COVID-19 vaccine update: Oxford vaccine close to the clinic and Sanofi turns to mRNA vaccine development

Recruitment of healthy volunteers for initial evaluation of ChAdOx1 nCoV-19, a candidate non-replicating adenovirus vaccine developed at the Oxford Vaccine Centre in underway. 

The same technology platform is being used in an experimental MERS vaccine (study ongoing). 

The COVID-19 vacccine study is a placebo-controlled, single dose study (n=560, split evenly but with 10 volunteers receiving two doses), monitored over six months and with an optional 12 month follow-up. 

Sanofi Pasteur, already active in COVID-19 protein subunit vaccine development have partnered with Translate Bio, an mRNA technology company which already has 100g scale capability for clinical grade material. The companies will develop several potential candidates over the coming months. 

Oxford Vaccine Centre study page https://covid19vaccinetrial.co.uk/ accessed 27th March 2020

Sanofi and Translate Bio collaborate to develop novel mRNA vaccine candidate against COVID-19. Company press release online 27th March 2020 https://tinyurl.com/yxyymu7x

COVID-19 drug study update: hydroxychloroquine a bust?

While there have been high (and certainly over-optimistic hopes) for the repurposed antimalarial drug, hydroxychloroquine, a small study (n=30, equal numbers in the test and control groups) conducted in Shanghai and reported today by Forbes did not find any benefit with time to viral  clearance over best standard of care. 

A real bust? Probably, but at this stage, even negative results are valuable if it helps redirect efforts towards more productive avenues. 

Hydroxychloroquine Is Ineffective In Treatment Of Patients Hospitalized With Covid-19, According To Small Controlled Trial From Shanghai. Haseltine WA Forbes online 25th March https://tinyurl.com/vjg75c4  

COVID-19 vaccine clinical development gets off the mark

Vaccine development has never lacked for innovation, although as a necessarily conservative industry, only a small number of evolutionary technologies have so far been exploited in large-scale “routine” childhood and adult vaccines.

This wealth of background ingenuity, along with experience gained in earlier pandemics (SARS, MERS) and the ongoing quest for better influenza vaccines, has allowed COVID-19 vaccine development to get off to a flying start, with an impressive number of candidates incorporating both established and novel technologies now under laboratory evaluation, and with a few in, or very close to, first in human studies.

A high-profile front runner is Moderna’s mRNA-1273, comprising synthetic mRNA encoding COVID-19 S (“spike”) protein, delivered in a lipid formulation which assists in getting the mRNA into cells and to ribosomes, where it’s translated into immunising protein. Dosing is now underway in healthy adults, with safety and immunogenicity read-out anticipated by mid-June next year[1]. 

However, on the 23^rd March, Moderna raised the possibility of being able to make the vaccine available to essential healthcare personnel before year end under an emergency provision.[2] 

Another mRNA player, CureVac, encouraged by early results from an mRNA rabies vaccine study, plans to enter its own COVID-19 mRNA candidate into trials by mid-year.  CureVac hopes that the vaccine might achieve useful responses at the same very low doses used in the rabies study, allowing it to meet early demand from its existing manufacturing capability. Several other mRNA vaccine candidates under development within academia and industry (from BioNTech, Arcturus, Fosun and Pfizer) are at earlier stages of preclinical development and include a nasally administered vaccine encoding highly conserved COVID-19 proteins (eTheRNA consortium) [3].

A Chinese developed non-replicating viral vector vaccine, Ad5-nCoV (CanSino Biological and the Beijing Institute of Biotechnology) will shortly enter the clinic[4]. This exploits an engineered adenovirus (the workhorse of gene therapy) to deliver DNA encoding coronavirus proteins. The technology has a track record, being the same as used in the first Ebola vaccine to receive regulatory approval.

