The Challenge Behind Challenge Studies: The Hepatitis C Perspective



As a third year immunology student in the University of Alberta’s Specialization program I spend most of my time learning about the dozens of different bacteria, virus, fungi and parasites that plague humanity. From memorizing virulence factors to drawing out countless mechanisms of infection all night, I can now say immunology and the immune system have become my specialty. However, little did I know that all this was about to change once I learned about one of Canada’s fastly growing public health issues.


Last Minute Coincidence

It was the last week of April and I had just finished my last exam. The time had come for me to settle down and finally make a decision about my summer stretch project. Thanks to the Peter Lougheed Leadership College’s Network and the Medical Microbiology Department’s professors I was able to find five different potential summer projects, ranging from research on bladder cancer treatment to designing laboratory grown meat. However, just as I was about to submit my project proposal after I had just spent a day or two thinking about the projects, I got an email early in the morning from Dr. Michael Houghton (professor at the University of Alberta). When I contacted him (earlier in March) I did not know much about him or his work, but I had an interest in his research topic, Hepatitis, and wanted to learn more about it. Nonetheless, I was very surprised that that morning he asked if we could meet later that same day and discuss his research work. So, with peaked interests and heighten curiosity I decided to postpone my proposal submission and made my way down to the University.

“…An estimated 170 million people worldwide including over 300,000 in Canada are infected with Hepatitis C…”

Canadian Liver Foundation

The Discovery That Started it All

That afternoon, as I met Dr. Houghton (photographed below, top right) at his office in the Li Ka Shing Centre for Health Research Innovation, I learned he was the world renown virologist who discovered the Hepatitis C virus and had a role in the identifying of the Hepatitis D virus too. However, regarding Hepatitis C, him and his team were able to identify the so-called at the time non-a, non-b Hepatitis virus, back in 1989 at Chiron Corporation, California, USA. Moreover, during our discussion, Dr. Houghton explained the current Hepatitis C epidemic in Canada, his current work at the university and his collaboration at the Li Ka Shing Centre with Dr. D. Lorne Tyrrell (photographed below, bottom right), focusing on Hepatitis B and C. Furthermore, I was able to learn that him and his team are currently working on a potential vaccine for Hepatitis C. I was starstruck! All of this groundbreaking work being done at the University of Alberta and I did not even know about it. Naturally, this really peaked my interests, not only because of my immunology background, but also because of the many challenges and obstacles he brought up as we were discussing the vaccine manufacturing and development. Specifically, what caught my attention was just how novel this pioneering work really was, being on the edge of ground breaking research. However, before we move on and discuss the details surrounding the stretch project, that day Dr. Houghton discussed that he thinks it would be beneficial to take a step back and educate ourselves on the topic of Hepatitis; thus, allowing us to really grasp the novelty and the challenge of my proposed human vaccine challenge research project.


The Li Ka Shing Centre for Health Research Innovation is the where the Li Ka Shing Institute of Virology (LKSIoV) is located. The institute’s vision is to lead the world in virology discoveries, cures and its mission is to discover new methods to prevent, treat and cure virus-related diseases; thus, reducing the burden of viral disease around the world.

Back to Basics: Another Reason to Learn your ABC’s

Now, before I was able to start my summer stretch research, I had to take a second and truly understand the scope of the project. Thus, I spent a long time educating myself on the field of Hepatitis and the Hepatitis viruses. As such, I think it would make more sense for me to provide you with some background into Hepatitis before we dive deep into my project.

In general, hepatitis is defined as inflammation of the liver. It can be either acute (short-term) or chronic (long-term). There are many causes of inflammation of the liver. However, the most common causes are chemicals (alcohol) or viruses (Hepatitis A, B or C). Specifically, viral hepatitis, mainly caused by the hepatitis viruses, is an inflammation of the liver that can progress to fibrosis, cirrhosis, liver cancer or ultimately death.

