Progress and Works in Progress: Update on Flavivirus Vaccine Development

Progress and Works in Progress: Update on Flavivirus Vaccine Development

Clinical Therapeutics/Volume ], Number ], 2017 Progress and Works in Progress: Update on Flavivirus Vaccine Development Matthew H. Collins, MD, PhD1;...

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Clinical Therapeutics/Volume ], Number ], 2017

Progress and Works in Progress: Update on Flavivirus Vaccine Development Matthew H. Collins, MD, PhD1; and Stefan W. Metz, PhD2 1

Department of Medicine, Division of Infectious Diseases, University of North Carolina, Chapel Hill, North Carolina; and 2Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina

ABSTRACT Most areas of the globe are endemic for at least one flavivirus, putting billions at risk for infection. This diverse group of viral pathogens causes a range of manifestations in humans from asymptomatic infection to hemorrhagic fever to encephalitis to birth defects and even death. Many flaviviruses are transmitted by mosquitos and have expanded in geographic distribution in recent years, with dengue virus being the most prevalent, infecting approximately 400 million people each year. The explosive emergence of Zika virus in Latin America in 2014 refocused international attention on this medically important group of viruses. Meanwhile, yellow fever has caused major outbreaks in Africa and South America since 2015 despite a reliable vaccine. There is no vaccine for Zika yet, and the only licensed dengue vaccine performs suboptimally in certain contexts. Further lessons are found when considering the experience with Japanese encephalitis virus, West Nile virus, and tickborne encephalitis virus, all of which now have protective vaccination in human or veterinary populations. Thus, vaccination is a mainstay of public health strategy for combating flavivirus infections; however, numerous challenges exist along the path from development to delivery of a tolerable and effective vaccine. Nevertheless, intensification of investment and effort in this area holds great promise for significantly reducing the global burden of disease attributable to flavivirus infection. (Clin Ther. 2017;]:]]]–]]]) & 2017 Elsevier HS Journals, Inc. All rights reserved. Key words: dengue, flavivirus, immunization, immunologic memory, vaccine development, Zika.

INTRODUCTION Flaviviruses are important human pathogens that cause widespread infections (Figure).1 The Zika virus

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(ZIKV) epidemic recognized in 2015 abruptly aroused international concern for this group of viruses as numbers of infected people expanded rapidly throughout Latin America and confirmed cases of ZIKV-associated microcephaly have now increased to 43000.2,3 Yellow fever virus (YFV) has continued to cause outbreaks in Africa4 and South America,5 leading to tens of thousands of deaths annually. Dengue virus (DENV) has been steadily expanding during the last decades and is now the most common vector-borne virus in the world.6 West Nile virus (WNV) has become endemic from the East Coast to West Coast in the United States since 1999,1 revealing that these infections are not confined to tropical nations affected by climatic and sociopolitical challenges. Although vector control could contribute to comprehensive control and prevention programs for flaviviruses,1 there are substantial limitations to these strategies because of the natural history and transmission ecology of these infections and dependency on sustained public will and infrastructure. Thus, vaccination is the most attractive approach to reduce the burden of human disease caused by flaviviruses. Vaccination is widely celebrated as a crowning achievement of modern medicine and a “best buy” in public health.7 However, there is ample room for improvement. Proper access and implementation of existing vaccines could prevent 43 million childhood deaths each year.8 Although our ability to immunize against many pathogens has expanded during the last 2 centuries, tools to prevent major global infections, such as tuberculosis, HIV, and malaria, remain elusive.7 Within the flavivirus family, YFV9 and Accepted for publication July 5, 2017. http://dx.doi.org/10.1016/j.clinthera.2017.07.001 0149-2918/$ - see front matter & 2017 Elsevier HS Journals, Inc. All rights reserved.

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A

Global distribution of TBEV and JEV by country

B

Global distribution of WNV by country

TBEV JEV Both

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Global distribution of DENV and ZIKV by country

ZIKV DENV Both

Figure. Distribution of infection and areas of overlap are shown for (A) tickborne encephalitis virus (TBEV) and Japanese encephalitis virus (JEV), (B) West Nile virus (WNV), and (C) dengue virus (DENV) and Zika virus (ZIKV).

Japanese encephalitis virus (JEV)10 are largely preventable, whereas DENV,11 and more recently ZIKV,12 vaccines represent unmet goals. In this review, we survey some success stories in flavivirus vaccinology and take a closer look at vaccine development for ZIKV and DENV as case studies to illustrate both particular aspects of the virology and immunology to these two viruses and general issues that may arise with related flaviviruses and other emerging pathogens for which effective vaccines are not yet available.

