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The discovery of a key protein could change the way psoriasis and psoriatic arthritis is treated in the future.

Researchers at Case Western Reserve University School of Medicine in Cleveland, Ohio — along with several other U.S. universities — found that an overabundance of a protein known as kallikrein-related peptidase 6 (KLK6) can produce and worsen the skin inflammation characteristic of psoriasis.

 — it is important to note that this is early, preliminary research — play a key role in determining which patients will go on to develop psoriatic arthritis, according to the article published earlier this year in 

About a third of people diagnosed with psoriasis also develop psoriatic arthritis (PsA), but reasons are not understood, the authors wrote.

Future research on KLK6 could be “paradigm-shifting” and would lead to a more personalized method for identifying which psoriasis patients will go on to develop PsA,” so we can modify their treatment accordingly," said Nicole Ward, the study's principal investigator and a professor of nutrition and dermatology at Case Western, in a university 

Researchers into many different kinds of disease are researching KLK6, and it may also play a role in the development of cancer, multiple sclerosis, Parkinson’s, and Alzheimer’s disease.

Ward and team sought to understand how the cellular and molecular mechanisms of KLK6 and another protein, protease-activated receptors (PAR)1, promote skin inflammation.

PAR1 is a receptor protein that receives chemical signals from outside a cell, such as from KLK6. “When such signals activate the receptor, they cause cellular/tissue responses, including inflammation,” said the press release.

In their previous research, Ward and colleagues found the skin of psoriasis patients contained as much as six times more KLK6 than normal. They also found that the PAR1 receptor was overproduced in skin and immune cells. Based on that, they theorized that KLK6 might drive inflammation by signaling through PAR1.

When they “turned down” the levels of KLK6 in mouse models, arthritis-like symptoms improved. They also found that "knocking out” PAR1 led to a reduction in skin inflammation and a significant improvement in bone and joint problems.

"To discover that turning down KLK6 eliminated the skin inflammation and even improved the arthritis-like changes — that was unbelievable,” Ward said. ”This suggests that clinicians need to aggressively treat patients with psoriasis to prevent the arthritis changes, which generally occur after the skin disease presents itself. Since the joint and bone damage are largely irreversible in patients, prevention becomes critical.”

Next, the researchers aim to study how skin inflammation causes arthritis-like damage and translate those findings to benefit patients. They also plan to study and compare models that do and don't develop arthritis to identify biomarkers that can predict the development of PsA.

Articles

Preliminary findings by Case Western researchers point to kallikrein-related peptidase 6 as possible culprit in the development of psoriatic arthritis.

Researchers Believe KLK6 Protein May Play a Role in the Development of Psoriatic Arthritis

Following the race to develop a COVID-19 vaccine is both heartening and dizzying. It’s heartening because it seems to be a race that will have a winner - perhaps several of them. It’s dizzying because the vaccines and their developers are jockeying for position, and projected timeline seems to change almost daily depending on the early results and who’s doing the talking.

Anthony Fauci, M.D., director of the National Institute of Allergy and Infectious Disease (NIAID), has been a cautious but optimistic voice about vaccine development for months now, although his institute does have a dog in this fight: NIAID is collaborating with Moderna on one of the most promising vaccines. Testifying before a Senate committee on May 12, Fauci stuck to the 12-18 month timetable he has mentioned often but added an “if” to the “when.” “You can have everything you think that’s in place and you don’t induce the kind of immune response that turns out to be protective and durably protective.” In an interview with NPR 10 days later, Fauci said, “We could have a vaccine that we could begin to deploy at the end of this calendar year - December 2020 or into January 2021.” And in a Q&A transcript that Stat posted on June 1, Fauci spoke of having a “significant number of doses” available by the end of this year or by early 2021. “So I think it’s aspirational, but it’s certainly doable,” said Fauci, in the transcript.  

