Modified mRNA Vaccines Protect against Zika Virus Infection

Abstract

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.

mRNA vaccines — a new era in vaccinology

“…A recent study demonstrated that sustained antigen availability during vaccination was a driver of high antibody titres and germinal centre (GC) B cell and T follicular helper (T FH ) cell responses 84 . This process was potentially a contributing factor to the potency of recently described nucleoside-modified mRNA–LNP vaccines delivered by the intramuscular and intradermal routes 20,22,85 . Indeed, T FH cells have been identified as a critical population of immune cells that vaccines must activate in order to generate potent and long-lived neutralizing antibody responses, particularly against viruses that evade humoral immunity 86 .…”

“…Unlike protein immunization, several formats of mRNA vaccines induce strong CD8 + T cell responses, likely owing to the efficient presentation of endogenously produced antigens on MHC class I molecules, in addition to potent CD4 + T cell responses 56,87,88 . Additionally, unlike DNA immunization, mRNA vaccines have shown the ability to generate potent neutralizing antibody responses in animals with only one or two low-dose immunizations 20,22,85 . As a result, mRNA vaccines have elicited protective immunity against a variety of infectious agents in animal models 19,20,22,56,89,90 and have therefore generated substantial optimism.…”

“…The first published report demonstrated that a single intradermal injection of LNP-formulated mRNA encoding Zika virus prM-E, modified with 1-methylpseudouridine and FPLC purification, elicited protective immune responses in mice and rhesus macaques with the use of as little as 50 μg (0.02 mg kg −1 ) of vaccine in macaques 20 . A subsequent study by a different group tested a similarly designed vaccine against Zika virus in mice and found that a single intramuscular immunization elicited moderate immune responses, and a booster vaccination resulted in potent and protective immune responses 85 . This vaccine also incorporated the modified nucleoside 1-methylpseudouridine, but FPLC purification or other methods of removing dsRNA contaminants were not reported.…”

“…This level of reactogenicity appears to be similar to that of more traditional vaccine formats 113,114 . Finally, the Zika virus vaccine described by Richner et al 85,112 is also entering clinical evaluation in a combined phase I/II trial (NCT03014089). Future studies that apply nucleoside-modified mRNA–LNP vaccines against a greater diversity of antigens will reveal the extent to which this strategy is broadly applicable to infectious disease vaccines.…”

An mRNA-based vaccine strategy against Zika

“…In a recent paper published in Cell, Richner et al [9] engineered and tested a modified mRNA-based vaccine against ZIKV in mice. The mRNA was chemically synthesized to contain a type 1 cap as well as 5′ and 3′ untranslated regions (with poly-A tail) to maintain intracellular stability and increase translation efficiency, the signal sequence from human IgE (IgEsig) for gene expression, and the full-length prM and E genes from an Asian ZIKV strain (IgEsigprM-E).…”