BASIC VIROLOGY AND EPIDEMIOLOGY FOR ZIKV AND DENV As is true of all flaviviruses (Family: Flaviviridae, genus: Flavivirus),13 ZIKV and DENV are enveloped viruses with positive-sense, single-strand RNA genomes of approximately 11 kb. The flaviviruses, including those discussed in this review, share a common genomic organization, life cycle, and several host-pathogen protein interactions. The subtler genetic and molecular determinants of variation among the members of this group in vector use, host cell tropism, pathogenesis, and immunity are largely still being investigated14 and are not discussed further here. After fusion and uncoating, a single polypeptide is translated in the cytoplasm of the host cell and cleaved into 3 structural (capsid [C], premembrane [prM], and envelope [E]) and 7 nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5).3 The virion has icosahedral symmetry and comprises 180 E monomers arranged in antiparallel dimers, which are further arranged into higher-order configurations.15 In addition to

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mediating host cell attachment, fusion, and entry, E protein is a major target of antibody (Ab) responses in flavivirus infection.16 Most infections by both viruses are mild or asymptomatic,13 which can be a major barrier to accurate determination of prevalence and surveillance. Clinically, DENV is a common cause of acute febrile illness in the tropics and in returned travelers. Common symptoms include headache, rash, and joint pain. Severe DENV, epidemiologically associated with a second DENV infection by a serotype distinct from the first infection, occurs in a small fraction of infected individuals and may manifest as hemorrhage, shock, end organ damage, or even death.6,17 The pathogenesis for severe DENV as it relates to vaccine development is discussed further below. Symptomatic ZIKV infection is difficult to clinically distinguish from DENV or other causes of rash or fever in the tropics because of overlapping symptoms.18 However, the recent ZIKV epidemic has also been associated with new diseases phenotypes. It is now well established that ZIKV crosses the placenta, infects the fetus, adversely affects neurodevelopment, and causes a range of birth defects collectively termed congenital Zika syndrome.19–22 Guillain-Barré syndrome was noted as a complication of ZIKV infection during the 2013 outbreak in French Polynesia23 and has since been observed in multiple countries in the Americas.24 Even if rare, these severe forms of illness constitute a large burden on health systems, particularly in resource-limited settings.25,26 Both viruses are primarily transmitted by the mosquito Aedes aegypti,27,28 which is an effective

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M.H. Collins and S.W. Metz vector over vast geographic ranges, including equatorial Africa, Latin America and the Caribbean, India, and Southeast Asia, making the potential for simultaneous or sequential infection by both viruses a major concern for billions worldwide. Despite conventional and new vector control efforts, DENV infections have continued to increase in recent decades.28 In addition to endemic transmission cycles, travel-associated DENV is frequently reported, and in combination with other factors such as climate change,29 the potential for establishing new areas of Aedes-borne arbovirus transmission in nonendemic areas, such as the United States and Europe, is a possibility for which there is precedent.30–34 An added public health challenge associated with the ZIKV epidemic is that multiple forms of sexual contact3,35–37 and even rarely close nonsexual contact38 are also viable routes for transmission along with potential for infections associated with blood transfusion or organ transplantation.39–41

SUCCESS STORIES FOR FLAVIVIRUS VACCINES YFV: The Original Breakthrough Among the strongest evidence behind the optimism that ZIKV and DENV can be controlled through vaccination comes from success with other flaviviruses, such as YFV, tickborne encephalitis virus (TBEV), and JEV. YFV is recognized as the prototypic flavivirus and is the notorious causative agent of the original hemorrhagic fever. For 4250 years, YFV has caused major public health problems in 450 countries in tropical regions all over the world.42 However, the disease has been controlled by effective attenuated virus vaccines. In the 1930s, the first YFV vaccine was derived from the wild-type French vicerotropic virus and was passaged 260 times in mouse brain until the virus lost its liver tropism and the ability to be transmitted by mosquitoes.43 This vaccine (referred to as French neurotropic virus because a neurotropic phenotype was acquired during attenuation) was responsible for a huge decline in YFV infections in the 1940s and 1950s. However, the acquired neurotropism of the attenuated virus caused an increase in the number of postvaccine encephalitis cases in children. Due to these severe side-effects, the vaccine was discontinued.42 French neurotropic virus was succeeded by the 17D vaccine strain,42 which was

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developed by passaging the Asibi strain (isolated from Mr. Asibi in Ghana, 192744) in mouse embryo, followed by 128 passages in chicken embryo tissue. Similar to French neurotropic virus, 17D lost its vicerotropism and mosquito transmissibility but did not acquire neurotropism. 17D is very immunogenic and induces neutralizing Abs in 99% of adults and 90% of children.45 Protective immunity is now presumed to be lifelong after a recent assessment by the World Health Organization,46 although some countries continue with 10-year boosters. The actual vaccine consists of three 17D substrains that each underwent a distinct passage history. The 3 strains are genotypically and phenotypically different from each other, but there has been no evidence that immunogenicity or attenuation has been affected.47– 50 Thus, a vaccine developed 480 years ago has led to substantial reduction in cases and deaths caused by YFV.51 The strategy of passaging a field isolate to arrive at a vaccine that recapitulates natural immunity while minimizing symptoms and adverse events continues to shape the field, including contemporary candidate vaccines for DENV and ZIKV.

