Zika Virus Overview and Impact
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What has been shown to be effective in preventing ZIKV acquisition?

  • Previous infections
  • Neutralizing antibodies from vaccines (correct)
  • Genetic polymorphisms
  • Lifestyle changes

    • Which stages of clinical trials have candidate ZIKV vaccines completed?

  • Phase III and IV
  • Phase II and IV
  • Phase I and III
  • Phase I and II (correct)

    • In which models has ZIKV's dynamics of viral replication been studied?

  • Human clinical trials
  • Cell cultures only
  • Rhesus macaque and non-human primates (correct)
  • Mice and rabbits

    • What action did the World Health Organization take regarding the ZIKV epidemic?

    <p>Declared an end to the epidemic</p> Signup and view all the answers

    Which type of contact has not been associated with ZIKV transmission, as per the content provided?

    <p>Respiratory droplets</p> Signup and view all the answers

    Why is vaccine development for ZIKV still a high priority?

    <p>ZIKV remains a concern despite low levels</p> Signup and view all the answers

    What characteristic of the rhesus macaque model is highlighted in the content?

    <p>It consistently reproduces features of ZIKV infection</p> Signup and view all the answers

    What does the presence of genetic polymorphisms relate to in the context of ZIKV?

    <p>Development of Congenital Zika Syndrome (CZS)</p> Signup and view all the answers

    What is the primary benefit of vaccination against ZIKV for pregnant rhesus macaques?

    <p>It prevents ZIKV distribution to fetal tissues.</p> Signup and view all the answers

    What was a significant consequence of ZIKV outbreaks in Brazil in late 2015?

    <p>An increase in cases of congenital ZIKA syndrome.</p> Signup and view all the answers

    Which type of antibodies are associated with vaccine efficacy in preventing ZIKV in pregnant rhesus macaques?

    <p>ZIKV neutralizing antibodies.</p> Signup and view all the answers

    ZIKV is primarily transmitted through which vector?

    <p>Aedes mosquitoes.</p> Signup and view all the answers

    What does CDC guidance recommend for pregnant women regarding travel to areas with ZIKV outbreaks?

    <p>They should consult with medical providers before traveling.</p> Signup and view all the answers

    What limiting factor currently affects the establishment of clinical trial sites for ZIKV vaccines?

    <p>Current low levels of ZIKV worldwide.</p> Signup and view all the answers

    Which virus family does ZIKV belong to?

    <p>Flaviviridae.</p> Signup and view all the answers

    Why is the development of a ZIKV vaccine considered feasible?

    <p>Research indicates a strong immune response can be generated.</p> Signup and view all the answers

    What was the method used to analyze the IFNγ ELISPOT responses in the study?

    <p>Friedman one-way ANOVA</p> Signup and view all the answers

    What was the criterion for indicating responses above 50 SFU per 106 PBMCs?

    <p>A dotted line</p> Signup and view all the answers

    What percentage of fetuses from non-vaccinated dams showed evidence of viral replication in tissues?

    <p>20%</p> Signup and view all the answers

    What characteristic of fetuses born to Ad26.M.Env vaccinated dams was confirmed via sonography?

    <p>Normal biometric parameters</p> Signup and view all the answers

    What was the timeframe after immunization in which colored responses were noted for the dams?

    <p>10 weeks to 22 weeks</p> Signup and view all the answers

    What type of animal was used in the study to evaluate the immunization effects?

    <p>Pregnant macaques</p> Signup and view all the answers

    What was the main purpose of collecting fetal tissues at necropsy?

    <p>To check for vRNA evidence</p> Signup and view all the answers

    How many fetuses from vaccinated dams were reported to have no evidence of viral replication in tissues?

    <p>5 out of 5</p> Signup and view all the answers

    What is a primary concern regarding the immunity provided by the Ad26 Ebola vaccine over time?

    <p>Immunity may wane, leading to re-emergence of ZIKV.</p> Signup and view all the answers

    Which mosquito species is identified as a vector for ZIKV in the southern United States?

    <p>Aedes aegypti</p> Signup and view all the answers

    What is the status of the Ad26.M.Env vaccine in relation to safety and tolerability based on the Phase I clinical trial?

