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Emerging and Reemerging Aedes-Transmitted Arbovirus Infections in the Region of the Americas: Implications for Health Policy

The increasing geographical spread Marcos A. Espinal, MD, DrPH, Jon K. Andrus, MD, Barbara Jauregui, MD, MSc, Stephen Hull Waterman, and disease incidence of arboviral MD, MPH, David Michael Morens, MD, Jose Ignacio Santos, MD, MSc, Olaf Horstick, PhD (DrMed), FFPH, infections are among the greatest MPH, MSc, MBBS, Lorraine Ayana Francis, DrPH, MHA, and Daniel Olson, MD public health concerns in the Americas. The region has observed — an increasing trend in dengue in- he ever-increasing geo- symptomatic infections way ZIKV, like CHIKV, had not Tgraphical spread and rising above the numbers reported to previously circulated within cidence in the last decades, evolv- disease incidence of arboviral PAHO.9 the Western Hemisphere, and ing from low to hyperendemicity. (arthropod-borne virus) in- In 2005, CHIKV caused an resulted in an explosive outbreak Yellow fever incidence has also in- fections are among the most outbreak on the island of in the Americas, with its identi- tensified in this period, expanding significant public health concerns Comoros, followed by a large fication first on Easter Island, from sylvatic-restricted activity in the Americas.1,2 In addition to outbreak in India, resulting in Chile, in 2014, followed by to urban outbreaks. Chikungunya the reemergence of dengue virus more than 1 million cases and northeast Brazil in 2015, and started spreading pandemically in (DENV) and yellow fever virus significant postinfectious mus- then spreading throughout the 2005 at an unprecedented pace, (YFV), new arboviral pathogens culoskeletal sequelae. Sub- Americas. By late 2015, Zika had reaching the Americas in 2013. The once confined to specific regions sequently, CHIKV spread become one of the greatest global following year, Zika also emerged in of the world, such as chikungu- pandemically at an un- health crises in years and was theregionwithanexplosiveout- nya virus (CHIKV) and Zika precedented pace, reaching the associated with devastating con- break, carrying devastating congen- virus (ZIKV), recently resulted in Americas in 2013, rapidly genital abnormalities including ital abnormalities and neurologic pandemics associated with sig- resulting in more than 1.3 million microcephaly (Figure 1), – disorders and becoming one of the nificant morbidity.3 6 infections reported in more than Guillain-Barré syndrome, and greatest global health crises in years. Dengue infection is an Aedes- 43 countries.2,10 Incidence rates other neurologic disorders, and The inadequate arbovirus sur- borne disease caused by flavivi- climbed as high as 137.1 in- with the ability to spread by – veillance in the region and the lack ruses and is second only to malaria fections per 1000 person-years sexual contact.6,12 16 By late of serologic tests to differentiate as a cause of vector-borne disease among Nicaraguan children 2016, ZIKV transmission had among viruses poses substantial mortality and morbidity. For during the peak of the extended to 48 countries and challenges. The evidence for vec- several decades, the Americas epidemic.11 territories in the Americas, with a tor control interventions remains have observed an increasing trend weak. Clinical management re- in dengue incidence, evolving mains the mainstay of arboviral from low to hyperendemicity, ABOUT THE AUTHORS disease control. Currently, only Marcos A. Espinal is with Communicable Diseases and Environmental Determinants of with epidemics recurring ap- Health, Pan American Health Organization/World Health Organization, Washington, DC. 3 yellow fever and dengue vaccines proximately every 3 to 5 years. Jon K. Andrus is with the Department of Global Health, George Washington University are licensed in the Americas, with In 2010, 1.7 million dengue Milken Institute of Public Health, Washington, DC, and the Division of Vaccines and several candidate vaccines in Immunization, Center for Global Health, University of Colorado, Boulder. Barbara Jauregui cases were reported to the Pan is with the Department of Global Health, Milken Institute of Public Health, George clinical trials. American Health Organization Washington University. Stephen Hull Waterman is with the Dengue Branch, Division of The Global Arbovirus Group of (PAHO), an incidence rate of Vector-Borne Diseases, National Center for Emerging and Zoonotic Diseases, Centers for Experts provides in this article an Disease Control and Prevention, San Juan, Puerto Rico. David Michael Morens is with the 174.6 cases per 100 000 pop- Office