Zika Virus: Medical Countermeasure Development Challenges

Introduction: Reports of high rates of primary microcephaly and Guillain–Barré syndrome associated with Zika virus infection in French Polynesia and Brazil have raised concerns that the virus circulating in these regions is a rapidly developing neuropathic, teratogenic, emerging infectious public health threat. There are no licensed medical countermeasures (vaccines, therapies or preventive drugs) available for Zika virus infection and disease. The Pan American Health Organization (PAHO) predicts that Zika virus will continue to spread and eventually reach all countries and territories in the Americas with endemic Aedes mosquitoes. This paper reviews the status of the Zika virus outbreak, including medical countermeasure options, with a focus on how the epidemiology, insect vectors, neuropathology, virology and immunology inform options and strategies available for medical countermeasure development and deployment. Methods: Multiple information sources were employed to support the review. These included publically available literature, patents, official communications, English and Lusophone lay press. Online surveys were distributed to physicians in the US, Mexico and Argentina and responses analyzed. Computational epitope analysis as well as infectious disease outbreak modeling and forecasting were implemented. Field observations in Brazil were compiled and interviews conducted with public health officials

Transmission of Asian Zika Lineage by Aedes aegypti and Ae. albopictus Mosquitoes in Florida

The Asian lineage of Zika virus (ZIKV), a mosquito-borne pathogen originally from Africa, caused an epidemic into Brazil in 2015 and subsequently spread throughout the Americas. Local transmission in the U.S. is a public health concern, especially for Florida where the mosquito vectors Aedes aegypti and Ae. albopictus are widespread, abundant, and there is a high potential for virus introduction due to imported cases. Here we evaluate relative susceptibility to infection and transmission of Zika virus among geographic populations of Ae. aegypti and Ae. albopictus in Florida. Both species have been implicated as ZIKV vectors elsewhere, but both virus and vector genotype are known to influence transmission capacities and, hence, the risk of outbreaks. We test the hypothesis that Ae. aegypti and Ae. albopictus show geographic differences in midgut and salivary gland barriers that limit ZIKV transmission, using local populations of the two vector species recently colonized from three regions of Florida to compare their susceptibility to ZIKV infection, disseminated infection, and transmission potential. Susceptibility to infection was higher in Ae. aegypti (range 76–92%) than Ae. albopictus (range 47–54%). Aedes aegypti exhibited 33–44% higher susceptibility to infection than Ae. albopictus, with Ae. aegypti from Okeechobee, FL having 17% higher susceptibility to infection than Ae. aegypti from Miami, FL. Similarly, disseminated infection was higher in Ae. aegypti (range 87–89%) than Ae. albopictus (range 31–39%), although did not vary by region. Enhanced infection and disseminated infection in Ae. aegypti were associated with higher viral loads in mosquito samples than in Ae. albopictus. Transmission rates did not vary by species or region (range 26–47%). The results support the hypothesis that Ae. aegypti, but not Ae. albopictus, exhibited regional differences in midgut infection barriers. Our observation of higher vector competence for Ae. aegypti than Ae. albopictus, together with this species greater propensity to feed on humans, lends support to the notion that Ae. aegypti is regarded as the primary vector for ZIKV and public health concern in continental U.S

The Extrinsic Incubation Period of Zika Virus in Florida Mosquitoes Aedes aegypti and Ae. albopictus

The Asian genotype of Zika virus (ZIKV) emerged in Brazil in 2015 and subsequently spread throughout the Americas. In July 2016, Florida experienced its first locally acquired ZIKV infection in the continental U.S. Concerns about health risks from ZIKV infection have increased the need to investigate the interactions between potential mosquito vectors and ZIKV. The time it takes for an arbovirus to propagate within a mosquito, and become transmissible, is the extrinsic incubation period (EIP). The EIP for potential mosquito vectors in Florida is unknown. To address this gap in the understanding of ZIKV epidemiology, Florida Aedes aegypti (L.) and Ae. albopictus (Skuse) were orally exposed to ZIKV infected blood meals and fully engorged mosquitoes were held at a constant temperature of 28 °C through the duration of the experiment. Saliva expectorates were collected from cohorts of mosquitoes and tested for the presence of ZIKV at three-day intervals over a period of 24 days to allow for an evaluation of the EIP of the emergent Asian lineage of ZIKV. High rates of infected bodies in Ae. albopictus (75–94%) and Ae. aegypti (68–86%) were observed throughout the incubation period, which did not differ by species. Higher rates of disseminated infection were observed later during the incubation period but did not differ between species. We calculated the 50% EIP to be shorter in Ae. albopictus than Ae. aegypti (16.2 and 18.2 days post infection, respectively). The competence for ZIKV observed in both species may contribute to high rates of ZIKV transmission in Florida populations

