Zika Virus Threat in the Americas: Origins and Spread

Introduction

The intense outbreak of Zika virus (ZIKV) disease occurring throughout Latin America, Central America, and the Caribbean islands — and potentially threatening the United States — is the most recent of four unexpected arrivals of significant arthropod-borne viral illnesses in the Western Hemisphere over the past two decades. This paper examines ZIKV, which causes Zika fever, with a particular emphasis on the Americas. The goal is to understand the risk that ZIKV poses to the American population. This will be accomplished by first reviewing the virus's background, then examining the extent of ZIKV within the Americas, exploring the factors that may have facilitated the virus's circulation among Americans, and finally discussing the challenges and prospects for control.

History of Zika Virus

Zika virus was identified accidentally in Uganda in 1947 during insect and primate monitoring (Fauci & Morens, 2016). Until recently, it had remained a largely hidden virus confined to a narrow tropical belt running through Africa and into Asia. The virus spread primarily among forest primates and arboreal mosquitoes such as Aedes africanus, and it rarely caused recognized "spillover" infections in human beings, even in highly enzootic locations (Pierson & Diamond, 2014).

Its current intense pandemic reemergence is therefore truly exceptional. Decades ago, African researchers observed that Aedes-transmitted Zika epizootics had a tendency to follow Aedes-transmitted chikungunya epizootics and outbreaks. In 2007, however, ZIKV emerged from obscurity, causing an outbreak of febrile illness on the Yap Islands in the Federated States of Micronesia. By 2014, ZIKV had spread throughout the Pacific Islands, and in early 2015 ZIKV was detected for the first time in Brazil (Waggoner & Pinsky, 2016). By the end of that year, ZIKV had spread throughout continental Latin America and into Central America, the Caribbean, and Mexico.

Through initial epidemiologic monitoring and human challenge studies, Zika was recognized as a mild or inapparent dengue-like illness characterized by fever, muscle cramps, eye discomfort, prostration, and a maculopapular rash (Fauci & Morens, 2016). In over six decades of surveillance, Zika was never observed to cause hemorrhagic fever or death. There is in vitro evidence that Zika virus mediates antibody-dependent enhancement of infection, a phenomenon seen in dengue hemorrhagic fever; however, the clinical significance of this finding remains uncertain.

There are no Zika vaccines in advanced development, although several existing flavivirus vaccine platforms — such as flavivirus chimera or glycoprotein subunit systems — might potentially be adapted. Zika vaccines may, however, face the same challenges as vaccines for chikungunya (Fauci & Morens, 2016), West Nile, St. Louis encephalitis, and other arboviruses: because outbreaks emerge erratically and unpredictably, preemptively vaccinating large populations in anticipation of outbreaks may be prohibitively costly, while vaccine stockpiling followed by rapid deployment may be too slow to counter sudden intense outbreaks.

Zika Virus in the Americas: Brazil and Beyond

In March 2015, 24 individuals presented with a febrile illness characterized by rash, arthralgia, and conjunctivitis at Santa Helena Hospital in the municipality of Camaçari, approximately 50 kilometers from Salvador, Brazil (Waggoner & Pinsky, 2016). Seven patients had detectable ZIKV RNA in serum while three had detectable chikungunya virus (CHIKV) RNA, confirming the circulation of ZIKV in continental Latin America and illustrating how difficult Zika fever is to identify on clinical features alone. The Salvador Epidemiologic Surveillance Office also investigated 14,835 cases of undetermined acute exanthematous illness documented across the 12 districts of Salvador, revealing the apparent co-circulation of DENV-1, CHIKV, ZIKV, and DENV-3 (Waggoner & Pinsky, 2016).

ZIKV was also retrospectively identified by RT-PCR in serum samples collected from eight patients in Natal, State of Rio Grande do Norte, Brazil, who presented with a "dengue-like fever" in early 2015 (Zanluca et al., 2015). Additionally, an HIV-infected individual in Rio de Janeiro, Brazil, presented in May 2015 with rash, malaise, myalgia, and conjunctival hyperemia; acute Zika fever was confirmed by flavivirus genus RT-PCR and sequencing. Furthermore, autochthonous ZIKV transmission has been documented throughout continental Latin America, Central America, Mexico, and the Caribbean, including Puerto Rico (Waggoner & Pinsky, 2016).

Phylogenetic analysis of ZIKV sequences obtained from Brazil and Suriname demonstrated that the virus belonged to the Asian lineage, and it is believed it was introduced to the Pacific Islands in the summer of 2014 during the World Cup or the Va'a World Sprint Championship canoe race (Waggoner & Pinsky, 2016; Zanluca et al., 2015).

Why Has ZIKV Penetrated the Americas?