of the Director, National Institute of Allergy and Infectious Diseases, National Institutes 7 overview of progress, challenges, ulation. In 2016, 2.2 million of Health, Bethesda, MD. Jose Ignacio Santos is with the Experimental Medicine Research and recommendations on arbo- cases were reported (220.0 Unit, Medical School, National Autonomous University of Mexico, Mexico City, Mexico. Olaf Horstick is with the Heidelberg Institute of Global Health, University of Heidelberg, viral prevention and control for 8 cases per 100 000 population), Heidelberg, Baden-Wuerttemberg, Germany. Lorraine Ayana Francis is with Communicable countries of the Americas. (Am J though rates were trending lower Diseases & Emergency Response, Caribbean Public Health Agency, Port-of-Spain, Trinidad. Public Health. 2019;109:387–392. in 2017.8 These rates are likely a Daniel Olson is with the Pediatric Infectious Disease Department, University of Colorado fi School of Medicine, and Epidemiology Department, Colorado School of Public Health, doi:10.2105/AJPH.2018.304849) signi cant underestimate; mod- Aurora. eling studies estimate as many as Correspondence should be sent to Jon Kim Andrus, 2811 Battery Place, Washington, DC 53.8 million DENV infections in 20016 (e-mail: [email protected]). Reprints can be ordered at http://www.ajph.org by clicking the “Reprints” link. Latin America and the Caribbean This article was accepted October 21, 2018. in 2010, including 13.3 million doi: 10.2105/AJPH.2018.304849

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created an unprecedented situa- identifying novel emerging These limitations in the perfor- tion: the cocirculation of 4 im- pathogens, genotypes, and out- mance of existing laboratory portant human arboviruses breaks. Regional laboratory systems became even more evi- transmitted by the same mos- networks exist to facilitate lo- dent during the introduction of quito, primarily Aedes aegypti,in gistical support, technical exper- new pathogens in the region such the same time and place. Intense tise, and data sharing such as as ZIKV. and prolonged rainy seasons and PAHO’s Arbovirus Diagnosis an increase of 2 degrees centi- Laboratories Network of the Source . Photo courtesy of the Pan grade in average temperature Americas.22 Surveillance Diagnostics American Health Organization. Printed with permission. probably also contributed to an Data analysis, reporting, and Given the challenge in clinical abundance of vectors.4,20 De- data sharing systems also vary. differential diagnosis among FIGURE 1—Brazilian Mother forestation has been associated Although many countries require DENV, ZIKV, and CHIKV, in With Her Baby With with yellow fever and Zika mandatory reporting of all 2016, the PAHO Directing Microcephaly, a Consequence outbreaks. Migration of un- arboviral diseases, case reporting Council proposed to its member of an Intrauterine Zika Virus Infection: Recife, Brazil, 2016 vaccinated populations to en- is often not performed, especially states a strategy for comprehen- demic areas has also been a key within the private sector. Many sive surveillance of arboviral factor in yellow fever occurrence countries publish routine case diseases. This strategy is based on total of 707 133 reported cases. in South America.4,20 counts of suspected and con- the coordination and strength- These estimates are also likely a firmed arboviral disease cases, ening of epidemiological sur- significant underestimate as though the quality and timeliness veillance, integrated vector reporting is passive and, there- of reporting varies. The PAHO control, and laboratory fore, they do not capture Health Information Platform diagnosis.24 17,18 SURVEILLANCE asymptomatic cases. Currently, the inconsistent for the Americas is a real-time, The clinical differential di- For decades, YFV persisted in and inadequate surveillance in voluntary, electronic reporting agnosis of DENV, ZIKV, and the Americas as sylvatic cycles of system that facilitates rapid CHIKV is challenging and un- the region along with the lack of 23 transmission. Beginning in 1997, laboratory serologic testing that reporting of data in the region. derscores the importance of lab- YFV circulation in Brazil and can consistently differentiate be- Existing surveillance sys- oratory diagnostic tests. Antibody neighboring countries in- tween closely related flaviviruses tems, including syndromic, detection tests can distinguish fi tensi ed. In 2008, Asunción, poses substantial challenges to laboratory-based, and other (e.g., among the alphaviruses (e.g., fi Paraguay, experienced its rst respond adequately to these postmortem, clinician-based, CHIKV, Venezuelan