Dropulic LK,  et.al.  A Randomized, Double-Blinded, Placebo-Controlled, Phase 1 Study of a Replication-Defective Herpes Simplex Virus (HSV) Type 2 Vaccine, HSV529, in Adults With or Without HSV Infection. J Infect Dis 2019;220:990.

 

Background

Both genital and oral herpes simplex virus (HSV) infections are common throughout the world.  Most infections are asymptomatic but many produce painful ulcerations that often recur.  Further, neonatal HSV infections produce a severe disease while genital HSV-2 infections are a major risk factor for the acquisition and transmission of HIV.

Methods and results

In this manuscript the authors describe the initial clinical evaluation of a replication defective herpes simplex virus vaccine.  A replication defective vaccine is one in which one or more essential genes have been deleted so the vaccine virus, which is grown in a cell line that provides the missing gene product(s),  can infect a cell but the virus produced is non-infectious because of the deletions.  Thus, another term used is a single cycle vaccine.  This is one of several new approaches to vaccine development discussed briefly below.

The vaccine HSV529 (HSV-2 dl5-29), a double deletion of  HSV-2 UL5 and UL 29, was evaluated in 60 healthy adults in a double blind study of participants who were either seronegative for HSV1 and HSV-2, or positive for either HSV-1 or HSV-2 or both.  The vaccine was provided in a 3 dose schedule administered IM at 0,1 and 6 months. Safety and both antibody and T cell responses were quantified.

The overall safety profile of the vaccine was acceptable although mild to moderate local reactions were common (89%).  There was no significant difference compared to placebo recipients in unsolicited adverse events.  A fourfold increase in neutralizing antibody titers was induced in 11 of 14 HSV seronegative participants after the third dose and titers remained elevated at 6 months. For those HSV seropositive, there was a mixed response but none of the recipients had a 4 fold increase.  There was also some evidence of T cell induction but CD8 responses were weak in seronegative participants and were even less for seropositive subjects.  CD4 responses were higher than CD8 for both groups.

 

Discussion

This is an interesting time for HSV vaccines.  The recent failure of a prophylactic (to prevent disease and persistent infection) monovalent glycoprotein D (gD) vaccine to protect against HSV-2 (1) and the sub optimal but significant decrease in recurrent HSV-2 disease and shedding by a bivalent therapeutic vaccine (to decrease recurrent disease and shedding in those already infected) (2) has led many to believe that a successful vaccine must present more HSV antigens.  Hence the development of this replication defective candidate as well as live attenuated vaccines that have deleted neuroinvasive HSV proteins (3,4) in order to present more HSV antigens.  On the positive side the prophylactic gD2 candidate did protect against HSV-1 genital disease and infection (1) and established a correlate of protection (5) providing encouragement to the field.  Similarly, the therapeutic vaccine established a proof of concept for therapeutic vaccines.  The vaccine evaluated in the current manuscript offers advantages to the subunit vaccines evaluated previously, in that it presents all the HSV antigens to the immune system.  However, it remains unclear as to whether a single round of virus replication will be sufficient to induce long lasting protection.  Also of interest, similar approaches have recently been used for cytomegalovirus (CMV) vaccines after the partial success of a monovalent glycoprotein B CMV vaccine (6).  Thus both replication defective (7) and live attenuated vaccines (8) are being developed.

Stay tuned for results of upcoming clinical trials for these and other herpes virus vaccines

References

  1. Belshe RB, Leone PA, Bernstein DI, et.al. Herpevac Trial for Women. Efficacy results of a trial of a herpes simplex vaccine. N Engl J Med. 366:34; 2012.
  2. Bernstein DI, Flechtner JB, McNeil et.al. Therapeutic HSV-2 vaccine decreases recurrent virus shedding and recurrent genital herpes disease. Vaccine.  37:3443; 2019.
  3. Bernstein DI, Pullum DA, Cardin RD, et.al.  The HSV-1 live attenuated VC2 vaccine provides protection against HSV-2 genital infection in the guinea pig model of genital herpes. Vaccine. 37:61; 2018
  4. Richards AL, Sollars PJ, Pitts JD, et.al.  The pUL37 tegument protein guides alpha-herpesvirus retrograde axonal transport to promote neuroinvasion. PLoS Pathog. 13: e1006741; 2017.
  5. Belshe RB, Heineman TC, Bernstein DI, et.al. Correlate of immune protection against HSV-1 genital disease in vaccinated women. J Infect Dis. 209:828; 2014.
  6. Bernstein DI, Munoz FM, Callahan ST, et. al.  Safety and efficacy of a cytomegalovirus glycoprotein B (gB) vaccine in adolescent girls: A randomized clinical trial. Vaccine.34:313; 2016
  7. Adler SP, Lewis N, Conlon A, et.al.  Clinical Trial of a Conditionally Replication-Defective Human Cytomegalovirus (CMV) Vaccine in CMV-Seronegative Subjects. J Infect Dis. 220:411; 2019
  8. Hansen SG, Marshall EE, Malouli D, et.al. A live-attenuated RhCMV/SIV vaccine shows long-term efficacy against heterologous SIV challenge. Sci Transl Med. Jul 17;11; 2019.

Reviewer

Joshua Wolf, MBBS, PhD, FRACP

Pediatric Infectious Diseases Physician and Medical Director of Antimicrobial Stewardship

Associate Member

Department of Infectious Diseases 

St. Jude Children's Research Hospital