Challenge trials for a Hepatitis C vaccine

 The Journal Clinical Infectious Diseases has a special supplement on challenge trials (human infection trials) of a Hep C vaccine (now that Hep C is a curable disease):

Volume 77, Issue Supplement_3, 15 August 2023

Controlled Human Infection Model for HCV Vaccine Development

SUPPLEMENT ARTICLES

Controlled Human Infection Model for Hepatitis C Virus Vaccine Development: Is It Time to Be Real? 

T Jake Liang and others

Clinical Infectious Diseases, Volume 77, Issue Supplement_3, 15 August 2023, Page S215, https://doi.org/10.1093/cid/ciad343

• Hepatitis C virus (HCV) elimination has been a goal of the public health and scientific communities since its identification in 1989. Despite the advance and availability of highly effective antiviral regimens to treat HCV infection, it is unlikely that global HCV elimination can be achieved without an effective preventive vaccine. Because of the lack of appropriate animal models for preclinical testing and the perception that highly effective treatments would suffice in addressing the global burden of HCV, HCV vaccine development has not been a high priority. To accelerate vaccine development, the concept of a controlled human infection model (CHIM) for HCV has been proposed, in which healthy human volunteers would be deliberately infected with HCV for the purpose of testing the efficacy of candidate vaccines. This concept of challenge studies is not new and has been applied to more than 25 infectious agents, including the cholera vaccine, for which all efficacy data that served as the basis for regulatory approval were obtained from CHIM studies. Without a CHIM strategy, HCV vaccine development may not be feasible. In a recent phase 2 randomized controlled trial, over 900 people who inject drugs were screened to enroll 548 individuals to receive a T-cell–based HCV vaccine candidate or placebo. After a monumental effort that took over 6 years to complete, the trial documented 75 incident HCV infections overall, with only 45 included in the final analysis, and showed no protection against initial infection or progression to chronicity with the vaccine. While this study demonstrated that vaccine testing in the at-risk population can be done, future testing of additional HCV vaccine candidates using a similar pathway may be impractical in light of the duration and cost. With the ability to cure those who do not clear the virus, HCV CHIM is now a conceivable approach that could be a critically important, if not necessary, intermediate stage of vaccine development. HCV CHIM could de-risk vaccine candidates, accelerate development, reduce cost, and allow the selection of more promising candidates for further testing in larger clinical trials. CHIM may conceivably be used for larger phase 2/3 efficacy trials as a basis for clinical approval. In developing such a model, many challenges and questions must be addressed. In this Supplement issue, we, the editors of this Supplement commissioned various articles written by respective subject matter experts who provide their perspectives and opinions on these challenges and questions, ranging from the source of viral inoculum and the safety of transient HCV infection to the perspective of potential volunteers and the ethics of CHIM. While we strive to be data-driven and evidence-based, some of the opinions represent the views of the authors of each article and may be controversial. Ultimately, we hope these perspectives will enable fulsome discussion about the feasibility of HCV CHIM and lead to the development of well-designed clinical protocols.

  Supplement sponsorship. This article appears as part of the supplement “Controlled Human Infection Model for HCV Vaccine Development,” sponsored by Toronto General Research Institute, United States National Institutes of Health, Johns Hopkins University, the Canadian Institutes of Health Research (CIHR), and the Canadian Network on Hepatitis C (CanHepC). CanHepC is funded by a joint initiative of CIHR (HPC-178912) and the Public Health Agency of Canada.

