5 Jun

Herpes simplex (HSV-1 and-2) viruses are  discussed in Chap- ter 3. The  search for a vaccine for herpes simplex virus (HSV-1 and-2) spans eight decades. In the  1920s, untreated  vesicu- lar  fluid  from  herpes lesions was  injected into  patients in an attempt to  induce immunity (212).  This  method, to  say  the least, did  not  withstand the  test of time. Inactivated  whole virus vaccines were  developed in  the  1930s  and  were  made from  HSV-infected animal tissue, such  as  rabbit brain (257). Despite the  many advances made with inactivated virus vac- cines  through the  years, none  of the  candidates proved to be sufficiently immunogenic. With  increasing technology, several different approaches for HSV vaccines are  currently in devel- opment and  evaluation.

A number of vaccine strategies could  be implemented to prevent and  protect against HSV disease. For example, a vac- cine  that prevents infection at the  route of entry would  be effective in combating establishment of latent reservoirs that could reactivate.

Also,  a  vaccine that  challenged mucocutaneous tissues would  be a good paradigm for human HSV infection. Vaccines for  prevention are   the  primary goal,  but  the  question of whether vaccines can be used to reduce the  severity of the  dis- ease  if it cannot completely eliminate HSV  infection is  also improtant (258).

Two  separate  recombinant subunit vaccines have been investigated in phase III trials. One such  candidate developed by Chiron contained HSV-2  surface glycoproteins gB and  gD and  the  adjuvant MF59.  The  development of this vaccine was halted prematurely because results demonstrated overall lack of efficacy  for both  preventive and  therapeutic use  (259,260). A second recombinant  vaccine contains the  glycoprotein  gD and  the  adjuvant monophosphoryl lipid  A immunostimulant (MPL).  Results of clinical trials with this candidate indicate that it has  clinical efficacy  in protecting women who are  sero- logically negative for both  HSV-1  and  HSV-2  from  acquiring HSV-2  disease (261).

A report of mixed  HSV-1  glycoproteins  (ISCOMS) pro- tected mice  from  latent HSV-1  infection, with a reduction of latent infection in the  brain of 93% of vaccinated mice.  Only 59% of the  controls were  free  of HSV  in the  brain (262). This may  be a promising area of future study in humans.

Another approach combines the  safety profile of a killed vaccine with the  immunogenic potential of a live virus vaccine (263).  The  disabled infectious single cycle  (DISC)  vaccine lacks the  glycoprotein H (gH) gene  necessary for virus entry into  cells. After  a single replication cycle, the  virus is unable to  spread to  surrounding cells  and  thus remains noninfec- tious. Studies in  guinea pigs  demonstrated encouraging results for  both   preventive and   therapeutic treatment (263,264). After  phase I  studies demonstrated DISC  to  be safe  and  well  tolerated, phase II trials are  currently under- way  to  evaluate the   vaccine as  a  therapeutic agent in infected persons. Trials are  also planned to evaluate the  effi- cacy in preventing infection in seronegative partners of dis- cordant couples (212).

DNA vaccines are  also  in development for HSV immuni- zation. Animal studies involving inoculations of plasmid DNA carrying the desired viral genes have shown promising results for the  prevention of infection (265,266). These vaccines are only able  to express one or two viral antigens, but  can  induce cell-mediated immunity without the  need  for  potent adju- vants. One  such  candidate  which encodes glycoprotein D2 (gD2) is currently in phase I clinical trials, and  several others are  in preclinical development.

Live attenuated HSV vaccines have been  rather difficult to  develop, as  viruses that are  the  safest and  most  attenu- ated tend to lack  immunogenicity. Research in  the  past has shown that stable attenuation of HSV was  not  achieved after passage in cell culture. After  immunization, the  vaccine strain would  then have the  potential to revert to its  virulent state and  cause disease. A genetically engineered HSV mutant vac- cine was found  to be safe and  effective in animal studies (267), but  in  humans was  overly  attenuated and  lacked sufficient immunogenicity (268). New genetically engineered strains are currently under development.

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