Meanwhile, President Donald Trump announced Operation Warp Speed in May to accelerate vaccine development for COVID-19 at an unheard of - some say unrealistic - pace. The selection of Moncef Slaoui, Ph.D., former head of GlaxoSmithKline’s vaccine division, as its chief adviser garnered praise. Later in May, the effort lived up to its name when it announced that it was plowing $1.2 billion into hastening development of a vaccine that University of Oxford researchers and AstraZeneca are working on. A press release about the funds from the Department of Health and Human Services (HHS) noted that HHS and AstraZeneca are collaborating to make 300 million doses, “with the first doses delivered as early as October 2020.”  

Others are also talking optimistically about a sooner-rather-later schedule for a COVID-19 vaccine that would might be ready before winter, when many experts expect a second wave of cases because coronaviruses are seasonal. Part of the U.S. vaccine strategy as described by Fauci and others is to start manufacturing doses of vaccine candidates before the evidence of efficacy is in. “Fortunately, the U.S. is in the situation to scale up manufacture of vaccines even before you know they are going to work - maybe as early as the fall with billions of doses. That is the hope,” said National Institutes of Health Director Francis Collins, M.D., Ph.D., in a 

 video event in May. “I don’t want to be over the top in confidence about that, but I can ensure you that everyone in the public-private partnership is doing everything they can to make that happen.”

Meanwhile, China also has an aggressive vaccine development program. Bloomberg reported recently that five vaccines developed by Chinese companies are in human trials and that one candidate, a joint project of the China National Biotec Group and the Beijing Institute of Biological Products, has completed phase 2 testing.

The go-go approach to COVID-19 vaccine development is causing some concern about consequences if anything goes seriously wrong with an approved vaccine. Anti-vaccine groups and social media influencers will certainly pounce if there are problems with safety and efficacy - especially safety. Conspiracy theories about the COVID-19 vaccines are already circulating on the internet. In May, a 26-minute video called “Plandemic” got millions of views before taken down by Facebook and YouTube. According to several articles about the video, it spins conspiracy theories about COVID-19 and big pharma, Bill Gates and the World Health Organization (WHO). 

So far, though, the speed of vaccine development has been mainly impressive. The public-private partnerships among pharmaceutical manufacturers, academic researchers and government agencies resulted in phase 1 trials starting in record time. “From the very first moment the viral RNA sequence was made public … the first trial (Moderna) got started 63 days later,” Collins said in the 

 video. “The phase 1 results look very promising - strong enough to say we are ready to go on to phase 2.”

Collins explained how the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) initiative is developing a harmonized master protocol for adaptive trials of multiple vaccines, as well as a trial network that could enroll as many as 100,000 volunteers in areas where COVID-19 is actively circulating. Although there are some surrogate markers for efficacy, such as levels of neutralizing antibodies, the clearest “efficacy signal” will be whether a vaccine has a protective effect - in areas where COVID-19 is actively circulating - against infection with SARS-CoV-2, the virus that causes COVID-19. 

“You have to test it in a place (where) the vaccine is actively circulating. You won’t know if it works if the vaccine is not actively around them,” Collins said.

Another possible way of assessing efficacy is through “challenge trials,” which would involve purposely exposing healthy volunteers to SARS-CoV-2; some volunteers would receive the experimental vaccine and some, a placebo. A difference in COVID-19 cases and severity between the two groups would indicate whether the vaccine was effective. However, challenge trials, which have been used to test other vaccines, raise troubling ethical issues in this case because they would involve exposing people to a possibly fatal illness. In an article in 

, Nir Eyal at Rutgers, Marc Lipsitch at the Harvard T.H. Chan School of Public Health, and Peter G. Smith at the Tropical Epidemiology Group at the London School of Hygiene & Tropical Medicine outlined how the health risk might be mitigated - healthy volunteers, careful monitoring and so on.

They also parried the ethical objections with examples of other situations where people volunteer to take on possibly deadly risks for others: “We ask volunteer firefighters to rush into burning buildings, relatives to donate a live organ to loved ones, healthy volunteers to participate in drug and vaccine toxicity trials with no prospect of improving their health.” 