equine urban yellow fever outbreak, diseases.21 event-based) systems are often encephalitis, Mayaro, and Ross which accounted for almost 50% not integrated, which limits their River viruses) and the flaviviruses of all yellow fever cases reported ability to link relevant data and (e.g., DENV, ZIKV, YFV, West that year in the Americas.19 Over Limitations of Existing leverage existing resources. Nile, and Japanese encephalitis the past 30 years, YFV activity Systems and Rationale Given limited resources, sur- viruses). However, because of had been restricted to an enzootic Existing arbovirus surveillance veillance systems may place a previous exposure to related fla- area shared by Bolivia, Brazil, systems have several limitations, large focus on current arboviral viviruses and extensive cross- Colombia, Ecuador, French including problems intrinsic to diseases and not dedicate suffi- reactions among flaviviruses, Guyana, Guyana, Panama, Peru, passive surveillance, lack of orga- cient resources to identify new or serological tests such as immu- Suriname, Trinidad and Tobago, nizational structure and integration emerging arboviral pathogens. noglobulin M (IgM) enzyme- and Venezuela. Since late 2007, within existing systems, and in- Cross-reactivity of serologic linked immunosorbent assay the region has experienced in- adequate laboratory capacity. testing between flaviviruses (ELISA) and neutralization assays tense circulation of YFV, with Triggered by syndromic fever (particularly DENV and ZIKV) are not reliable in many situa- extensive epizootics and spillover and rash reporting, most coun- makes interpretation difficult. tions for distinguishing among outbreaks in humans. The en- tries in the Americas collect Numerous rapid diagnostic tests flaviviruses. demic area has extended to in- clinical and laboratory data for of varying quality make labora- The most reliable diagnostic clude Paraguay and northern arboviral diseases through vol- tory interpretation difficult, tests include nucleic acid tests Argentina, with human cases and untary passive case reporting especially in the context of such as reverse-transcription po- epizootics detected in 2008.4 within health care systems. Most changing arboviral epidemiol- lymerase chain reaction, and the Yellow fever continues to be a national laboratories have access ogy. Inadequate attention to lo- nonstructural glycoprotein-1 significant public health concern to serologic and molecular di- gistics of sample transport and ELISA. The latter detects acute- for these 13 countries of the agnostic testing for existing subsequent testing leads to delays phase infections. Only the non- Americas.19 arboviral pathogens, but fewer in the availability and reporting of structural glycoprotein-1 ELISA The recent emergences of laboratories have sequencing results. Many laboratories do not is currently commercially avail- ZIKV and CHIKV in 2016 and genotyping capability for perform postmortem testing. able, and only for DENV.25

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Until a decade ago, IgM and socioeconomic burden.29 range than A aegypti and, thus, contingency planning, including ELISA was the diagnostic Clinical diagnosis is challenging, may play a significant role in an algorithm to predict and detect method of choice for yellow initial prodromes are similar, and arboviral transmission in some dengue outbreaks.38 Although fever diagnosis. However, the sensitivity and specificity of clin- regions.32,33 global eradication of mosquito cross-reactivity among flavivi- ical algorithms to distinguish Early results of genome se- vectors is not possible, routine ruses again is a major limitation. CHIKV, DENV, YFV, and quencing indicate that mosqui- vector control and emergency In endemic areas, immunity to ZIKV have not been estimated.30 toes carry large numbers of operations can significantly re- other flaviviruses is very com- As noted, serologic diagnosis may known and unknown viruses that duce vector populations.35 mon, and some severe dengue be impeded by cross-reactivity infect humans and, because of However, in many countries, patients present with the clinical among related viruses. their high mutation rates, many integrated vector control is manifestations of yellow fever. In In the absence of specific an- new pathogenic arboviruses may poorly implemented.39,40 For an addition, IgM may persist for tiviral agents, case management potentially emerge. In accor- integrated approach, combining months and is therefore not a of arboviral disease is symptom- dance, vector control has a po- different vector-control methods reliable marker of a recent YFV atic and