TBEV: Trade-offs for Safety In addition to culture-based attenuation methods, inactivation is an alternative approach for protecting vaccinees from iatrogenic disease. This point is illustrated by the history of TBEV vaccination. Three subtypes (European, Siberian, Far Eastern) of TBEV cause severe neurologic disease that can result in death. TBEV is endemic in many countries, spanning from Scandinavia to northeast China and Japan,52–54 and the burden of disease is unfortunately increasing despite the availability of a vaccine.55 Initial vaccine development started in the 1930s when TBEV was causing major health concerns in the former Soviet Union.56 Although the first generation of TBEV vaccines were efficacious, they were quickly phased out because of an association with severe adverse effects.57 The Western European vaccines and Russian vaccines are now composed of formalin-inactivated virus preparations of the European and Siberian strains, respectively. The trade-off for tolerability with virus inactivation is the potential for reduction in immunogenicity. Chemical inactivation poses a risk of altering the molecular structure of important antigens, whereas a nonreplicating viral vaccine may not stimulate the full complement of immune

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Clinical Therapeutics responses necessary to confer long-term protection. For example, formalin inactivation is known to affect the protein structure of the WNV particle and thereby influence vaccine immunogenicity, whereas inactivation through other means induces high levels of WNV-specific Abs that protect mice from challenge.58 Kyasanur Forest disease virus is a tickborne flavivirus that causes small epidemics, typically in southern India. A formalin-inactivated tissue culture–derived virus vaccine has been a primary public health tool in responding to this threat in recent years; however, effectiveness remains modest and immunity appears to be short-lived in the absence of repeat boosting.59 Inactivated TBEV vaccines used in children and adults have been reported to induce protective neutralizing Ab responses after three doses.60–64 A head-to-head comparison between vaccines is difficult because of the lack of international standards of immunogenicity.65 Protection has been reported to last three years and longer in both adults and children. Extended time between boosters does not affect protection efficiency.66 In mice, the different vaccines have cross-protection to all three TBEV subtypes, but clinical data about cross-protection in endemic regions are limited.55,67

JEV: Harnessing Advances in Science and Technology Efforts to prevent JEV have further extended the armamentarium for vaccine strategies. JEV causes approximately 68,000 cases each year, mostly in children o15 years of age, with at least half of these resulting in death or neurologic sequelae.68 The first vaccine candidates were inactivated crude antigens prepared in chicken embryos or mouse brain. The mouse brain–derived inactivated vaccine was the only available vaccine for humans for many years;69,70 however, production of this vaccine has been halted because of suspected correlations of acute disseminated encephalomyelitis in vaccinated individuals and other adverse events in immunized individuals.71,72 A licensed live-attenuated vaccine (strain SA14-14-2) was derived from attenuating passages of a wild-type virus, and it remains available today, extensively used in China as part of the routine pediatric immunization series.71 This vaccine is completely attenuated for mice, is tolerable for human use in both adults and children, and does not replicate in mosquitoes.73

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In addition to these traditional approaches, JEV marks an important step forward by using new techniques in molecular biology to create a chimeric virus for the purpose of vaccination. The portion of the JEV genome that encodes structural proteins (targets of the human immune response) was combined with the portion of the YF 17D vaccine strain genome that directs attenuated replication in the human host.71,74 Permutations of this principle have been repeated many times in vaccine development efforts, seeking to combine the right antigens from a pathogen of interest with the most effective vector to strongly induce immunologic memory with no adverse effects. The JE-ChimeraVax produces low levels of viremia in nonhuman primates and humans but induces sustained neutralizing Ab responses after two doses.75 The only licensed JEV vaccine in the United States is an inactivated vaccine of Vero cell culture–derived virus. Effectiveness studies are lacking for both of these vaccines; however, a recent study found that chimeric JEV vaccine induced seroprotection (defined as neut50 ≥1:10; neut50 is the serum dilution at which 50% of complete in vitro neutralization occurs76) to multiple genotypes of JEV at 5 years beyond vaccination.77 The use of JEV vaccines has helped the control of JEV-induced disease in endemic countries, and all licensed vaccines induce durable protective responses. However, the effect of vaccination, especially during childhood, needs further evaluation.71 Another interesting and pertinent point is highlighted by JEV. The live-attenuated vaccine is efficacious and induces high neutralizing Ab titers in many Asian countries, but the same efficacy has not been observed in Indian populations.78 The explanation for this observation is still unclear, but potential factors include inaccurate reporting, different genetic backgrounds of the vaccinees, or vaccine strain mismatch with circulating JEV strains. As a generalization, pathogen diversity is a critical consideration in developing vaccines. Viruses circulating in human populations may evade vaccine-induced immunity if antigenically distinct from vaccine strains. For JEV, there is evidence that most isolates represent a single serotype (although these can be subdivided into 5 genotypes based on nucleotide sequences of E),79,80 which favors vaccine success. For viruses such as DENV, cocirculation of multiple serotypes further complicates vaccine design.81