“…HCV IS AN ENORMOUS PUBLIC HEALTH PROBLEM IN CANADA. IN FACT, IT’S THE PUBLIC HEALTH INFECTIOUS DISEASE WITH THE GREATEST PUBLIC HEALTH BURDEN OF ANY, CAUSING THE GREATEST NUMBER OF YEARS OF LIFE LOST IN THE COUNTRY…”

-Dr. Jordan Feld, Blue Print Launch, 8th Canadian Symposium on Hepatitis C Virus (CSHCV)

Globally, an estimated 1.4 million annual deaths result from viral hepatitis – a loss comparable to that of HIV and tuberculosis1. Of those deaths, the majority are due to hepatitis B virus (HBV) and hepatitis C virus (HCV) infections.2

Viral hepatitis is a pandemic affecting hundreds of millions of people worldwide, with some areas more endemic than others. Furthermore, different risk groups are more prone to a viral hepatitis infection than others. Approximately 300 million people are predicted to be living with viral hepatitis and unaware of their condition3. If left untreated, many of these individuals may unknowingly transmit the virus to others. These individuals may also be met with a fatal outcome, such as fatal liver disease or liver cancer. Now, focusing specifically in Canada more than 300,000 individuals are infected with Hepatitis B and about 250,000 are living with Hepatitis C, most unaware of their infection. For simplicity I have provided a quick summary of the current Hepatitis C statistics within the Canadian population.


Summary of the Hepatitis C epidemic in Canada. “1 in a 100 Canadians have been infected with Hepatitis C in their lifetime” as estimated by Statistics Canada.

Now, without going into too much depth about hepatitis, the infectious agents that are able to cause hepatitis are Hepatitis A, B, C, D and/or E. However, all of these similar sounding viruses should not be taking lightly, as they are completely different and separate from one another, each with their own unique route of transmission and disease history.

Hepatitis A and E both causes acute hepatitis via oral-fecal transmission, meaning they are a food and water borne diseases. Hepatitis B, spread via blood and bodily fluids, and Hepatitis C, spread via blood contact only, are the two most common causes of chronic hepatitis worldwide. Lastly, Hepatitis D occurs as a co-infection (together) with Hepatitis B. For more information take a look at the simplified chart overview below.


Simple diagram giving an overview of the different viral hepatitis viruses.

University of Alberta Researchers Leading the Pack in the Battle Against Hepatitis C

Now, going back to the initial meeting I had mentioned above with Dr. Houghton, I learned that currently, him and Dr. Tyrrell, are leading the pack in the battle against Hepatitis C worldwide. Specifically, with their vaccine that is being developed at the moment they believe they have a real chance at one day eliminating this infectious disease once and for all. However, as most of you may imagine, developing a vaccine and testing its effectiveness is not a short or easy task. And this is where my summer stretch project comes into play.

“…Liver cancer incidence has tripped in Canadian men and doubled in women since the 1970s…”

Canadian Cancer Society

Initially, Dr. Houghton opened up the discussion of a potential research project by proposing to tackle the challenge behind human challenge studies. Specifically, the challenge of investigating the possibility of a human challenge vaccine trial for Hepatitis C through a secondary research project. Specifically, he proposed a project where I would be marshaling a balanced argument for and/or against the implementation of a human challenge vaccine trial for Hepatitis C, all in hopes of aiding his vaccine research.

However, lets take a second and ask what in the world is a human challenge vaccine study?


The Challenge Behind Challenge Studies

So, by definition the purposeful infection of healthy volunteers with a microbial pathogen is generally termed “controlled human infectious studies” or human challenge studies for short. Such research is commonly utilized in the development and testing of vaccines. However, as you may imagine, these types of studies have not always had the most ethical means. Specifically, many studies using this model done by the Nazis during World War II were shown to be highly unethical and cruel.

“…70% of Canadians who have Hepatitis C are unaware of their infections…”

Statistics Canada: Canadian Health Measures Survey, November 2013

However, with today’s many strict ethical university boards and large transparent scientific communities, such tyranny is entirely impossible. Therefore, many researchers around the world are beginning to look at challenge studies as potential models for their vaccine testing. But why are they coming back to this model?


