Expanding the armory of anti-viral approaches

Winter can be the worst time for respiratory diseasesAs the nights draw in and we huddle together against the cold and dark, sneezing and wheezing, wspread our coughscolds, and worseMany people can find breathing a struggle in normal winter, and this year there ithe COVID-19 virus stalking the land, seeking lungs to infiltrate, causing the terrible pandemic that we are all caught up in. 

Whilst the news is, finally, full of promising updates on vaccines, the world will need a wide range of prophylactic and therapeutic approaches to defeat the coronavirus. Biopharma companies have been working furiously to address the critical need for new ways to treat and heal people and lay better foundations to enhance resilience against the next pandemic. 

With the coronavirus, many people do not necessarily die from the virus itself, but from an inadequate immune response against it. This allows SARS-CoV2 to mediate a catastrophic inflammatory response and weaken the bodymore often than not opening the door to bacterial superinfections. According to The Lancet [1], early research found that nearly 15% of all COVID-19 patients acquire deadly secondary bacterial infections. These bugs can cause or worsen a patient’s pneumonia and lead to septic shock, a life-threatening complication. What can be done? 

We talked to ISA Pharmaceuticals’ Chief Scientific Officer, Professor Cornelis (‘Kees’) Melief, for an expert view on novel ways to fight viral respiratory infections. We focused on using immunotherapeutics to prevent SARS-CoV2 induced pneumoniabased on the company’s ‘Synthetic Long Peptide’ (SLPtechnology, and itCOVID asset ISA106. He explained the basics of SLP Technology and what it could add to the expanding armory of anti-viral approaches. 

Prof. Melief, “Right from the inception of ISA Pharmaceuticals in 2004 we have been working on synthetic long peptide technology, originally using it as a therapeutic vaccine to stimulate T cells against virus-induced cancers. This approach eradicates the Human Papilloma Virus (HPV), and this should also work with SARS-CoV2. 

One fundamental part of the immune system receiving a lot of attention recently, after months of talk about antigens and antibodies, are T cells. Why is T cell immunity so important, both in general, and for treating coronavirus? 

Prof. Melief, “Viruses are obligatory cellular parasites – they hide within cells and hijack the molecular machinery. Once infection has taken place they replicate inside cells, and most of their proteins are not expressed at the cell surface. Antibodies that would normally want to bind to these proteins cannot get to them unless the cell bursts. In contrast, T cells can identify and remove infected cells. The body relies on T cells for protection after viral infection has taken place. So, if patients have T cell deficiencies they get long lasting viral infections. You need T cells to eradicate established viral infections. Convalescent plasma which has been advocated for SARS-CoV-2 because it contains antibodies against the virus, has shown no appreciable activity [2]. Cocktails of engineered antibodies, if administered very early, can catch the virus released from dying cells, but can’t attack virus infected cells as these are not expressing proteins at the cell surface.” 

A lot of attention at the molecular level has been devoted to targeting the club shaped spike protein of SARS-CoV2.  How has ISA106 been engineered to treat SARS-CoV2, and what is the significance of including S (Spike), M (Membrane) and N (Nucleoprotein) sequences, and sequences from conserved regions? 

Prof. Melief, “We have looked at scientific papers, including from the Karolinska Institute, on those patients who developed mild, or no, symptoms. Many had no measurable neutralizing antibodies but had good levels of T cells, active against S, M and N proteins, effectively eradicating the virus from infected cells, without any indication of antibodies being activeThis gave a strong and broad response, including memory response, making it very difficult for the virus to escape as it was being attacked on multiple of its proteins, not just part of the spike. With tens of millions of people infected it seems quite likely an escape variant of the virus will occur, that no longer responds to the current vaccines targeting the spike alone”. Since this coronavirus is related to certain common cold viruses, and a similar situation exists with influenza, it may be that a new prophylactic vaccine may be needed every year, but this is a speculative assumption 

The timing of when someone receives a vaccine or therapy can be critical. For vaccines, ideally people have these long before they are exposed to the virus. For those infected with the virus, the timing of administration of antivirals could be crucial. Where does ISA106, as a potential therapeutic for SARs-CoV2 infection, fit into the treatment plan for patients? 

