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Vaccines protect mice against Zika virus

Zika virus causes a mild, flu-like illness in most people, but to pregnant women the dangers are much worse. The virus can reduce fetal growth, cause microcephaly, an abnormally small head associated with brain damage, and even trigger miscarriage. Now, a study in mice shows females vaccinated before pregnancy and then infected with Zika, bear pups who show no trace of the virus.


These findings offer the first evidence of an effective vaccine given prior to pregnancy that can protect the fetus from Zika infection and resulting injury.
"There are several vaccines in human trials right now, but to date, none of them has been shown to protect during pregnancy. We tested two different vaccines, and they both provided substantial protection."

Michael S. Diamond MD PhD, the Herbert S. Gasser Professor of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA and the study's co-senior author.

The study was published July 13 in the journal Cell.

Zika made international headlines when it was linked to an epidemic of babies born with microcephaly in Brazil. There is no specific medicine or vaccine to prevent or treat disease caused by the mosquito-borne virus.

Last year, Diamond and others developed a mouse model of Zika infection that mimics the effects of the infection in pregnant women. Using this model, Diamond, along with co-senior authors Pei-Yong Shi PhD, of the University of Texas Medical Branch (UTMB), and Ted Pierson PhD, of the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIH), evaluated the ability of two vaccines to protect fetuses of mothers infected during pregnancy.

One, a so-called subunit vaccine based on the genetic blueprint of two proteins from the virus's outer shell, was developed by Moderna Therapeutics and is in safety testing in women who are not pregnant and in men. The other, a live but weakened form of the virus developed at UTMB, is being tested in animals.

As part of that study, groups of 18 to 20 female mice were vaccinated with one of the vaccines or a placebo. Some animals received a second dose of the same vaccine or placebo a month later. Three weeks afterwards, researchers measured antibody levels in the mice to measure the strength of their immune response. Both vaccines had elicited very high levels of neutralizing antibodies against Zika, while the placebos had not.

After the mice became pregnant, they were infected on the sixth day of pregnancy, to mimic the experience of a woman bitten by a Zika-carrying mosquito early in pregnancy.

One week after infection, the researchers measured the amount of virus in the mothers and fetuses.
With both vaccines, fetuses and placentas from vaccinated mice contained very low levels of Zika's genetic material.

For the subunit vaccine, more than half of the placentas and fetuses had no detectable viral genetic material at all.

The live-virus vaccine was even more effective: In 78 percent of the placentas and 83 percent of the fetuses no viral genetic material was found.

"The amount of viral genetic material in the placentas and fetuses from the vaccinated females was just above the limit of detection," said Diamond, who also is a professor of molecular microbiology, and of pathology and immunology. "It's not totally clear whether it was infectious virus or just remnants of viruses that had already been killed."

In contrast, the amount of detectable viral material in the placentas and fetuses of unvaccinated mice was hundreds to thousands times higher.

Researchers repeated the experiment with different mice to evaluate the pups at birth. None of the mothers in the placebo group made it to term. The mothers became seriously ill, many of the fetuses showed high levels of infection and died in utero, and the placentas showed severe damage. In contrast, the vaccinated mothers remained healthy, all of their pups were born without obvious signs of injury, and the newborn pups had no measurable Zika virus in their heads.
"In general, most doctors don't want to vaccinate during pregnancy on the outside chance that the immune response itself could harm the fetus. But, if you're in an area where Zika is circulating, you might vaccinate during pregnancy because the risk of Zika infection is worse than some theoretical risk of immune-mediated damage."

Michael S. Diamond MD PhD, the Herbert S. Gasser Professor of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA and the study's co-senior author.

The study did not look at whether the vaccines are safe and effective for use during pregnancy. Such studies can't really be done in mice, Diamond explained, because mouse pregnancies only last 19 days which is not enough time for a protective immune response to develop before the pups are born.

This study also does not address the question of whether the vaccines work when pregnant women are infected with Zika through sexual contact, as it is possible that Zika virus in semen can travel to the uterus and then to the fetus without passing through the bloodstream.
"Would the immunity still hold up if the virus does not pass through the bloodstream? We think it will hold up, but that has [yet] to be tested."

Michael S. Diamond MD PhD.

Highlights
A modified mRNA vaccine encoding prM-E protects in 3 different mouse strains
Extraordinarily high titers of neutralizing antibodies (>1/100,000 EC50) are produced
Sterilizing immunity was achieved with a single prime-boost strategy
A fusion loop mutant vaccine reduced production of enhancing anti-DENV antibodies

Summary
The emergence of ZIKV infection has prompted a global effort to develop safe and effective vaccines. We engineered a lipid nanoparticle (LNP) encapsulated modified mRNA vaccine encoding wild-type or variant ZIKV structural genes and tested immunogenicity and protection in mice. Two doses of modified mRNA LNPs encoding prM-E genes that produced virus-like particles resulted in high neutralizing antibody titers (~1/100,000) that protected against ZIKV infection and conferred sterilizing immunity. To offset a theoretical concern of ZIKV vaccines inducing antibodies that cross-react with the related dengue virus (DENV), we designed modified prM-E RNA encoding mutations destroying the conserved fusion-loop epitope in the E protein. This variant protected against ZIKV and diminished production of antibodies enhancing DENV infection in cells or mice. A modified mRNA vaccine can prevent ZIKV disease and be adapted to reduce the risk of sensitizing individuals to subsequent exposure to DENV, should this become a clinically relevant concern.



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Jul 17, 2017   Fetal Timeline   Maternal Timeline   News   News Archive




The amount of viral material in the placentas and fetuses of vaccinated female mice
was just above the limit of detection, according to Michael S. Diamond MD PhD.



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