I received the following email from a blog follower last week, which I think eloquently makes a fair and important point that I had previously overlooked.
“I watched the 75 minute video presentation you created [on the RVx website], and thought it was very, very good, even entertaining. however, it seemed to me to only provide the “first half,” which basically was an expository description of these infections, and how they work. I would like to see the second half, which to me would be how your vaccines work and why they work; that is, why they overcome what you describe in the first half.”
I reply to Zorro, as follows: “Great Idea. I will do exactly this, and post it on my blog for starters. This will give you and other people who similarly want to know the back story a way to prepare for and/or better appreciate the October 16 Press Release that is coming following the SIU Tech Expo on October 13.” Enjoy!
– Bill H.
Rational Vaccines (RVx) has a major press release coming in about two weeks. The topic of this press release will be the practical culmination of the past 20 years of its Chief Science Officer’s research dating back to 1995.
This post is for those who are interested in the back story of what happened between 1995 and 2015 to convince William Halford (a science geek / lab rat) to Co-Found Rational Vaccines (RVx) with an Emmy / Oscar-winning movie producer, Agustin Fernandez III (Co-Founders of RVx pictured above). Below are segments of about 4 hours worth of lectures, broken up into 4- to 34-minute segments, that distill 24 years of research and 50+ publications into something approaching “normal English” that will hopefully be more accessible to a lay or general medical audience trying to understand the scientific evidence that supports the acute need for the technologies that RVx is offering the world. Global eradication of herpes (or a 99.9% reduction in disease burden) sounds like a big goal. However, the past 10 years of Dr. Halford’s research indicate that this is the most likely outcome of deploying live HSV-1 and HSV-2 ICP0¯ mutant vaccine strains that will, for the first time ever, be highly effective in reducing the global burden of herpetic disease.
Lecture 1. The Basics: Understanding persistent microbial infections.
RVx’s Chief Science Officer, William Halford, has been teaching future doctors about infectious disease since 2000. Below are slides that summarize the basic biology of persistent infections, and which use HSV-1 as a model system to illustrate how an infectious agent may establish a life-long infection. A video and audio recording of this 75-minute lecture, broken up into five parts, offers a broader context to understand how HSV-1 and HSV-2 establish persistent infections in humans that alternate between periods of latency and recurrent disease.
- View slides on “Microbial Immune Evasion & Persistence” (α-herpesviruses considered in Slides 45 – 142)
- Hear audio and see slides of a 75-minute lecture on “Microbial Immune Evasion & Persistence” broken up into five parts:
- Introduction to Persistent Infections (10 minutes)
- Strategies that Promote Microbial Persistence (13 minutes)
- Introduction to the α-Herpesviruses (26 minutes)
- Immunity to HSV (11 minutes)
- Viral Countermeasures & Recurrent Herpes (17 minutes)
Lecture 2. HSV’s Latency-Replication Balance (1995 – 2006)
From 1992 – 1996, William Halford obtained his PhD under the mentorship of two immunologists, Bryan Gebhardt and Daniel Carr, studying the persistent cytokine response that occurs in trigeminal ganglia latently infected with herpes simplex virus 1 (HSV-1). From 1997 – 2000, he then performed his postdoctoral studies under the mentorship of Priscilla Schaffer, one of the pillars of the herpesvirus research community, and there focused on developing new methods and approaches to help determine if ICP0 truly served as a master-regulator of HSV-1’s latency-replication balance in latently infected trigeminal ganglion neurons.
As an Assistant Professor at Tulane (2000 – 2004) and Montana State University (2004 – 2007), William Halford’s lab was pivotal in articulating two new and inter-related concepts that (1) host interferons served as a silent partner in the regulation of HSV latency and (2) ICP0 and an adjacent protein (ICP34.5) were interferon-resistance factors whose differential expression likely explained how HSV rapidly pivots between periods of latency versus productive viral replication. This is reviewed in Halford & Gebhardt, 2010.
Below are slides that summarize the take-home message from Dr. Halford’s research between 1995 – 2006 that offers a different view of how HSV’s latency-replication balance is controlled relative to what is presented in most textbooks. This alternative view of HSV-1’s latency-replication balance is supported by more than a dozen research publications from Dr. Halford and is highly consistent with the available evidence of the past 50 years.
A video and audio recording of this 85-minute lecture, broken up into five parts, offers a simpler and more rational way to think about how HSV-1 regulates the “decision-making process” that regulates its ability to rapidly pivot between periods of latency and recurrent herpetic disease.
- View slides on “Antigenic Breadth: a Missing Ingredient in HSV-2 Vaccines” (HSV’s Latency-Replication balance considered in Slides 1 – 54)
- Hear audio and see slides of a 85-minute lecture on “HSV’s Latency-Replication Balance” broken up into five parts:
- Prologue to Halford Research Talk (6 minutes)
- Overview of entire 101-slide Halford Research Talk (4 minutes)
- Equilibrium Model of HSV-1 Infection (34 minutes)
- Is Interferon really a silent partner in regulating HSV-1 latency? (25 minutes)
- HSV-1 ICP0¯ viruses are interferon-sensitive and profoundly attenuated (16 minutes)
Lecture 3. HSV ICP0¯ viruses: a new class of HSV vaccines that work (2007 – present)
Based on the conclusions of Halford, et al, 2006, William Halford first proposed in Halford, 2007 that (1) there were some obvious reasons that past HSV-2 vaccines had failed and (2) a new class of live HSV ICP0¯ mutant virus vaccines might succeed where past HSV-2 vaccines had failed.
NIH Grant Reviewers have systematically rejected Dr. Halford’s grant proposals requesting support to advance this promising line of inquiry with the potential to eradicate herpetic disease. Rather the NIH has chosen to support research into the same gD-2-based vaccines that have been continually failing in U.S. Clinical Trials conducted between 1986 and 2016. GEN-003 is one of the latest iterations of this failed HSV-2 vaccine concept.
Below are slides that summarize the take-home message from Dr. Halford’s research between 2007 – 2016, conducted at the Southern Illinois University School of Medicine, that took the initial proposal of Halford, 2007 from a hypothesis to what is now, beyond a reasonable doubt, a clear explanation for why past HSV-2 vaccines have failed and why live HSV-2 ICP0¯ mutant vaccines will succeed where past approaches have failed. The bulk of the evidence that supports these conclusions may be found in the publications of Halford, 2014; Geltz, et al., 2015; Halford, et al, 2015; and Royer, et al, 2016.
A video and audio recording of this 75-minute lecture, broken up into four parts, summarizes the evidence that (1) the failure of past HSV-2 vaccines is predicable and (2) live HSV-2 ICP0¯ vaccines will almost certainly succeed in eradicating herpes. Yes, past HSV-2 vaccines have been lame. However, these past failures have no bearing on the future prospects of a live-and-appropriately attenuated HSV-2 ICP0¯ mutant vaccine to succeed where subunit vaccine garbage has failed.
- View slides on “Antigenic Breadth: a Missing Ingredient in HSV-2 Vaccines” (A Better HSV-2 Vaccine approach considered in Slides 54 – 101)
- Hear audio and see slides of a 75-minute lecture on “Better HSV-2 Vaccines” broken up into four parts:
- Is a live HSV-2 ICP0¯ mutant vaccine safe (avirulent)? (7 minutes)
- Missing Principle #1: Antigenic Breadth (34 minutes)
- Missing Principle #2: Need for a Balanced B- and T-cell response (25 minutes)
- Conclusion: In baseball and vaccines, batting averages should matter (9 minutes)
Lecture 4. Next Steps (today – future)
Coming Soon: SIU Technology & Innovation Expo (October 13)