    <p>Well tolerated with no safety concerns identified.</p> Signup and view all the answers

    What type of responses did the Ad26.M.Env vaccine induce in study participants?

    <p>Robust ZIKV neutralizing titers similar to macaques.</p> Signup and view all the answers

    What challenge is posed by the lack of exposure to ZIKV during the 2016 epidemic for the U.S. population?

    <p>Heightened vulnerability to future ZIKV epidemics.</p> Signup and view all the answers

    Which type of vaccines have been shown to be immunogenic and protective against ZIKV?

    <p>mRNA based vaccines.</p> Signup and view all the answers

    What was the outcome of transferring immune sera from vaccinated study participants to mice?

    <p>Mice were protected against ZIKV vRNA in blood.</p> Signup and view all the answers

    What is a key consideration for developing vaccines to protect naïve individuals during future ZIKV outbreaks?

    <p>Developing a well-tolerated and safe vaccine.</p> Signup and view all the answers

    What was the mean peak vRNA level found on day 7 post-amniocentesis samples?

    <p>5.5 log10</p> Signup and view all the answers

    How long did non-vaccinated, challenged animals have detectable virus on average?

    <p>42 days</p> Signup and view all the answers

    What method was used to measure fetal biometric analyses in dams after confirmation of pregnancy?

    <p>Biparietal diameter</p> Signup and view all the answers

    Which sample types were reported to be negative for ZIKV vRNA?

    <p>Saliva and vaginal</p> Signup and view all the answers

    What type of immune response does the Ad26.M.Env vaccine induce?

    <p>Cellular immune anti-Env response</p> Signup and view all the answers

    How many weeks was the vaccination response measured after immunization?

    <p>4 weeks</p> Signup and view all the answers

    Which of the following was NOT mentioned as a type of sample collected?

    <p>Amniotic fluid</p> Signup and view all the answers

    After vaccination, what was observed in all samples from the challenged dams?

    <p>Negative for ZIKV vRNA</p> Signup and view all the answers

    In which animals was the peak vRNA reported?

    <p>Challenged dams regardless of vaccination status</p> Signup and view all the answers

    What was the focus of the monitoring conducted on dams post-pregnancy confirmation?

    <p>Fetal biometric analyses</p> Signup and view all the answers

    Which specific immune response was examined in the statistical figures?

    <p>Env specific Cellular IFN- response</p> Signup and view all the answers

    What was the detectable viral load trend over the 42 days observed in non-vaccinated challenged animals?

    <p>Gradually decreasing</p> Signup and view all the answers

    Which of the following was NOT a response measured post-vaccination?

    <p>Immune pressure</p> Signup and view all the answers

    Neonates born to vaccinated dams had evidence of ZIKV vRNA in their tissues.

    <p>False</p> Signup and view all the answers

    Fetal biometric parameters showed abnormalities in all study groups.

    <p>False</p> Signup and view all the answers

    C-section was performed approximately 2 weeks before the estimated delivery date.

    <p>True</p> Signup and view all the answers

    Vaccinated animals showed no detectable anti-Env cellular immune responses prior to challenge.

    <p>False</p> Signup and view all the answers

    The geometric mean response per group was indicated with a vertical line.

    <p>False</p> Signup and view all the answers

    2 out of 5 fetuses from non-vaccinated dams had evidence of viral replication in tissues.

    <p>True</p> Signup and view all the answers

    No adverse events were reported in either the vaccinated or non-vaccinated groups prior to the ZIKV challenge.

    <p>True</p> Signup and view all the answers

    Responses above 50 SFU per 106 PBMCs were indicated by a solid line.

    <p>False</p> Signup and view all the answers

    Pregnant females in the non-vaccinated group were not infected with Zika virus.

    <p>False</p> Signup and view all the answers

    Fetal brain weights and body weight ratios were similar across all groups studied.

    <p>True</p> Signup and view all the answers

    Vaccinated dams had detectable virus in confirmed pregnancy.

    <p>False</p> Signup and view all the answers

    All samples from challenged dams showed evidence of ZIKV vRNA after vaccination.

