Assessing the global threat from Zika virus

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Science  12 Aug 2016:
Vol. 353, Issue 6300, aaf8160
DOI: 10.1126/science.aaf8160


  • The effect of ZIKV is a function of the local transmission regime and viral pathogenesis.

    (A) Many countries cannot maintain ongoing vector-mediated ZIKV transmission and are only at risk from importation by travelers and limited onward transmission (e.g., through sex). (B) If conditions are appropriate, importations can lead to postinvasion epidemics with high incidence across age ranges, after which the virus may go locally extinct or remain endemic. (C) There is evidence of ongoing ZIKV incidence in humans over years (e.g., a 1952 serosurvey in Nigeria), but it is unknown whether this is the result of ongoing circulation in humans or frequent spillover infections from a sylvatic cycle. (D) In other areas, ZIKV appears to have been maintained in animals with few human infections. (E) The majority of infections are asymptomatic, and severe outcomes, such as Guillain-Barré syndrome, are rare. (F) However, there is considerable risk of microcephaly and other fetal sequelae when infection occurs during pregnancy.

  • Fig. 1 Factors determining the global risk from ZIKV.

    (A) As long as ZIKV circulates anywhere, periodic introductions into ZIKV-free regions will occur. Whether these lead to an epidemic depends on the reproductive number R, a measure of transmission efficiency determined by local ecology and population susceptibility to ZIKV. (B) When R > 1, introductions can result in major epidemics, after which the virus may go locally extinct or become endemic. (C) ZIKV could be maintained endemically either in local nonhuman primates (the sylvatic cycle) or through ongoing human transmission. (D) Most ZIKV infections (75 to 80%) are asymptomatic, and those with symptoms are likely at highest risk for rare neurological complications (6, 63, 92), particularly Guillain-Barré (45). Adverse fetal outcomes, notably microcephaly, may also be more common when the mother is symptomatic. Owing to its association with pregnancy, ZIKV’s health effects depend on the fertility rate and the age distribution of infections. The age distribution mirrors the general population in ZIKV-free (A) and epidemic (B) settings but is a function of the force of infection in endemic settings (C) (4, 45). Appropriate control measures can reduce R, decreasing the probability of successful ZIKV invasion (A) and its subsequent effect [(B) and (C)] [see (116)].

  • Fig. 2 Current and potential distribution of ZIKV.

    (A) Spread of ZIKV across the globe to date. Countries are colored by the timing of the first indication of local ZIKV transmission by serologic evidence or confirmation of human cases. Solid shading indicates clusters of confirmed cases or seropositivity to ZIKV of >10% in some subpopulations, whereas hatched colors indicate 5 to 10% seropositivity (serosurveys showing <5% seropositivity are not shown). Symbols indicate locations and timings of viral isolations from mosquitoes (triangles) and humans (circles). (B) Map of the global occurrence of the widely distributed ZIKV vectors A. aegypti and A. albopictus. Adapted from (100). (C) Map of the occurrence of dengue, a closely related Aedes-transmitted flavivirus. Adapted from (103). Shaded regions correspond to areas with predicted probability of vector or dengue occurrence of >30%. *Somalia did not report the total percentage of those who were ZIKV seropositive, but there was a small percentage of subjects seropositive to ZIKV and no other flavivirus and a large percentage seropositive to two or more flaviviruses, so Somalia’s data are included.

  • Fig. 3 Schematic of the course of human and mosquito infection.

    Symptoms develop, on average, 6 days (95% range, 3 to 11 days) after ZIKV infection (64). Approximately 9 days (95% range, 4 to 14 days) after infection, antibodies start increasing: The first antibodies detectable will be IgM, which will later decline as IgG antibodies increase, then persist indefinitely (the timing of the IgM/IgG switch is for illustrative purposes only and is not meant to indicate the actual length of IgM persistence). Viremia likely starts to increase before symptoms appear, and the magnitude and length of viremia will shape the risk of infection of susceptible mosquitoes that bite this host. After an incubation period, this infected mosquito will be able to transmit infection to susceptible humans (19). The interval from the initial to the subsequent human infection is the generation time of ZIKV, Tg [for estimates, see (116)].

  • Fig. 4 Age-stratified serosurveys provide important clues to local ZIKV epidemiology.

    Results must be interpreted with caution because of the possibility of cross-reactivity with other flavivirus antibodies. (A to C) Ongoing ZIKV transmission, whether from endemic human transmission or a constant risk of zoonotic infection, manifests as a smooth increase in the proportion of the population seropositive with increasing age. This pattern is also consistent with frequent reintroductions leading to periodic outbreaks. If we assume that the risk of ZIKV infection is constant over a lifetime, we can estimate the force of infection (FOI), the proportion of the susceptible population infected each year. Serosurvey results consistent with ongoing transmission include (A) Uburu, Nigeria, 1952 (13); (B) Central African Republic, 1979 (pink, female; cyan, male) (118); and (C) Malaysia, 1953 to 1954 (16). Blue dashed lines and text represent the expected distribution from the estimated FOI. (D and E) In areas without substantial ZIKV transmission, there will be very low levels of seropositivity across age groups and no clear age pattern. Some individuals may still be seropositive due to cross-reactivity in serological assays, infection of travelers, and limited imported cases. Examples include (D) Central Nyanza, Kenya, 1966 to 1968 (121) and (E) Mid-Western Region, Nigeria, 1966 to 1967 (120). (F) Substantial shifts in seropositivity between age groups inconsistent with ongoing transmission suggest past epidemics—e.g., results from a 1966 to 1968 serosurvey in the Malindi district of Kenya are consistent with one or more epidemics of ZIKV occurring 15 to 30 years previously (121). Similar patterns could also occur due to differences in infection risk by age or a sharp reduction in transmission intensity at some point in the past.

  • Fig. 5 ZIKV phylogenetics.

    (A) Maximum likelihood tree of phylogenetic relationships between 43 flaviviruses (numbers indicate support from 1000 ultrafast bootstrap replicates), with antigenic clusters from Calisher et al. indicated by color (162). (B) The phylogenetic relationship between ZIKV strains isolated from throughout the globe. Whole-genome nucleotide sequences were aligned using Clustal Omega (163), and trees were constructed using IQ-TREE (164) under a GTR+G+I evolutionary model.

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