By many counts, more than 100 COVID-19 vaccines are in some stage of development. At the beginning of the June, the WHO published a list that included 10 candidates in “clinical evaluation” - meaning in human clinical trials - and 123 in preclinical evaluation. Stat is keeping a COVID-19 vaccine tracker (and a separate one for treatment). As we went to press, it listed six vaccines as being in phase 1 trials and Moderna’s as the only one in phase 2. The company said volunteers for the phase 2 trial, which is designed to eventually include 600 study subjects, started getting the vaccine on May 29.

Moderna reported partial results from the phase 1 trial in a press release, but Fauci and others were critical of the lack of full report. The Regulatory Affairs Professionals Society is also keeping a user-friendly vaccine tracker that listed eight vaccines as being in clinical trials as we went to press. Topping its list (and absent from Stat’s and WHO’s) is a phase 2/3 trial of the 100-year-old bacillus Calmette-GuÃ©rin, a vaccine used to protect against tuberculosis.   

Christine Blank is a freelance writer based in Orlando, Florida.

A safe, effective vaccine by December 2020 or January 2021?

An Update on COVID-19 Vaccine Development

At the March 16 daily press briefing by the White House Coronavirus Task Force, Anthony Fauci, M.D., seemed excited in his buttoned-down way. This was before Fauci, director of the National Institute of Allergy and Infectious Diseases, became a household name; before millions of Americans grew familiar with his gravelly, Brooklyn-accented voice and carefully qualified statements; and well before Brad Pitt played him on “Saturday Night Live.”

Fauci told reporters and the TV audience that earlier that day, thefirst volunteer for a phase 1 trial of a candidate vaccine against COVID-19 had been injected. The volunteer was later identified as Jennifer Haller, an operations manager at a tech company in Seattle.“You might recall when we first got started that I said it would be two to three months, and if we did that, that would be the fastest we had ever gone from obtaining the sequence (of a virus) to being to a phase 1 trial,” Fauci said, with President Donald Trump standing to his left at a pre-social-distancing distance. “This has now been 65 days, which I believe is the record.”  

Now it seems like that record was for the first 100 meters of what may turn into a full, 26.2-mile marathon. Fauci has since said repeatedly in interviews that it will probably be a year or more before a COVID-19 vaccine is not only tested but also deemed both safe and effective.

“It isn’t just the timetable. It has to be safe and it has to be effective,” Fauci said in an inter-view with a Canadian TV network.

As Fauci tapped the brakes, some vaccine developers raced ahead, raising hopes that more records would be set. At the end of April, CanSino Biologics, a Chinese company, said it was poised to start a phase 2 trial of its vaccine and would enroll 500 people in Wuhan, China, where the pandemic started.

Vaccine developers at Oxford University in England were going at an unheard-of speed. They collapsed the normally sequenced phase 1 safety and phase 2 efficacy trials into a single trial designed to enroll more than 500 volunteers. And as we went to press, they were gearing up for a phase 2/3 trial that would include 5,000 volunteers.


	By some accounts, there are 86 COVID-19 vaccine candidates; by others, 115. In those two tallies, and in every other reasonable count, the vast majority of the COVID-19 vaccine candidates are in a preclinical stage and not ready to be tested in people. “There will be fierce attrition,” wrote Derek Lowe in his widely read blog for 

“and only a few (low single digits) will make it deep into the process.”

As COVID-19 vaccine kicked into gear, Regulatory Focus, the online publication of the

 Regulatory Affairs Professionals Society

, started a helpful COVID-19 vaccination tracker to keep tabs on. At the end of April, the tracker listed one COVID-19 candidate, the bacillus Calmette-Guerin vaccine used primarily against tuberculosis, in as being in a phase 2/3 trials, six in phase 1, 10 in preclinical development, and 27 in a catchall “research in additional vaccine candidate” category.

In many ways, SARS-CoV-2, the virus that causes COVID-19, is an inviting target for a vaccine. Because of today’s powerful sequencing technology and prior experience with other coronaviruses, the RNA genome of the virus was sequenced quickly, giving researchers a handle on the virus’s reproduction and the encoding of its spherical outer shell, including those now-familiar spikes that give it the menacing look of the head of a medieval mace.

