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Rhesus macaques provide scientists with model to study Zika, could lead to vaccine, treatments

We have a problem with Zika virus and the consequences of this virus seem to keep getting worse.

Zika virus causes microcephaly and other fetal brain abnormalities. It might be associated with the autoimmune, neurological disorder Guillain-Barré syndrome. It can be sexually transmitted. It has been declared a Public Health Emergency of International Importance by the World Health Organization. And cases in America (travel associated only thus far) keep popping up—more than 800 as of the end of June 2016. 

Prevention methods involve avoiding or minimizing exposure to mosquitoes and the current recommended treatment is rest, hydration, and Tylenol. There is no human vaccine. If we don’t come up with some answers about this disease we risk derailing more than just the 2016 summer Olympics. Luckily, efforts are underway and rapidly advancing toward a vaccine. 

On June 28, in Nature, scientists reported the identification of two potential vaccines that provide protection from infection in mice but have not yet reached human clinical trials. But to move on from mice scientists need a better model to study the virus and how it infects people and the developing fetus. That same day, scientists announced they may have an answer—monkeys. 

Why macaques as models?

A collaborative group of scientists at the University of Wisconsin, Madison reported the successful infection of healthy, pregnant rhesus macaques with Zika virus. The study, published June 28 in Nature Communications, establishes rhesus macaques as the first nonhuman primate model for Zika and could lead to new treatment and prevention strategies as well as provide insight into how Zika infection affects pregnancies.

The lead authors of the study made themselves available via a press briefing and two independent scientists provided statements to the Genetic Expert News Service (GENeS), a sister site to GLP. According to experts, rhesus macaques provide a more relevant model to humans than mouse models do.

“Different from the small animal models currently used, the macaques are not immune compromised so the natural course of infection and immune response can be studied,” said Amelia Pinto, a professor Saint Louis University who was not involved with the study, told GENeS. The study’s authors chose these primates over others because, in addition to being immunocompetent, the macaques share more similar gestational periods and fetal development with humans. An integral characteristic necessary to study Zika.

Zika Immunity

The authors injected six non-pregnant and two pregnant macaques with Zika dosages designed to mimic the amount of virus delivered by a mosquito. After injection, the researchers monitored the macaques for the presence of viral RNA in their blood plasma, urine, and saliva. One key observation? Infected monkeys became immune to the virus.

Upon challenging the macaques with the same strain used for infection 60 days after clearing the virus, Dawn Dudley, a co-lead author of the study said they observed “complete protection.”

“We were unable to detect viral RNA in the blood, saliva, or urine of the animals for up to 9 days after rechallenge. In fact, since this publication we’ve followed the animals for 28 days without detecting virus,” Dudley said. “This is a key finding because it means that a vaccine could be quite effective against the virus.” 

This is promising news for any individual who has already been infected with Zika, suggesting that they may be immune from reinfection. However, Dudley cautioned that it is unknown how long the immunity lasts.

Peter Barry of the California National Primate Research Center at the University of California, Davis, who was not involved in the study, told GENeS that he was encouraged by the results:

Since infection of macaques with Zika has been established, multiple vaccines can be efficiently and rigorously optimized prior to clinical trials in humans. It is encouraging for vaccine development that a second round of Zika infection did not appear to result in any detectable viral RNA in plasma, urine, or saliva.  Presumably the animals developed anti-Zika immune responses that conferred protective immunity against Zika reinfection.

Pregnancy Increases Duration of Infection

One result that caught the eye of many experts was that the Zika virus was detectable for longer in the blood of two pregnant macaques, both infected during the mid-first trimester, than in the non-pregnant or male macaques. Pinto noted

The infection of pregnant female macaques provides some of the most interesting data within this study. Particularly interesting is the continued detection of virus in the plasma of the pregnant females that is not seen in the non-pregnant females and male macaques and does appear to mimic at least one report of persistent infection during pregnancy in humans.

While first to admit they don’t know why the pregnant macaques stayed infected longer, the scientists do have one theory that they think explains the extended infection.

“Our leading hypothesis is that the fetus is infected and the fetus is shedding virus back into the mother’s bloodstream,” said David O’Connor, who is the head of the lab where the research took place.

The duration of the sustained infection varies, but the research team is hoping to determine whether longer infections are associated with more severe symptoms. They expect to have a better idea next month, when they deliver the two baby macaques via C-section and examine them for abnormalities and detectable virus.

Proof-of-Concept for an Open Science Model

In addition to providing a primate model for Zika, the authors also established a proof-of-concept for modern, open-access research practices. The O’Connor lab has been posting real-time updates to the Zika Open-Research Portal, which has accelerated access to the lab’s experimental design and results, months before publication in a journal.

“[The reaction] has been very positive from all the different types of stakeholders,” O’Connor said. “From people who are nonscientists who have emailed us, thanking us for putting it online to our colleagues who have said that it’s helped them design their experiments more efficiently.”

The authors provided updates to the research portal and also posted the pre-print article on BioRxiv a full month and a half before its publication in Nature Communications. It’s a model that some scientists hope will become the norm.

“The online updates prior to this publication and since is in itself a major step forward in sharing research that should be a model for resource sharing going forward,” said Pinto.

“The most positive part is that we have been able to get the data out there very quickly and that data has been used by different groups to inform their decision making,”  O’Connor said.

Access to early research findings, sometimes many months in advance, could be critical during a time-sensitive crisis like the Zika virus outbreak, especially as funding for additional Zika resources continues to stall in Congress.

Mikel Shybut is a CLEAR Fellow at the Genetic Expert News Service. He has a Ph.D. in Plant Biology from the University of California, Berkeley. Follow him on Twitter @MShybut

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