• View article

Ethics of Controlled Human Infection Studies With Hepatitis C Virus 

Annette Rid and others

Clinical Infectious Diseases, Volume 77, Issue Supplement_3, 15 August 2023, Pages S216–S223, https://doi.org/10.1093/cid/ciad382

• Global elimination of hepatitis C virus (HCV) will be difficult to attain without an effective HCV vaccine. Controlled human infection (CHI) studies with HCV were not considered until recently, when highly effective treatment became available. However, now that successful treatment of a deliberate HCV infection is feasible, it is imperative to evaluate the ethics of establishing a program of HCV CHI research. Here, we evaluate the ethics of studies to develop an HCV CHI model in light of 10 ethical considerations: sufficient social value, reasonable risk–benefit profile, suitable site selection, fair participant selection, robust informed consent, proportionate compensation or payment, context-specific stakeholder engagement, fair and open collaboration, independent review and oversight, and integrated ethics research. We conclude that it can be ethically acceptable to develop an HCV CHI model. Indeed, when done appropriately, developing a model should be a priority on the path toward global elimination of HCV.

• View article 
• Supplementary data

Volunteering for Infection: Participant Perspectives on a Hepatitis C Virus Controlled Human Infection Model 

Jake D Eberts and others

Clinical Infectious Diseases, Volume 77, Issue Supplement_3, 15 August 2023, Pages S224–S230, https://doi.org/10.1093/cid/ciad350

The perspectives of former challenge study participants and a survey of other potential volunteers can inform the design of hepatitis C virus controlled human infection models, including on topics such as transparency, volunteer safety and risk, and compensation.

• Ethical human subjects research requires participants to be treated safely and respectfully, yet much bioethical debate takes place without participants. We aim to address this gap in the context of controlled human infection model (CHIM) research. Based upon our own experience as study participants, and bolstered by a survey of 117 potential hepatitis C virus CHIM participants, we present ideas to inform efficient, ethical, and scientifically useful study design. We advocate for full protocol transparency, higher compensation, commitment to the rapid dissemination of study results, and proactive efforts to detail risk-minimization efforts as early as possible in the recruitment process, among other measures. We encourage researchers to proactively partner with volunteer advocacy organizations that promote collective representation of volunteers to maximize their agency, and guard against ethical issues arising from healthy human subjects research.

• View article 
• Supplementary data

First Do No Harm? Modeling Risks and Benefits of Challenge Trials for Hepatitis C Vaccine DevelopmentGet access

Alyssa Bilinski and others

Clinical Infectious Diseases, Volume 77, Issue Supplement_3, 15 August 2023, Pages S231–S237, https://doi.org/10.1093/cid/ciad379

• Background

  In 2019, about 58 million individuals were chronically infected with hepatitis C virus. Some experts have proposed challenge trials for hepatitis C virus vaccine development.

  Methods

  We modeled incremental infections averted through a challenge approach, under varying assumptions regarding trial duration, number of candidates, and vaccine uptake. We computed the benefit-risk ratio of incremental benefits to risks for challenge versus traditional approaches. We also benchmarked against monetary costs of achieving incremental benefits through treatment.

  Results

  Our base case assumes 3 vaccine candidates, each with an 11% chance of success, corresponding to a 30% probability of successfully developing a vaccine. Given this probability, and assuming a 5-year difference in duration between challenge and traditional trials, a challenge approach would avert an expected 185 000 incremental infections with 20% steady-state uptake compared to a traditional approach and 832 000 with 90% uptake (quality-adjusted life-year benefit-risk ratio, 72 000 & 323 000). It would cost at least $92 million and $416 million, respectively, to obtain equivalent benefits through treatment. BRRs vary considerably across scenarios, depending on input assumptions.

  Conclusions

  Benefits of a challenge approach increase with more vaccine candidates, faster challenge trials, and greater uptake.

• View article 
• Supplementary data
• **********
  Earlier:

  Monday, May 15, 2023

  Eliminating Hepatitis C, now that there's a cure (even though it's expensive

  and here are my posts on challenge trials (and Covid vaccines).

Freezing (and then carefully warming) donor organs breaks the organ transplant time barrier (for rats, for the time being)

 Here's a note in Nature Reviews Nephrology pointing out the longer term promise of the recent successful freezing, thawing, and transplantation of rat kidneys.