For vaccine developers, those spikes, called S proteins, are something of a dream come true because they are the means by which the virus binds to and infects cells, and antibodies that home in on and stick to S proteins can block that process. Many of the current crop of vaccines are designed to deliver this S protein (or a fragment of it) to trigger an immune response and unleash antibodies that will fend off future infection by SARS-CoV-2.

Vaccine developers also seem to have a relatively stable target in SARS-CoV-2. Decades of research into vaccines for HIV and hepatitis C have come up empty-handed partly because those viruses are elusive shape-shifters.


	But perhaps the principal reason for the momentum behind COVID-19 vaccine development is the blossoming of recombinant DNA and other related technologies over the past few decades. Vaccine developers have at their disposal any number of techniques for tweaking genomic material so it produce antigens that will provoke an antibody response and another workshop full of choices for how to assemble the vehicle for delivering it. The abundance  explains the large field of candidates at the starting line of COVID-19 vaccine development and the large number of private companies involved, each betting that it has the smartest idea.

By one count, private companies are developing three-quarters of the COVID-19 vaccine candidates, with academic, government and nonprofit organizations developing the remaining quarter.The classic vaccine against viral diseases produces immunity using a live attenuated (or weakened) version of the virus. The smallpox; chickenpox; and measles, mumps and rubella vaccines - among the most effective available - use live attenuated vaccines. But with recombinant protein and genetic engineering tools, vaccine developers don’t need to use the whole virus. They can create vaccines that depend on crucial fragments of the antigen that provokes an antibody response; in the case of COVID-19, the go-to antigen is that spiky S protein.

In some cases, instead of employing a live attenuated virus, vaccine developers can patch together a facsimile of one, using the genomic material of re-engineered virus to express the parts of the antigen that trigger antibodies. Some current technologies, including some COVID-19 vaccine candidates, use DNA to get into cells and express the antibody-provoking antigens. Others hire RNA to do the job.
	
	


	There might be some wind in the sails right now, but enthusiasm about a COVID-19 should be kept on a short leash. For one thing, there are no coronavirus vaccines on the market. A small number of vaccines against another coronavirus, SARS-CoV-1, made it into phase 1 trials but were abandoned when the 2003 SARS outbreak caused by that virus reced-ed. 

The story is similar regarding a vaccine against the coronavirus that causes Middle East respiratory syndrome (MERS). The lack of a vaccine against other coronaviruses means aspects of testing and manufacturing a putative COVID-19 vaccine will be created more or less from scratch. Vaccines must be developed according to strict manufacturing. If one of the vaccine candidates that uses a new technology is deemed safe and effective, scaling up production will be uncharted territory. Researchers don’t have an agree-upon animal model. Fauci has spoken about a mouse model, and the Oxford group’s vaccine has been tested in rhesus monkeys. If several different types of animals are used for vaccines in the preclinical phase, comparing results may be difficult. Another challenge: identifying a vaccine that produces an enduring immune response. Coronaviruses also cause the common cold, and the immune response to those viruses is fleeting, a concern despite the significant differences between the common cold coro-naviruses and SARS-CoV-2. Also, to produce long-lasting immunity, a vaccine must produce an antibody response. A branch of the immune system called innate immunity doesn’t depend on antibodies or recognition of an antigen; it’s more of an all-purpose response to an invasive organism.

A vaccine that stirs up a transitory innate response won’t a  ord the specific protection against SARS-CoV-2 that the world is hoping for. Many vaccines require booster shots. In a perspective piece published in the April issue of the medical journal Immunity, Fatima Amanat and Florian Krammer of Icahn School of Medicine at Mount Sinai in New York City said that it is “highly likely” that more than one dose of a COVID-19 vaccine will be needed because the population is currently naive to SARS-CoV-2. Full protective immunity probably won’t kick in till one or two weeks after the second vaccination. Some people won’t come back for the second shot, so even if a vaccine is identified, real-world effectiveness may fall short.