Prof. Melief, “It looks like those patients that get sick have a paucity of virusspecific T cells. The T cell population appears to crash, which causes a huge compensatory expansion of other immune cells, leading to a cytokine storm and potentially severe complications. This also explains why more elderly people get severe disease, as they have strongly reduced T cell repertoire and a sluggish T cell response which is insufficient against the new virus. The new virus gets the chance to descend into the deeper lung tissues where there is a receptor that the virus binds to preferentially, thereby starting the tissue damage.  

With the multitude of new COVID-19 vaccines and therapies being developed, companies have had to be fast moving to set up clinical trials in places where the virus is at its worst, to ensure enough people are exposed to virus in the placebo and dosed groups, in order to promptly assess efficacy. We asked about the clinical plans for ISA 106, and whether ISA will be able to find enough eligible patients quickly enough to complete a clinical study in good time. 

Prof. Melief, “We looked at peripheral blood mononuclear cells (PBMC) from convalescent patients and selected twelve SLPs against which their T cells among the PBMC reacted strongly. We are planning a quick phase I trial in healthy volunteers, to assess toxicity and immunogenicity, followed by a trial in Feb/March 2021 in high risk groups. We do not anticipate any problems in recruiting patients in this time period, the more so because by then there will still be high numbers of infections despite the prophylactic vaccines making their appearance (as their introduction and wider distribution will essentially be too late to prevent this).  

There are several problems for society to solve with large scale vaccines roll out, including, for some, the need for a complex cold chainplus questions of exactly how and by whom, the vaccine is administered, and for how long it may provide protectionPlus, whether vaccines work equally well in all age groups, something that is not usually the case with flu viruses for example. Our immune systems become weaker with agea process known as ‘immuno-senescence’so flu-like vaccines are not expected to give as good ‘coverage’ (effective protection) in older age cohorts, yet these are the people most at risk from coronavirus. We asked how ISA106 measures up against these parameters. 

Prof. Melief, “The problem will not be solved by vaccines alone. None are 100% effective, and there is considerable public resistance to these rapidly developed vaccines. This is a politicized issue, and I am afraid it will take years before herd immunity is established sufficiently over the world to eradicate the virus. Moreover, we are still in uncharted territory as regards the duration of immunity after a prophylactic vaccine. For other viruses, such as Hepatitis B, we have had vaccines for decades, yet hundreds of millions still have infections. So, for all these reasons we need additional approaches. 

“It is no problem to make large quantities of our peptideswhich can be stored long term as a powder at 4°CThere is no biohazard involved as it is entirely syntheticISA106 would be given as an injection together with an easily made adjuvant. I am excited as we are the only company making a therapeutic vaccine, focused on inducing a rapid T cell response. If vaccinated early after an infection, there are around 7-10 days before people get sick and need hospitalization. That provides a window of opportunity, early after infection is detected via test and trace. This works well in many countries in the world, including the Netherlands, where someone can get treatment to boost their T cell response. The raging inflammation in the lungs, due to insufficient local T cells is then reduced by an auxiliary army of T cells generated in the skin which comes to the rescue of the lungs. We also know from our HPV efforts that immune memory lasts for years, because of the strength of the T cell response generated by our SLPsThis is a completely different concept to antibodies or antiviral drugs that target viral enzymes, and one that could be used alongside them. Whave to persist and prevail. 

If we as a society take time to rethink our approach to infectious disease preparedness – which has been shown in many places to be painfully lacking – it is clear we need long-term strategic investment to have more diagnostics, therapies and vaccines under development, along with the infrastructure and finances to support them. ISA pharmaceuticals’ SLP technology could prove to be an important piece of this pandemic preparedness jigsaw. 

[1] Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study – The Lancet

[2] A randomized trial of convalescent plasma in Covid-19 severe pneumonia – The New England Journal of Medicine, 24 Nov 2020