Navigating the Zika panic

The epidemics of Ebola virus in West Africa and Zika virus in America highlight how viruses can explosively emerge into new territories. These epidemics also exposed how unprepared we are to handle infectious disease emergencies. This is also true when we consider hypothesized new clinical features of infection, such as the associations between Zika virus infection and severe neurological disease, including microcephaly and Guillain-Barré syndrome. On the surface, these pathologies appear to be new features of Zika virus infection, however, causal relationships have not yet been established. Decades of limited Zika virus research are making us scramble to determine the true drivers behind the epidemic, often at the expense of over-speculation without credible evidence. Here we review the literature and find no conclusive evidence at this time for significant biological differences between the American Zika virus strains and those circulating elsewhere. Rather, the epidemic scale in the Americas may be facilitated by an abnormally warm climate, dense human and mosquito populations, and previous exposure to other viruses. Severe disease associated with Zika virus may therefore not be a new trait for the virus, rather it may have been overlooked due to previously small outbreaks. Much of the recent panic regarding Zika virus has been about the Olympics in Brazil. We do not find any substantial evidence that the Olympics will result in a significant number of new Zika virus infections (~10 predicted) or that the Olympics will promote further epidemic spread over what is already expected. The Zika virus epidemic in the Americas is a serious situation and decisions based on solid scientific evidence - not hyped media speculations - are required for effective outbreak response.

) and severe disease such as microcephaly and Guillain-Barré syndrome (since 2013 -French Polynesia 5 ). The epidemic in the Americas has proven to alarmingly increase these trends -0.5 to 1.5 million suspected infections and ~4 ,000 cases of microcephaly in Brazil alone 6 . What are the real reasons behind the severity of this epidemic? We will explore aspects of 1) viral genetics that might alter transmission and pathogenicity in humans, 2) the ecological conditions in the Americas, 3) the potential impact of dengue virus on Zika virus-associated pathology, and 4) how small sample sizes and under reporting may have skewed our previous assumptions of Zika virus and the disease it can cause. Using this knowledge, we will discuss whether a global event like the Olympics would really impact further Zika virus emergence and the expansion of the epidemic.

Is Zika virus different today than it was when it was first discovered?
Undoubtedly, yes, Zika virus circulating today is genetically different from the Zika virus of the past. A key aspect of Zika virus is that it has an RNA genome. Central features of RNA virus biology is that these viruses replicate, produce large population sizes, but do so with lots of errors (mostly because their polymerases lack proofreading mechanisms, adding ~1 mutation per genome replication) [7][8][9] . Therefore, all RNA viruses have the ability to evolve fast relative to most DNA-based organisms 10  strains has yet to discover any appreciable patterns associated with adaptation towards humans, vector species, or disease outcome 28 . This is not to say that it has not occurred, only that at this point in time our sampling is too insufficient to make any conclusions. Therefore, more experimental evidence is required before we can say whether Zika virus genetics or phenotype has changed in any significant way.

