TWiV 402: The plight of the bumblebee

Polio returns to Nigeria, Zika virus spreads in Miami, and virus infection of plants attracts bumblebees for pollination, from the virus gentlepeople at TWiV.

You can find TWiV #400 at microbe.tv/twiv, or listen below.

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Zika Virus in the USA

On this episode of Virus Watch we cover three Zika virus stories: the first human trial of a Zika virus vaccine, the first local transmission of infection in the United States, and whether the virus is a threat to participants in the 2016 Summer Olympic and Paralympic Games.

TWiV 401: Vector victorious

Zika virus spreads in the USA, a Zika virus DNA vaccine goes into phase I trials, and how mosquito bites enhance virus replication and disease, from the friendly TWiFolk Vincent, Dickson, Alan, and Kathy.

You can find TWiV #401 at microbe.tv/twiv, or listen below.

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Antibodies aid dengue and Zika virus infection

Antibody dependent enhancementFlaviviruses are unusual because antibodies that cross-react with different viruses can enhance infection and disease. This property, called antibody-dependent enhancement or ADE, has been documented to occur among the four serotypes of dengue virus. It has implications for infection with or vaccination against Zika virus or dengue virus.

Earlier this year (virology blog link) it was shown that antibodies to dengue virus – in the form of serum from infected patients, or two human monoclonal antibodies – bind to Zika virus and can enhance infection of Fc-receptor bearing cells (Fc receptors bind the antibody molecule, allowing uptake into cells – illustrated). When the antibodies to dengue virus were omitted, Zika virus barely infected these cells. The conclusion is that dengue antibodies enhance infection of cells in culture by Zika virus.

This early work was first published as a preprint on the bioRxiv server – which lead some to criticize me for discussing the work before peer review. However, I subjected the paper to my own peer review, of which I am entirely capable, and decided it was worthy of discussion on this blog.

The results have now been confirmed by an independent group (paper link). Sera from patients that were infected with dengue virus, as well as dengue virus specific human monoclonal antibodies, were shown to bind Zika virus and enhance infection of Fc receptor bearing cells. These are the same findings of the group who first published on bioRxiv. That paper still has not been published – apparently it is mired in peer review, with many new experiments requested. I do hope that none of the authors of the second paper are involved in delaying its publication – something that happens all too often in science. As a colleague once remarked, ‘the main function of peer review is to prevent your competitors from publishing their work’.

Whether or not antibodies to dengue virus enhance Zika virus disease in humans is an important unanswered question.

If you are wondering whether antibodies to Zika virus can enhance dengue virus infection, the answer is yes (paper link). Monoclonal antibodies were isolated from four Zika virus-infected patients, and shown to enhance infection of Fc receptor bearing cells with either Zika virus or dengue virus. Furthermore, administration of these antibodies to mice before infection with dengue virus led to severe disease and lethality, a demonstration of antibody-dependent enhancement in an animal model.

Of interest is the finding that ADE mediated lethality in this mouse model can be completely prevented by co-administering the same antibody that has been modified to block binding to Fc receptors on cells. This result suggests a modality for treating patients with enhanced disease caused by either dengue virus or Zika virus.

These observations suggest that we need to be careful when deploying vaccines against Zika virus or dengue virus – it is possible that the antibody response could enhance disease. Recently a dengue virus vaccine called Dengvaxxia was approved for use in Brazil, Mexico, and the Philippines. However, the vaccine is not licensed for use in children less than 9 years of age because in clinical trials, immunization lead to more severe disease after infection compared with non-immunized controls. Analysis of the clinical trial data (paper link) indicates that seronegative individuals of all ages were at increased risk for developing severe disease that requires hospitalization. The authors suggest that severe disease is a consequence of enhancement of infection caused by antibodies induced by the vaccine (see CIDRAP article for more information).

These observations lead to the question of whether immunization against dengue and Zika viruses might enhance disease caused by either virus. Could a solution to this potential problem be to use a vaccine that combines the four serotypes of dengue virus with Zika virus? If so, the dengue virus component should not be Dengvaxia, but possibly another vaccine (e.g. TV003 – virology blog link) that does not induce disease enhancing antibodies.

Zika virus vaccine

The first experimental Zika virus vaccine has been published, and in this episode of Virus Watch, I explain how it works – it’s a DNA vaccine – and I compare it with all the other vaccines out there.

TWiV 399: Zika la femme

The latest Zika virus news from the ConTWiVstadors, including a case of female to male transmission, risk of infection at the 2016 summer Olympics, a DNA vaccine, antibody-dependent enhancement by dengue antibodies, and sites of replication in the placenta.

You can find TWiV #399 at microbe.tv/twiv, or listen below.

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Congress fails on Zika virus

Zika virusAndrew W. Gurman, M.D., President of the American Medical Association, has expressed disappointment in the failure of Congress to support the US public health response to Zika Virus:

At a time when concerns continue to mount about the nation’s readiness to protect the public from the Zika virus, the AMA is disappointed by Congress’ failure to pass legislation before adjourning for summer recess that would provide the resources necessary for our country to respond to this looming public health crisis.

