Are the TheravaxHSV and ProfavaxHSV vaccines safe?
The TheravaxHSV and ProfavaxHSV vaccines are rationally-engineered live vaccines (RELVs) based upon live-attenuated herpes simplex viruses 1 or 2 (HSV-1 or HSV-2) bearing engineered deletions within the ICP0 gene. Mutations in the viral ICP0 gene profoundly impair viral spread and eliminate the HSV vaccine strains’ ability to cause disease. More than 20 years of basic science indicates that RELVs based on HSV ICP0– mutant viruses would be as safe, or safer, than the randomly isolated live-attenuated viral vaccines (i.e., accidents of nature) currently administered to children in the U.S. (e.g., chickenpox & MMR vaccines).
The ICP0 protein functions as a gas pedal (positive regulator) that accelerates the HSV replication cycle by 50-fold. Like a car without a gas pedal, HSV ICP0– mutants are able to move forward through their replication cycle, but do so much more slowly than wild-type HSV and are thus easily overtaken by the innate immune response of vaccine recipients. Hence, HSV ICP0– mutant viruses are grossly impaired in their spread and establish only self-limited, asymptomatic infections in vaccine recipients. At a more biochemical level, ICP0 is an E3 ubiquitin ligase that plays a critical role in (1) co-activation of viral mRNA synthesis in the nucleus and (2) in destabilization of nuclear PML bodies and cytoplasmic microtubules.
HSV-1 ICP0– mutants are avirulent in normal and severely-immunocompromised SCID mice (Halford, et al, 2006), and likewise HSV-2 ICP0– mutants have been shown to be profoundly attenuated in normal mice, SCID mice, and guinea pigs (Halford, et al, 2010; Halford, et al, 2013). The fact that HSV ICP0– mutants are profoundly interferon-sensitive explains their extraordinary safety and attenuation in animal models (Härle, et al, 2002; reviewed in Halford and Gebhardt, 2011). Phase 1 Clinical Trials remain to be conducted to verify the safety of HSV-1 and HSV-2 ICP0– mutants in humans, but there is every scientific reason to expect these RELVs will be safe, or safer than the chickenpox & MMR vaccines currently used in the U.S.
What is the active ingredient in RVx’s TheravaxHSV and ProfavaxHSV vaccines?
The TheravaxHSV and ProfavaxHSV vaccines are based on genetically-engineered ICP0– mutants of herpes simplex viruses 1 or 2 (HSV-1 or HSV-2). This represents a new class of viral vaccines that has yet to be advanced to routine clinical usage. At Rational Vaccines (RVx), we refer to these 3rd Generation Vaccines as Rationally-Engineered Live Vaccines or RELVs. In principle, RELVs offer the effectiveness of traditional live-attenuated viruses used in the smallpox (developed in 1798), yellow fever, oral polio, mumps, measles, rubella, and chickenpox (developed in 1974) vaccines. However, RELVs contain one or more large deletions of genetic code to improve their safety over traditional live-attenuated vaccines.
The advantage of “live-attenuated vaccines” is that, for 200 years, if a vaccine was sufficiently attenuated to make it safe for most recipients, then the approach never failed to protect the human population from the intended viral disease. The downside of traditional live vaccines is that they were based on random “accidents of nature” (e.g., genetic point mutations) and did not always achieve the desired level of safety. For example, the oral (live) polio vaccine deployed in 1962 was plagued by issues of “genetic metastability.” This means that during the production of the live poliovirus vaccine, the attenuating mutation could revert at any time and regain its capacity to cause human disease. Thus, about 3 out of every million oral polio vaccine doses would produce disease in vaccine recipients that would leave some children crippled. This specific situation caused a great deal of fear and anxiety about the risks of traditional live-attenuated vaccines.
In the 21st century, technology has moved forward and there is no need to accept such risks to achieve the desired benefit of live-vaccine-induced eradication of a human disease. The technology involved with genetic engineering became available in the 1970s, and is routinely used in research laboratories today. Using these powerful new tools, we may now custom design RELVs by removing large segments of genetic code to obtain interferon-sensitive viral “deletion mutants” that are (1) genetically stable, (2) profoundly spread-impaired, and (3) highly effective vaccines that introduce the body’s immune system to nearly 100% of the viral pathogen. Together, these properties maximize the odds of safely vaccinating the human population and eliciting durable, herd immunity against the intended viral disease.
