This is the second of two papers on mRNA vaccines for Zika by this group. Click here to read the first.

Summary:

Lately there has been intense effort to develop vaccines for Zika virus, in part due to the recently established link between Zika infection and congenital birth defects such as microcephaly and the rapid spread of Zika in Oceania and the Americas by mosquito vectors. Though vaccines based on attenuated viruses, plasmid DNA, and mRNA are being developed, with some in advanced stages of clinical trials, no study has yet established protection against birth defects. In this study, published in Cell, Dr. Michael S. Diamond’s lab at the Washington University School of Medicine in St. Louis, MO, in collaboration with the University of Texas Medical Branch, Valera (a subsidiary of Moderna), and others, has reported vaccine-mediated protection against congenital birth defects in mice. This study follows on from their February 2017 publication demonstrating sterilizing immunity conferred by immunization with a non-replicating modified mRNA lipid nanoparticle (LNP) vaccine in mice.

In this study, the Diamond lab tested whether vaccination by mRNA-LNPs and more traditional live attenuated viruses (LAVs), could confer protection against the fetal transmission of Zika and the resulting birth defects in future pregnancy. Female mice were immunized with either an mRNA-LNP vaccine, a LAV vaccine or placebo and later mated to healthy male mice. Pregnant females where then infected with an African strain of Zika at the sixth day of embryonic development. Viral burden was then evaluated in maternal and fetal tissue 7 days after viral challenge.

The mRNA vaccine, consisting of non-replicating nucleoside-modified mRNA encoding the Zika pre-membrane and envelope proteins, and an undisclosed lipid mix were formulated into mRNA-LNPs using NanoAssemblr™ technology. LNPs have been widely studied as gene delivery agents for small RNAs, mRNA, and plasmid DNA, and are known to protect nucleic acid payloads and mediate both their uptake into cells and release into the cytoplasm. Following transfection of antigen presenting cells, the Zika pre-membrane and envelope proteins are expressed from the mRNA template where they are processed similarly to virus particles and presented as antigens. mRNA vaccines, especially non-replicating ones containing nucleoside modifications to avoid unwanted immune activation, are ostensibly safer for use than LAVs and may be the only option for immune-deficient or pregnant people.

Mice treated with either the mRNA or the LAV vaccine had high levels of neutralizing antibodies in their serum. Additionally, compared to placebo-treated mice, a substantial reduction in viral mRNA was observed in the maternal, placental, and fetal tissues. Specifically, when compared to the placebo, maternal brain tissue had a 15,000-fold mean reduction in viral mRNA, while placental and fetal head tissues respectively exhibited a 200-fold and a 13,000–fold reduction. Essentially complete protection was observed in 53% of placentas and 58% of fetal heads where viral RNA levels were near the limit of detection. While no evidence of in utero transmission to fetuses was found in most vaccinated mice, embryos of placebo-treated mice did not survive to full term.

While differences in timing and methods of treatment in this study make comparison between the mRNA and LAV vaccines difficult, the authors suggest LAV-treated mice had slightly less placental and fetal breakthrough of viral RNA, which warrants further study to determine the practical significance.  Hence the authors suggest developing both vaccines especially in light of potential safety advantages of mRNA vaccines in treating pregnant or immune-deficient people.  Taken together, these results suggest a promising path to the vaccine-mediated prevention of the congenital birth defects caused by Zika infection in humans.

Abstract:

The emergence of Zika virus (ZIKV) and its association with congenital malformations has prompted the rapid development of vaccines. Although efficacy with multiple viral vaccine platforms has been established in animals, no study has addressed protection during pregnancy. We tested in mice two vaccine platforms, a lipid nanoparticle-encapsulated modified mRNA vaccine encoding ZIKV prM and E genes and a live-attenuated ZIKV strain encoding an NS1 protein without glycosylation, for their ability to protect against transmission to the fetus. Vaccinated dams challenged with a heterologous ZIKV strain at embryo day 6 (E6) and evaluated at E13 showed markedly diminished levels of viral RNA in maternal, placental, and fetal tissues, which resulted in protection against placental damage and fetal demise. As modified mRNA and live-attenuated vaccine platforms can restrict in utero transmission of ZIKV in mice, their further development in humans to prevent congenital ZIKV syndrome is warranted.