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M.H. Collins and S.W. Metz

The Imperfections of Success Unfortunately, these “success stories” remain incomplete. Recent YFV outbreaks in South America (2007–2008) and in Angola and the Democratic Republic of the Congo in 2016 exhausted emergency stocks of the vaccine. The practice of fractional dosing of one of the 17D substrains helped to control these major outbreaks and is now implemented in emergency situations.82,83 Efficacy and effectiveness of the dose fractionation are now being evaluated to prepare better for future outbreaks.84 Preparedness includes stockpiling vaccines or proactive immunization, but these measures do not come without complications. Because there is a risk of vaccine-induced adverse effects, such as neurologic and liver disease, preemptive vaccination needs to be carefully considered in regions not endemic or experiencing a YFV outbreak. As part of the ambitious Eliminating Yellow Fever Epidemics program, 1.5 billion individuals are planned to be immunized in the next 5 years in endemic areas or regions with sporadic outbreaks.42 Finally, the experience with YFV reveals the complexity of successful implementation, even of the most effective public health tools. Many factors affect implementation, including mismatches of supply and demand, corruption, poor public health infrastructure, divergent policies in neighboring states, negative perceptions diminishing vaccine uptake, fraudulent vaccines or vaccine cards, and cold chain compromise, just to name a few.85–88

FLAVIVIRUS VACCINES STILL IN PROGRESS WNV: Success and Shortcomings Although a better use of existing tools may be sufficient for infections such as YFV, TBEV, and JEV, other flavivirus vaccines are works in progress. WNV vaccine developmental studies gained considerable traction after introduction of the virus into the United States in 1999. Shortly thereafter, WNV accounted for 3500 cases, resulting in 200 deaths in the United States in 2002. WNV affects areas from Africa to Europe, India, and the Middle East. As with many flaviviruses, a large proportion of infections are asymptomatic; o1% of infections result in neurologic manifestations. Disease can be severe, including seizure, cranial neuropathy, visual disturbances, ataxia, or fatality, and many individuals experience lasting neurologic sequelae. Certain groups, such as the

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elderly, those with chemokine receptor deficiency, and immunocompromised hosts, may be at particular risk for poor outcomes because of WNV infection.1,89 Although an effective WNV vaccine remains an unmet goal for humans, successful prevention of WNV has already been achieved in veterinary practice. Disease in horses have been decreased after licensing of a formalin-inactivated virus vaccine and a canarypox chimeric vaccine in the early 2000s.90,91 Several formalin-inactivated veterinary vaccines are now used to immunize horses. Beyond these veterinary vaccines, other candidates are being studied. Genetic modification of capsid, E, or NS1 has been used to produce live-attenuated WNV strains that induce neutralizing Abs that protect mice or nonhuman primates from lethal challenge.92–94 The most advanced WNV vaccine candidate (ChimeraVax) replicates the strategy discussed above for JEV by expressing WNV antigens in a YF 17D backbone. This live-attenuated vaccine induces high titers of WNV-specific neutralizing Abs and has passed Phase II clinical trials.95,96 Alternatively, subunit vaccines and DNA vaccine approaches are also being developed. Recombinant E has been expressed in various expression systems and formulated with different adjuvants. Two Escherichia coli produced E-ectodomain vaccine prototypes exhibited protection in animal models but required high antigen doses, and both depended highly on the adjuvant coadministered.97,98 Recombinant E protein produced in insect cell lines appeared protective in mice and hamster models and are being used as booster antigens for other equine WNV vaccines.99–102 DNA vaccine prototypes have been developed for WNV and have promise for improved immunogenicity and tolerability over other vaccine platforms. Expression plasmids that encode WNV prM and E sequences theoretically lead to the formation of subviral particles, which morphologically mimic the virus particle. This strategy is effective in smaller animals and horses but has never reached later phases of development.103 Similar vaccine candidates that express subviral particles or the ectodomain of E induce WNV-specific neutralizing Abs.104,105 Despite the effectiveness in smaller animal models, DNA vaccines require high doses of plasmid because of inefficient delivery of the expression construct. In summary, there are multiple vaccines with the potential for eventually preventing WNV in