    <p>False</p> Signup and view all the answers

    The prM-specific cellular responses were noted to be generally high in both groups.

    <p>False</p> Signup and view all the answers

    Animal monitoring included evaluation of white blood cell count and total lymphocyte counts.

    <p>True</p> Signup and view all the answers

    Some animals experienced trauma that required clinical intervention, which was linked to vaccination status.

    <p>False</p> Signup and view all the answers

    Animals in the vaccinated group maintained normal reference ranges throughout the study period.

    <p>True</p> Signup and view all the answers

    The Ad26 Ebola vaccine is recommended as a childhood vaccine in Ebola endemic regions.

    <p>True</p> Signup and view all the answers

    A lack of exposure to ZIKV in the US population during the 2016 epidemic makes individuals immune to future outbreaks.

    <p>False</p> Signup and view all the answers

    Aedes aegypti mosquitoes are primarily found in the northern United States.

    <p>False</p> Signup and view all the answers

    The Ad26.M.Env vaccine was found to have safety concerns during clinical trials.

    <p>False</p> Signup and view all the answers

    The development of a well-tolerated vaccine for ZIKV is essential for protecting naïve individuals.

    <p>True</p> Signup and view all the answers

    Adenoviral based vaccines have shown variable efficacy in inducing neutralizing antibody responses in monkeys.

    <p>True</p> Signup and view all the answers

    Transferring immune sera from vaccinated study participants to mice resulted in protection against ZIKV.

    <p>True</p> Signup and view all the answers

    Immune-mediated thrombocytopenia and thrombosis have been fully understood regarding their mechanisms after COVID-19 vaccinations.

    <p>False</p> Signup and view all the answers

    A significant consequence of the ZIKV study included the detection of viral replication in the tissues of all fetuses from vaccinated dams.

    <p>False</p> Signup and view all the answers

    The Ad26.M.Env vaccine was produced using the human PER.C61 cell line.

    <p>True</p> Signup and view all the answers

    The live infants delivered to the vaccinated group included a total of six males.

    <p>False</p> Signup and view all the answers

    ZIKV-specific neutralizing antibodies were measured using fold reduction neutralization assays.

    <p>True</p> Signup and view all the answers

    Reproductive failure rates were observed to be outside the historical control range for primates in the study.

    <p>False</p> Signup and view all the answers

    All dams and fetuses in the study were euthanized for physiological assessments.

    <p>True</p> Signup and view all the answers

    A total of five live male infants and three live female infants were delivered to the non-vaccinated, challenged group.

    <p>False</p> Signup and view all the answers

    The virus input for the assays was incubated with serum samples for one hour at 37 °C.

    <p>True</p> Signup and view all the answers

    Optical density at 280 nm was used to determine Ad26 particle concentrations.

    <p>False</p> Signup and view all the answers

    Microneutralization assays involve serially diluting serum samples in a total volume of 100 uL.

    <p>True</p> Signup and view all the answers

    Vero cells were maintained in EMEM media supplemented with 10% FBS.

    <p>True</p> Signup and view all the answers

    Ultrasounds were performed only on ZIKV-infected pregnant rhesus monkeys.

    <p>False</p> Signup and view all the answers

    The absorbance during cell development was read at 550 nm.

    <p>False</p> Signup and view all the answers

    Serum/virus mixtures were incubated with Vero cell monolayers for 1 hour at 35 °C.

    <p>False</p> Signup and view all the answers

    Animals were sedated with Telazol at a dose of 10 mg/kg for the procedures.

    <p>False</p> Signup and view all the answers

    The monoclonal antibody 6B6-C1 was developed with HRP for the assays.

