Vaccines to prevent genital herpes

Abstract

Genital herpes increases the risk of acquiring and transmitting Human Immunodeficiency Virus (HIV), is a source of anxiety for many about transmitting infection to intimate partners, and is life-threatening to newborns. A vaccine that prevents genital herpes infection is a high public health priority. An ideal vaccine will prevent both genital lesions and asymptomatic subclinical infection to reduce the risk of inadvertent transmission to partners, will be effective against genital herpes caused by herpes simplex virus types 1 and 2 (HSV-1, HSV-2), and will protect against neonatal herpes. Three phase 3 human trials were performed over the past 20 years that used HSV-2 glycoproteins essential for virus entry as immunogens. None achieved its primary endpoint, although each was partially successful in either delaying onset of infection or protecting a subset of female subjects that were HSV-1 and HSV-2 uninfected against HSV-1 genital infection. The success of future vaccine candidates may depend on improving the predictive value of animal models by requiring vaccines to achieve near-perfect protection in these models and by using the models to better define immune correlates of protection. Many vaccine candidates are under development, including DNA, modified mRNA, protein subunit, killed virus, and attenuated live virus vaccines. Lessons learned from prior vaccine studies and select candidate vaccines are discussed, including a trivalent nucleoside-modified mRNA vaccine that our laboratory is pursuing. We are optimistic that an effective vaccine for prevention of genital herpes will emerge in this decade.

Figure 1.. Blocking immune evasion by HSV-2 gC2 and gE2.

Left: gC2 on virus or infected cells (brown) binds to complement component C3b (blue) and blocks downstream complement activation to protect the virus against complement-mediated neutralization or cell lysis. Virus-specific antibody (purple), shown as anti-gD2, binds to gD2 by the F(ab’)₂ domain while the Fc domain of the same antibody binds to gE2, which blocks activities mediated by the Fc domain, such as complement activation and ADCC. Right: Adding gC2 and gE2 immunogens to the gD2 vaccine produces antibodies (red and blue) that bind and block the ability of gC2 to bind C3b and gE2 to bind the Fc domain of IgG (shown as purple gD2 antibody), which results in the generation of the membrane attack complex (C5-9) and virus neutralization.

Figure 2.. Schema of the high throughput biosensor antibody competition assay.

Left bottom: Cartoon of the biosensor chip that has different monoclonal antibodies at each position that recognize overlapping epitopes within a group (shown as the same color) or non-overlapping epitopes (shown in different colors). Middle section: Blowup of the biosensor chip. Right side, middle of figure: Monoclonal antibody MC23 from the red group is plated on the chip. IgG purified from serum of a gD2-immunized animal is incubated with gD2 antigen and floated over the chip. gD2 does not bind to MC23 on the chip; therefore, the animal produced antibodies to the epitope recognized by MC23. Right side, bottom of figure: IgG from the same immunized animal does not contain antibodies that block gD2 binding to a blue monoclonal antibody, DL6, on the chip; therefore, the animal did not produce antibodies to the epitope recognized by the DL6 monoclonal antibody.

Figure 3.. Trivalent nucleoside-modified mRNA-LNP vaccine.

The trivalent gC2, gD2, gE2 nucleoside-modified mRNA-LNP vaccine combines the concept of blocking immune evasion with the use of nucleoside-modified mRNA for vaccine delivery. Modifications in mRNA include substitution of uridine residues with 1-methyl-pseudouridine to reduce triggering innate immune sensors that degrade mRNA, and altering the 5’ cap, 5’ and 3’ UTRs and poly(A) tail to improve mRNA stability. Modified mRNA is purified to remove double stranded RNA using HPLC followed by encapsulation in LNPs.