The big difference between live vaccines and subunit vaccines is their rate of success. There has never been a live vaccine in the history of the world that has failed to prevent the intended infectious disease. In contrast, hundreds of subunit vaccine candidates have failed to prevent their intended infectious disease because subunit vaccines do not present 90 – 99% of the natural pathogen to the human immune system.
At RVx we believe that it is time to put the interests of patients first and acknowledge that over 5,000 people per day are dying of AIDS, tuberculosis, and malaria, which may all be vaccine-preventable diseases. Likewise, more than one million people per week are newly infected with HSV-1 or HSV-2 each week. Given the depth of human suffering being caused by these potentially vaccine-preventable diseases, we believe it is time to determine if a New Generation of Live Vaccines, RELVs, might succeed in preventing diseases such as genital herpes, which traditional subunit vaccines have failed to control for 30 years.
RVx was founded on the core principle that RELVs represent a clear and unexplored path with the potential to control and eradicate many infectious diseases that remain major global health problems. RVx is the first company to pioneer the use of the RELV approach, using HSV ICP0– mutant viruses, to control and eventually eradicate all forms of herpetic disease.
How would the Theravax and Profavax vaccines be administered?
Herpes simplex virus (HSV) has a tropism (affinity) for cells in the human epithelium and nervous system. Therefore, in early phase clinical trials, Rational Vaccines plans to administer the TheravaxHSV and ProfavaxHSV vaccines as an intradermal immunization in order to put the attenuated HSV ICP0– mutant viruses in the dermis where it may infect and replicate within epithelial cells that support HSV replication.
It is likely that, like the chickenpox vaccine (VZV Oka strain), the attenuated HSV ICP0– mutants in the Theravax and Profavax vaccines will not only replicate in the epithelium of the dermis, but may also enter nerve endings and be carried up to the ganglia where they may establish a latent infection in neuronal cell bodies of the ganglia. If a recipient were immunized in the skin of the left calf, that would place the latent vaccine infection in left ganglia of the lower spine.
What are the risks associated with a latent infection initiated by RVx’s live TheravaxHSV or ProfavaxHSV vaccine strains?
The prospect for a latent infection with a live herpes simplex virus 1 or 2 (HSV-1 or HSV-2) vaccine has been a major theoretical concern of virologists for decades. However, there is no evidence that a latent infection with a HSV vaccine strain would, in and of itself, pose a risk to recipients. To the contrary, a latent infection with a live HSV vaccine strain may be required to elicit durable, life-long immunity to the natural HSV-1 or HSV-2 pathogens. There are several facts that one should consider when trying to put the risks of a live-attenuated alpha-herpesvirus vaccine into perspective.
First, the chickenpox vaccine is based on a live-attenuated alphaherpesvirus known as the varicella-zoster virus (VZV) “Oka” strain. VZV is very closely related to HSV-1 and HSV-2, as illustrated by the facts that all three viruses share about 60 (out of 75) genes in common, and establish latent infections in the peripheral nervous system of infected individuals. The live VZV Oka vaccine has been administered to more than 100 million people over the past 35 years and has proven to be an overwhelmingly safe and hugely successful vaccine. Importantly, the live VZV Oka vaccine routinely establishes latent infections in the peripheral nervous system of these >100 million recipients. Therefore, practical experience with the live VZV Oka vaccine indicates that there are, 35 years later, still no known risks of vaccinating millions of people with a live alphaherpesvirus vaccine strain.
