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Overview of Zika

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Overview of Zika Overview of Zika Alan D.T. Barrett Department of Pathology Sealy Center for Vaccine Development University of Texas Medical Branch Galveston TX Disclaimer • Over 700 papers in pubmed on Zika in the last 12 months. • Impossible to stay up to date as field is moving so fast. • Only including material in public domain. ZIKV: 1947-2006 • Zika virus (ZIKV) causes Zika fever (ZF), an acute febrile illness characterized by a rash, conjunctival injection, arthralgia, myalgia and headache. • The disease appears in all age groups with an incubation period on the order of 3-14 days and a symptomatic phase lasting about 2-7 days. • Treatment is largely symptomatic. • The illness is mild in nature with a very low rate of hospitalization. • The vast majority of patients make a full recovery and while death is rarely reported, it has primarily occurred in the immunocompromised or those with other complicating medical conditions. • Only 14 clinical cases in the literature from 1951-2006. Map showing the known distribution of Zika virus based on serosurveys, virus detection, and laboratory-diagnosed cases. Blue arrows show recent patterns of spread deduced from phylogenetic studies Weaver et al Antiviral Research, Volume 130, 2016, 69–80 ZIKV in the Americas Current ZIKV activity ZIKV transmission • ZIKV is primarily transmitted by Aedes spp. Mosquitoes. • Infectious ZIKV particles have been demonstrated in urine, saliva, semen, blood products, and breast milk possible vehicles of transmission. • Male-to-female and male-to-male transmission of ZIKV have been reported, but only from individuals with clinical signs/symptoms of ZIKV infection. • Establishing person-to-person transmission is difficult, as contacts frequently have the same environmental exposures. • Epidemiologic relevance of person-to-person transmission has yet to be elucidated. • Although viremia during infection is short-lived, typically lasting less than 4 days, it appears that infectious virus may persist in semen and body organs much longer (perhaps months) making it much more difficult to prevent human-to-human transmission. ZIKV serology Serologic evidence in Africa of infection in forest-dwelling birds, horses, cattle, ducks, bats, elephants, goats, hippopotamuses, impala, kongoni, water buffalo, sheep, wildebeest, rodents, and zebras Serologic evidence in the Americas of infection in monkeys and humans. No other species examined? ZIKV 2007- present (ADEM and GBS) • Most ZIKV infections are asymptomatic (75-80%). • ZIKV outbreaks have been associated with increased rates of rare autoimmune neurologic disorders such as Acute Disseminated Encephalomyelitis (ADEM) and Guillain-Barre syndrome (GBS). • Both conditions can result from a number of infectious diseases. • The incidence is ADEM around one tenth that of GBS and little is known about its occurrence following ZIKV infection. • There appears to be about a 10- to 20-fold increase in GBS during ZIKV outbreaks from the baseline incidence of 1-2 cases per 100,000 people. • It has been reported that the clinical onset of ZIKV outbreak associated GBS cases is more rapid than typical, with a median of 6 days from the onset of signs of ZIKV infection to GBS symptoms. Congenital Zika Syndrome • Vertical transmission from mother to the fetus during pregnancy. • Outcomes: placental insufficiency, fetal growth restriction, oligohydramnios, ocular disorders, auditory impairments, CNS injury and fetal death. • Signs of CNS injury associated with ZIKV include congenital microcephaly, ventricular calcifications, migration defects, simplified gyral patterns, dysgenesis of the corpus collosum and cerebellar hypoplasia. • Congenital microcephaly is present at birth and is defined as having a head circumference at least two standard deviations smaller than the mean for gestational age, sex and ethnicity. • The risk of congenital microcephaly is likely to be highest if women are infected during the first trimester, and is estimated to be 1-15 in 100 pregnant women. • Studies have demonstrated poor outcomes including microcephaly from infections occurring in the second and third trimester. It is currently not known whether intra-uterine transmission can occur in pregnant women who have asymptomatic ZIKV infections. Cumulative Zika suspected and confirmed cases reported by countries and territories in the Americas, 2015-2016 Updated as of 2 June 2016 Sub-Region Country / territory Suspected Zika Confirmed Zika Deaths among Zika cases North America Mexico 0 314 0 Subtotal 0 314 0 Central America Belize 0 2 0 Costa Rica 2,090 58 0 El Salvador 11,631 46 0 Guatemala 1,089 1,162 0 Honduras 21,025 44 2 Nicaragua 0 207 0 Panamá 638 274 0 Subtotal 36,473 1,793 2 Latin Caribbean Cuba 0 1 0 Dominican Republic 2,370 73 0 French Guiana 6,700 483 0 Guadeloupe 6,320 379 0 Haiti 1,777 5 0 Martinique 26,650 12 0 Puerto Rico 10,535 1,170 1 Saint Martin 425 109 0 Subtotal 54,777 2,232 1 Andean Bolivia 99 11 0 Colombia 80,953 6,402 0 Ecuador 393 143 0 Peru 0 5 0 Venezuela 31,224 352 0 Subtotal 112,669 6,913 0 South Cone Argentina 1,613 19 