A Second Chance for Challenge Studies

Currently, vaccine and drug testing proceeds through a typical phase I/II clinical trial (you may have heard of this being the industry gold standard). However, such trials take a long time to complete, require a large number of investments resulting in them costing researchers and/or companies much more and most importantly require a higher amount of study participants. To put this into perspective, a normal phase I clinical trial may cost anywhere form $3,000 to $5,000, while a phase II trial ranges from $7,000 to $60,000. That is a substantial amount of money for the opportunity of a company or research team to just test their potential vaccine or therapeutic drug. Likewise, the number of participants in a, phase I averages roughly around 20-80 people, phase II somewhere around 100-300, and phase 3 is about 300-3,000 people. In conclusion, this is a lot of people who are being exposed to a potential treatment, drug or vaccine being tested in hopes of showing some clinical efficacy.

“…Hepatitis C is a leading cause of cirrhosis, liver cancer and liver transplants…”

Canadian Liver Foundation

As as result, many researchers are beginning to look at challenge studies as replacements because they significantly decrease vaccine development and testing time. As well, they are associated with reducing costs in terms of time and money saved in production and testing of the vaccine. They also allow for the faster development of effective vaccines, while at the same time, halting the progression of ineffective candidates early on. Lastly, they require fewer participants (10-40 individuals on average) when compared to standard phase II/III trials.


Secondary Research: A New Experience

In my three years of undergraduate research experience I have never been exposed to the area of secondary research (research involving the summary, collation and/or synthesis of existing research). Therefore, Dr. Houghton’s propositions really presented itself as a new and potentially challenging experience. One which was both fresh and novel. An experience I could undertake in hopes of expanding my research knowledge.

Currently, I am in the middle of my stretch experience, and reflecting back on the last few months I must say that this has been a real career-changing experience. So far, it has been filled with many challenging moments, given the nature and novelty of the research topic. However, the constant excitement I receive when working on pioneering new and unique research has been quite fulfilling. Reflecting on a few of the challenges I have faced during my stretch experience, so far, a few things come in mind. First of all, delving into a new unfamiliar area of research, such as Hepatitis, personally, involved a lot of learning. Specifically, not just learning the basic virology of these viruses, specifically Hepatitis C, but also the public which it effects. As well, understanding its substantial toll on our country and the millions affected worldwide (71 million individuals to be exact).

“…Hepatitis C causes more years of life lost than any infectious disease, including HIV/AIDS, in Ontario and likely Canada…”

Ontario Burden of Infectious Disease Study

On the other hand, investigating such a novel topic has been filled with many obstacles. Although it has been quite exhilarating pioneering research in the field of challenge studies, it has also been quite a lonely journey, as not many researchers in the community have and/or are exploring this topic. As a result, I am currently doing a lot of background work, gathering the necessary knowledge to build a foundation on the topic.

Likewise, being a student whose always main experience has been in primary research, specifically, doing different kinds of tests/assays in the laboratory, I have had to learn a whole new set of methodologies. Specifically, to learn the unique field of systemic reviewing and meta analysis (several approaches used to maximize the synthesis of current literature). However, reflecting on my stretch at this current point in time, there have been many breakthroughs, both in my research topic, as well as my overall stretch experience. Additionally, all of these share one common theme among them; group effort and peer support. Thanks to different researchers, such as, Dr. Timothy Caulfield, Dr. Lorne Tyrrell, Dr. Michael Houghton, Dr. Michael Good, Dr. Carla Salvado and Ms. Bonnie Bock there have been many aspects of my research that have been, in some way or another, supported and encouraged. Specifically, during my first week of my stretch experience, having been a novice undergraduate student in the field of Hepatitis C at the time, Dr. Lorne Tyrrell supported me by bringing me to the 8th annual Canadian Symposium on Hepatitis C Virus organized by CanHepC (Canadian Network on Hepatitis C) in Montreal, Quebec.