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Clinical Therapeutics humans.89 Factors to weigh include the cost of vaccine production and distribution as well as the tolerability of the vaccine, given that WNV is a relatively rare cause of severe disease. ZIKV and DENV can be maintained and spread in transmission cycles of only mosquito and humans. In contrast, WNV is primarily sustained by a number of bird species, whereas humans are a dead-end host for this virus.89 Therefore, depending on the transmission ecology of a given flavivirus, vaccination may contribute to control, elimination, or eradication—control in at risk human populations is likely the loftiest achievable goal for WNV. Finally, WNV indicates how well-adapted flaviviruses can be in filling new geographic niches. Phylogenetic analyses indicate there was likely a single introduction of WNV into the United States from the Middle East in 1999, after coast-to-coast dissemination in a few short years.1 Therefore, constant vigilance and improved surveillance are required to manage flavivirus infections from a public health perspective.

FOCUS ON DENV AND ZIKV VACCINES DENV Vaccines: So Close and So Far Of all flaviviruses, vaccine development against DENV infections is among the most complex challenges. There are two major issues. First, DENV comprises four antigenically distinct serotypes with several genotypes within each serotype. Infection with one serotype generally confers lifelong immunity to the infecting serotype and transient cross-protection to heterologous serotypes. Secondary infection expands sustainable cross-reactive immunity such that symptomatic infections by a third DENV serotype are unusual.6,16,81,106–108 However, inducing protection to all four DENV serotypes by one vaccine has proved a high bar to meet. Second, severe manifestations of DENV are most commonly observed in secondary infection. The leading explanatory model is that crossreactive but nonneutralizing Abs from primary infection by a heterologous DENV serotype enhance disease in the second DENV infection.16,109–111 Thus, a DENV vaccine must give rise to lasting, protective immunity to all serotypes lest it run the risk of doing more harm than good. In addition, the emergence of ZIKV in many DENV-endemic areas has invigorated interest in a pan-flavi vaccine or at least one that protects against ZIKV and all four DENV serotypes.

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Although some data support claims that a pan-flavi vaccine may be possible,112–116 we believe that ZIKV and DENV are serologically distinct and that crossreactive Abs will not engage the critical viral epitopes targeted by strongly neutralizing Abs required for protection.81,117–120 Since the onset of vaccine development in the early 1920s, DENV vaccine researchers have cycled through many vaccine platforms. Methods such as inactivated virus, live-attenuated virus, subunit, DNA, and viral vectors have recently been in tested in preclinical or in clinical trial studies.121 Currently, there are multiple candidate vaccines in clinical development, and one vaccine, CYD-TDV (Dengvaxia), has recently been licensed in Mexico, Brazil, El Salvador, Paraguay, and the Philippines. Dengvaxia is a quadrivalent combination of four monovalent chimeric attenuated viruses that comprise the prM and E sequence of each DENV serotype grafted onto the nonstructural protein backbone of YF 17D.122,123 The vaccine was genotypically and phenotypically stable and tolerable in Phase I trials.122,124 A subsequent Phase II trial revealed protection against DENV3 and DENV4, modest protection against DENV1, but failure to induce protection against DENV2.125 In 2011, the vaccine underwent Phase III clinical trials, including 430,000 individuals in 10 endemic countries throughout Asia and Latin America.126,127 Pooled data indicated an unsatisfactory 59.2% efficacy against all clinically diagnosed DENV cases one year after a three-dose vaccine regimen. The vaccine efficacy against severe DENV was 76.9%. Per serotype, the overall efficacy was 54.7% (DV1), 43.0% (DV2), 71.8% (DV3) and 76.9% (DV4).126,127 In the third year of trial in Asia, increased hospitalized cases with mild or severe DENV were observed in young children from 2 to 5 years old.126,128 The reasons for these results are not entirely clear but may include unbalanced replication of the different chimeric viruses that represent the various DENV serotypes.129 Vaccinees with preexisting DENV immunity clearly had better outcomes than DENV-naive vaccinees, indicating that CYD-TDV may be better suited to broaden existing DENV immunity rather than provoke complete protection against all DENV serotypes in individuals without any prior flavivirus exposure.11,81,129 Two other live-attenuated DENV vaccines are in Phase III trials, whereas still others, such as a purified