Adenovirus-based vaccines are not without their problems, but as a relatively well-understood platform, it’s no surprise that several companies and institutes are pursuing non-replicating adenovirus candidate vaccines, including J&J, GeoVax, Altimmune, Greffex and Vaccitech. An arguably riskier route is the use of replicating viral vectors such as measles (Institute Pasteur) and horsepox viruses (Tonix Pharma).

DNA delivery does not require a living carrier, replicating or otherwise. Inovio is applying its electroporation to push COVID-19 protein encoding DNA through the skin. Zydus Cadilla is also looking at a DNA, although has not disclosed how the encoding plasmid might be delivered.

Protein subunit vaccines are well-understood, with several candidates developed in response to the SARS pandemic. Importantly, the manufacture of protein subunit vaccines is well-established and can be accomplished to high yields in in standard bacteria and yeast expression systems, although several COVID-19 candidates involve insect cell (Sanofi, ExpreS2ion) or plant-based manufacture (IBio/CC Farming).

And, in the midst of all this experimental vaccine tech, let’s not ignore the old school approaches of formalin-inactivated virus (Sinovac) and attenuated live vaccines (Codagenix/Serum Institute of India) which have proved their worth in existing viral vaccines.

Nor should we ignore the slog ahead. The correlates of protection for COVID-19, that is what should we be looking for with respect to the quality and magnitude of a neutralising antibody response, are unknown: analysis of the immune response from recovering (and infected but asymptomatic) individuals may shed much needed light.  The phenomenon of “antibody dependent enhancement” (ADE), where the virus hijacks the host antibody response to infect certain cell types has been observed in both  non-SARS human and animal coronavirus infection. Early SARS vaccine development pointed up a potential risk of severe hypersensitivity reactions in immunised animals when challenged with virus.  

Despite the pressing need to at least be able to protect those on the front line, history dictates caution[5]. A possible silver lining of the pandemic is that revolutionary approaches such as mRNA vaccination may prove their worth much earlier than would normally be the case.  Vaccine development failures, and there will be many, will, at hte very least, will add to preparedness for the next pandemic by eliminating blind alleys. 

With a fair wind, we might see limited release of a vaccine within 18 months. Until then, and with the gradual development of what will hopefully be protective natural immunity, we all need to accept that lockdown and social distancing save lives and takes some of the pressure off our healthcare systems.

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[1] Safety and Immunogenicity Study of 2019-nCoV Vaccine (mRNA-1273) to Prevent SARS-CoV-2 Infection https://tinyurl.com/vnvl7wd

[2] Moderna: Virus Vaccine May Be Available to Aid Workers by Fall, Wider Provision in 12-18 Months https://tinyurl.com/s3tm6as

[3]eTheRNA Launches an International Consortium and Starts Development of Cross-strain Protective CoV-2 mRNA Vaccine for High Risk Populations https://tinyurl.com/wdmkk6d

[4] A phase I clinical trial for recombinant novel coronavirus (2019-COV) vaccine (adenoviral vector) https://tinyurl.com/vqemt6u

[5] h Don’t rush to deploy COVID-19 vaccines and drugs without sufficient safety guarantees https://tinyurl.com/swybbya

Early COVID-19 drug studies: what have we learned?

The past week has seen first results from studies of existing antiviral drugs and repurposed agents in those hospitalised with COVID-19, raising at least as many questions as answers. A combination of two antivirals (lopinavir–ritonavir: Kaletra®) used to treat HIV infection did not reduce mortality in a randomised study conducted in almost 200 severely-ill Chinese patients[1], although with a hint that earlier treatment might just be of some benefit[2].

Avigan® (avilavir/ favipiravir), an influenza drug approved in Japan and China has been reported as clearing the COVID-19 virus in four days, versus those treated with another antiviral agents. However, this was not a randomised study and involved less severely ill subjects, with benefit confined to those receiving early treatment. Although while broadly hailed as “highly effective in media reports, Avigan’s developer (Fujifilm) has been cautious in making claims around efficacy. Avigan® has been associated with severe adverse events, limiting its use as an influenza treatment.

