Monkey study to show whether Zika really causes birth defects

The link between the virus and birth defects like microcephaly seems strong, but isn’t proven just yet.

Koen Van Rompay is a veterinary infectious disease expert who is launching a study on Zika virus in pregnant monkeys. This model could offer the scientific community the answers it needs to issue informed public health recommendations, develop treatments, and slow the virus’s spread. 

ResearchGate: When did you decide to study Zika and birth defects in monkeys and why?

Koen Van Rompay: It all started in early January, when I began to read the news reports about Zika virus causing birth defects in Brazil. I was shocked. Having spent much of my career trying to protect infants from becoming HIV-infected, I felt I couldn’t just sit still and do nothing. Very little is known about Zika virus and how it affects the fetus. I knew that an animal model would be extremely useful in making progress, so I started reaching out to collaborators. 

RG: Could you introduce your research?

Van Rompay: We want to study whether Zika virus infection of macaques can be a useful animal model. A good animal model can teach us about the virus and how it causes disease, in turn helping the research community develop effective intervention strategies. We are currently still in the planning stages, but we expect to start the experiments very soon.

We already know there’s a good chance rhesus monkeys can become infected with Zika virus, because it was originally isolated in 1947, from a sentinel rhesus macaque that was kept in a cage in the Zika forest in Uganda. In the over 60 years since, Zika virus in macaques remains largely unstudied. Our plan is to do stepwise studies. First, we will test whether Zika virus isolates from recent outbreaks in humans are infectious to macaques by exposing a few animals. If we can see that they are, we will subsequently infect a few pregnant monkeys and monitor them closely to investigate whether Zika virus affects the development of the fetus.

“Data obtained in monkey models have generally been very predictive of what happens in humans.”

RG: To what extent does learning about the virus’s impact on monkeys and their offspring teach us about how it works in humans?

Van Rompay: Monkeys resemble humans closely in many aspects of physiology, including fetal development. Although no animal model is 100% perfect, data obtained in monkey models have generally been very predictive of what happens in humans. Examples are discoveries that led to vaccines against polio, measles, and many other diseases, as well as drugs to treat infections like HIV.

While it seems that Zika virus infection of pregnant mothers during the first trimester is associated with the development of microcephaly, we are still left with many questions. It is currently unclear whether it is direct infection of the fetus, immune responses generated by the mother or fetus, or a combination of all these and other potential factors that is responsible for the harmful effects to the fetus. When we infect monkeys, we can control variables like the timing of infection, and we can monitor the course of infection much more closely than in humans. The knowledge we gain from this, combined with data that are reported from studies on aborted fetuses or born babies, will help us know how to move forward in addressing Zika virus. If it turns out that direct replication is the main culprit, then we have to develop vaccines or drugs that vigorously attack virus replication. If it’s immune response, we have to be very careful to design a vaccine that induces the right kind of immune response to protect against infection while avoiding immune responses that may cause harm to the fetus.

RG: What results are you expecting?

Van Rompay: I expect that we can infect monkeys with Zika virus, and that just like in healthy human adults, the symptoms will be generally absent or mild. Whether we will see harmful effects on the fetus remains to be seen.

RG:  Defects occur only in a small percentage of pregnancies. How will you deal with that issue in your research?

Van Rompay: It is likely that birth defects only occur in a small percentage of human fetuses because only a small percentage of mothers are infected when brain development in the fetus is most susceptible to harmful effects. In macaques, we can control this; we will use available knowledge about fetal brain development and about other viruses that cause congenital defects (such as cytomegalovirus and rubella) to infect a few pregnant animals at defined times most likely to induce microcephaly. If we don’t see birth defects under those conditions, we will go back to the drawing board.

“Conflicting reports emphasize the need to do well-controlled studies in an animal model.”

RG: Can you speak to recent claims that pesticides, rather than Zika virus, may be the culprit behind the spike in microcephaly?

Van Rompay: A recent report suggested that the increased use of a larvicide in drinking water, not Zika virus, is responsible for the sudden increase in microcephaly in Brazil. On the other hand, a recent publication in the New England Journal of Medicine reported findings of an aborted fetus with microcephaly, in which high levels of Zika virus were found in the brain and associated with major brain lesions; this observation provides strong evidence for a direct link to viral infection. Altogether, such conflicting reports emphasize the need to do well-controlled studies in an animal model to determine whether it is Zika virus infection, a chemical, or a combination of factors that is the culprit of the abnormal brain development.

RG: What are some of the ethical considerations to working with monkeys?

Van Rompay: Throughout the whole process, we do our best to minimize the number of animals involved, and we think of their welfare, following the three R’s of biomedical research: replacement (using non-animal methods when possible), reduction (working with fewer animals when possible), and refinement (pursuing methods that minimize animal distress). We plan to stick to those principles in our studies on Zika virus.

The study will have benefits for monkey populations as well. Many Zika virus-affected countries in South-America and other parts of the world have wild populations of nonhuman primates, some of them endangered, that may likely also become infected through mosquito bites. Recently there have been some reports of unexpected mortality in primate populations in South-America, but we don’t yet know if it has anything to do with Zika. Our research can also be relevant in that regard. If it turns out that Zika virus can also cause disease in monkeys, collaborative research can then lead to strategies to help protect these populations.

RG: What will the next steps in your research be?

Van Rompay: If the current pilot study demonstrates proof-of-concept of the animal model, we plan to do more studies to better refine it, so it can be used to address many new questions. An example would be investigating the risk of virus transmission through blood, which is highly relevant to blood banks.  We can also use this model to test interventions, such as vaccines or drugs, as they are developed.

ResearchGate has put together a comprehensive collection of emerging Zika virus research, including scientific papers, interviews with researchers, and discussions among them. 

Featured image courtesy of Cloudtail.