What’s more, Amanat and Krammer noted, the two-shot schedule lengthens any vaccine timeline by about a month because the initial injection and the booster shot usually have to be given several weeks a part. Another possible complexity with COVID-19 vaccination is the need for an adjuvant, an additive that enhance the antibody response. Sometimes adjuvants make a vaccine safer by lowering the dose required to get the same, or an even stronger, antibody response. Several companies, including GlaxoSmithKline and Dynavax, have promised to make adjuvants available for use with COVID-19 vaccines developed by other entities.

So far, COVID-19 appears to be far more harmful for older people than younger people. CDC data show that the gradient for COVID-19 hospitalizations steepens with age; for example, the rate for people ages 85 and older is twice that of those 65 to 74.   This is a problem for vaccine development, as Amanat and Krammer point out, because the immune system wanes with age and becomes less responsive to vaccines. A COVID-19 vaccine that doesn’t protect what appears to be one of the most vulnerable parts of the population would obviously be a rather flawed vaccine. Higher doses or different adjuvants might be needed for older people.

Another obstacle may be antibody-depen-dent enhancement, a risk Fauci has discussed in several interviews. Instead of blocking viral infection, the antibodies that a vaccine produces can latch onto the virus and abet rather than block infection. Antibody-dependent enhancement can also trigger an out-of-control immune response. Enhancement has been an issue with vaccines against dengue and respiratory syncytial virus, according to Fauci, and results from lab tests when the vaccines against SARS and MERS were in development suggested that enhancement might be a problem. The risk of a vaccine resulting in more COVID-19, not less, is one of the many reasons Fauci and others have stressed the need for careful evaluation of COVID-19 vaccines.

Christine Blank is a freelance writer based in Orlando, Florida. Peter Wehrwein is the senior editor of Managed Healthcare Executive.®

Testing remains ongoing in the search for treatment drugs and a vaccine for COVID-19.

The Search is on For Treatment Drugs and a Vaccine 

FDA cleared two new coronavirus disease (COVID-19) tests via Emergency Use Authorization.

FDA Commissioner Stephen M. Hahn, MD, also outlined other ways the agency is working to get more tests available.

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The agency expedited approval of Panther Fusion SARS-COV-2 Assay (Hologic), and Laboratory Corporation of America (LabCorp) for its COVID-19 RT-PCR test.

“Staff at FDA have been working nonstop to expedite the review and authorization of diagnostics during this public health emergency,” Hahn says in a 

. “Our device center has been in continual contact with the medical device community, in particular diagnostic developers, since January -- providing technical assistance to test developers to help facilitate the availability and distribution of tests so that health care professionals can accurately detect the COVID-19 virus.”

More than 40 labs have notified FDA that they are testing or intend to begin testing COVID-19 assays, Hahn added.

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In addition, FDA’s new policy will allow states to take responsibility for tests developed and used by laboratories in their states.

“States can set up a system in which they take responsibility for authorizing such tests and the laboratories will not engage with the FDA,” Hahn says in a separate 

FDA’s updated policy also provides recommendations for test developers that may wish to develop serological tests for use during the coronavirus outbreak.

“Serological tests measure the amount of antibodies or proteins present in the blood when the body is responding to a specific infection. We recognize that serology tests are less complex than molecular tests and are solely used to identify antibodies, which limits their effectiveness for diagnosis; however, as stated in the updated guidance, the FDA does not intend to object to the distribution and use of serology tests to identify antibodies to SARS-CoV-2 where the test has been validated, notification is provided to the FDA, and warning statements are included with the tests…” Hahn says.

FDA has engaged with more than 100 test developers since the end of January, providing templates and advice about the Emergency Use Authorization  process.

“More than 80 developers have sought our assistance with development and validation of tests they plan to bring through the EUA process. We’ve granted multiple diagnostic EUAs during this outbreak,” he says said.

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The agency takes other steps to make COVID-19 tests more available.

Author | Christine Blank

Articles

Researchers Believe KLK6 Protein May Play a Role in the Development of Psoriatic Arthritis

An Update on COVID-19 Vaccine Development

The Search is on For Treatment Drugs and a Vaccine

FDA Expedites Coronavirus Testing Kits