An mRNA vaccine to prevent genital herpes

Abstract

The rapid development of two nucleoside-modified mRNA vaccines that are safe and highly effective against coronavirus disease 2019 has transformed the vaccine field. The mRNA technology has the advantage of accelerated immunogen discovery, induction of robust immune responses, and rapid scale up of manufacturing. Efforts to develop genital herpes vaccines have been ongoing for 8 decades without success. The advent of mRNA technology has the potential to change that narrative. Developing a genital herpes vaccine is a high public health priority. A prophylactic genital herpes vaccine should prevent HSV-1 and HSV-2 genital lesions and infection of dorsal root ganglia, the site of latency. Vaccine immunity should be durable for decades, perhaps with the assistance of booster doses. While these goals have been elusive, new efforts with nucleoside-modified mRNA-lipid nanoparticle vaccines show great promise. We review past approaches to vaccine development that were unsuccessful or partially successful in large phase 3 trials, and describe lessons learned from these trials. We discuss our trivalent mRNA-lipid nanoparticle approach for a prophylactic genital herpes vaccine and the ability of the vaccine to induce higher titers of neutralizing antibodies and more durable CD4⁺ T follicular helper cell and memory B cell responses than protein-adjuvanted vaccines.

Fig 1

Model of antibody responses produced by the trivalent mRNA vaccine. The goal of the trivalent mRNA vaccine is: 1, To block gD2 binding to receptor. Antibody to gD2 (yellow) binds to gD2 on the virus and prevents entry into the cell. 2, To block gC2 on virus or infected cells from binding complement component C3b. Antibody to gC2 (blue) blocks the binding of C3b to gC2 allowing complement activation to proceed. 3, To block binding of IgG Fc to the virus IgG Fc receptor, gE2/gI2. Antibody to gE2 (green) binds to gE2 and blocks the ability of gE2/gI2 to bind the Fc domain of IgG. In the absence of gE2 antibody, antibody to gD2 (yellow) binds to gD2 by its F(ab’)₂ domain and the Fc domain of the same antibody binds to gE2/gI2 (green) to block activities mediated by the IgG Fc domain such as ADCC and complement activation. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Fig 2

Nucleoside-modified trivalent mRNA-LNP vaccine. The trivalent nucleoside-modified mRNA-LNP encodes the ectodomain of gC2, gD2, and gE2. Uridine residues are replaced by 1-methyl-pseudouridine (ψ), and 5′ cap, 5′, and 3′ UTRs and poly(A) tails are modified to improve mRNA stability and translation efficiency. The mRNA is purified to remove double stranded RNA using high-performance liquid chromatography followed by encapsulation into LNPs. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Fig 3

Stimulating immune responses by immunization. The trivalent nucleoside-modified mRNA-LNP vaccine is delivered to antigen presenting cells (APC) and endocytosed. The mRNA is released in the cytosol and translated into gC2, gD2, and gE2 proteins by ribosomes. The proteins are degraded in endosomes and presented on the cell surface to helper T cells by major histocompatibility complex (MHC) class II proteins. The helper T cells stimulate B cells to produce antibodies. The intracellular antigens are also broken down into smaller fragments by the proteasomal complex, and the fragments are then presented on the cell surface to cytotoxic T cells by major MHC class I proteins. The activated cytotoxic T cells kill HSV-2 infected cells by secreting cytolytic molecules, such as perforin and granzymes. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)