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M.H. Collins and S.W. Metz inactivated vaccine, is in Phase I trials.130,131 An attenuated DENV2 strain is the scaffold for one such candidate. To achieve immunity to all four DENV serotypes, the coding sequences for structural proteins (prM and E) of each serotype have been introduced into the attenuated DENV2 vaccine backbone to create three distinct recombinant viruses. This vaccine has been licensed by Takeda Vaccines Inc and is currently being evaluated in a large Phase III study in Asia and Latin America.132–134 The second candidate, which is four genetically attenuated virus strains of each serotype developed by the National Institutes of Health, is now in Phase III evaluation in Brazil. These vaccines have produced encouraging results for tolerability, immunogenicity, and protection in Phase II trials. In addition, the attenuated strains are being used as challenge strains in the human DENV infection model and have great promise for moving to Phase III clinical trials.135–137

Second-Generation DENV Vaccines Because the need for cold chain can be avoided and the risk of reversion to pathogenicity and other adverse effects can be reduced in nonreplicating vaccines, there continues to be interest in subunit vaccines and other modes of antigen delivery. DENV E is being pursued as the main antigen in several subunit-based vaccines. Harboring the major epitopes targeted by neutralizing Abs, E is being delivered as a recombinant protein as individual E domains or through DNA vaccination. Immunization of mice and nonhuman primates with recombinant E-domain III induces protective neutralizing Abs.138 Combining recombinant E-domain III subunits from all four serotypes into one tetravalent vaccine formulation resulted in the induction of long-term neutralizing immunity against DENV1-4.139,140 This strategy may require further optimization because most DENVinduced neutralizing Abs in humans are not specifically directed against E-domain III.141 The use of intact recombinant E may therefore be a more promising platform. E is expressed in a large variety of expression systems that differ in preservation of viral antigen processing.142 Furthermore, display of complex epitopes formed by multiple E monomers is likely to be critical to effective DENV vaccination given recent findings in studies of DENV-neutralizing Ab form humans.143–146 The use of nanomaterials and nanoparticles to deliver recombinant E is now being

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evaluated in preclinical studies. We and others have observed that particulation of recombinant E augments induction of neutralizing responses compared with soluble antigen.147,148 DNA plasmids are used to deliver other subunit-based vaccine candidates. A mix of vectors that express monovalent prM and E constructs is being further developed after clearing a Phase I clinical trial.130,149–151 Several studies have found that in addition to DENV E, NS1 immunization can induce protective immune responses in mice. NS1 alone, delivered by DNA vaccination, as well as in combination with other antigens, such as recombinant E, induces both humoral and cellular immunity to protect against DENV disease.152–157 However, the use of NS1-based vaccines may also be associated with enhanced DENV disease and increased morbidity in animal models.130,158,159

ZIKV Vaccination Several vaccine platforms are being investigated for ZIKV vaccine development, and leading vaccine candidates, some of which are in Phase I human trials, have produced promising results in preclinical studies. A formalin-inactivated virus strain with alum adjuvant induced potent neutralizing Ab responses after a single immunization.160 A modest amount of antigen (5 µg) of the same vaccine candidate in a prime-boost regimen protected rhesus monkeys from developing viremia on subsequent challenge.161 Deletion of 10 nucleotides in the 3’ untranslated region of ZIKV resulted in the first live-attenuated vaccine candidate.162 In mice, this candidate induced neutralizing Abs, and the immunocompromised mice were protected against lethal challenge. Other efforts to develop a live-attenuated ZIKV vaccine use strategies similar to those from DENV vaccine development.135 The ZIKV prM and E sequences have been cloned into an attenuated DENV2 backbone, and this vaccine candidate is currently being tested for immunogenicity and safety. Additional vectors for delivery of ZIKV antigens are under evaluation and include a rhesus adenovirus serotype 52 vector that expresses ZIKV prM and E, which would lead to the formation of subviral particles. A single immunization in rhesus monkeys resulted in potent neutralizing Ab responses that completely protected the animal from challenge.161 Another adenovirus vector was designed to express ZIKV E fused to a fibritin trimerization domain.

