New ways to treat Zika

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The pandemic outbreak of the Zika virus in Central and South America as well as the Caribbean, and its link to microcephaly in newborn babies led the WHO to declare the virus a global emergency. No vaccine or therapy currently exists, but the correlation between Zika and microcephaly in newborn babies started a race to develop a treatment.

Zika belongs to the family of Flaviviruses and is spread by day-time active Aedes mosquitoes. Other well-known members of the Flavivirus family are Yellow and Dengue Fever. In contrast to these two serious and sometimes fatal diseases, Zika causes mostly no or only mild symptoms (such as a rash and mild fever). Treatment is normally simply resting up or, if needed, medication (such as paracetamol) to treat the fever.

Vaccines to prevent Zika infections

Classically, vaccines consist of live or attended viruses or virus particles. Most childhood-vaccines are based on this approach. While this strategy is reliable, it can take years to develop a successful vaccine.

Sanofi, its vaccines global business unit Sanofi Pasteur and the Walter Reed Army Institute of Research (WRAIR) are co-developing a Zika vaccine candidate based on WRAIR’s Zika purified inactivated virus vaccine technology. With funding from the US government (BARDA), Takeda is another pharma company working on an inactivated, adjuvanted, whole Zika virus vaccine. As of November 2016, the National Institute of Allergy and Infectious Diseases (NIAID) has a phase I trial recruiting volunteers to test the safety of a purified inactivated vaccine.

A newer class of DNA-based vaccines can be faster in research and development as they do not require the growth of live virus. Researcher simply produces a DNA molecule from the virus. This engineered DNA is, after being introduced into host cells, translated into proteins that can activate the immune system to respond against the virus.

And indeed, the first Zika vaccine entering Phase I trials in healthy volunteers in the summer of 2016 was a DNA-vaccine developed by Inovio and GeneOne Life Science. The immunotherapy called GLS-5700 SynCon® targets the membrane and envelope region of the Zika virus. The vaccine induced robust antibody and T cell responses in animal models. In addition to safety and tolerability, the ongoing open-label, dose-ranging study will test if similar immune responses are induced in healthy volunteers. In addition to Inovio, the NIAID is recruiting participants for two phase I trials (VRC-ZKADNA085-00-VP and VRC-ZKADNA090-00-VP) to test safety and immunogenicity of their DNA-based vaccines.

Blocking the infection of cells with antibiotics

Research out of UCSF, published in PNAS in December 2016, suggests that besides vaccinations, Zika infections may be controlled by already FDA approved, save to use during pregnancy antibiotics.

Antibiotics block bacterial growth and are routinely prescribed to patients suffering from bacterial infections. They do not help against viruses as they specifically affect bacterial pathways, such as the bacterial ribosome inhibiting protein synthesis. Viruses, unlike bacteria, do not have their own protein synthesis machinery. They infect cells and utilize the host ribosomes to produce viral proteins – which is why antibiotics cannot affect viruses. At least not in their classical mode of action.

What the UCSF study shows, is a non-classical function besides blocking of bacterial ribosomes. Azithromycin somehow hinders Zika from infecting brain cells, potentially by blocking Zika entering and thereby infecting host cells such as neural stem cells via susceptibility factor AXL.

The data in this study is mainly derived from cell culture experiments; it is therefore unclear if azithromycin will have the same protective effect in humans. Previous studies on azithromycin have shown that the antibiotic can enter the placenta and fetal tissues, suggesting it may have a good chance at blocking Zika infecting fetal brain cells, the cause of microcephaly. A clinical trial to test this is currently being planned in Brazil.

This hasn’t been the first report showing that an antibiotic may help against Zika. A study published in July 2016, found that duramycin can block the infection of placental cells and thereby the transmission of the virus from mother to fetus. A molecule called TIM1 was identified susceptibility factor in placental cells – similar to AXL in the brain.

The advantage of using antibiotics against Zika is that, it can protect the developing embryos after an infection already occurred, a scenario where vaccines are of no help. Given their FDA approval, their use, once proven azithromycin and duramycin hinder Zika from infecting the brain or placenta, respectively, could be rolled out quickly.

Picture of the mosquito from flickr;  licence: CC BY 2.0

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