supportive. The aim is to tentially predominant role in the following the integrated vector infection. The development of prevent mortality by monitoring context of arboviral control, as management concept requires an molecular diagnostic tools has for shock and hemorrhage and is the case with the integrated assessment of the specific diseases significantly advanced the di- managing exacerbated un- vector management strategy of and vectors to be targeted.41,42 agnosis of yellow fever and the derlying medical conditions. In the World Health Organization However, the use of chemical ability to distinguish severe in- areas where Aedes-transmitted (WHO).34 methodsisalmostalwaysincluded, fections caused by wild-type virus arboviral disease is endemic, cases Vector-control methods for particularly indoor residual spray- versus the 17D vaccine strain.26 should be monitored until clini- Aedes control can be broadly ing, insecticide-treated nets, and cally stable.31 divided into biological, chemical, insecticide-treated materials. Bi- Several recent studies have and environmental.35 Biological ological methods and environ- addressed possible therapeutic methods include Bacillus thur- mental methods may also be used. INTEGRATED CASE options, including the use of ingiensis israelensis (Bti), larvivo- In general, the effectiveness of MANAGEMENT AND traditional antiviral compounds, rous fish, and copepods for the vector control, in terms of primary VECTOR CONTROL the synthesis of designer com- control of larval stages. The use of prevention of transmission, has pounds, high-throughput and in the bacteria Wolbachia, geneti- been assessed for dengue but re- Response to Aedes-trans- silico screening for existing cally modified mosquitoes, and mains controversial.36,43 mitted arboviral infections can products with possible efficacy, mosquitoes modified by sterile benefit from integrated ap- and the use of nucleic acid insect technique are currently proaches to case management compounds, therapeutic mono- being evaluated for public health and vector control, which can clonal antibodies, and drugs that use.36 Chemical methods include improve the response to Aedes- target host cell proteins.2 How- insecticides for residual sprayings, VACCINES AGAINST transmitted arboviral infections. ever, none are routinely recom- such as peridomestic or intra- AEDES-TRANSMITTED A combination of resources and mended, and they essentially domiciliary spraying (including ARBOVIRUS efforts such as water, sanitation, need further research. indoor residual spraying); long- Because of the challenges re- and hygiene; maternal, newborn, lasting insecticide treated mate- lated to vector control described and child health; and integrated rials or insecticide-treated nets previously, vaccines may well management of childhood ill- Vector Control or insecticide-treated curtains, emerge as the most efficient tools ness, among others, are needed The number of arthropod mostly targeting adult mosqui- for controlling and preventing for more effective and timely 27,28 species potentially capable of toes; and larvicides to control Aedes-transmitted arbovirus in- solutions. transmitting arboviruses is enor- larval stages. Environmental fections. Currently, there are mous, though 2 mosquito spe- methods target productive only 2 licensed vaccines against Case Management cies, A aegypti and Aedes albopictus, breeding sites, such as emptying emerging and reemerging arbo- Asymptomatic arbovirus in- are the primary and most im- of water containers, waste man- viruses in the Americas: the live fections are common. Symp- portant vectors for arboviruses agement, provision of piped attenuated yellow fever 17D tomatic cases are often mild and that infect humans in the water or physical barriers, win- vaccine and a recently licensed resolve spontaneously after 1 to 2 Americas. A aegypti is primarily an dow screens, and water con- live attenuated chimeric yellow weeks. However, some arboviral urban, peridomestic, and indoor tainer covers. Community fever–derived tetravalent dengue infections result in high fever, mosquito and is the main vector involvement is considered a vaccine (CYD-TVD). Although hemorrhage, meningitis, en- for DENV, CHIKV, ZIKV, and crucial element for any vector- no vaccines are yet licensed cephalitis, hepatitis, and other YFV. A albopictus is a secondary control strategy.37 against ZIKV or CHIKV, several serious clinical outcomes and even vector for these pathogens but has Recently a WHO handbook candidate vaccines are in different death, causing a significant clinical a more extended geographical recommended the use of phases of clinical trials.

