Review Development of vaccines against Zika virus Gregory A Poland, Richard B Kennedy, Inna G Ovsyannikova, Ricardo Palacios, Paulo Lee Ho, Jorge Kalil Zika virus is an emerging pathogen of substantial public health concern to human beings. Although most infections are Lancet Infect Dis 2018; asymptomatic or present with benign, self-limited symptoms, a small percentage of patients have complications, such 18: e211–19 as congenital anomalies in the developing fetus of pregnant women infected with the virus and neurological Published Online complications (eg, Guillain-Barré syndrome). To date, there is no vaccine, antiviral drug, or other modality available to January 25, 2018 http://dx.doi.org/10.1016/ prevent or treat Zika virus infection. In this Review, we examine vaccine development efforts for Zika virus to date and S1473-3099(18)30063-X research gaps in the development of candidate vaccines against Zika virus. Top research priorities should include Mayo Clinic Vaccine Research development of a better understanding of immunity to Zika virus to establish clear correlates of protection; determination Group, Mayo Clinic, Rochester, of what effect, if any, Zika vaccine-induced immune responses will have on subsequent dengue virus infection; MN , USA (Prof G A Poland MD, evaluation of vaccine immunogenicity and efficacy in healthy adults and in the various subpopulations affected by Zika Prof R B Kennedy PhD, Prof I G Ovsyannikova PhD); virus infection (children, pregnant women, women of childbearing age, and eldery people); and identification of the Instituto Butantan, São Paulo, molecular mechanisms that underlie birth defects and neurological sequelae related to Zika virus. Brazil (R Palacios MD, P L Ho PhD); and Medical School Introduction Review, we evaluate those efforts and outline scientific, and Heart Institute, University of São Paulo, São Paulo, Brazil Sometime in the early 1900s, probably in Uganda, the regulatory, and ethical issues related to the development (Prof J Kalil MD) ancestral Zika virus emerged and went undetected for of a vaccine against Zika virus. Correspondence to: decades. It was not until 1947, when sentinel rhesus Dr Gregory A Poland, Mayo monkey number 776 had a febrile illness, that researchers Zika virus Vaccine Research Group, looking for the yellow fever virus at the Ugandan Viral Zika virus is an arbovirus that belongs to the Flaviviridae Mayo Clinic, Rochester, 1 MN 55905, USA Research station identified Zika virus. Ugandans from family, which includes dengue, West Nile, and yellow fever [email protected] four different locations were studied and six (6·1%) of viruses. Zika virus has a single-stranded, positive sense 99 were positive for antibodies to the virus. At the time, RNA genome that encodes structural (capsid, precursor the importance of this emerging virus was unknown membrane [prM], and envelope [E]) and non-structural and unanticipated. The response to Zika virus as a proteins (1, 2A, 2B, 3, 4A, 4B, and 5). The genome is curiosity was justified, because at the time there were no translated as a single polyprotein and then is proteolytically known infections or outbreaks of importance in human cleaved into individual proteins. The prM, E, and non- beings. structural protein 1 have the greatest sequence divergence The first human case of Zika infection was reported in from other flaviviruses. Three main lineages of Zika virus 1952.2 Although Zika infection had been reported a decade have been found, east African, west African, and Asian. earlier,3,4 this infection was later identified as Spondweni These strains might be differentially associated with the virus.5 Other isolated cases of Zika infection were reported neurological defects seen during the outbreaks in the through the 1960s and 1970s.1,6 Nonetheless, Zika virus was Pacific and South America. Strains from Polynesia and not recognised as a human pathogen of importance until South America have high degrees of similarity (about 2007, when an outbreak of rash and fever occurred on Yap 99% sequence identity),9 while strains from the western Islands and led to 49 confirmed—and 59 probable—cases hemisphere are about 89% identical to the African of Zika virus infection in human beings.7 At the time, a genotypes.10 household survey of 557 people revealed that 412 (74%) had The virus was first isolated from rhesus macaques and antibodies for Zika virus. A larger second outbreak was subsequently found in mosquito vectors (including occurred in 2013–14 in French Polynesia, involving Aedes aegypti, Anopheles spp, and Mansonia spp).1 Specific 333 confirmed cases and 19 000–32 000 suspected cases.8 antibodies against Zika virus have been found in sheep, For the first time, Guillain-Barré syndrome was observed