Cryopreservation breaks the organ transplant time barrier by Marlon J. A. de Haan & Ton J. Rabelink, in Nature Reviews Nephrology (2023)

"The pressing issue of organ shortages for transplantation is fuelled by the rising incidence of kidney failure and the declining quality of organs from an ageing donor pool. However, the main bottleneck in organ transplantation is time; indeed, the current clinical standard for kidney preservation necessitates immediate transplantation following organ recovery1. This urgency often results in suboptimal matches between donors and recipients. Cryopreservation has emerged as a potential solution to this challenge. Such an approach would enable organs to be preserved in a suspended state for extended periods and ready for transplantation on demand. The prospect of long-term banking of cryopreserved organs holds promise for transforming organ transplantation into an elective procedure, thereby enhancing donor–recipient matching, improving equity in access, optimizing patient preparation, refining transplant tolerance protocols, increasing organ utilization and improving graft and patient survival. However, even though cryopreservation has successfully been used to store human embryos, extending the process to preserve whole organs has remained a scientific aspiration — until now. A study by Han et al. introduces an approach to cryopreservation that seemingly extends the shelf life of organs indefinitely2."

...

"By rapidly cooling rat kidneys to –150°C, Han et al. were able to halt the biological clock of the organs, effectively inducing a glass-like state — a process known as vitrification2 (Fig. 1). Specifically, the researchers perfused a cocktail of cryoprotective agents (CPAs) and iron oxide nanoparticles into the organ’s vasculature, which they followed by rapid cooling to ultralow temperatures to achieve a state of vitrification. This vitrified kidney, with its hard, smooth, glasslike appearance, was then transferred to a –150°C freezer for long-term banking. When these kidneys were later rewarmed and transplanted into nephrectomized recipients, they regained life-sustaining renal function. The rewarming stage poses more challenges to the process of cryopreservation: it requires both speed to avoid ice formation during devitrification and uniformity to prevent thermal stresses and mechanical cracks. Here, the iron oxide nanoparticles had a crucial role. Placing the vitrified kidney in a coil that generates electromagnetic fields activates these nanoparticles, generating heat. This innovative approach enabled rapid rewarming at an impressive rate of approximately 72 °C per minute throughout the entire organ, ensuring uniform warming rather than limiting warming to the organs’ surface. This ground-breaking milestone marks an extraordinary achievement in ‘reviving’ a complex organ like the kidney and is the culmination of decades of research into methods to prevent the destructive formation of ice during the cooling process, minimize toxicity from CPAs, and enable fast and uniform rewarming3.

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Recently:

Wednesday, June 28, 2023

Freezing, thawing and transplanting a rat kidney: a first step towards organ banking

Homelessness and fentanyl, in Oregon and California

 Both the criminal justice system and the harm reduction movement seem to be facing an intractable problem with fentanyl and homelessness.  (We lost the war on drugs, but surrender isn't working either.)

Here are two NYT stories, from Oregon and California.

The Struggle to Save Portland, Oregon. The city has long grappled with street homelessness and a shortage of housing. Now fentanyl has turned a perennial problem into a deadly crisis and a challenge to the city’s progressive identity.  By Michael Corkery

"This city of 635,000 ...  has long grappled with homelessness. But during the pandemic this perennial problem turned into an especially desperate and sometimes deadly crisis that is dividing Portland over how to fix it.

...

"In 2022, Portland experienced a spate of homicides and other violence involving homeless victims that rattled many in the community.

...

"The search for answers points in many directions — to city and county officials who allowed tents on the streets because the government had little to offer in the way of housing, to Oregon voters who backed decriminalizing hard drugs and to the unrest that rocked Portland in 2020 and left raw scars.

"But what has turbocharged the city’s troubles in recent years is fentanyl, the deadly synthetic drug, which has transformed long standing problems into a profound test of the Portland ethos.

"Outreach workers in Portland say rampant fentanyl use has coincided with the increasing turmoil among many homeless residents.

"Doctors who care for people living on the streets say fentanyl addiction is proving harder to treat than many other dependencies."