    <p>True</p> Signup and view all the answers

    Study Notes

    Zika Virus (ZIKV) and its Impact

    • ZIKV is a member of the Flaviviridae family, first identified in Uganda in 1954.
    • Prior to 2015, ZIKV was associated with mild, flu-like symptoms.
    • In late 2015, a ZIKV epidemic in Brazil led to a surge in cases of fetal microcephaly, prompting global efforts to develop a vaccine.
    • ZIKV is primarily spread through Aedes mosquitos, but can also be transmitted transplacentally, through blood transfusions, and sexually.
    • Genetic polymorphisms have been linked to the development of congenital Zika syndrome (CZS).
    • The World Health Organization (WHO) declared the end of the ZIKV epidemic in late 2016, but vaccine development remains a priority due to the potential for resurgence.
    • ZIKV is a concern for individuals traveling to or living in endemic areas, particularly pregnant women.
    • While ZIKV transmission is currently at low levels, vaccine development is challenging due to the difficulty in establishing clinical trial sites and enrolling participants.

    Vaccine Development and Research

    • Vaccination prevents ZIKV distribution to fetal tissues, including the brain.
    • ZIKV-associated neuropathology was absent in offspring of Ad26.M.Env vaccinated dams, while pathology was limited in fetuses from unvaccinated, challenged dams.
    • Vaccine efficacy is linked to the induction of ZIKV neutralizing antibodies in pregnant rhesus macaques.
    • Clinical trials for ZIKV vaccines are underway, with several candidates completing Phase I and II safety studies.
    • The rhesus macaque model has proven useful in studying the dynamics of viral replication and shedding during ZIKV infection.
    • Studies in mice and non-human primates have demonstrated that inducing neutralizing antibodies through various vaccine platforms effectively prevents ZIKV acquisition.

    Future Directions

    • Ideally, a ZIKV vaccine could be deployed quickly in the event of a resurgence and administered safely to pregnant women.
    • Continued research and development are crucial for creating an effective and readily available ZIKV vaccine to protect vulnerable populations from the devastating effects of CZS.

    Study Background

    • The study investigated the effectiveness of an investigational Ad26.M.Env vaccine against Zika virus (ZIKV) in pregnant macaques.
    • The vaccine used a modified adenovirus type 26 (Ad26) vector expressing the ZIKV envelope (Env) protein as a potential ZIKV immunogen.
    • The study compared the vaccine's effect on vaccinated pregnant macaques versus unvaccinated pregnant macaques challenged with ZIKV.

    Vaccine Efficacy

    • Following ZIKV challenge, both vaccinated and unvaccinated macaques exhibited peak viral RNA (vRNA) levels on day 7 post-challenge.
    • Importantly, all vaccinated macaques remained negative for detectable vRNA in body fluids (colorectal, vaginal, saliva) throughout the study.
    • In contrast, unvaccinated macaques showed detectable viral loads for an average of 42 days.

    Immune Responses

    • The Ad26.M.Env vaccine induced low-level cellular immune responses, primarily against the Env protein, in vaccinated pregnant macaques.
    • The study measured interferon-gamma (IFNγ) production by peripheral blood mononuclear cells (PBMCs) as an indicator of cellular immunity.
    • Although responses were generally lower than expected, they indicated some degree of immune priming by the vaccine.

    Fetal Development

    • The researchers closely monitored fetal development using ultrasound throughout the pregnancies.
    • No significant differences were observed in fetal biometric parameters or brain development between vaccinated and unvaccinated macaques.
    • This suggests that the vaccine did not adversely affect fetal growth or neurological development in pregnant macaques.

    Protection from ZIKV Infection

    • At term, all fetuses born to vaccinated dams were negative for ZIKV vRNA, indicating complete protection from ZIKV infection.
    • Histopathological evaluation of fetal tissues revealed no evidence of viral replication in any of the vaccinated fetuses.
    • In contrast, two out of five unvaccinated dams gave birth to fetuses with detectable ZIKV vRNA in their tissues, suggesting transmission from the infected mothers.

    Summary

    • These results demonstrate that the Ad26.M.Env vaccine effectively protected pregnant macaques from ZIKV infection and prevented vertical transmission to their offspring.
    • While the vaccine induced lower than expected immune responses, it proved sufficient to confer complete protection against ZIKV infection in this animal model.
    • Further research is warranted to optimize the vaccine and explore its potential application in human pregnancies.