Little is known about the precise circumstances of ZIKV's introduction into the Americas. Phylogenetic studies suggest that the virus originated from the French Polynesian ZIKV strain and entered Brazil between May and December 2013 (Lessler et al., 2016). Although there has been speculation about introduction during specific sporting events, Brazil receives over six million tourists each year, providing numerous opportunities for ZIKV introduction. Regardless of how and when ZIKV entered the Americas, the reasons for the scale and severity of this outbreak remain uncertain.

The unprecedented scale and impact of the ZIKV pandemic in the Americas may be a natural consequence of a novel introduction into a large population with no pre-existing immunity. Like the Americas, the communities of Yap Island and French Polynesia were entirely susceptible when ZIKV was introduced, and each experienced large outbreaks infecting more than 65% of their populations (Waggoner & Pinsky, 2016). Nevertheless, given the size and severity of the outbreak in the Americas, it seems implausible that, if similar outbreaks had been occurring, none would have been identified for over six decades. Hypothesized changes in the ecological and environmental drivers of ZIKV transmission must be carefully evaluated, as they will affect how we assess the risk posed by ZIKV worldwide.

Higher temperatures and increased rainfall associated with the 2015–2016 El Niño event may have facilitated ZIKV transmission throughout the region and expanded the geographic range of Aedes mosquitoes. Elevated temperatures have been linked to more efficient transmission of related flaviviruses and greater production of adult mosquitoes (Morin et al., 2013). El Niño-associated flooding (which increases mosquito breeding sites) and extreme dry periods (which may intensify human-insect contact) could facilitate ZIKV transmission. However, it should not be assumed that increased heat or rainfall will universally enhance ZIKV distribution, as climatic changes have complex effects across food webs and the thermal effects on the virus itself may be nonlinear (Lessler et al., 2016). Over a longer timeframe, urban growth and expansion has led to the spread of A. aegypti and A. albopictus in densely populated areas, which may have created conditions favorable for ZIKV circulation.

There is also the possibility that immunological interactions with other flaviviruses may be facilitating the spread or pathogenesis of ZIKV in the Americas. Antibody-dependent enhancement (ADE) may increase susceptibility to infection, the likelihood of developing severe illness, and the probability of transmission (Bhattacharyya et al., 2015). Evidence from several in vitro studies and epidemiological research has demonstrated both protective and enhancing effects between immunity to Japanese encephalitis and dengue, and multiple in vitro studies have indicated enhancement of ZIKV replication in the presence of antibodies against other flaviviruses (Paul et al., 2016; Lessler et al., 2016).

The severity of outcomes in recent outbreaks, compared with earlier reports of mild illness, has led some to hypothesize that the virus may have mutated to become more pathogenic (Lessler et al., 2016). Recent evidence points to distinct codon usage patterns between African and Asian ZIKV lineages; while adaptive genetic changes may affect viral replication and titers, the genetic diversity of viruses isolated from ZIKV-associated microcephaly cases suggests that recent mutations may not be directly implicated (Fajardo et al., 2016). Epidemiologic and laboratory research is needed to determine whether these changes have had a meaningful impact on viral pathogenesis. Until the significance of ZIKV evolution is better understood, caution is warranted in balancing lessons from earlier research against the possibility that the virus has fundamentally changed.

Human genetic variation may exert a powerful influence on the pathogenesis of many infectious diseases, and there are some signals that this may hold true for flaviviruses as well (Lessler et al., 2016). While there is evidence of historical admixture between Polynesian and American populations, there are currently no indications of a link between ancestral background and severe outcomes from ZIKV. Similarly, genetic variation in A. aegypti may affect vector competence for transmitting flaviviruses (Lessler et al., 2016); it is therefore possible that changes in the composition of vector populations also influence ZIKV distribution and account for regional variation in ZIKV outcomes.

Conclusion

The emergence of ZIKV following its long persistence as an illness of apparently modest significance illustrates how little we truly understand about the global circulation of flaviviruses. Recent diagnostic and molecular tools have significantly expanded the capacity to predict risk and monitor the spread of these viruses, but a thorough understanding of what makes one virus a global threat while another does not remains elusive.

The research highlighted in this review is both encouraging and sobering. On one hand, the speed with which the Americas and the broader global community gathered and disseminated clinical, epidemiologic, and laboratory data on ZIKV following recognition of the threat is remarkable. On the other hand, the development of therapeutics and diagnostics has clearly been hampered by a lack of prior investment, despite awareness of ZIKV's existence for over five decades. As a result, relatively little was in place to slow the virus's rapid spread through the Americas.

New threats from infectious diseases may emerge from unexpected sources. There is an urgent need for systems that enable rapid characterization of the distribution, pathogenesis, and management of previously obscure pathogens in order to protect global human health. Strengthening these systems is essential for reducing the lag between the emergence of a novel threat and an effective coordinated response.

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