Battling Against Hepatitis: The Canadian Frontier

Like I said, being new to the field of Hepatitis C, I was quite fortunate to have been given the chance to accompany Dr. Lorne Tyrrell to this year’s 8th Canadian Symposium on Hepatitis C Virus organized by CanHepC (Canadian Network on Hepatitis C). Here, I was exposed to a vast amount of information surrounding Hepatitis C and the current research being done in the field. It was a unique learning experience, and I was extremely fortunate to have had the chance to see all of the different types of research in virology and epidemiology. It was informative and really provided me with the appropriate foundation of knowledge regarding the current Hepatitis C problem in Canada. As well, through this experience I was able to engage with the scientific community on the topic of Hepatitis C, through partaking in small breakout discussion, poster showings, lectures and panel discussions. It was in Montreal, Quebec, where I first engaged with the CanHepC community, a research network established to connect researchers on the topic of Hepatitis C, whom later on aided me with my community engagement event. To learn about their newly release Blueprint designed to tackle the Hepatitis C problem in Canada, click the link below.


This year’s 8th Canadian Symposium on Hepatitis C Virus organized by CanHepC (Canadian Network on Hepatitis C). Learn more about Canada’s efforts in eliminating hepatitis C through their newly released “Blueprint to Inform Hepatitis C Elimination Efforts In Canada” here.

Overall, this experience has allowed me to gain a vast amount of knowledge in the field of Hepatitis C and has provided me with the ability to hit the ground running when I would later return to my research. Lastly, reflecting back on this experience, I was quite lucky to be in Montreal at the time as coincidentally Dr. Timothy Caulfield (U of A’s own professor in the Faculty of Law and host of the Netflix show “A User’s Guide to Cheating Death”) was giving a guest lecture at McGill University. It is there that we were able to connect and discuss my stretch project after his lecture, titled ” Talking Science in the Age of Fake News”. In closing, I want to thank both Dr. Caulfield and Dr. Tyrrell for their support!


Another lucky coincidence at McGill University where I was able to connect with Dr. Timothy Caulfield (a University of Alberta professor in the Faculty of Law) whom gave an informative lecture on “Talking Science in the Age of Fake News” (click here for the full presentation) and connect with over my stretch project, discuss some of the ethical dilemmas surrounding challenge studies.

The Realization: Myths and Misnomers

During my period of learning and engaging with the topic of Hepatitis C I stumbled across a well-produced documentary on Hepatitis C in Canada, called “Deal with it: Untold Stories of Hepatitis C in Canada”. In the beginning, the producers show several shots of the documentary, in which, random people on the streets of Toronto were asked about their knowledge of Hepatitis C. Many of the individuals interviewed, spoke unsure about their knowledge of Hepatitis C. In summary, what I was able to glean from this documentary was the many different forms of misinformation and myths present in the public’s eyes. Specifically, when talking about Hepatitis C several individual’s believed that you could be vaccinated against this disease. Moreover, others believes this disease was normally picked up by individuals when going abroad to different vacation spots in the tropical regions around the world. Some even believed Hepatitis C is transmitted through normal daily interactions. Nonetheless, it was obvious to me that all of those claims were completely wrong and what really stuck with me as I was watching this documentary was the last man’s comment surrounding Hepatitis C:

“… The issue with Hepatitis C is that I did not know it was an issue…”

Deal with it: Untold Stories of Hepatitis C in Canada

So, I thought to myself, if I, a third year University of Alberta student in the Immunology and Infection Specialization program, was completely unaware of this increasing public health issue then, what was the public’s knowledge of this? Or even worse, if I was unfamiliar with this growing problem of Hepatitis around the world, the different subset of hepatitis viruses and most importantly, their different routes of transmission, what does the public know? Virtually Nothing!


Deal with it: Untold Stories of Hepatitis C in Canada is an excellently produced documentary on the public issue of Hepatitis C in Canada. The link for this documentary on YouTube can be found here.

World Hepatitis Day: Engaging with the Community

So, having realized this large gap in knowledge surrounding the Hepatitis C public health issue, within not only in the general scientific community, but as well, in the general public; I knew I had to do something!

I decided I would organize an event at one of the most frequently visited places in Edmonton, West Edmonton Mall, on July 28th, for World Hepatitis Day. To be frank with all of you, this event was not an easy toll to organize, as I was the only one spearheading this initiative. However, I believed and still believe this is a serious issue and want to do my due diligence and effectively spread awareness on this growing public health issue. However, before we get into the nitty-gritty of this event, I think it is important to take a second and learn more general information on the topic of Hepatitis C. Specifically, whom might this virus effect and whom belongs to the so called vulnerable population?

