Academics Hone in on Human Antibodies to Fight Zika and Dengue Viruses
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The Zika virus was first identified in 1947. Since then, the World Health Organization (WHO) has kept tabs on the virus as researchers learned more of its lineage and infectivity profile.
In November 2015, the WHO declared the ZIKA virus outbreak an epidemic.
The Zika virus is a flavivirus primarily transmitted via the Aedes mosquito, which is also the vector for dengue virus and chikungunya virus. In adults, it produces flu-like symptoms and is generally cleared from the blood in a week. However, it is known to hide-out in immune-privileged tissues, such as the nervous system, eyes and placenta for longer.
Read more: Zika virus infectivity
In the unborn fetus, symptoms are more severe. The Zika virus has been shown to selectively target neuronal precursor cells leading to microcephaly, mental retardation and under-development of the central nervous system.
This video explains more about how infectious the virus is and the risks it poses to human health.
Zika virus- causes, outbreak, symptoms and pathology explained in this video from Osmosis
Searching for antibodies to fight the Zika Virus
Since the epidemic in 2015, there has been a research explosion to find vaccines, preventative therapies and drugs to combat the disease.
One such approach is to find human monoclonal antibodies that can target the virus.
Prof. Gavin Screaton’s group at Imperial College London, UK and Prof. Michael Diamond’s group at Washington University St. Louis, USA, set out to do just this.
Published in Nature Immunology, their findings build on previous work in which the group isolated a class of antibodies, Y-shaped proteins that stick to the virus and mark it for destruction by the body’s immune cells, produced by patients infected with the dengue virus. The group found that these antibodies, EDE1 antibodies, were also effective against the closely-related Zika virus.
As Prof. Screaton says, “This paper shows for the first time that antibodies we had previously found to be effective against dengue potently protect against Zika virus in mice and can treat the early stages of infection."
Published in Nature Immunology, their findings build on previous work in which the group isolated a class of antibodies, Y-shaped proteins that stick to the virus and mark it for destruction by the body’s immune cells, produced by patients infected with the dengue virus. The group found that these antibodies, EDE1 antibodies, were also effective against the closely-related Zika virus.
As Prof. Screaton says, “This paper shows for the first time that antibodies we had previously found to be effective against dengue potently protect against Zika virus in mice and can treat the early stages of infection."
Assessing antibody efficacy
The researchers began by comparing the virus neutralizing ability of the EDE1-B10 antibodies against four different type of dengue virus and the African and Asian-American strains of the Zika virus in cells in culture. They found that the antibody neutralized 3 of the 4 types of dengue and both strains of Zika. However, they also noted that at sub-neutralizing concentrations, there was a risk of an unwanted interaction which could lead to antibody-dependent enhancement. This is akin to the Zika virus using the immune cells as trojan horses and overcoming the immune system which fails to control and kill off the virus.
To overcome this, the researchers tweaked the protein make-up of the antibody. They generated the EDE1-LALA variant which does not interact with the Fcg cell surface receptor preventing antibody-dependent enhancement.
The researchers began by comparing the virus neutralizing ability of the EDE1-B10 antibodies against four different type of dengue virus and the African and Asian-American strains of the Zika virus in cells in culture. They found that the antibody neutralized 3 of the 4 types of dengue and both strains of Zika. However, they also noted that at sub-neutralizing concentrations, there was a risk of an unwanted interaction which could lead to antibody-dependent enhancement. This is akin to the Zika virus using the immune cells as trojan horses and overcoming the immune system which fails to control and kill off the virus.
To overcome this, the researchers tweaked the protein make-up of the antibody. They generated the EDE1-LALA variant which does not interact with the Fcg cell surface receptor preventing antibody-dependent enhancement.
Protection in immune-privileged tissues
The group tested the engineered antibody, EDE1-LALA, in Zika-infected mice. The mice were given the antibody at either one-day, three-days or five-days following Zika virus infection.
The researchers first showed that administering the antibody to infected-mice improved survival outcome in all scenarios compared to the control infected mice.
Interestingly, the researchers investigated the EDE1-LALA antibody’s ability to protect immune-privileged tissues from Zika virus infection, and they showed that administering the antibody after one to three days following viral infection reduced viral load in the blood serum, brain, epididymis and eyes, but not the testis, of male mice, when they looked five-days following infection. When they looked after 21-days of infection, they found strong protection of the testis from the virus.
Suggesting that, overall, the antibody is protective. It reduces Zika virus lethality and the viral burden on cells in immune-privileged tissues known to be infected by the virus.
Antibody protects pregnant mothers and their fetuses
The researchers also investigated the efficacy of the engineered antibody on pregnant mice infected with the Zika virus. They showed that the antibody reduced viral load in the mother’s blood (by 240-fold), brain (by 3,000-fold), placenta (by 633,000-fold) and fetal head (by 4,600-fold); compared to controls.
The group tested the engineered antibody, EDE1-LALA, in Zika-infected mice. The mice were given the antibody at either one-day, three-days or five-days following Zika virus infection.
The researchers first showed that administering the antibody to infected-mice improved survival outcome in all scenarios compared to the control infected mice.
Interestingly, the researchers investigated the EDE1-LALA antibody’s ability to protect immune-privileged tissues from Zika virus infection, and they showed that administering the antibody after one to three days following viral infection reduced viral load in the blood serum, brain, epididymis and eyes, but not the testis, of male mice, when they looked five-days following infection. When they looked after 21-days of infection, they found strong protection of the testis from the virus.
Suggesting that, overall, the antibody is protective. It reduces Zika virus lethality and the viral burden on cells in immune-privileged tissues known to be infected by the virus.
Antibody protects pregnant mothers and their fetuses
The researchers also investigated the efficacy of the engineered antibody on pregnant mice infected with the Zika virus. They showed that the antibody reduced viral load in the mother’s blood (by 240-fold), brain (by 3,000-fold), placenta (by 633,000-fold) and fetal head (by 4,600-fold); compared to controls.
Furthermore, the antibody treatment reduced the number of deaths of unborn pups to just one in ten, compared to the ninety-percent loss seen in Zika virus infected control animals.
One antibody, two viruses
Tantalisingly, the findings suggest several variants of the EDE1 antibodies could be effective against both the Zika virus and dengue virus. However, several steps need to be overcome before this can be proven to protect humans.
As Prof. Screaton explains: "This group of antibodies is unique in being able to target Dengue and Zika. The next step is to see whether they are effective in larger animal models, and potentially even humans."
It’s exciting to think that this academic collaboration has developed monoclonal antibodies that could directly overcome two of the most prevalent mosquito-borne viruses in the world.
One antibody, two viruses
Tantalisingly, the findings suggest several variants of the EDE1 antibodies could be effective against both the Zika virus and dengue virus. However, several steps need to be overcome before this can be proven to protect humans.
As Prof. Screaton explains: "This group of antibodies is unique in being able to target Dengue and Zika. The next step is to see whether they are effective in larger animal models, and potentially even humans."
It’s exciting to think that this academic collaboration has developed monoclonal antibodies that could directly overcome two of the most prevalent mosquito-borne viruses in the world.
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