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.