An investigational antiviral with a similar mechanism of action, remdesivir (GS-5734; Gilead Sciences, Inc), and which is known to be active against the SARS and MERS coronaviruses is in late-stage testing in China, the US and South Korea. Anecdotal findings from a small number of severely ill patients infected while aboard a cruise ship have suggested remdesivir may have reduced reliance on ventilator support. Despite an absence of hard evidence, the drug was approved for compassionate use in the US on March 19^th. As of today (Sunday 22^nd March), Gilead was forced to temporarily limit patient access to remdesivir due to “overwhelming demand”[3].

Similarly, chloroquine, a decades old antimalarial drug, has also been approved for compassionate use on the back of anecdotal evidence, with the hope that it may also have a prophylactic effect. A related drug, hydroxychloroquine, in combination with the antibiotic azithromycin, has been reported as reducing viral burden in a small study[4]. Both drugs have been reported to be in short supply through high demand in the US, leading to problems for autoimmune disease patients dependent on the same drugs.

Actemra®, a biologic developed for rheumatoid arthritis targets the cytokine IL-6, an immune system component responsible for the “cytokine storm” observed in CAR-T therapy and apparently a contributor to the pathology of severe COVID-10 infection has been observed to be of benefit in a small and uncontrolled study in China. A similar anti-IL-6 biologic, Kevzara® (Regeneron) is moving towards Phase III studies in COVID-19 infection.

No big wins, but, and perhaps the most you can hope for from early, essentially empirical interventions and anecdote are hints and glimmers of possible ways forward. More such early and empirical, will light the way, with China, not surprisingly, ahead of the curve with over thirty medicines (including traditional Chinese medicines) identified as having an anti-COVID-19 effect in the laboratory.

[In case you missed it in my Favourites sidebar, check out Derek Lowe's blog: 
https://blogs.sciencemag.org/pipeline/archives/2020/03/24/the-latest-coronavirus-clinical-trials#comment-314221]

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[1] A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19. Cao B et al. NEJM

Online March 18^th 2020 March 18, 2020 DOI: 10.1056/NEJMoa2001282 https://tinyurl.com/ulpek4c

[2] Covid-19 — The Search for Effective Therapy. Baden LR et al. NEJM online March 18^th 2020 DOI: 10.1056/NEJMe2005477 https://tinyurl.com/yx6jrrxe

[3] Gilead pauses access to experimental Covid-19 drug due to ‘overwhelming demand’. Herper M. STAT online March 22^nd 2020 https://tinyurl.com/tum92s6

[4] Information for Clinicians on Therapeutic Options for COVID-19 Patients. CDC website accessed 22^nd March 2020. https://tinyurl.com/rx7ujpz

Life During Wartime

As you may have noticed, there’s a lot happening on this small planet of ours. One small personal bright spot is that, having spent years involved in infectious disease, from diagnostic test design through vaccine and drug development, I’ve been able to help family, friends and colleagues make sense of the pandemic and have been fortunate to engage with those whose knowledge and experience goes well beyond mine.

Let’s start with the good news. While in no way underplaying the threat posed by COVID-19, the biopharma industry has been quick off the mark, with both well-trodden and new paths to treatment and prevention under very active exploration. Experience gained from past SARS and MERS epidemics (and seasonal influenza) mean that industry and public health and regulatory agencies are not starting from scratch.

That’s not to imply that treatments and vaccines will be here a week come Tuesday. Problems encountered in early SARS vaccine studies are a reminder of just how steep the learning curve might prove to be, and, at the time of writing, early clinical data for studies of repurposed drugs in ameliorating the effect of COVID-19 infection is equivocal at best. But, every hint of potential benefit will assist in identify strategies with a higher probability of success.

My white coat-days are long gone, and my battle against COVID-19 is essentially confined to taking the obvious practical measures to keep family, friends and myself at low-risk for infection. Lord, how I miss the pub already….