Transmission of Asian Zika Lineage by <i>Aedes aegypti</i> and <i>Ae. albopictus</i> Mosquitoes in Florida

The Asian lineage of Zika virus (ZIKV), a mosquito-borne pathogen originally from Africa, caused an epidemic into Brazil in 2015 and subsequently spread throughout the Americas. Local transmission in the U.S. is a public health concern, especially for Florida where the mosquito vectors Aedes aegypti and Ae. albopictus are widespread, abundant, and there is a high potential for virus introduction due to imported cases. Here we evaluate relative susceptibility to infection and transmission of Zika virus among geographic populations of Ae. aegypti and Ae. albopictus in Florida. Both species have been implicated as ZIKV vectors elsewhere, but both virus and vector genotype are known to influence transmission capacities and, hence, the risk of outbreaks. We test the hypothesis that Ae. aegypti and Ae. albopictus show geographic differences in midgut and salivary gland barriers that limit ZIKV transmission, using local populations of the two vector species recently colonized from three regions of Florida to compare their susceptibility to ZIKV infection, disseminated infection, and transmission potential. Susceptibility to infection was higher in Ae. aegypti (range 76–92%) than Ae. albopictus (range 47–54%). Aedes aegypti exhibited 33–44% higher susceptibility to infection than Ae. albopictus, with Ae. aegypti from Okeechobee, FL having 17% higher susceptibility to infection than Ae. aegypti from Miami, FL. Similarly, disseminated infection was higher in Ae. aegypti (range 87–89%) than Ae. albopictus (range 31–39%), although did not vary by region. Enhanced infection and disseminated infection in Ae. aegypti were associated with higher viral loads in mosquito samples than in Ae. albopictus. Transmission rates did not vary by species or region (range 26–47%). The results support the hypothesis that Ae. aegypti, but not Ae. albopictus, exhibited regional differences in midgut infection barriers. Our observation of higher vector competence for Ae. aegypti than Ae. albopictus, together with this species greater propensity to feed on humans, lends support to the notion that Ae. aegypti is regarded as the primary vector for ZIKV and public health concern in continental U.S

Transmission Potential of Zika Virus by \u3ci\u3eAedes aegypti\u3c/i\u3e (Diptera: Culicidae) and \u3ci\u3eAe. Mediovittatus\u3c/i\u3e (Diptera: Culicidae) Populations From Puerto Rico

Recurrence of local transmission of Zika virus in Puerto Rico is a major public health risk to the United States, where mosquitoes Aedes aegypti (Linnaeus) and Aedes mediovittatus (Coquillett) are abundant. To determine the extent to which Ae. mediovittatus are capable of transmitting Zika virus and the influence of viremia, we evaluated infection and transmission in Ae. mediovittatus and Ae. aegypti from Puerto Rico using serial dilutions of infectious blood. Higher doses of infectious blood resulted in greater infection rates in both mosquitoes. Aedes aegypti females were up to twice as susceptible to infection than Ae. mediovittatus, indicating a more effective midgut infection barrier in the latter mosquito species. Aedes aegypti exhibited higher disseminated infection (40–95%) than Ae. mediovittatus (\u3c5%), suggesting a substantial midgut escape barrier in Ae. mediovittatus. For Ae. aegypti, transmission rates were low over a range of doses of Zika virus ingested, suggesting substantial salivary gland barriers

Summary of Brazilian States (Federated units), current Zika circulation patterns, and increased incidence of primary microcephaly.

<p>Summary of Brazilian States (Federated units), current Zika circulation patterns, and increased incidence of primary microcephaly.</p

Countries and territories with active Zika virus transmission.

<p>Countries and territories with active Zika virus transmission.</p

Projection of Zika virus infections in states with laboratory confirmation of Zika virus circulation during 2015 (18 of 27 Brazilian states or federated units).

<p>Projection of Zika virus infections in states with laboratory confirmation of Zika virus circulation during 2015 (18 of 27 Brazilian states or federated units).</p

Zika virus, past and current distribution.

<p>Source: Centers for Disease Control and Prevention [<a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0004530#pntd.0004530.ref083" target="_blank">83</a>].</p

States in Brazil investigating microcephaly cases for association with Zika virus infection (above), and with confirmed circulation of Zika virus (below).

<p>After [<a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0004530#pntd.0004530.ref099" target="_blank">99</a>]. Information sources include Brazilian Health Ministry (Ministério da Saúde);WHO (World Health Organization); PAHO (Pan American Health Organization).</p