Baby Boomer Generation: What’s All the Noise About?

Viral hepatitis caused by HBV or HCV is treatable. In fact, HBV is even preventable with effective vaccines. The annual death rate can be significantly lowered, while also hindering viral transmission through education, awareness and treatment. Finding the “missing millions” – the undiagnosed – is of upmost importance in the step towards eliminating viral hepatitis.

In Canada, guidelines have been set by the Canadian Association for the Study of the Liver to find undiagnosed HCV-infected individuals.  Risk groups requiring screening for HCV include Baby Boomers born between 1945 and 1975, blood transfusion recipients or organ transplant recipients prior to 1992, individuals born outside of Canada in endemic countries, or persons who may have used an unsterilized needle-syringe. Once identified, HCV-infected individuals can then be treated and ultimately cured in as little as 8 weeks with a daily dose of just one pill. 

Testing should also be carried out for people who may be at risk of an HBV infection.  Risk groups for undiagnosed HBV carriers include individuals born outside of Canada in endemic countries, Aboriginal Canadians and individuals who have other risk factors for viral hepatitis. HBV vaccines and treatments are available in Canada. To learn more, check out this video made by the World Hepatitis Alliance on Hepatitis C below.


World Hepatitis Day awareness film produced by the World Hepatitis Alliance made to raise awareness of viral Hepatitis around the world.

“Finding the Missing Millions” Edmonton

The goal objective I had in mind for World Hepatitis Day Edmonton was to increase awareness of viral hepatitis not only in my own local community, but also across Edmonton. Therefore, after spending several days producing my campaign, setting up social media platforms to promote the event, producing promotional material, ordering brochures and pamphlets from CATIE (a Canadian company providing free awareness material for Hepatitis C and HIV, [thank you CATIE for your support and contribution]), informing my self of the World Hepatitis Alliance’s campaign “finding the missing millions”, arming my self with crucial statistics around Hepatitis, I decided to reach out to others for more support.

I contacted several different news and radio stations. Thankfully, CBC Radio Active Edmonton saw the importance of this event and reached out to Dr. Tyrrell and I to come and talk about Hepatitis in Canada. Click the link below to learn more about the University of Alberta’s major leaps in battling with Hepatitis C.


CBC News Edmonton’s article titled “University of Alberta researchers making strides toward Hepatitis C vaccine” containing the interview and radio broadcast that Dr. Tyrrell (on the left) and I (on the right) did on CBC Radio Active discussing the Hepatitis public health problem in Canada, the University of Alberta’s efforts in eliminating Hepatitis C and generally promoting World Hepatitis Day in Edmonton. Learn more here.

Furthermore, I was able to reach out and connect with Ms. Su-Ling Goh from Global’s Health Matters news segment and she was able to provide her take on this initiative through her social media platform. Secondly, I was able to reach out to my community’s Member of Parliament, Mr. Ziad Aboultaif, who was able to also spread awareness on this topic through his following.


Ms. Su-Ling Goh (Edmonton’s only dedicated health reporter with more than 12 years of experience on the Global News Health Matters news segment) sharing her thoughts on World Hepatitis Day (on the left) and Mr. Ziad Aboultaif (Member of Parliament) promoting the event by sharing the World Hepatitis Day awareness video with his following (on the right).

Lastly, I knew this event was going to be a great opportunity for me to spread the message of what Canada was doing this public health problem. Specifically, having had the pleasure to accompany Dr. Tyrrell to this year’s CanHepC meeting and learning about the newly released Blueprint, on battling Hepatitis C in Canada, I sat down and got to work. In the end, with a tremendous amount of support from my fellow supervisors, CanHepC and the World Hepatitis Alliance I was able to produce a concise brochure explaining in depth the problem of Hepatitis C within Canada and what Canada was exactly doing about this. Give it a read you might learn something new!



Canadian Network on Hepatitis C: Blueprint to Inform Hepatitis C Elimination Efforts in Canada brochure I produced for World Hepatitis Day 2019. It is a short pamphlet designed to inform the public of the growing public health issue within Canada, Hepatitis C around the world and Canada’s response. Learn more here.

