The R2 non-neuroinvasive HSV-1 vaccine affords protection from genital HSV-2 infections in a guinea pig model

David I Bernstein,Gary E Pickard,Rajamouli Pasula,Gregory A Smith,Patricia J Sollars,Rhonda D Cardin,David A Dixon,Fernando J Bravo

doi:10.1038/s41541-020-00254-8

Abstract

Herpes simplex virus (HSV) infections are common and can cause severe illness but no vaccine is currently available. The recent failure of subunit HSV vaccines has highlighted the need for vaccines that present a diverse array of antigens, including the development of next-generation live-attenuated vaccines. However, most attenuated HSV strains propagate poorly, limiting their ability to elicit protective immune responses. A live-attenuated vaccine that replicates in non-neural tissue but is ablated for transmission into the nervous system may elicit protective immune responses without evoking neurologic complications or establishing life-long infections. Initial studies of R2, a live-attenuated vaccine that is engineered to be unable to invade the nervous system, used the guinea pig genital HSV model to evaluate the ability of R2 to replicate at the site of inoculation, cause disease and infect neural tissues. R2 was then evaluated as a vaccine using three routes of inoculation: intramuscular (IM), intradermal (ID) and intravaginal (IVag) and compared to IM administered gD2+MPL/Alum vaccine in the same model. R2 replicated in the genital tract but did not produce acute or recurrent disease and did not infect the neural tissue. The R2 vaccine-induced neutralizing antibody and decreased the severity of acute and recurrent HSV-2 disease as well as recurrent shedding. The ID route was the most effective. ID administered R2 was more effective than gD2+MPL/Alum at inducing neutralizing antibody, suppressing acute disease, and acute vaginal virus replication. R2 was especially more effective at reducing recurrent virus shedding, the most common source of HSV transmission. The live-attenuated prophylactic HSV vaccine, R2, was effective in the guinea pig model of genital HSV-2 especially when administered by the ID route. The use of live-attenuated HSV vaccines that robustly replicate in mucosal tissues but are ablated for neuroinvasion offers a promising approach for HSV vaccines.

Highlights

The development of an effective vaccine for herpes simplex virus (HSV) is a priority[1,2,3] because it is a common infection that causes physical and emotional stress as well as increasing the risk for HIV infection[4,5,6]
HSV type 1 (HSV-1) is the most prevalent form of the virus, worldwide about 400 million people are infected with HSV type 2 (HSV-2), the predominant cause of genital herpes[11]
Both HSV-1 and HSV-2 can cause neonatal herpes, a devastating disease most often acquired during birth from infected mothers[12]

Summary

Introduction

The development of an effective vaccine for herpes simplex virus (HSV) is a priority[1,2,3] because it is a common infection that causes physical and emotional stress as well as increasing the risk for HIV infection[4,5,6]. HSV can invade the central nervous system and cause life-threatening encephalitic infections[8], and may contribute to dementias such as Alzheimer’s disease[9,10]. HSV type 1 (HSV-1) is the most prevalent form of the virus, worldwide about 400 million people are infected with HSV type 2 (HSV-2), the predominant cause of genital herpes[11]. Both HSV-1 and HSV-2 can cause neonatal herpes, a devastating disease most often acquired during birth from infected mothers[12]. The initial trials of the latter were promising, at least in HSV seronegative women[13], a larger trial in seronegative women failed to protect from HSV-2 but did demonstrate some protection against HSV-114

Methods

Results

Conclusion