0 Brazil 154,270 39,993 3 Paraguay 273 8 0 Subtotal 156,156 40,020 3 Non Latin Aruba 0 17 0 Caribbean Barbados 316 7 0 Bonaire 0 3 0 Curacao 0 73 0 Dominica 203 28 0 Grenada 0 1 0 Guyana 0 6 0 Jamaica 646 14 0 Saint Barthelemy 19 7 0 Saint Lucia 0 2 0 Saint Vincent and the Grenadines 0 2 0 Sint Maarten 0 7 0 Suriname 2,503 527 4 Trinidad and Tobago 0 16 0 United States Virgin Islands 228 21 0 Subtotal 3,915 731 4 Total 363,990 52,003 10 Countries and territories in the Americas with GBS in the context of Zika virus circulation. (WHO, June 2, 2016) . Countries and territories in the Americas reporting confirmed and suspected cases of Zika virus disease in pregnant women (WHO, June 2, 2016) . Countries and territories in the Americas with reported congenital syndrome associated with Zika virus infection (WHO, June 2, 2016) . Number of investigated cases of microcephaly and other congenital malformation of the CNS in Brazil by epidemiological week, EW 3 – EW 21 of 2016 Source: Data published by the Brazil Ministry of Health and reproduced by PAHO/WHO West Nile Clinical Manifestations (1999-2011) Death 0.1% 1,352 Central nervous system <1% 13,204 20% West Nile Fever 350,000 80% Asymptomatic Infections 1,600,000 “The Iceberg” Zika Clinical Manifestations (2015-2016) Death 0.0%? 10 Guillain-Barre syndrome 1%? Congenital Zika Syndrome 1-15% ???? 20% Zika Fever ????? 80% Asymptomatic Infections ????? “The Iceberg” Viremia (active virus multiplication) “FACTS” • Viremia – low and transient in humans and NHPs (104 pfu/ml; 107 genome equivalents/ml) • Sometimes can detect viremia by RT-PCR but cannot recover infectious virus from serum. What does this mean? • Hard to isolate virus from serum • Sometimes no isolates from outbreak (Yap) or one (French Polynesia) QUESTIONS: • Human - mosquito - human transmission cycle? (like dengue) • Humans are dead-end hosts? (like West Nile) • Non-mosquito-transmission important? • What are we missing? • Will ZIKV be like “dengue” or “West Nile”? • What do we do if ZIKV activity disappears in Summer 2016? Complexities of evaluating flavivirus immune responses • Flavivirus serology is a “minefield”. Hard to serologically identify an infection as due to a particular flavivirus unless the individual is flavivirus-naïve. • Karl Johnson called flaviviruses the “Hall of Mirrors” • Challenging to assess and interpret immunological data due to cross-reactivity. Zika cross-reactivity – flavivirus naive Lanciotti et al., 2008 Zika cross-reactivity – Zika as a secondary flavivirus infection Lanciotti et al., 2008 Yap Island results and flavivirus vaccines • The neutralizing antibody titer may be higher against a previous (primary?) flavivirus infection rather than the most recent heterologous flavivirus (secondary?) infection. • Individuals who have been previously vaccinated against yellow fever, Japanese encephalitis, (candidate) dengue, or tick-borne encephalitis can have a rapid and high neutralizing antibody titer following infection by a heterologous flavivirus. Usually, seen with mosquito-borne flavivirus infections (JE, YF and DEN vaccine). • Will be complex interpreting immune responses following immunization with candidate ZIKV vaccines in areas where other flaviviruses co-circulate. Candidate ZIKV vaccines Candidate ZIKV vaccine candidates • Estimated to be approximately 40 candidates. Not all in public domain. • All either in discovery or preclinical. • “Advanced” candidates in mice and NHPs for immunogenicity. • Phase I in Fall 2016? Candidate ZIKV vaccines Live attenuated (4): Recombinant ChimeriVax™ – Sanofi Pasteur; Recombinant dengue-2 – Instituto Butantan/US NIH; Recombinant chimeric 17DD – Bio-Manguinhos/Fiocruz; Recombinant ZIKV infectious clone – UTMB/Evandro Chagas Institute/Brazil Ministry of Health. Formalin inactivated purified whole virus (5): Bharat Biotech; ChimeriVax – Sanofi Pasteur; Bio-Manguinhos/Fiocruz; NewLink Genetics; Instituto Butantan/ US NIH Live vectored (4): Measles virus vector - Themis Bioscience/Institut Pasteur; Lentivirus-vector – Institut Pasteur; MVA-VLP – GeoVax; Simian Adenovirus – Jenner Institute Candidate ZIKV vaccines DNA/RNA (4): DNA – Bio-Manguinhos/Fiocruz; DNA plasmid expressing VLP – US CDC; GLS-5700 DNA – Inovio/GeneOne Life Science; DNA –prM/E – US NIH Subunit E protein (5): Recombinant N-terminal 80% E plus Alhydrogel or proprietary adjuvant from collaborator – Hawaii Biotech; Synthetic Replikins peptides – Replikins; Recombinant E protein – Protein Sciences/Sinergium Biotech/Mundo Sano; Recombinant flagellin/E protein – VaxInnate; E protein/nanoparticles –Novavax VLP-based (3): VLP - Bharat Biotech; VLP – Bio- Manguinhos/Fiocruz; VLP - PaxVax Animal models Mice deficient in either interferon αβ (A129) and αβγ (AG129) receptors • ZIKV not lethal (only viremia) in immunocompetent mice. • Number of mouse strain/virus strain combinations where ZIKV strains cause 100% lethal infections. • A129 mouse model: MP1751 (Uganda, mosquito, 1962; East African lineage), 106 pfu, intraperitoneal route in 6 week old mice. • AG129 mouse model: 259249 (Panama, 2015; Asian Lineage), 104 pfu, intraperitoneal route in 12 week old mice.
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