Without ensuring there are sufficient resources available for research, prevention, control and treatment of illnesses associated with the Zika virus, the United States will be ill-equipped to deploy the kind of public health response needed to keep our citizens safe and healthy—especially since the spread of mosquito-borne illness is accelerated during the summer months.

I could not agree more with the AMA – Congress has so far failed to do the right thing with respect to Zika virus. Even if the virus does not spread within the continental United States, this country has an obligation to be a leader in scientific research that would benefit the entire world. Zika virus is clearly a threat to other parts of the globe, and by refusing to fund research on this virus, Congress is sending the message that it doesn’t care about the health problems of others.

Zika Zoo

When we decided to work on Zika virus in February 2016, experiments in mice were certainly part of our plans. However, one does not simply walk into a mouse facility and start inoculating animals with viruses! Carrying out animal experiments requires approval of a detailed protocol by the Institutional Animal Care and Use Committee (IACUC). I have filed many IACUC protocols in the past 30 years, and to work on Zika virus in mice, we had to file a new one. Here is how the process works.

Read the remainder of this article at Zika Diaries.

TWiV 393: Lovers and livers

Possible sexual transmission of Zika virus, and a cell protein that allows hepatitis C virus replication in cell culture by enhancing vitamin E mediated protection against lipid peroxidation, are the subjects discussed by the TWiVerati on this week’s episode of the science show This Week in Virology.

You can find TWiV #393 at microbe.tv/twiv, or listen below.

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Zika virus and mosquito eradication

Aedes aegyptiThe Aedes aegypti eradication campaign coordinated by the Pan American Health Organization led by 1962 to elimination of this mosquito from 18 countries, including Brazil. Ae. aegypti transmits not only Zika virus, but dengue virus, chikungunya virus, and yellow fever virus. Could control measures be implemented today to achieve similar control of this mosquito? Two articles in PLoS Neglected Tropical Diseases revisit the successful PAHO mosquito control campaign and suggest that its approaches should be revived.

The elimination of Ae. aegypti in 18 countries, which was accompanied by a marked reduction in dengue hemorrhagic fever, was achieved by removing mosquito breeding sites or spraying them with DDT. Determining whether households harbored such breeding sites was essential for the effectiveness of the campaign.

The United States did not participate in the PAHO campaign, even though Ae. aegypti was (and still is) present in that country, and was a vector for outbreaks of dengue fever from the 1920s through the 1940s. Peter Hotez (link to paper) cites a “lack of funds and political will” and “logistical difficulties due to lack of access to private homes or cultural norms of privacy in the US”. As a consequence, by 1970 the US became one of the last reservoirs of Ae. aegypti in the Americas.

Eventually the PAHO campaign fell apart and Ae. aegypti returned, followed by outbreaks of dengue fever in the 1980s in Latin America and the Caribbean, and Chikungunya virus and Zika virus in 2013.

Hotez argues that while control of Ae. aegypti is labor intensive and involves house-to-house spraying, PAHO demonstrated its feasibility. He further suggests that by not participating in the PAHO campaign, the US failed to establish a generation of mosquito control expertise, which is now needed as Zika virus and other mosquito-borne viruses threaten to spread. He calls for an “unprecedented campaign against the Ae. aegypti mosquito”. However, he does not specify exactly what kind of control should be implemented, only saying that “these activities might not closely resemble the Latin American programs of the 1960s”.

Paul Reiter (link to paper) believes that the success of the PAHO campaign “can be attributed to a single aspect of the behavior of the mosquitoes: female Ae. aegypti do not lay all their eggs in one basket”, but rather place them at multiple locations. During the PAHO campaign, infested containers were identified and sprayed with DDT, increasing the likelihood that a female would lay eggs at a site that had been treated. This approach is called perifocal.

The current use of fogging machines to spray residential areas with insecticides has a low impact on mosquito populations, according to Reiter, because they only work for a few minutes when the droplets are airborne. He believes that we should return to perifocal treatments to eliminate mosquitoes, but not using DDT. Rather he suggests the use of other, novel insecticides, such as crystals of deltamethrin embedded in a rain and sun-proof polymer that ensures release for three months.

Reiter acknowledges that long-term use of insecticides leads to resistance, in which case we should turn to the new anti-mosquito approaches that are being developed, including the release of mosquitoes containing Wolbachia bacteria or a lethal gene. But he indicates that these approaches “are some way from mass application”, and meanwhile, perifocal approaches could reduce mosquito populations (although the newer insecticides would first need to be tested).

The best way to prevent viral infection is with a vaccine, but one for Zika virus is likely years away. Meanwhile, mosquito control can make a difference, as it could for the next emerging virus well before a vaccine can be developed.