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Clinical Therapeutics Immunization elicited ZIKV-specific IgG that was maternally transferred to pups and protected the suckling mice from lethal challenge.163 As previously done for pathogens, including Ebola virus, influenza virus, and Toxoplasma gondii, alphavirus replicons have also been used to express ZIKV antigens, the replicons being delivered through nanoparticles and successfully inducing ZIKV-specific IgG.164,165 The DNA vaccine platform has yielded one of the most promising vaccine candidates to date. An expression plasmid encoding ZIKV prM-E produces ZIKV subviral particles that induce high titers of protective, ZIKV-specific neutralizing Abs in both mice and nonhuman primates.160,161 Passive immunization with purified IgG from vaccinated animals rendered mice completely protected against ZIKV challenge. DNA vaccine prototypes that express recombinant E did not elicit protection or any neutralizing Abs, clearly indicating that higher-order E-protein structures are essential for the induction of neutralizing Abs.160,166 Other nucleotide approaches use mRNA transfection of host cells as the mode of vaccination, using lipid nanoparticles to deliver mRNA encoding ZIKV prME. In different murine models, this approach induced neutralizing Abs. Interestingly, mutation in the conserved fusion loop region of ZIKV induced the same efficient protective immune response but diminished the production of Abs that cross-react with DENV,167 achieving a key goal given concerns of Ab-dependent enhancement in sequential infection by closely related flaviviruses.118,168,169 ZIKV vaccine development has engendered caution and optimism. As with DENV, preclinical models offer advantages and limitations.170,171 The 2 major issues are that neither mice nor nonhuman primates replicate human disease manifestations very well and that mice are naturally resistant to flavivirus infection and productive infection requires manipulation of the murine immune system.172 Next-generation mouse models may improve available systems for preclinical research by deletion of viral restriction factors in select cells or tissues173 or introducing human transgenes. For example, HLA transgenic mouse experiments have found utility in identifying T-cell epitopes that are relevant to cellular immunity after natural human infection.174 Recently, related mouse studies have significantly advanced our knowledge of T-cell responses to ZIKV.175 Furthermore, primate and mouse models of ZIKV have demonstrated

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transmission, vertical transmission, and neuropathologic findings in offspring of ZIKVinfected pregnant females.172,176,177 On the clinical end of the development spectrum, serologic testing is an essential tool in vaccine development because precisely knowing an individual’s flavivirus exposure status before, during, and after experimental vaccination is critical to assessing tolerability and efficacy of flavivirus vaccines. However, existing assays for diagnosing flaviviruses are compromised by cross-reactive Ab elicited after flavivirus infection,178–180 a problem clearly observed with prior and current ZIKV outbreaks.181,182 Because of extensive overlap in transmission patterns between DENV and ZIKV, this issue complicates ongoing and future vaccine trials for these 2 viruses.181 Fortunately, next-generation assays that detect virus type–specific Abs are currently under development.117–119,180 Coming on the heels of DENV (and other flavivirus epidemics), ZIKV vaccine development has benefited from a “head start,” which has led to an unprecedented pace of research toward attaining an effective vaccine.12,163,183 Finally, whereas the antigenic diversity represented among the four DENV serotypes has been a major challenge, ZIKV appears to have remained antigenically similar over space and time. ZIKV-immune serum and monoclonal Abs neutralize ZIKV strains from the African and Asian lineages as well as various field isolates.13,117,184,185 Thus, achieving global protection against ZIKV should be possible with a vaccine of single-antigen formulation.

ADDITIONAL CONSIDERATIONS FOR FUTURE FLAVIVIRUS VACCINE DEVELOPMENT T-Cell Responses Although much attention has been given to Ab responses in flavivirus vaccinology, less progress has been made in identifying key determinant of protective cellular immunity to flaviviruses. A particular consideration is that the only approved DENV vaccine is a chimeric virus constructed by grafting the structural proteins from each DENV serotype onto a backbone of YFV nonstructural proteins. Thus, potentially important DENV-specific Tcell epitopes derived from DENV nonstructural proteins are omitted in this platform.129,186 Although cross-reactive T-cell responses were originally implicated in a dysfunctional immune response that may contribute to

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M.H. Collins and S.W. Metz more severe cases of secondary DENV infection,187 more recent work points to the value of more robust T-cell immunity in reducing the risk of developing symptoms or severe manifestations of DENV infection.186 There is an emerging body of literature that points to the importance of cellular responses in ZIKV infection and vaccination as well.160,161,175,188–190 Interestingly, infection with DENV elicits cross-reactive T-cell responses that protect against subsequent ZIKV challenge in HLA transgenic mice.188 As with Ab response to closely related flaviviruses, much remains to be learned regarding the interplay between type-specific and cross-reactive immune responses that occur after natural infection or vaccination and what the effect of these responses will be on the human host’s next encounter with a flavivirus infection.

