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Overview of Zika Alan D.T. Barrett Department of Pathology Sealy Center for Vaccine Development University of Texas Medical Branch Galveston TX

Overview of Zika - WHOreported congenital syndrome associated with Zika virus infection (WHO, June 2, 2016) . Number of investigated cases of microcephaly and other congenital malformation

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  • 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.

  • 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

    Caribbean

    Aruba 0 17 0

    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

    Cumulative Zika suspected and confirmed cases reported by countries and territories in the Americas, 2015-2016

    Updated as of 2 June 2016

  • 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

  • Asymptomatic

    Infections

    1,600,000

    West Nile Fever

    350,000

    Central nervous system

    13,204

    West Nile Clinical Manifestations (1999-2011)

    “The Iceberg”

    Death

    1,352 0.1%

  • Asymptomatic

    Infections

    ?????

    Zika Fever

    ?????

    Congenital Zika Syndrome

    ????

    Zika Clinical Manifestations (2015-2016)

    “The Iceberg”

    Death

    10 0.0%?

    1-15%

    20%

    80%

    Guillain-Barre syndrome 1%?

  • 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

  • Lanciotti et al., 2008

    Zika cross-reactivity – Zika as a secondary flavivirus infection

  • 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.

  • Mouse pregnancy models

    • Miner et al. Zika Virus Infection during Pregnancy in Mice

    Causes Placental Damage and Fetal Demise. Cell

    • Cugola et al. The Brazilian Zika virus strain causes birth

    defects in experimental models. Nature.

    • Li et al. Zika virus disrupts neural progenitor development and

    leads to microcephaly in mice. Cell Stem Cell.

    Models use immunocompetent mice.

    SJL looks best mouse model?

  • ZIKV in NHPs

    • Indian-origin rhesus macaques infected with French Polynesia Asian

    lineage Zika virus were rechallenged with 104 PFU of the same virus

    In all three animals, there is no evidence of plasma viremia at any

    timepoint following rechallenge. Similar data with Uganda MR766

    strain. (Wisconsin National Primate Research Center)

  • Human Challenge Model

    • Interest in developing human challenge models as has

    been done for dengue.

    • Alternative/supplement traditional clinical trials.

    • Ethical and safety considerations?

  • Correlates of Protection for flaviviruses How do we define protection?

    Neutralizing antibody – surrogate for licensed flavivirus

    vaccines

    Lack of clinical disease

    Reduced/lack of viremia

    Memory? Important for live vaccines…. YF 17D

    vaccine appears to give life-long protective immunity

    after one dose. Inactivated vaccines need boosters

    every 3-5 years.

  • Surrogate of protection for licensed flavivirus vaccines Flavivirus Live, subunit or

    inactivated? Serotypes Test Quantity

    Japanese encephalitis

    Live and inactivated

    1 PRNT/neutralization 1 in 10

    Yellow fever Live 1 Log neutralization index PRNT/neutralization

    0.7+ 1 in 10-50*

    ???

    Tick-borne encephalitis

    Inactivated 1? PRNT/neutralization 1 in 10

    dengue Live 4 PRNT/neutralization? ?????

    Zika ???? 1? PRNT/neutralization? ????

    + The level of antibody considered to be protective was an log10 neutralization index of 0.7

    originally based on studies in nonhuman primates

    * Seroprotective levels of neutralizing antibodies, measured by PRNT, have not been determined

  • Passive protection in animal models

  • Cell Host & Microbe 2016 19, 696-704DOI: (10.1016/j.chom.2016.04.013)

    Dai et al. Cell Host & Microbe 2016 19, 696-704

    DOI: (10.1016/j.chom.2016.04.013)

    Passive protection of mice demonstrated

    with mouse Fab

  • Flavivirus “serotypes”

    • Studies to date indicate each mosquito-borne flavivirus species

    has multiple genotypes, but only one serotype…. Except maybe

    dengue?

    • Yellow fever: 7 genotypes; one serotype

    • Japanese encephalitis: 5 genotypes; one serotype

    • Zika: 3 genotypes?; One serotype?

    • Dengue: “Four serologically and genetically related viruses”; 4

    serotypes? 4-6 genotypes per “serotype”.

  • Is ZIKV one serotype?

  • Amino Acid ML Tree: E Protein

  • Can we infer from other flaviviruses?

    • Yes… but some caveats?

    • Monovalent vaccine

    • Induction of neutralizing antibodies could be potentially a surrogate

    of protection…. But how would we measure a Zika-specific

    neutralizing antibody response in vaccinees?

    • Passive protection studies has been used in licensure of JE, TBE

    and YF vaccines… what about Zika?

  • How do you do a flavivirus neutralization test? • De ja vue!

    • Cell type, virus strain, and assay type will influence results.

    • Plaque reduction neutralization test (PRNT)

    PRNT50?

    PRNT60?

    PRNT80?

    PRNT90?

    • Micro-neut

    • Flow cytometry

    • A standardized, validated assay will be important to quantitate

    neutralizing antibodies

  • What would be needed to develop a surrogate marker of protection

    • Standards: Antibodies and validated assay to

    measure marker of protection (NIBSC).

    • Standards: qRT-PCR to measure viremia in

    validated assay (PEI)

  • Use Zika vaccine development as the “blueprint” for “Vaccine development pathway” for emerging diseases?