Yet Another Lucky Coincidence

Finally, after two weeks of intense work recruiting volunteers, ordering campaign materials, printing brochures, setting up posters, reaching out to different clinics to hang up the clinical posters I made, distributing event posters around Edmonton, ordering cool plush prize toys, candy and going back and forth with West Edmonton Mall everything was set in place. Lucky, with the weather forecast predicting rain on the last day of K-Days, many people decided to stay indoors and swing by the mall instead. Overall, the awareness event was quite a success, many brochures, pamphlets and coloring pages of microbes were distributed throughout the day. Several of the volunteers and I were able to engage with members of the public who were cures, worried or suffering from Hepatitis in our local community. However, if you are reading this and you think you might be at risk (meaning you are apart of the vulnerable population, a member of the baby boomer generation, an immigrant from another endemic area, and/or have received blood transfusion prior to 1992), talk to your doctor and get tested. Do not be one of the “missing millions”.


Collage showing some of the promotion material handed out throughout the day and a few of the children who came out to color different microbes at the child friendly area. Learn more about World Hepatitis Day (Edmonton) from CTV News Edmonton’s article “Awareness Raising on World Hepatitis Day” and news coverage here.

Additionally, the team and I were able to reach out to more Edmontonians thanks to CTV’s News Edmonton and their news coverage on the event. Hence, if you would like to learn more about World Hepatitis Day Edmonton and check out the fill extent of the event click on the link above. Lastly, I want to take a second and send out a special thank you to all the volunteers, CanHepC personal, Dr. Tyrrell, Ms. Bonnie, Dr. Salvado, the CATIE team, and the World Hepatitis Alliance for their support! This event would not have be possible without their efforts and support.


Preventing Hepatitis: It’s up to you

So, if I could leave you all with one last statement about Hepatitis, it would be this:


Go and get tested!


If you or any one you know is a member of the vulnerable population detailed above, don’t hesitate, go and get tested! Don’t be one of the “missing millions”! And if you are one of the ones not yet immunized against Hepatitis A and B talk to your doctor.


Get vaccinated!


A safe and effective vaccine that offers a 98-100% protection against hepatitis A and B (twinrix) is available in Canada, offering virtually over twenty-five years of protection in adults. Remember, everyone from politicians to physicians, from the general public to the affected population, can take part in the battle with Hepatitis. So, let’s join hands against Hepatitis! Let’s join hands for a Hepatitis free generation!


Final Reflections: You Never Know Where Life Will Take You

Looking back I never could have thought that a single one paragraph email would lead me to organizing an awareness event at West Edmonton Mall, nor would I have imagined that I would be working with some of most humble, yet brilliant scientists at the University of Alberta. However, if I could leave a piece of advice to any future stretch experience students, it would be this:

“Trust the Process! Trust yourself!”

Unknown

Having to choose a project outside your comfort zone, without knowing the outcomes, can be a scary and nerve-racking experience. However, this is an opportunity that can provide you with an immense amount of growth. Specifically, reflecting back on my stretch experience so far, I know that I would not have had the same professional development opportunities if I had done another regular summer research stipend project.

In closing, I believe the stretch experience is a direct comparison to life. It is a high risk, high reward in-devour. It is an opportunity without a ceiling and the possibilities are endless. But with that comes the problem of what I like to call ‘the too many options”. And some times too many options can make an anarchists out of all of us. However, if you are up for the challenge, up for stepping outside of your comfort zone and seek the road uncommon, then the sky is the limit! So with that, I would like to thank the Peter Lougheed Leadership Collage for this opportunity. As well, would like to thank my two mentors, Dr. Houghton and Dr. Tyrrell, without whom I would not have had this opportunity, and lastly, I would like thank Sir Edward Jenner, the man who established the first ever challenge study.


References:

1 Global health sector strategy on viral hepatitis 2016-2021 (WHO)

2 Global Burden of Disease and WHO/UNAIDS estimates

3 World Hepatitis Alliance “What is Viral Hepatitis”


By Martin Pasev- Edmonton, AB

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