Original studies evaluating vaccines for HSV date back to 1920's. These studies used inactivated virus preparations treated with formalin. [66]

Experimental Subjects:
 
 

Goals

        Realistically,  the current goal of a HSV vaccine is to prevent disease but not infection, although this action is desired. It would take a vaccine capable of "sterilizing immunity" at all portals of entry: eye, genital tract, nasal and oro-pharyngeal mucosa. [24] [67] Therefore, a favored route of administration would be nasal (intraperitoneal) for inducing wide range mucosal protection; which is, not surprisingly, a stronger stimulation site. [19] [69] [70] However, it is considered that prevention of infection may not be feasible, unless neuronal protection is established. [24] (NOTE: HSV is a possible vector for gene therapy.) [81]
 

    Because of HSV's ability to avoid the Immune Response (IR) and establish Latency (LAT), as an intracellular virus, makes it very difficult for the host to effectively clear infection. In able to induce protection, an immune response involving the Th1 segment of immune system is thought to be needed. Specifically, cellular immunity recruiting cytotoxic T-cells and initiating DTH. [68] This is a response generated by CD4+ and CD8+ T-cells. [68]
Current investigation found that serum IgG antibodies and various functions of T-cells included in the CTL response is in fact needed for viral clearance and to help stop neuronal invasion. [19] [70] The correlates of immunity, although not essentially known, seem to be related to epitopes for CD4+ lymphocytes. Presently, studies using a battery of vaccinia virus-HSV glycoprotein recombinants expressing the major HSV glycoproteins gB, gC, gD, and gH are being investigated for their immunogenicity. Also, a major tegument protein, VP16 which is a late protein, is being investigated. A comparative study using a cocktail of surface glycoproteins has ranked their overall efficacy, gDgBgC=gE=gIgGgH. [67] These studies are considered important for the current trials involving recombinant glycoproteins, to be used as candidate HSV vaccines for primary prophylaxis and therapeutic efficacy. [16] [24]

Experimental Vaccines:

    Currently experimental vaccines have not shown to prevent infection but they have shown to protect animals from developing clinical manifestations of initial disease. [24] Also, experimental vaccines can reduce the magnitude of latent infection (decrease lesions decrease surface area for secondary infection). In general, experimental animal studies suggest that HSV vaccines may protect humans against developing severe primary genital herpes and may reduce the likelihood, that if infected, of experiencing recurrent infections. Also vaccinated individuals will be at reduced risk for transmitting HSV virus to a fetus or a newborn infant or any other susceptible organism. [24]
 

PREPS vaccine

           Researchers at the MRC in Glasgow discovered that cultured herpes viruses secreted into the surrounding growth media include virus particles lacking viral DNA and capsid. These particles are found in equal quantities in comparison with packaged HSV. These particles are non-infectious and are only composed of the virion tegument and envelope proteins. They are produced by all alpha-herpesviruses, (HSV 1 and 2 and VZV) and they absorb and penetrate host cells by normal mechanisms. (MOI)[26]
 

Since the media contains both infectious and non-infectous virions a purification process is needed to separate the two subunits from each other. An improvement to the current method has been the development of pre-(viral DNA replication) enveloped particles (PREPS) which effectively eliminates the presence of the infectious virions . PREPS differ from virions and L-particles by being assembled prior to viral DNA replication, thereby incorporating no viral DNA. It is thought that both L-particles and PREPS can serve as vaccines for the parent herpes virus from which they are derived. Alternatively, in the case of PREPS, the coding sequence of any desired true-late gene may be placed under the control of a suitable early virus promoter such that the protein is incorporated in the particle. [26]

            Optimistically, PREPS may be used as an effective HSV vaccine, their greater potential lies with the ability to serve as delivery vectors for other proteinaceous immunogens. In this case, foreign proteins are engineered into the virus stock genome under the control of a suitable promoter. The protein is then incorporated into the PREPS, which are excreted into culture medium and readily purified. PREPS are non-toxic to recipient cells up to a loading of 10,000 particles per cell, delivering proteins at levels similar to those found in virulent infections. Furthermore, neither PREPS nor L-particles express the HSV-1 US-12 gene protein which impairs normal cellular antigen processing pathways. All these qualities suggest that PREPS and L-particles provide a novel, safe and versatile vehicle for vaccination in both humans and animals. PREPS may also have potential for delivery of therapeutic neuropeptides expressed under the control of suitable viral promoters engineered into the virus stock, as they are anticipated to exhibit normal herpesvirus cell tropism. [26]

Skinner Vaccine

        The Skinner Vaccine, developed by GR Skinner of the U. of Birmingham, UK, has undergone various trials over the past 15 years. Presently, anecdotal data and open studies indicate a degree of  usefulness but the vaccine has yet to prove itself in a double blind - placebo controlled study. [28] Even though the vaccine efficacy is not known, this vaccine is currently available in England for about $150. The Skinner Vaccine is an intracellular sub-unit vaccine which appears to offer several advantages over existing recombinant sub-unit vaccines. Rather than using individual viral proteins, this vaccine uses the virus infected cells as the starting point of manufacture. The infected cell is subjected to a patented process which extracts all viral particles and virtually all of the DNA. This process also retains almost all of the antigenic proteins and glycoproteins found in the infected cell to then be used as the vaccine. This seems to give the vaccine a very high immunogenicity. [27]

 Summary of clinical studies in named patients:
 

Other Vaccines

    Bulgarian Vaccine:
            Since 1975 over than 20,000 patients in Bulgaria have been immunized with whole herpes vaccines with good
            therapeutic effect. [29]

    Lupidon Vaccine:
            Is a vaccine that has been researched since the 1977, and is commercially available in Europe and South America.
            Effectiveness seems to be similar to a permanent dose of  Famvir® or Valtrex. [30]

    Dr. Suarez's Curative Herpes Vaccine:
            Doctor Suarez was appointed head of the State Laboratory at the University of Morelia (Mexico), he claims to
            have found a way to modify the herpes virus, so as to make it completely "visible" to the immune system, and
            so that it may become entirely targeted by the human antibodies. Vaccination consists of inoculation of a solution
            prepared from the patient's own blood, available in Mexico. [31]

FAILED VACCINES

Chiron Corp.:
       NIAID scientists have completed their study of a genetically engineered vaccine against herpes simplex virus type 2  (HSV-2).  In very carefully designed studies, NIAID researchers determined  the vaccine's safety, then went on to do dose ranging studies and immune response studies. They also completed two placebo controlled studies to see whether vaccination would reduce outbreaks in people already infected. The vaccine did reduce the outbreaks by about 30 percent (similar to the effectiveness of the antiviral acyclovir), but that was less reduction than expected. Even though the vaccine proved to be safe and induced an immune response in the vaccinated volunteers, the vaccine failed in two clinical trials by not protecting HSV-negative recipients exposed to their infected partners. [24] At present, neither Chiron Corp., the vaccine's manufacturer, nor the NIAID researchers have determined why the vaccine was ineffective. However, in its development, for nearly a dozen years, it worked extremely well as a preventive vaccine and as a treatment vaccine in several different species of experimental animals.  As of now more needs to be known about the human immune response to herpes before NIAID can initiate new vaccine or treatment studies. [32] [66]

Inactived Virion Derived Vaccines

    No known companies are pursuing the development of this type of vaccine [24] [66]
 
 
 

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