Second, switching to HSV, to put the risk of a latent HSV ICP0– mutant vaccine in proper perspective, one should appreciate that about four billion people are currently latently infected with wild-type HSV-1 or HSV-2. The wild-type variants of these viruses are at least 1,000 times more dangerous than Rational Vaccines’ HSV ICP0– mutant vaccines. There are no known complications of carrying an asymptomatic infection of wild-type HSV-1 or HSV-2 provided that the latent virus does not reactivate and resume productive replication. Because ICP0 is required for HSV to reactivate from latency (Halford and Schaffer, 2001), any latent HSV-1 or HSV-2 ICP0– mutant virus that would remain after receiving the TheravaxHSV or ProfavaxHSV vaccines could not reactivate to cause disease. Therefore, while it is anticipated that Rational Vaccines’ live HSV ICP0– mutant vaccines will have the capacity to latently infect vaccine recipients, it is unclear that this will pose any additional risks to recipients and in fact may be required to maintain durable immunity against genital herpes and other herpetic diseases.
Why might a therapeutic HSV-2 vaccine work better than antiviral drugs?
Two relevant studies were published in 1988 that raise the question of whether or not there is a potential downside of prophylactic (daily suppressive) antiviral drugs to suppress HSV recurrences. These studies are:
- Gold D, Ashley R, Solberg G, Abbo H, Corey L. 1988. Chronic-dose acyclovir to suppress frequently recurring genital herpes simplex virus infection: effect on antibody response to herpes simplex virus type 2 proteins. J Infect Dis. 158:1227-34. read more.
- Erlich KS, Hauer L, Mills J. 1988. Effects of long-term acyclovir chemosuppression on serum IgG antibody to herpes simplex virus. J Med Virol. 26:33-9. read more
The study of Gold, et al (1988) convincingly showed that patients who go on prophylactic acyclovir (and presumably valtrex or famvir) experience a significant decrease in their antibody response to HSV-2. At the time, this should have raised concerns about whether or not the use of prophylactic antiviral drugs erode the body’s natural ability to combat HSV-2 infection. In particular, if one reads the study of Gold, et al (1988), Figure 1 demonstrates that patients taking daily acyclovir for 6 or 12 months exhibit a marked decrease in their antibody response to HSV-2 proteins. In contrast, patients taking a placebo for 6 or 12 months show a steady level of antibody to HSV-2, which remains constant over time because subclinical and/or symptomatic HSV-2 reactivation events keep the immune system engaged such that HSV-2-specific B cells remain activated, and hence produce HSV-2-specific antibodies at a rate in balance with the natural decay rate of antibodies (i.e., half-life = 21 days). The results are convincing, and are consistent with how the biological systems of “persistent infections” generally behave.
Recently, it has become more apparent that HSV-specific antibodies play a critical role in rapid immune control of HSV-1 and HSV-2 infections (Halford, et al, 2015; Royer, et al., 2016; Iijima and Iwasaki, 2016). Therefore, any prophylactic antiviral drug regimen that reduces the antibody response to HSV-1 or HSV-2 should make people’s immune systems less competent to control HSV infection, and thus increasingly vulnerable to more frequent outbreaks and/or nerve pain (caused by a non-protective immune response to subclinical HSV reactivation in the ganglia).
The study of Erlich, et al (1988) offers a parallel conclusion. Therefore, it is possible that the most responsible way for patients to use valtrex or acyclovir is by episodically taking these drugs as needed to curb the duration of outbreaks so that their body’s immune system may learn to fight the virus better in the in-between times when they are not having full-blown outbreaks.
Against that background, RVx is proposing that an effective therapeutic HSV-2 vaccine might completely eliminate the need for antiviral drugs such as valacyclovir, famvir, and acyclovir, which suffer from the serious limitations of (1) poor solubility / absorption from the intestines to the bloodstream (i.e., poor bioavailability) and (2) failure to meaningfully limit HSV shedding to the point where HSV transmission rates are curbed and decrease over time. If these drugs meaningfully curbed HSV transmission rates, then the seroprevalence of HSV-2 in young adults should have started declining in the year 2000. However, more than one million people per week continue to be newly infected with HSV-1 or HSV-2.
A therapeutic HSV vaccine regimen that actually works for patients, combined with effective prophylactic HSV vaccines, represent real medicine that represents a real opportunity to end the herpes epidemic once and for all.
Why would ProfavaxHSV-2 be superior to past prophylactic HSV-2 vaccine candidates?