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Homeless Camps Are Being Cleared in California. What Happens Next? One of the state’s largest homeless encampments was recently shut down in Oakland, but that didn’t stop the problem of homelessness.  By Livia Albeck-Ripka

"The evictions have brought into sharp relief one of the most intractable challenges for American cities, particularly those in California. As homelessness has surged, more people have congregated in large encampments for some semblance of security and stability. But such sites are often unsanitary and dangerous, exhausting neighbors and the owners of nearby businesses.

"What happens after the closure of Wood Street and other camps in California will serve as the latest test of how effectively the state is addressing homelessness. Nearly half of the nation’s unsheltered population — those who sleep on the streets, in tents, in cars or in other places not intended for human habitation — resides in California, according to last year’s federal tally of homelessness. The state makes up about 12 percent of the country’s overall population.

"In California, Democratic leaders who previously tolerated homeless camps have lost their patience for the tent villages and blocks of trailers that proliferated during the pandemic.

"Governor Newsom has helped clear homeless camps himself and has told mayors he was trying to set an example. San Diego recently banned encampments on public property. And Karen Bass, the mayor of Los Angeles, has moved more than 14,000 homeless people into temporary housing since taking office in December, her office said last month.

...

"Community cabins and safe camping sites usually provide only temporary shelter, falling short of the permanent housing that is considered ideal. But they seem to be the best that California can do, with a severe housing shortage and high costs. Despite the state’s spending of more than $30 billion since 2019 on housing-related programs, the homeless population there has continued to grow.

“This is a very difficult population to serve, with very complex needs. And if we can bring someone inside even for a little bit, that’s a victory for that person,” said Jason Elliott, the deputy chief of staff for Governor Newsom. “We may not have permanent housing stick the first time, or the fourth time or the fifth time, but we’re going to keep trying.”

"According to a September audit of Oakland’s homelessness services, close to half of the people housed in community cabins ended up back on the street in the 2020-21 fiscal year."

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Earlier:

Friday, July 14, 2023

Harm reduction is not a panacea: drug use and drug policy in Portugal, and San Francisco

Compensating kidney donors: a call to action by Brooks and Cavanaugh in the LA Times

 Here's a clarion call for compensation of living kidney donors, from two nondirected kidney donors.  It's not the first, and very likely not the last, given the difficulty of modifying the existing law.  But it makes the case very clearly (and proposes that a tax credit spread over ten years might be the way to move foreward).

Opinion: A single reform that could save 100,000 lives immediately BY NED BROOKS AND ML CAVANAUGH, JULY 9, 2023 

"Never in the field of public legislation has so much been lost by so many to one law, as Churchill might’ve put it. The National Organ Transplant Act of 1984 created the framework for the organ transplant system in the United States, and nearly 40 years later, the law is responsible for millions of needless deaths and trillions of wasted dollars. The Transplant Act requires modification, immediately.

"We’ve got skin in this game. We both donated our kidneys to strangers. Ned donated to someone who turned out to be a young mother of two children in 2015, which started a chain that helped an additional two recipients. And Matt donated at Walter Reed in 2021, after which his kidney went to a Seattleite, kicking off a chain that helped seven more recipients, the last of whom was back at Walter Reed.

"Ned founded, and Matt now leads, an organization that represents nearly 1,000 living donors

...

"eight years ago, when Ned donated, the number of living kidney donors was 6,000. With all the work we’ve done since, the number of living donors is still about 6,000 annually. In the United States, nearly 786,000 people suffer from end-stage kidney disease, more people than can fit in the 10 largest NFL stadiums combined.

...

"More Americans die of kidney disease than of breast or prostate cancer, and one in three of us is at risk. This illness is widespread, but what makes it worse is the staggering financial burden borne by everyone. The head of the National Kidney Foundation testified in March that Medicare spends an estimated $136 billion, nearly 25% of its expenditures, on the care of people with a kidney disease. Of that, $50 billion is spent on people with end-stage kidney disease, on par with the entire U.S. Marine Corps budget.

