I’ve been doing some reading on HSV vaccine development. The...

I’ve been doing some reading on HSV vaccine development.

The first thing I’ve learned is that developing an HSV vaccine is acknowledged as being very difficult. Very, very difficult. As stated in a recent article, developing a successful HSV vaccine is “something that is very challenging, perhaps impossible”. Researchers have been working on a HSV vaccine since at least the early 1930s, with little success. While various herpes vaccines have been developed which initially looked promising, more stringent testing resulted in them faring no better than placebo.

There are numerous barriers to success in developing an HSV vaccine. Firstly, there is no good animal model in which to test the vaccines. Although mice and guinea pigs can be infected with herpes, their infections are apparently quite different from human herpes infections. This means that vaccines that may have shown promise in animals haven’t fulfilled that promise in humans. No human trials have shown high enough efficacy to bring a herpes vaccine to market. To add to the challenges, the nature and prevalence of HSV means that clinical trials are very large, slow and expensive.

Worldwide, ∼90% of people are believed to have one or both Herpes Simplex viruses - HSV-1 (associated with cold sores) and/or HSV-2 (associated with genital herpes). HSV-2 is a lifelong and incurable infection and it is the fastest growing STD in America. While it may seem obvious that any HSV vaccine would target HSV-2, rather than HSV-1, recent studies suggest that 20%-50% of incident episodes of genital herpes are caused by HSV-1. To add to the complication of two potential targets, there are two types of vaccines that are required - prophylactic vaccines to help prevent people from ever getting herpes and therapeutic vaccines, which would reduce the number of outbreaks in those who have already contracted the disease.

Last year, the World Health Organization defined a series of priorities for developing both therapeutic and prophylactic HSV vaccines. A slide presentation from a WHO group workshop, held mid-last year, included an examination of HSV vaccine pipeline and early clinical trials. At the time there were four companies which had reached Phase 2 development stage (see Slide 16 onwards) – Admedus, Genocea, Vical and Agenus.  All these programs were for therapeutic vaccines targeting HSV-2. The Admedus and Vical candidates are described as DNA vaccines, whereas the Genocea candidate is a recombinant subunit (synthetic) vaccine and the Agenus candidate is described as a “synthetic peptide complex with HHSP 70.”

Although all four companies have now reported at least Phase 2a results, there are no firm plans to date to advance any of the vaccine programs into Phase 3 trials.

Australian biotech Admedus announced results of its Phase 2a trial in May 2017. Safety was confirmed in the trial but efficacy results were seemingly modest. Phase 2b results are still to be delivered.

Genocea announced “successful” Phase 2b results of its vaccine, GEN-003, in July 2017 but then announced two months later that it was ceasing further development activity. After putting GEN-003 up for licensing, the company announced last month that GEN-003 has attracted interest from potential partners and it is hopeful that this might lead to further development of its vaccine.

In June this year Vical announced that a Phase 2 trial of its HSV vaccine candidate had failed to meet primary endpoint and that the company was terminating the program.

As for Agenus, it concluded a successful Phase 2 trial of its vaccine candidate in 2014. A significant reduction of the incidence and severity of recurring outbreaks and reduced viral transmission was demonstrated. However, since then, there have been no further announcements and the vaccine no longer appears as part of Agenus’ pipeline.

I’m intrigued as to why Phylogica has chosen to initiate its head-to-head in vivo trials with a CPP-cargo targeting HSV and why the competitor product chosen is Amal Therapeutic’s ZEBRA CPP. Why such a difficult target, particularly when animal models have been proven to be a poor indicator of HSV vaccine success in humans and why Amal Therapeutics' CPP when their current pipeline is devoted to oncology vaccines?

Keeping in mind TonyIndo’s post about the PYC CPP antigen having stimulated both a CD8 and CD4 response, I note that in a paper on its animal trials of its GEN-003 HSV vaccine, Genocea researchers commented

T cells have been shown to play a major role in anti-HSV immunity in both animal models and humans. While CD8+ T cells have been shown to be important for the clearance of HSV infection, CD4+ T cells are necessary to provide helper functions that sustain anti-HSV CD8+ T cell immunity and promote antibody class switching. Reactivation of HSV-1 in infected mouse trigeminal ganglia is blocked by CD8+ T cells secreting gamma interferon (IFN-γ, and CD4+ T cells secreting IFN-γ are critical for immune protection against lethal genital HSV-2 infection in mice. #

I also note that Amal Therapeutics researchers commented on their ZEBRA CPP( Z12/Z13), albeit it with respect to cancer rather than HSV

….the Z12/Z13 facilitates induction of a robust integrated immune response, comprising both CD4+ and CD8+ T cells. For anticancer immune response, this is a major advance over the previously reported CD4+ T cell-bias for protein vaccines.