The only small additional effort I can make is in using this (very) modestly visited blog to pull together what’s relevant and important in controlling COVID-19, with the hope that it just might assist in developing a sense of perspective for anyone interested in the how and why of the science and industry effort.

So, until the world has adjusted to the new normal, this blog will be mainly dedicated to selected COVID-19 news, with at least a once a day update. Comments and questions, all and any feedback more welcome than ever.

Vaping and lung injury: No smoke without fire

E-cigarette use (generically “vaping”) is nothing if not controversial with respect to public health benefit.

Widely cited pluses are that vaping results in far lower exposure to the smoke, tar and carbon monoxide that make traditional coffin nails so dangerous, with the level of potential harm from vaping being close to that of nicotine replacement products of the patch, gum or spray variety. 

A 2018 report from Public Health England estimated that e-cigarettes were “95% less harmful” than regular cigarettes and were an aid to smoking cessation[1].

The European Public Health Association is not convinced when it comes to quantifying the relative safety of e-cigarettes (“statements that they are some percentage safer than conventional cigarettes are entirely unjustified”) and is more cautious over benefit in smoking cessation.[2] Expert authorities,  including the British Heart Foundation, recommend that non-smokers should not take up vaping[3].

Vaping has never been considered risk-free. Vaping products contain a variety of additives and solvents, including propylene glycol and glycerol: when heated, these give rise to known carcinogens and toxicants readily detectable in the urine of e-cigarette users[4]. And while vaping products may contain flavourings with a long history of safe use in the food industry, little is known about their toxic potential when heated and delivered to the lungs.

Uptake of vaping by otherwise non-smoking teenagers is of broad concern.  Teenage vapers might never adopt the less attractive smoking habits of their parents and older siblings, but there is apprehension that, despite an overall decline in tobacco use, a new generation of nicotine addicts is in the making.

The estimated 78% increase in e-cigarette use by American high school students in 2018 may prove to be a short-lived phenomenon driven by slick vaping technology and stealthy promotion, but it has prompted responses at state and federal level. A previous FDA Commissioner, Scott Gottlieb, described e-cigarette use as “an epidemic among teenagers[5], necessitating restrictions on the marketing of flavoured vaping products and tougher retail regulation[6].

The regulatory hammer now looks set to fall harder and faster with growing evidence for an association between potentially fatal lung injury and vaping, first reported in the US in August this year, and now designated as “e-cigarette, or vaping, product use associated lung injury (EVALI)” by the US Centers for Disease Control and Prevention in a newly-released interim guidance document[7]. At publication, 1,229 EVALI cases had been reported in the US or US territories, with 26 fatalities.[As of 22nd October, there were 1,604 reported EVALI cases and 34 deaths. Updates are available from the CDC website: http://tinyurl.com/y29saqdd]

Affected vapers, and their preferred products and vaping habits, are unlikely to be conveniently similar enough to easily pin down common causes of EVALI. Available data hints at a contribution from the tetrahedral cannabidiol (THC), with 76% of EVALI patients having used THC-containing products in the 90 days prior to onset of EVALI symptoms, and 32% using THC-containing products exclusively.  However, 58% reported use of nicotine-containing products, with 13% using nicotine-containing products exclusively, meaning that nicotine (or one of the many additives in vaping products) cannot be ruled out as either cause or contributor.[On November 5th, CDC announced that vitamin E acetate, often used to cut THC oil and as a thickening agent in vaping liquid, was detectable in lung fluid samples from EVALI patients. Although considered safe as a dietary supplement, vitamin E acetate is known to impair lung function  http://tinyurl.com/y29saqdd]

Analysis of lung biopsies by Mayo Clinic investigators found signs of acute lung injury in vapers consistent with chemical or toxic by-product damage, rather than suggestive of a rare form of pneumonia associated with the inhalation of oily substances (“exogenous lipoid pneumonia”)[8].