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Yellow Fever Vaccines caused by wild-type YFV. Over Dengue Vaccines viruses with adequate protection The live, attenuated yellow the next 10 years, a total of 65 Vaccine development against against DENV3 and DENV4, fever 17D vaccine developed in cases have been recorded, with a DENV infections is among the modest protection against 1936 is one of the oldest live at- high case fatality rate of 63%. most complex challenges in DENV1, and inadequate pro- 49–51 tenuated vaccines in current use.44 Fortunately, yellow fever vac- vaccinology, complicated by 2 tection against DENV2. The vaccine is widely used for the cine–associated neurotropic dis- major issues. First, DENV com- In 2011, the vaccine un- prevention of yellow fever in ease remains rare. The risk is prises 4 antigenically distinct se- derwent phase III clinical trials, travelers, for routine immunization higher with advancing age, rotypes with several genotypes including more than 30 000 in- of infants in endemic areas, and for reaching 1.0 to 2.3 per 100 000 in within each serotype. Infection dividuals in 10 endemic countries emergency response during persons aged older than 60 years, with 1 serotype generally confers throughout Asia and Latin outbreaks. Twenty to 60 million and is associated with impaired lifelong immunity to the infect- America. Pooled data indicated a fi doses are distributed annually.26 immunity. Despite the higher ing serotype and only transient 59.2% ef cacy against all clini- Yellow fever 17D vaccine reporting rate in the elderly, cross-protection to heterologous cally diagnosed dengue cases, and fi elicits a rapid, exceptionally severe disease and deaths have serotypes. Secondary infection 76.9% ef cacy against severe strong, and essentially lifelong also occurred in young persons expands the cross-reactive im- dengue 1 year after a 3-dose and in women of childbearing vaccine regimen. In May 2016, adaptive immune response. 26 munity, making symptomatic Vaccinologists have harnessed age. infections by a third DENV se- the PAHO Technical Advisory Countries in the Americas Group stated that there was in- 17D as a vector for foreign rotype unusual. However, in- 26 follow PAHO’s Technical Ad- sufficient safety and effectiveness genes, a promising area for ducing protection to all 4 DENV visory Group’s recommendations evidence to recommend the in- continued research. serotypes by 1 vaccine has been to prevent and control yellow troduction of the DENV vaccine Two types of severe adverse difficult. Second, severe mani- fever in the region, which in- into routine national immuni- events are temporally associated festations of dengue occur at a clude (1) universal introduction zation programs of the region.52 with the yellow fever 17D vac- higher rate in secondary in- of the yellow fever vaccine in In November 2017, the vaccine cine: neurotropic and viscero- fections. Antibody-dependent national immunization programs manufacturer announced study tropic disease. Both are enhancement has been proposed for children aged 1 year in results that showed increased fortunately rare. Yellow fever as a mechanism to explain the countries with endemic trans- hospitalized cases with severe vaccine–associated neurotropic more severe presentation of mission, (2) preventive vaccina- dengue observed in young chil- disease is manifest in more than dengue in a secondary infection. tion campaigns for populations dren from 2 to 5 years of age who half of the cases by meningitis or During antibody-dependent en- 53–55 aged younger than 2 years living were DENV-na¨ıve. On the encephalitis, and the remainder in enzootic areas during in- hancement, cross-reactive but basis of these findings, in April have clinical or radiological evi- terepidemic periods, (3) vacci- nonneutralizing antibodies from 2018, the WHO