    Adenovirus-based Vaccines for Zika Virus

    • An Ad26.ZEBOV Ebola vaccine is licensed and recommended for childhood use in Ebola endemic regions.
    • The Ad26.M.Env (Ad26.ZIKV.001) vaccine for Zika Virus has been tested in a Phase I clinical trial.
    • All tested vaccine regimens were well-tolerated, with no safety concerns identified.
    • Vaccination with Ad26.M.Env induced robust Zika Virus neutralizing titers in humans similar to those achieved in macaques.
    • Immune sera from vaccinated humans transferred to mice could protect mice against Zika Virus.
    • Adenoviral-based vaccines combatting COVID-19 were associated with immune-mediated thrombocytopenia and thrombosis.
    • The mechanisms for these adverse effects remain unclear.
    • Further research is required to determine if these adverse effects are linked to the interaction between the Adenovirus-based vaccine and the COVID-19 spike protein, or the Adenovirus vaccine platform itself.
    • Adenoviral constructs are still widely studied and will likely remain an important platform for global use.

    Zika Virus Pandemic Risk

    • Previous Zika Virus outbreaks in Malaysia have shown a cyclical re-emergence due to waning immunity over time.
    • The United States faces a risk of future Zika Virus pandemics due to the presence of the Aedes aegypti mosquito vector in the Southern United States.
    • The lack of exposure to Zika Virus during the 2016 epidemic makes the US population vulnerable to future outbreaks.
    • A well-tolerated and safe vaccine is needed for pre- and perinatal use to protect susceptible individuals.

    mRNA-based Zika Virus Vaccines

    • mRNA-based vaccines against Zika Virus have demonstrated immunogenicity and protective effects in non-human primate challenge studies.
    • These vaccines have shown variable efficacy in inducing neutralizing antibody responses in humans.

    Ad26.M.Env Vaccine and Protection Against Zika Virus in Pregnant Macaques

    • A study investigated the safety and efficacy of an Ad26.M.Env vaccine against Zika virus (ZIKV) in pregnant rhesus macaques.
    • Pregnant macaques were divided into two groups: vaccinated with Ad26.M.Env and non-vaccinated control.
    • Both groups were challenged with ZIKV at 6 weeks post-conception (~10-30 weeks post-vaccination).
    • Key finding: Vaccinated dams remained completely protected from ZIKV infection in blood and tissues.
    • Key finding: All fetuses born to vaccinated dams were also negative for ZIKV, and had no ZIKV-associated histopathological abnormalities.
    • Key finding: Non-vaccinated dams and their fetuses exhibited ZIKV infection.
    • The study suggests that the Ad26.M.Env vaccine is safe and efficacious in protecting pregnant macaques and their fetuses from ZIKV infection.
    • The Ad26.M.Env vaccine elicited strong cellular immune responses in vaccinated animals.
    • The vaccine also induced robust ZIKV neutralizing antibody titers, comparable to human volunteers in a Phase 1 clinical trial.

    Neutralization Assays

    • The study measured ZIKV-specific neutralizing antibodies using two methods: fold reduction neutralization (FRNT) and micro-neutralization (MN) assays.
    • FRNT assay is based on the principle of measuring the reduction in virus infectivity after exposure to serum containing neutralizing antibodies
    • MN assay involves serially diluting serum samples in microplates, adding ZIKV, and then observing the effect of the serum on viral replication in Vero cells.
    • Both FRNT and MN assays confirmed the presence of neutralizing antibodies in vaccinated animals.

    Zika Virus Challenge

    • ZIKV challenge stock was prepared from the 2015 Brazilian epidemic strain.
    • Pregnant macaques were infected with 1x103 PFU (1×106 vp) of ZIKV via subcutaneous route at 6 weeks post-conception.

    Clinical Monitoring

    • All animals were monitored for clinical signs, body weight, and complete blood cell count (CBC) throughout the study period.
    • Ultrasonography was performed bi-weekly to assess pregnancy status and fetal development.
    • No serious adverse events were reported in relation to vaccination or ZIKV challenge.

    Fetal Evaluation

    • Dam were euthanized at term and fetuses underwent C-section.
    • Fetal and placental tissues were collected for histopathology, viral RNA analysis, and gross examination.

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