Vaccine Safety Careful assessment of vaccine safety is an obvious and essential part of all modern vaccine development. A principle determinant of risk is the type of vaccine. YFV vaccine, which is a live-attenuated virus, has rarely caused cases of severe neurotropic and viscerotropic reactions during decades of use,191 and possible teratogenic effects have been investigated. Potential for reversion to wild type or fully virulent virus, pathogenicity in immunocompromised hosts, or recombination events between vaccine and circulating strains that lead to new, deleterious phenotypes have all been put forward as reasons for trepidation with these vaccines,191 although the latter phenomenon has never been observed in nature.13 Live virus vaccines are generally avoided during pregnancy, which is an important target population for ZIKV vaccines (further discussed below). The quality of reports on YFV that was inadvertently administered to pregnant women preclude definitive conclusions, but several reports suggest adverse effects in pregnant women are not increased above baseline rates.192 Despite the guarded view of a few authors, the YFV vaccine is widely regarded as one of the most tolerable vaccines in use.193 Tolerability data from human ZIKV vaccine trials are not yet available, but monitoring is largely colored by experience with DENV vaccines.183,194 The first DENV vaccine was approved in 2015 and remains somewhat controversial from a safety perspective,11,195 particularly in young children.196 Phase III studies revealed an increased risk of hospitalization among children o9 years of age, ] 2017

with the effect being most pronounced in those o5 years of age.110,128 Various hypotheses have been proposed to explain differences in the efficacy observed, the most convincing being that vaccination of DENV-immune individuals leads to sustained, broad protection against all 4 DENV serotypes.129 Indeed, greater efficacy was measured in seropositive (DENV immune) patients compared with seronegative (DENV naive) patients in these trials.129 The combination of these findings led some to advocate for serologic testing of DENV immune status before vaccine administration as a precaution.197 Ongoing safety monitoring for Dengvaxia and two other liveattenuated vaccine candidates in late-phase development121 must be balanced with efficacy data to arrive at optimal implementation. Lastly, we have alluded to the possibility that Abs induced by DENV infection or vaccination may exacerbate disease phenotypes after ZIKV infection via Ab-dependent enhancement.118,168,169 Although there is in vitro and mouse-model data to support this concern, this phenomenon has not been proven in primate models198 or clearly observed in humans.199 Safety must be the top priority, and it may be that achieving protective immunity in a portion of the population is sufficient to reduce the burden of DENV (or ZIKV) infection.129

Vaccines for Pregnant Women Women’s health is at the center of the ZIKV epidemic, and the adverse pregnancy outcomes associated with ZIKV emergence have placed new emphasis on the status of women’s health in the larger context of global health. As an example, in Puerto Rico, it is estimated that 20% of women of reproductive age do not intend to become pregnant and are not using effective contraception.200 These disparities are multifactorial but generally indicate shortcomings of public health education and access to women’s health and family planning services. Lack of availability or banning of such services has also been associated with maternal morbidity and mortality.201 From the perspective of vaccine development, Phase III trials would ideally be superimposed on existing health infrastructure; shortcomings in providing primary care to women of reproductive age represent additional barriers to evaluating vaccines and thus delivering the end product to the population that needs them most. Furthermore, pregnant women

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Clinical Therapeutics are often systematically excluded from clinical trials. However, if the objective is to develop an intervention meant for use in women during or before pregnancy, this may be the most essential group to include in studies, and leaving them out of the process may lead to greater risk suffered by larger numbers of women globally. We hope additional work to establish ethical standards for clinical trials in pregnant women will improve this situation.202

OUTLOOK FOR FUTURE There are tremendous prospects for preventing substantial morbidity, mortality, and economic losses attributable to flavivirus infections worldwide, and to quote leading experts in the field,203 “Simply put: Vaccination saves lives.” However, hurdles remain to realize this great potential, and it will take additional time and effort to deliver the emerging tools and technologies to the vulnerable populations that will most benefit from vaccination. Investment and careful studies are still needed to establish immunogenicity and protective efficacy as well as ensure safety in general and in special groups, such as pregnant women. Ultimately, vaccine-mediated prevention of all flavivirus infections is a solvable problem. The solutions will offer huge public health benefit and teach us much about human immune responses that confer protection against viral pathogens, and help us manage and prepare for current and future epidemics.

ACKNOWLEDGMENTS We thank Cory Keeler for creation of maps and discussion of flavivirus epidemiology. We thank Aravinda de Silva for critical appraisal of the manuscript. MHC and SWM both searched the literature independently, developed the concept, drafted and edited the manuscript. SWM worked with Cory Keeler on figure development. MHC managed final edits and revisions.

FUNDING SOURCES This research was funded by the grants 5T32AI00715139 (Dr. Margolis, principal investigator), 1-R01AI107731-01 (Dr. de Silva, principal investigator), and U19 AI109784-01 (Dr. Ting, principal investigator) from the National Institute of Health.

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CONFLICTS OF INTEREST The authors report no conflicts of interest.

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Address correspondence to: Matthew H. Collins, MD, PhD Department of Medicine, Division of Infectious Diseases, University of North Carolina, CB 7292, 160 Dental Circle, 9024 Burnett Womack, Chapel Hill, NC 27599-7292. E-mail: matthew.colli[email protected]

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