Scientific Ad- dence for Guillain-Barré or acute nation campaigns in response primary infection by a heterolo- visory Group of Experts recom- disseminated encephalomyelitis. to outbreaks or epizootics, and gous DENV serotype enhance mended conducting serologic Neurotropic adverse events occur (4) vaccination of travelers entry and replication of virus testing of DENV immune status between 0.2 (Europe) and 0.8 to areas with a risk of YFV particles in immune cells, espe- before vaccine administration (United States) per 100 000 pop- transmission.45 cially macrophages, resulting in and avoiding vaccinating ulation vaccinated. Most cases are Unfortunately, the limited high titers of virus in blood and DENV-na¨ıve individuals.56 in infants aged younger than 7 vaccine availability does not allow consequently severe disease dur- Two other live-attenuated months. In 1960, recommenda- countries to fully implement these ing the second DENV infection. DENV vaccines are in phase III tions were made contraindicating recommendations. The vaccina- Thus, a DENV vaccine carries the trials, whereas still others, such as vaccine use in infants up to 6 tion coverage in children at 1 year potential for increasing the risk of a purified inactivated vaccine, are 26 months of age. Recent reports of age is approximately 70% in the severe disease in DENV-na¨ıve in phase I trials. In addition, at- have documented yellow fever region. Recent outbreaks of yel- individuals unless the vaccine tenuated strains are being used as 17D virus transmission, with low fever in Angola and the gives rise to lasting, protective challenge strains in the human 48 resulting yellow fever vaccine– Democratic Republic of Congo immunity to all serotypes. DENV infection model and have associated neurotropic disease, in depleted the global vaccine Currently, multiple candidate great promise for moving to 3 breastfed newborn babies from stockpile, highlighting the chal- vaccines are in clinical develop- phase III clinical trials.53 DENV mothers who had been recently lenges to maintaining supply. ment and 1 vaccine, CYD-TDV E protein is being pursued as the vaccinated.26 To address the shortage, on the (Dengvaxia), has recently been main antigen in several subunit- In 2001, 7 cases (6 fatal) of basis of existing published data, licensed in 19 countries, in- based vaccines.53 Research on viscerotropic disease were re- experts have recommended cluding Mexico, Brazil, El Sal- plant-based vaccines will poten- ported with acute multiorgan fractional doses to administer vador, and Paraguay. Dengvaxia tially revolutionize the way vac- failure. Such cases are caused by reduced volumes of the is a tetravalent combination of 4 cine can be produced, if proven the 17D virus and resemble cases vaccines.46,47 monovalent chimeric attenuated successful.57

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Other Arboviral Vaccines of Experts, including leading in- Allergy and Infectious Diseases of the chief, Dengue Branch, Division of ternational and regional experts National Institutes of Health, and Lynn Vector-Borne Diseases, Centers for Dis- Zika vaccines in the pipeline. Goldman, the dean of the George Wash- ease Control and Prevention. ZIKV vaccine development has from PAHO, the Centers for ington University Milken Institute of Public benefited from the head start that Disease Control and Prevention, Health, for their contributions during the CONFLICTS OF INTEREST the National Institutes of Health, proceedings of the meeting. The authors D. Olson served as a consultant in an ad- DENV research has provided. As would like to recognize the work and sup- visory meeting to Sanofi Pasteur regarding with DENV, ZIKV also presents and the Center for Global Health port of the Global Arbovirus Group of its CYD-TDV (Dengvaxia) dengue vac- some human immunologic chal- at the University of