibration Mortality and biting rates for A aegypti and Zika-specific parameter estimates were drawn from published literature (Supplement Tables 7 and 8). We calibrated the model in a 3-step process. First, we fixed the mosquito-to-human Zika transmission rate relative to the human-to-mosquito transmission rate, as estimated in previous models of Zika in the Americas (12, 26). Second, we varied the human-to-mosquito transmission rate and simulated the corresponding Zika epidemics. On the basis of projections of decade intervals between Zika outbreaks due to herd immunity (13), we used a 10-year horizon. Third, we determined the best-fit parameter sets for the epidemiologic variables using a least-squares approach. For Puerto Rico, we computed the human-to-mosquito transmission rate that produced a 23.5% attack rate, as observed during the chikungunya outbreak there (27), and computed the mosquito seasonality parameters that best fit the observed Zika epidemic trajectory from 17 January 2016 through 21 July 2017 (Supplement Figure 3) (28, 29). When not otherwise specified, we used the best-fit attack rate for Puerto Rico as our base case. Given the uncertainty about these