Several US states have been quick to respond to the heightened perception of serious risk from vaping, with Michigan, New York, California, Massachusetts and Rhode Island introducing outright bans or other controls on flavoured tobacco products last month[9]. India also announced an intention to ban vaping products, prompting the perhaps unfair observation that, in a country where the government is a major stakeholder in tobacco firms (and with some of the highest rates of smokeless tobacco use and oral cancer incidence in the world), public health might not be the only concern[10].

EVALI will undoubtedly precipitate widescale re-evaluation of vaping benefit versus harm, but this may only be the start of the vaping industry’s woes. A recent animal study suggests that chronic exposure to nicotine-containing e-cigarette smoke can give rise to potentially carcinogenic nitrosoamines, perhaps through chemical reaction with nitrosonium ions naturally present in mammalian cells, and result in higher rates of lung and bladder cancer than in unexposed animals.[11]

The relevance to real-life vaping product use and cancer risk awaits larger and more sophisticated investigation but the possibility exists that the carcinogenic potential of nicotine delivered via vaping is currently underestimated.

Photo credit: Lindsay Fox (Creative Commons Licence)

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[1] Evidence review of e-cigarettes and heated tobacco products. McNeill A et al. February 2018. http://tinyurl.com/ycake739

[2] Facts and fiction on e-cigs. European Public Health Association. August 2018. http://tinyurl.com/y4358wuj 

[3] Is vaping safe? Trevallion L. Heart Matters (British Heart Foundation blog) http://tinyurl.com/y3shysk4

[4] Adolescent exposure to toxic volatile organic chemicals from e-cigarettes. Pediatrics 2018: 141(4). Published online April 02, 2018 doi: 10.1542/peds.2017-3557

[5] Statement from FDA Commissioner Scott Gottlieb, M.D. on new steps to address epidemic of youth e-cigarette use . Press release online September 12^th 2018. http://tinyurl.com/y32z4yb2

[6] FDA considers regulatory action as vaping among US teens jumps 78% in a year. Dyer O. BMJ 2019;364:741 https://doi.org/10.1136/bmj.l741   Online February 14^th  2019.

[7] Update: Interim guidance for health care providers evaluating and caring for patients with suspected e-cigarette, or vaping, product use associated lung injury — United States, October 2019. Siegel DA et al. MMWR online October 11th, 2019. http://dx.doi.org/10.15585/mmwr.mm6841e3external icon 

[8] Pathology of vaping-associated lung injury. Butt YM et al. Correspondence, NEJM online 2^nd October 2019
https://www.nejm.org/doi/10.1056/NEJMc1913069 

[9] As the number of vaping-related deaths climbs, these states have implemented e-cigarette bans. Ducharme J Time Magazine online September 25^th 2019.  http://tinyurl.com/y573z8l7 

[10] India banned e-cigarettes — But beedis and chewing tobacco remain widespread. Frayer L and Pathak S. Goats and Soda. National Public Radio online 9^th October 2019 http://tinyurl.com/y5ltu3lo

[11] Electronic-cigarette smoke induces lung adenocarcinoma and bladder urothelial hyperplasia in mice. Tang M-S et al. PNAS online October 7^th 2019 https://doi.org/10.1073/pnas.1911321116

Improving autoimmune disease treatment: tolerance required

Hand of a rheumatoid arthritis patient

The author and dramatist Friedrich Dürrenmatt wrote that “Without tolerance, our world turns into hell”.  Nothing could be truer for sufferers of autoimmune conditions such as rheumatoid arthritis, multiple sclerosis, psoriasis, Crohn’s  disease (an inflammatory bowel condition) and Type 1 diabetes, where faults in one or more of the mechanisms that normally prevent the immune system from attacking the body (“immune tolerance”) result in chronic tissue and damage.