Colorado, Experts, who discussed and agreed upon cine in 2018. All other authors have no among others, to discuss current the recommendations provided in this potential conflicts of interest to declare. lenges for vaccine development. In article. Lastly, the authors would like to many areas affected by ZIKV, se- challenges for Aedes-transmitted thank Halley Petersen-Jobsis for her HUMAN PARTICIPANT ropositivity for DENV is very high. arbovirus infections in the administrative support in the implemen- PROTECTION tation of this project. Although ZIKV differs from Americas. The Global Arbovirus No protocol approval was necessary be- The members of the Global Arbovirus cause no research involving human par- DENV by 41% to 46% in the Group of Experts issued the fol- Group of Experts were Sylvain Aldighieri, ticipants was conducted. genetic sequence of its envelope lowing technical recommenda- chief, Epidemic Alert and Response and Zika Incident Managment, Pan American REFERENCES protein, some experts argue that the tions with the overriding priority to Health Organization (PAHO)/World 1. Fauci AS, Morens DM. Zika virus in the data suggest that cross-reactivity prevent unnecessary morbidity and Health Organization (WHO); Jon K. Americas—yet another arbovirus threat. between DENV with ZIKV may mortality of arbovirus infections: Andrus, adjunct professor, The George N Engl J Med. 2016;374(7):601–604. Cases need to be detected earlier so Washington University Milken Institute drive antibody-dependent en- of Public Health; Edwin Asturias, associate 2. Powers AM. Vaccine and therapeutic hancement of infection in people essentialclinicalandpublichealth professor, Pediatrics-Infectious Diseases, options to control Chikungunya virus. Clin Microbiol Rev. 2017;31(1):e00104–16. previously exposed to DENV who interventions can be implemented University of Colorado; Juliet Bryant, ar- 58 in a more timely fashion. To that bovirus expert, Merieux Foundation, 3. San Martín JL, Brathwaite O, Zam- are later infected with ZIKV. Lyon, France; Jose Cassio de Moraes, ad- brano B, et al. The epidemiology of Several vaccine platforms are being end, efforts to improve the fol- junct professor, Medical School of Santa dengue in the Americas over the last three investigated for ZIKV vaccine de- lowing will be critical: laboratory Casa de São Paulo, Brazil; Jose Esparza decades: a worrisome reality. Am J Trop – capacity and diagnostics, case Bracho, adjunct professor, University Med Hyg. 2010;82(1):128 135. velopment. Leading vaccine can- Maryland School of Medicine; Marcos A. reporting and management, in- 4. Hamrick PN, Aldighieri S, Machado G, didates, some of which are in phase Espinal, director of the Department of et al. Geographic patterns and environ- I and II human trials, have pro- tegrated surveillance system with Communicable Diseases and Health mental factors associated with human an emphasis on data quality, and Analysis, PAHO/WHO; Peter Figueroa, yellow fever presence in the Americas. duced promising results in pre- professor of Public Health, Epidemiology, 59 community communication to PLoS Negl Trop Dis. 2017;11(9): clinical studies. Future challenges and HIV/AIDS, University of the West e0005897. for ZIKV vaccine development minimize exposures. Research, Indies, Kingston, Jamaica; Lorraine Ayana fi 5. Paixão ES, Teixeira MG, Rodrigues fi including that for vaccine devel- Francis, technical of cer, Communicable include having suf cient cases to Diseases and Emergency Response, Ca- LC. Zika, Chikungunya and dengue: the enable successful phase III trials. opment, improved diagnostics, and ribbean Public Health Agency; Eduardo causes and threats of new and re-emerging Chikungunya vaccines in the operational research for best prac- Gotuzzo, director of the “Alexander von arboviral diseases. BMJ Glob Health. 