...

"The National Organ Transplant Act prohibits compensating kidney donors, which is strange in that in American society, it’s common to pay for plasma, bone marrow, hair, sperm, eggs and even surrogate pregnancies. We already pay to create and sustain life

...

"The ethical concerns regarding compensation are straightforward. Nobody wants to coerce or compel those in desperate financial straits to do something they would not have done otherwise. The challenge, then — until artificial or nonhuman animal substitutes are viable options — is to devise a compensation model that doesn’t exploit donors.

"Compensation models have been proposed in the past. A National Institutes of Health study listed some of the possibilities, including direct payment, indirect payment, “in kind” payment (free health insurance, for example) or expanded reimbursements. After much review, we come down strongly in support of indirect payment, specifically, a $100,000 refundable federal tax credit. The tax credit would be uniformly applied over a period of 10 years, in the amount of $10,000 a year for those who qualify and then become donors.

"This kind of compensation is certainly not a quick-cash scheme that would incentivize an act of desperation. Nor does it commoditize human body parts. Going forward, kidney donation might become partly opportunistic rather than mostly altruistic, as it is now. But would it be exploitative? Not at all."

...

Ned Brooks and ML Cavanaugh are living kidney donors, and Brooks is the founder of the Coalition to Modify NOTA.

********

Here are all my posts that mention Ned Brooks, starting with this one:

Friday, February 26, 2016

A Freakonomics listener was inspired to become a non-directed kidney donor by the podcast on kidney exchange

Cryopreservation of organs for transplants, and Sebastian Giwa in Forbes

 Forbes has a long, interesting, somewhat breathless story about the progress and promise of freezing organs for transplants, including not only the usual eight organs, but also bone marrow/blood stem cells. It focuses on one of the entrepreneurs in the field, Dr. Sebastian (Seb) Giwa, and his colleague Jedd Lewis among others

New Breakthroughs In Cryopreservation Poised To Transform Organ Transplantation, by Alex Zhavoronkov, PhD, Jul 5, 2023

"To understand how this came about I delved into the career of the founder and CEO of Sylvatica Biotech, Dr. Sebastian Giwa (called “Seb” by his friends). Seb is credited by many as the chief architect of the surge of scientific interest in cryopreservation over the last several years.

Sebastian Giwa, PhD, MBA 

BRIDGET BENNETT

...

"Trying to donate organs (without cryopreservation) is a lot like trying to donate perishable (non-canned) food: there are certainly a lot of starving people in the world, but good luck finding a recipient for every single ounce before it expires. 

...

"[Organ Preservation Alliance]  partnered ... to publish position papers, including a peer-reviewed article in Nature Biotechnology outlining the need for an organ cryopreservation research effort. The paper was co-authored with all of the major U.S. transplant societies and a star-studded lineup of scientists including Robert Langer, George Church, and Ed Boyden, and even Nobel Prize-winning economist Alvin Roth – whose work has focused on finding new ways to ameliorate the organ shortage. It is currently in the top 1% of the most widely read scientific articles published since its release.

...

"Donor bone marrow is lifesaving for many kinds of  cancers and a variety of other blood diseases. Successful bone marrow transplants have been performed since the 1950s, but the challenge is finding a source of bone marrow to transplant – especially since donors and recipients must be matched for genetic factors even more precisely than some organ transplants.

...

" if bone marrow could be cryogenically banked, why not procure it from deceased organ donors who were already providing hearts, livers, and other organs for transplantation? There are nearly 40,000 such donors worldwide each year, and each could potentially donate enough marrow for multiple patients in need. For many patients, when a transplant was needed the matching bone marrow would already be available in the bone marrow bank.