A strength and weakness of the immune system is that, for speed and breadth of recognition of foreign antigens, the white blood cells responsible for antibody production (B cells) and those active in cell-mediated responses (T cells) express a broad repertoire of randomly-generated surface receptors. Probability dictates that a number of T and B cell clones will possess receptors that recognize “self” molecules (“autoantigens”).

Policing of the immune system to weed out or otherwise inactivate self-reactive T and B cell occurs in the thymus gland and bone marrow, respectively, and in peripheral sites including the lymph nodes. Not all bad actors are recognised and dealt with:  escapee self-recognising T cells are held in check by another subset of T cells (regulatory T cells- “Treg”). Through quirks in genetics and a contribution from environmental factors, one more of the mechanisms involved in self-tolerance fail in some individuals, leading to autoimmune disease.

Current therapies for autoimmune conditions are aimed at reducing inflammation using steroids or inducing remission through “disease modifying” drugs (DMARDs), either biologics which neutralise the signalling molecules (“cytokines”) involved in the inflammatory cascade or with small molecules such as methotrexate  and, more recently, Janus kinase inhibitors. All result in some degree of immune suppression and may not result in satisfactory disease control: up to a quarter of those receiving DMARDs for rheumatoid arthritis fail to obtain sustained benefit.

The therapeutic potential of restoring self-tolerance has been actively pursued for close to two decades. Purging the immune system of mature T and B cells through aggressive chemotherapy, followed by its restoration through stem cell transplantation has had some success in multiple sclerosis and Crohn’s disease patients, but comes with high risk of mortality.

More viable approaches applicable across a range of autoimmune conditions involve the targeting of autoantigen-recognising T cells or the generation of Treg cells to restore self-tolerance.Paradoxically, tolerance can be restored by presentation of the offending autoantigen(s) in the form of a “tolerizing vaccine” containing whole proteins or peptides, or DNA or mRNA encoding the autoantigen of choice.  

Tolerization through presentation of insulin or other autoantigens recognised in Type 1 diabetes (caused by the autoimmune destruction of insulin-producing beta cell in the pancreas) has the potential to preserve insulin levels but clinical studies have been largely disappointing, as has been the case in multiple sclerosis and rheumatoid arthritis studies.

Cellular immunotherapies that more effectively present autoantigens or increase numbers of Treg cells have great promise in severe or refractory autoimmune diseases. Dendritic cells (DCs) are specialised at presenting antigens to the immune system, a property exploited in cancer vaccine development, [Dendritic cell vaccines: back to the future] but are also effective at inducing Treg cells. Some degree of clinical benefit has been observed in studies involving local administration of autoantigen-loaded and non-antigen specific “tolerogenic” DCs  (tolDC) into the knee joints of subjects with rheumatoid arthritis. Other studies with tolDC therapy are ongoing in subjects with Type 1 diabetes and Crohn’s disease and in preventing rejection in solid organ transplantation.

Other cellular immunotherapy strategies in active development involve the isolation, expansion and (re)infusion of Treg cells or mesenchymal stem cells which have multiple effects on the immune system, including Treg induction. In another twist, Treg cells may be genetically engineered to express autoantigen-recognising receptors and early-stage development of this approach is underway in the prevention of transplant rejection. An advantage of mesenchymal stem cell immunotherapy is that cells can be readily obtained and expanded from donated cord blood or fatty tissue (“allogenic” therapy).

While relatively complex and expensive, and currently at a very early stage of development, cellular immunotherapies may eventually become established as a means of managing severe or refractory autoimmune conditions without requiring constant medication or continual switching of drug regimens.  The quality of life and economic implications for effective treatment are significant: in the developed economies, around 1% of adults develop rheumatoid arthritis, with the majority being first diagnosed while still of working age. Multiple sclerosis and Crohn’s disease patients are generally diagnosed while still in their early 30s.

Photo credit: Bernd Brägelmann Braegel Mit freundlicher Genehmigung von Dr. Martin Steinhoff