2018; ” 3(suppl 1):e000530. pipeline. After the reemergence of tices such as vector control within Humboldt Institute of Tropical Medi- cine & Infectious Diseases, Cayetano 6. Hoen B, Schaub B, Funk AL, et al. CHIKV in 2004, there was an integrated approach and vacci- Heredia University, Lima, Peru; Akira Pregnancy outcomes after ZIKV infection renewed interest in developing a nation achieving high coverage Homma, director, Bio-Manguinhos, in French territories in the Americas. N rates among communities most at Fiocruz, Brazil; Olaf Horstick, director, Engl J Med. 2018;378(11):985–994. vaccine. Options including virus- Teaching Unit at the Institute of Public 7. Pan American Health Organization. like particles, subunit vaccines, risk will also be essential. A more Health, University Hospital Heidelberg, Number of reported cases of dengue and Germany; Dan Olson, pediatrician, vectored or chimeric vaccines, detailed list of recommendations is severe dengue (DS) in the Americas, by Children’s Hospital of Colorado, Colo- included as Appendix A (available country: figures for 2010. 2011. Avail- nucleic acid vaccines, and live at- rado University; David Morens, Senior able at: http://www1.paho.org/hq/ tenuated vaccines have all been as a supplement to the online Scientific Advisor, National Institutes of dmdocuments/2011/dengue_cases_2010_ Health; Lyle Petersen, director, Division explored as possibilities. One sig- version of this article at http:// May_20.pdf. Accessed August 4, 2018. fi www.ajph.org). of Vector-Borne Diseases, Centers for ni cant challenge is that there are Disease Control and Prevention; Ann 8. Pan American Health Organization. numerous different virus strains CONTRIBUTORS Powers, chief, Alphavirus Laboratory, Number of reported cases of dengue and Division of Vector-Borne Diseases, severe dengue (SD) in the Americas, by used, different animal models with M. A. Espinal and J. K. Andrus jointly Centers for Disease Control and Pre- country: figures for 2016. 2017. Avail- conceptualized the review and co-led the different routes of both vaccination vention; Alba Maria Ropero Alvarez, able at: https://www.paho.org/hq/ writing. B. Jauregui compiled the recom- and challenge, and different regional advisor, yellow fever vaccine, dmdocuments/2016/2016-cha-dengue- mended references and supported the fi 2 PAHO/WHO; Cuauhtemoc Ruis Matus, cases-jan-26-ew-52.pdf. Accessed August methods for evaluating ef cacy. preparation of the draft. D. Olson con- chief, Comprehensive Family Immuniza- 4, 2018. tributed substantial content and provided tions Unit, PAHO/WHO; Jose Ignacio extensive revisions and additional refer- 9. Bhatt S, Gething PW, Brady OJ, et al. Santos, professor, Experimental Medicine ences. S. H. Waterman, D. M. Morens, J. I. The global distribution and burden of Unit, School of Medicine, National Au- Santos, and L. A. Francis contributed ad- dengue. Nature. 2013;496(7446): tonomous University of Mexico; Carlos – ditional content and revisions and provided 504 507. Torres, pediatrician, infectologist, Bogota references. O. Horstick was the primary fi RECOMMENDATIONS Children’s Hospital, Bogota, Colombia; 10. Espinal M. Chikungunya: rst emer- expert and contributor to vector control. In June 2018, the George Pedro Vasconcelos, head, Brazil’sNational gent arbovirosis in the XXI century in the Institute of Science and Technology for Americas [in Spanish]. Pan Am J Public Washington University Milken – ACKNOWLEDGMENTS Viral Hemorrhagic Fevers, Brazil; Linda Health. 2017;41(e108):1 3. Institute of Public Health con- The authors would like to thank Antony Venczel, director, Global Health Security 11. Gordon A, Gresh L, Ojeda S, et al. vened a Global Arbovirus Group Fauci, Director of the National Institute of program, PATH; and Steve Waterman, Differences in transmission and disease

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