Why is the epidemic in the Americas so bad?
Zika virus is not the first, nor likely the last mosquito-borne virus, to explosively emerge in the Americas. In 1999, West Nile virus was introduced into the New York area and quickly spread across the continent, killing thousands of people and millions of birds (reviewed by 29). Even more recently, in 2013, chikungunya virus emerged throughout the Caribbean and much of the tropical regions in the Americas (reviewed by 30). By 2015, there were already more than one million suspected cases 31 . Since chikungunya and Zika viruses share similar ecologies (humans and Ae. aegypti), the current Zika virus outbreak should not be so surprising, given recent histories. Even the 2007 Yap Island outbreak gave us some indication of its potential -it is estimated that 73% of the population became infected with Zika virus 4 . A large outbreak in the Americas almost seemed inevitable, but why?
Well, likely because the Americas are home to large and dense populations of hosts (humans) without previous Zika virus immunity, and vectors (mosquitoes) capable of transmission. The climate may also have contributed to the scale and intensity of the epidemic; 2015 was the warmest year on record in the Americas 32 , which could have enhanced Zika virus transmission. Warmer temperatures can increase mosquito abundance, survival, blood feeding rates, and vector competence 33-36 . Therefore, the extreme circumstances caused by El Niño and global climate change may have contributed to a higher density of mosquitoes 37 . Together, these factors represent an ideal recipe for an infectious disease epidemic.
The unfortunate surprise was the discovery of an association between severe neurological complications and Zika virus infection, especially among newborns 38 . This, however, could just be a consequence of numbers and reporting. Previous outbreaks may have missed these links because they were too small. In Brazil, the current estimate is that between 1-13% of pregnant women who become infected with Zika virus in their first trimester will deliver babies with microcephaly 17,39 . There may also be immunological explanations for pathology associated with Zika virus infection in the Americas. Zika and dengue viruses co-occur in many parts of the world. The fastest growing numbers of dengue cases occur in Latin America and the Caribbean with more than 10 million apparent infections a year 48 , a ~2 50% increase since 1990 49 . One interesting hypothesis is that antibodies produced from a previous dengue virus infection may enhance subsequent Zika virus infection 50-53 . The proposed mechanism is that antibodies targeting dengue virus can bind to Zika virus during an active infection, but cannot always neutralize it. Instead, the bound antibodies can actually help Zika virus infect monocytes by attaching to the cell surface receptors (Fc gamma) and mediating efficient entry. This process of antibody-dependent enhancement is also known to occur between different serotypes of dengue virus and is a risk factor for severe dengue disease (reviewed by 54). Since 2010, between 600,000 and 1.6 million annual dengue virus cases in Brazil have been reported 55 . Therefore the high incidence of dengue virus infection may be increasing the observed pathogenicity of Zika virus in the Americas. On the other hand, dengue and Zika viruses co-occur elsewhere, so the Americas may not be so unique. Indeed, further research is urgently needed to determine if dengue virus is not only exacerbating the Zika virus epidemic in the Americas, but also anywhere the two viruses co-circulate.

How many visitors will become infected with Zika virus during the Olympics?
Now turning our attention from the biology and genetics of Zika virus, to the different risks associated with Zika virus and the Olympics. There are two main risks to consider: 1) the risk of further spread and 2) personal risk to visitors. These are two very different questions, but often they get blurred together. Here we will discuss them separately. Moreover, only a small portion (5-50%) of infected mosquitoes can actually transmit the virus 13 . So even if you get fed upon by hundreds of mosquitoes, odds are that you will not get exposed to Zika virus.

Will the Olympics enhance the further spread of Zika virus?
The world is interconnected. Zika virus and many other mosquitoborne viruses have already utilized this interconnectivity to travel great distances. Does a global event like the Olympics really enhance this problem? One estimate indicates that 100 to 400 people infected with Zika virus will enter Europe in 2016 due to normal travel from endemic regions 66 . That is already 7-80× greater than the number of people predicted to become infected during the Games (~10 -see above The 'single introduction' hypothesis put forward by Faria et al. 28 has often (wrongly) been used to suggest that it only takes one infected traveler to start an outbreak (i.e., giving the sense that this could happen anytime) 2 . That is not correct and was also not suggested by the authors. Instead, what the Faria et al. data show, is that the chance of starting an outbreak is extremely low. If it had been high, we would have seen multiple introductions of Zika virus into Brazil (and elsewhere), due to travelers arriving from Zika endemic countries. We don't see that, hence it likely takes many -not just one -infected travelers for the chance occurrence to start an outbreak.
Direct human-to-human transmission is another possible route of Zika virus infection. These routes notably include transmission from mother to child during pregnancy and sexual transmission from a man to a woman 69 . Other forms of human-to-human transmission scenarios also appear to exist 70 . Therefore, could sustained Zika virus transmission occur without mosquitoes and should this be a concern for further spread of the epidemic? Again, let's use an example: an infected man returns home from the Games and has sex with his partner. There are numerous reports of Zika virus infection associated with sex with a man (or woman 71 ) returning from an endemic region 72-74 . Therefore, in this scenario, there is immediate risk to his partner. Importantly, however, in each of these reports, Zika virus spread was limited to just those single contacts. Thus, sex and other modes of direct contact with an infectious individual is highly unlikely to lead to sustained transmission in a new population. It has also been estimated that the role of sexual transmission in Brazil is minimal compared to mosquitoes 75 , and without mosquitoes, transmission would dissipate. The single most compelling piece of evidence to support that Zika virus is primarily mosquito-borne is that it is only known to occur in regions with Ae. aegypti 67 . Therefore, Zika virus is still considered to be primarily transmitted by mosquitoes and sexual transmission (or other yet-to-be-discovered human-to-human means of transmission) will likely not expand the expected range of the Zika virus epidemic.