Past prophylactic HSV-2 vaccine candidates have largely been based upon HSV-2 glycoprotein “subunit” vaccines, which have been failing in human clinical trials for 30 years. In contrast, Rational Vaccines’ live HSV-2 ICP0– mutant vaccine strains, such as the HSV-2 0ΔNLS strain, introduce vaccine recipients to 9 to 19 different HSV-2 proteins. This more “polyvalent” immune response elicits a protective immune response that is about 50 times more potent than a HSV-2 subunit vaccine. Numerous pre-clinical studies demonstrate that HSV-2 0ΔNLS is vastly superior to the HSV-2 subunit vaccines that have been the mainstay of failed HSV-2 vaccine efforts for the past 30 years. Specific citations that support these statements include the following: Halford, et al, 2011; Halford, et al, 2013; Halford, 2014; Geltz, et al., 2015.
Why should TheravaxHSV-2 be superior to the GEN-003 or HerpV vaccines?
The GEN-003 vaccine is very similar to the failed Herpevac vaccine, which was based on a “HSV-2 glycoprotein D subunit vaccine.” The primary difference is that GEN-003 includes 30% of another HSV-2 protein, ICP4. At issue, the GEN-003 vaccine can, at best, introduce the body’s immune system to 2% of HSV-2’s foreign protein signature. In contrast, Rational Vaccines’ live HSV-2 ICP0– mutant vaccine strains have 50 times greater antigenic breadth and introduces vaccine recipients to 99.3% of HSV-2’s foreign protein signature. Thus, the live HSV-2 0ΔNLS vaccine elicits an antibody response to 9 to 19 different HSV-2 proteins, and less than 5% of those antibodies target HSV-2’s glycoprotein D and ICP4 proteins. The more “polyvalent” immune response elicited by a live HSV-2 ICP0– mutant vaccine elicits a protective immune response that is about 50 times more potent than a HSV-2 gD subunit vaccine. Numerous pre-clinical studies demonstrate that a HSV-2 ICP0– mutant referred to as ‘0DNLS’ is vastly superior to the HSV-2 subunit vaccines that have been the mainstay of failed HSV-2 vaccine efforts for the past 30 years.
The Agenus HerpV vaccine only elicits a T-cell response and is incapable of eliciting an antibody response against HSV-2. This vaccine concept was developed based on the assumption that antibodies are irrelevant in host defense and protective immunity against HSV-2. This premise appears to be incorrect. Several recent publications establish that HSV-specific antibodies are required for robust vaccine-induced protection against HSV-1 and HSV-2 infections (Halford, et al, 2015; Royer, et al., 2016; Iijima and Iwasaki, 2016). The Agenus HerpV vaccine cannot elicit an antibody response against HSV-2. In contrast, the live HSV-1 0ΔNLS and HSV-2 0ΔNLS vaccine strains elicit robust vaccine-induced protection against HSV-1 and HSV-2 (Halford, et al, 2015; Royer, et al., 2016).
How do the TheravaxHSV and ProfavaxHSV vaccines differ?
The primary difference between the two vaccines will likely be a matter of virus dosage. Because prophylactic vs therapeutic HSV vaccines are still in development, it is easier to explain why this is the case by focusing on comparable vaccines that are currently used in practice like the live-attenuated varicella-zoster virus (VZV) Oka vaccine that is used to prevent both chickenpox (primary infection with VZV) and shingles (reactivation of latent VZV).
The main difference between the chickenpox and shingles vaccines is that the dose of VZV Oka virus is 13 times greater than in the shingles vaccine. This is because a child receiving the chickenpox vaccine as a 1-year-old has no immunity to VZV and so a low dose will suffice and will be better tolerated. In contrast, a 55-year-old who already had chickenpox as a child and is worried about getting shingles due to VZV reactivation, has pre-existing immunity to VZV. Thus, a 13-fold higher dose of VZV Oka is used in the shingles vaccine to overcome pre-existing immunity to VZV.
The same would be true for TheravaxHSV (therapeutic vaccine) versus ProfavaxHSV (prophylactic vaccine), but the details of dosage and delivery schedule remain to be determined in Clinical Trials.