"From the perspective of the deceased organ donor and the OPOs, this would be like providing an opportunity to donate an additional lifesaving organ. Traditionally, each donor can provide up to eight lifesaving vital organs: a heart, two lungs, two kidneys, a liver, intestines, and a pancreas. In essence, bone marrow would be the ninth. And if a donor could provide bone marrow to multiple recipients, this might even double the number of lives that each donor could save.

...

"Alex: What’s something we haven’t covered that excites you about what cryopreservation can do for the organ shortage?

"Seb: In the long-term, one of the things that I’m most excited about is how these technologies can remove barriers to developing transplant systems in new countries. Most of the world still doesn’t have access to deceased donor transplantation. For instance, Africa has 16% of the world’s population but only 0.5% of transplants are done there. Meanwhile the U.S. has less than 5% of the world’s population but does about 25% of the world’s transplants. Many developed countries, like my father’s home country Ghana, have limited live kidney donation programs. But they don’t have deceased donor programs, which are needed to carry out large numbers of kidney and liver transplants as well as any sort of heart or lung transplantation.

"That’s partly because the logistical demands to source organ donations prospectively require so much infrastructure: a waitlist, rapid matching of donors to recipients, OPOs that need to be overstaffed in order to deal with unpredictable surges in organs available, rushed activities that require tight coordination between donor hospitals, OPOs, transplant centers, and even third party service providers like organ couriers. Many organs have also needed expensive transportation (private jets and helicopters).

"It’s a very different situation when there’s a source of cryopreserved hearts, livers, etc., that can be donated in a much more flexible way and are simply waiting to be matched to patients. Even things like Doctors without Borders and perhaps “OPOs without Borders” become possible for transplantation, helping train and develop new organ recovery, heart, lung, and liver transplant programs. So many more possibilities open up when you don’t need to create every part of a transplant system from scratch and have all of those parts acting in synchrony on Day 1."

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Here's the original article referred to:

The promise of organ and tissue preservation to transform medicine 
 Sebastian Giwa, Jedediah K Lewis, Luis Alvarez, Robert Langer, Alvin E Roth, George M Church, James F Markmann, David H Sachs, Anil Chandraker, Jason A Wertheim, Martine Rothblatt, Edward S Boyden, Elling Eidbo, W P Andrew Lee, Bohdan Pomahac, Gerald Brandacher, David M Weinstock, Gloria Elliott, David Nelson, Jason P Acker, Korkut Uygun, Boris Schmalz, Brad P Weegman, Alessandro Tocchio, Greg M Fahy, Kenneth B Storey, Boris Rubinsky, John Bischof, Janet A W Elliott, Teresa K Woodruff, G John Morris, Utkan Demirci, Kelvin G M Brockbank, Erik J Woods, Robert N Ben, John G Baust, Dayong Gao, Barry Fuller, Yoed Rabin, David C Kravitz, Michael J Taylor & Mehmet Toner

Nature Biotechnology 35, 530–542 (2017) doi:10.1038/nbt.3889
Published online 07 June 2017

Abstract: The ability to replace organs and tissues on demand could save or improve millions of lives each year globally and create public health benefits on par with curing cancer. Unmet needs for organ and tissue preservation place enormous logistical limitations on transplantation, regenerative medicine, drug discovery, and a variety of rapidly advancing areas spanning biomedicine. A growing coalition of researchers, clinicians, advocacy organizations, academic institutions, and other stakeholders has assembled to address the unmet need for preservation advances, outlining remaining challenges and identifying areas of underinvestment and untapped opportunities. Meanwhile, recent discoveries provide proofs of principle for breakthroughs in a family of research areas surrounding biopreservation. These developments indicate that a new paradigm, integrating multiple existing preservation approaches and new technologies that have flourished in the past 10 years, could transform preservation research. Capitalizing on these opportunities will require engagement across many research areas and stakeholder groups. A coordinated effort is needed to expedite preservation advances that can transform several areas of medicine and medical science.

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Here's a recent related post:

Wednesday, June 28, 2023

Freezing, thawing and transplanting a rat kidney: a first step towards organ banking