Take-home message
Our rapidly expanding knowledge about Zika virus is starting to reveal important information about the current epidemic and suggests that we may have misjudged its epidemic potential for decades. We explored four key areas to demonstrate how the epidemic severity may be more related to the conditions in the Americas rather than new disease caused by Zika virus. 1) There is currently no definitive evidence that the strain of Zika virus in Brazil has altered potential for transmission or pathogenicity in humans compared to the strains circulating in Africa and Asia (although this does not mean that the Brazilian strain does not have an altered phenotype compared to other strains, only that no good evidence is currently available to suggest that is the case).
2) Major factors for the scope of the epidemic were likely large urban settings housing people without immunity and an abnormally warm climate leading to a large population of mosquitoes.
3) Previous exposure to dengue virus could increase Zika virus disease severity, though such a connection is yet to be demonstrated as an important risk factor. 4) The recent associations of some Zika virus infections with severe neurological conditions, such as microcephaly and Guillain-Barré syndrome, may be simply a reflection of sample sizes -large numbers of infections are often required to discover rare pathologies.
The risks regarding Zika virus and the Olympic Games in Brazil are 1) whether it will enhance the epidemic spread and 2) personally to people attending the games. The numbers of Olympic visitors expected to get infected with Zika virus in Brazil and travel home is far lower than the total numbers of these occurrences already expected to happen throughout the year. Therefore, the Olympics will not be a significant conduit for further epidemic spread. There is a personal risk of infection, though it is also predicted to be low. Obviously, pregnant women have the greatest risk as they could pass the virus to their developing fetus, with the possibility of causing severe neurological complications. Therefore each family needs to evaluate the consequences and likelihood of Zika virus infection to determine if they should travel to any region of the world with active Zika virus transmission. The Zika virus epidemic is a severe problem, but decisions should be based on scientific evidence 78,79 and not fear-mongering 2 . These should be lessons to keep in mind when we argue about some other relatively unknown virus before the start of Tokyo Olympics in 2020.
Author contributions NDG and KGA conceived the ideas and wrote the manuscript. In this interesting and well-executed review, Grubauch and Andersen 'navigate' the literature to provide a clean, well-driven and totally enjoyable text about the current situation generated for the Zika outbreak in the Americas. Based on the bibliography, they conclude there is no scientific evidence that the Brazilian Zika strain presents a higher pathogenicity compared to others circulating elsewhere. In addition, as was discussed in previous reports, they agreed with the role played by urban and weather factors to particularly enhance this outbreak. The authors also believe that is totally necessary to confirm the connection between Dengue and Zika as a risk factor in disease severity. Finally, given the sample size of the recent outbreak, we could have under estimated rare diseases associated to this virus in the past.
The article itself is very nicely written and provides a very balanced viewpoint of Zika virus, which is something that has been lacking from several media sources. The authors have put significant thought into the attributes that affect the severity of the outbreak, but perhaps the most important statements concerning the evolution of the virus and the neurological phenotypes recently observed. With their calculations for the number of microcephaly cases that could have been detected on Yap Island (quite possibly none due to the size of the outbreak), they suggest that statistics and surveillance, rather than genetic differences, affect disease severity. Of course, additional research is necessary into understanding the severity of the Zika virus outbreak and its connections to microcephaly and Guillain-Barre syndrome and whether the genetic differences between the strains of Zika virus are or are not responsible for these newly observed phenotypes.
The authors also expand on the details on how Zika virus could infect a traveler in Brazil and then induce an outbreak in their home country, which they estimate to have a much lower probability than popular media sources might suggest. Though the commentary surrounding the possibility of the Olympics enhancing Zika virus comes after the games, the thoughtful consideration of the risks supplies rational thinking that has been lacking, especially when juxtaposed with the hysteria prior to the games. The review superbly quells the hyperbole that has surrounded the Zika outbreak in the Americas. Regardless of this low possibility of traveler-associated transmission of Zika virus in new locales, regions with the proper conditions for Zika virus transmission should remain vigilant, and continued campaigns of mosquito control, especially given the breadth of viruses spread by mosquitoes (including dengue, chikungunya and West Nile viruses).
We would like to highlight that the authors didn't cite any of their previous works, which surprised us in a positive way, showing the author's will to deliver a clean and not biased opinion about the topic.