cows, goats, horses, water buffalo, ducks, rodents, bats, in conjunction with these infections. During the non-human primates, and other wild animals.11–17 This 2014–15 outbreaks of Zika virus in Brazil, public health large and diverse pool of animal hosts facilitates the authorities reported a noticeable increase in children born spread of the virus and can contribute to the emergence with microcephaly. of recombinant strains. Since 2007, local transmission has been documented in Barba-Spaeth and colleagues18 studied the crystal 52 countries and territories, including in continental structure of the Zika virus E protein complexed to USA. Despite the scale of the outbreak, it was not until two cross-reactive antibodies specific for dengue virus, February, 2016, that WHO declared Zika virus to be a which provided important data on conserved epitopes Public Health Emergency of International Concern. targeted by cross neutralising antibodies. Since then, the Before this announcement, there were no known efforts crystal structures of the mature19 and immature20 Zika to develop a vaccine against the Zika virus. Since then, virus have been resolved, allowing us to evaluate the researchers in this field have tried to understand Zika effect of mutations that have occurred since the start of virus and to develop a vaccine against Zika virus. In this the epidemic, to identify conserved regions with other www.thelancet.com/infection Vol 18 July 2018 e211 Review flaviviruses, to map neutralising epitopes, and to better Zika virus is mostly suppressed. As a result, sexual understand viral attachment and entry. transmission of the virus has been documented,33,34 and perinatal transmission has been described during Zika virus infection pregnancy.35,36 Thus, vaccines and treatments designed to Zika virus, which has rapidly emerged as a threat to fight Zika virus infection in all organs is an important public health, is transmitted by A aegypti mosquitoes.21 consideration in vaccine development. An improved Zika virus spread beyond its historical range in equatorial understanding of interactions between the virus and host Africa and Asia to the Federated States of Micronesia will inform the public health response to this pathogen. (Yap Islands). In 2015, the virus spread to the Caribbean, South America, and Central America, where it has Immune responses to Zika virus caused epidemics.22 22·7 million people in the USA live Many cellular proteins could act as potential entry receptors in areas with active mosquito populations that are (dendritic-cell-specific ICAM-3 grabbing non-integrin, conducive to year-round transmission of Zika virus.23 The Axl receptor tyrosine kinase, hepatitis A virus cellular Aedes species of mosquitoes known to transmit Zika receptor 1, tyrosine protein kinase 3).37,38 Cellular infection virus—A aegypti and A albopictus—are present in more with Zika virus is characterised by expression of Toll-like than 30 states and territories in the USA. Furthermore, receptor 3, retinoic acid inducible gene-I, and melanoma 60% of people in the USA live in areas that might allow differentiation associated gene 5, secretion of type 1 seasonal transmission of Zika virus due to the and type 2 interferons, and upregulation of interferon- geographical distribution of Aedes spp mosquitos.23 The stimulated genes that mediate antiviral responses (OAS2, mosquito vectors carrying Zika virus are expanding in ISG15, or MX1).38 Glycosaminoglycans can aid the geographical location, and currently cover Africa, South attachment and entry of Zika virus.39 and Central America, India, Singapore, Puerto Rico, and Initial reports indicated that immune responses to the USA, and will probably spread to other parts of Asia.24 Zika virus were similar to that of other flaviviruses in that As of March 10, 2017, people in 84 countries and neutralising antibodies (primarily directed at E protein) territories had been infected with Zika virus.25 are thought to play a major part in protection against 80% of Zika virus infections are asymptomatic, while infection.40–43 In fact, there is considerable serological the other 20% of infections typically present as a mild crossreactivity between Zika virus and other flaviviruses, form of dengue-like disease with mild fever, skin rash, and this reactivity has hindered the use of diagnostic muscle and joint pain, conjunctivitis, vomiting, tests and seroprevalence studies in geographical areas headache, malaise, prostration, and oedema of the hands where antibody responses to other flaviviruses are also and feet.26 These symptoms usually last for 2–7 days, and present.1,44 In some geographical areas, monoinfection the incubation period of Zika virus typically ranges from with Zika virus is less common than co-infection