Minor comments:
Minor comments: The article is written for any kind of reader, which we found excellent, but in that case would be nice to clarify what is . Even if wouldn't be necessary for most of the readers.

El Niño
The paragraph that starts with "One main reason behind …August is winter in Brazil…" Brazil is huge, is the he largest country in South America and in the Southern Hemisphere. Is placed 5 in the list sovereign states and dependencies by area in the world. Particularly, the weather in Rio, still in august, can be warm enough for mosquitos. Last August the lower temperature registered was 71 F and the higher 78 F.
We have read this submission. We believe that we have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.
No competing interests were disclosed. In an attempt to justify the disastrous Iraq invasion in 2002, the then 13th Secretary of Defense of the USA, Donald Rumsfeld, stunned reporters when he uttered his (in)famous reflection on "known knowns", "known unknowns" and "unknown unknowns" (Rumsfeld, 2011).
In their interesting review on Zika epidemics, Grubauch and Andersen address the panic ensued by the overwhelmed number of cases in Latin America and elsewhere. They call the attention to several "known knowns" and "known unknowns" of the current Zika epidemics, although they do not shy away of pointing to possible "unknown unknowns".
Grubauch and Andersen find no conclusive evidence in the literature for significant biological differences between the Latin American Zika virus strain and those circulating elsewhere. They argue that the epidemic scale in the Americas has been influenced by climate, humans and mosquitoes population densities and local prevalence of other viruses, in particular flaviviruses, like dengue and yellow fever. The severe neurological abnormalities associated with Zika virus would not be a new trait of the Latin America strain, but rather may have been overlooked due to previously small outbreaks.
Every time the world is hit by an emergent or re-emergent pathogen with pandemic potential, panic ensues ( due to the prompt discovery of the ultimate cause and the possible control mechanisms. Unlike Londoners of the XVII century (Bell, 2001), who burnt witches and culled thousands of cats (by the way, both excellent rat killers), we have the scientific tools and mechanisms to face the threat with the necessary rationality.
In the case of Zika virus, however, many "known unknowns" still remain, like the true phenotypic repercussion of genotypic differences between the strains circulating in different parts of the world, differences in mosquito competences, the actual number of people that has already been infected, the competition by the vector of different viruses transmitted by the same aedes mosquitoes, vertical transmission of the virus in hosts and vectors, neuropathogenic potential of different strains, cross-immunity, antibody-enhancement by previous infection, just to mention a few. In addition, it is not well known the actual role of sexual transmission of Zika in triggering or maintaining an outbreak. As for the "unknown unknowns", just time will disclose.
One important unknown currently being discussed in the literature is whether Zika will disappear from the affected regions and whether and when it will recur. Mathematical models, very useful in the understanding and control of previous epidemics, have been widely applied in an attempt to describe and make prediction about the current Zika outbreak (Massad et al., 2016)). We now know that the Basic Reproduction Number, , of Zika is around 3, slightly higher than that of Dengue (Coelho et al., 2008) R and it is even possible to predict the likelihood of Zika being exported to unaffected regions of the world, either causing a single and self limited outbreak or establishing itself, depending on whether localis lesser or greater than 1.
For the sake of completeness, two additional speculative unknowns are worth mentioning. The circulation of Zika virus and its potential interaction with dengue raises new concerns regarding vaccination strategies against the latter. The subtle trade-off justifying the recommendation of the vaccine might no longer hold. On the other hand, the patchy distribution of serious outcomes due to Zika has not been satisfactorily explained. Our navigation map cannot overlook the apparent clustering of cases of microcephaly reported in northeastern Brazilian states so far.