COVID-19 update: on hydroxychloroquine, an old vaccine and convalescent plasma

A belated and somewhat bitty update, due to illness over the past week (respiratory, although thankfully ticking very few of the COVID-19 boxes. Living in the UK, it might be 2025 before I get tested...).

While the FDA has granted emergency approval for the use of hydroxychloroquine and chloroquine in COVID-19 patients (with the EMA limiting use to clinical trials only), definitive evidence for benefit remains elusive. 

A (non-peer reviewed) study from Wuhan involving patients with mild to moderate COVID-19 symptoms suggests that hydroxychloroquine treatment may have shortened the time to clinical recovery[1]. A second study[2] from the French group which first claimed benefit from treatment with hydroxychloroquine in combination with the antibiotic azithromycin is proving as controversial as the first with respect to flaws in design and interpretation (I recommend Derek Lowe's incisive analysis as a place to start- "More on Chloroquine/Azithromycin. And On Dr. Raoult.. ", online 23rd March).

New vaccine candidates seem to appear every other day, with around 50 or so (most at early lab or even concept stage) now listed. The latest into the clinic, LV-SMENP-DC (Shenzhen Geno-Immune Medical Institute)[3]  borrows heavily from experimental cancer vaccines, using antigen-presenting dendritic cells genetically engineered to express a selection of COVID-19 antigens in combination with antigen-specific cytotoxic T cells. Primary read out is several years away. 

At the other end of the vaccine innovation spectrum, Australian researchers are about to kick off studies of the centenarian Bacillus Calmette–Guérin (BCG) tuberculosis vaccine among healthcare workers[4]. BCG is a powerful immunostimulant in its own right and the hope is that boosting the innate immune system, our first line of defence before specific (adaptive) immune responses develop, might induce some degree of early protection. 

The use of convalescent plasma is gathering pace, with the FDA now coordinating passive immunotherapy studies, with the Mayo Clinic taking point on clinical studies[5]. A second pilot study out of Wuhan appears to echo earlier encouraging results[6]. 

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[1] Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. Chen Z et al. https://tinyurl.com/s46woam

[2] Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: an observational study. Gautret P et al. https://tinyurl.com/rdsnhoq

[3] Immunity and Safety of Covid-19 Synthetic Minigene Vaccine. https://tinyurl.com/wmvn8es

[4] BCG Vaccination to Protect Healthcare Workers Against COVID-19 (BRACE). https://tinyurl.com/qndc9lm

[5] Coronavirus (COVID-19) Update: FDA Coordinates National Effort to Develop Blood-Related Therapies for COVID-19. Online April 3^rd 2020. https://tinyurl.com/s9x4qqy

[6] The feasibility of convalescent plasma therapy in severe COVID-19 patients: a pilot study. Duan, K et al. https://tinyurl.com/sbaqc25

COVID 19 drug study update: passive immunotherapy first results

Passive immunotherapy- the use of donor antibodies from those either recovered from infection or who have been immunised to produce protective antibodies has been used for many decades for conditions where no drug treatment is available. 

Pooled human plasma can be used "as is" or  treated to isolate the antibody-containing gammaglobulin fraction (giving a low volume, "hyperimmune" globulin formulation). A more modern twist is to use manufactured antibodies of a single specificity (monoclonal antibodies), either on their own or combined as a cocktail. 

Passive immunotherapy works and is logistically simple (plasma collection on an industrial scale is routine) and hence an obvious choice for evaluation in COVID-19 treatment. 

First results from a (very) small Chinese study of five critically ill (ventilator dependent) COVID-19 patients hint at benefit from convalescent plasma transfusion, with three patients taken off mechanical ventilation within 2 weeks of treatment. Three were discharged after hospital stays of 51-55 days, the other two being in stable condition 37 days after transfusion.

Several industrial and academic groups are pursuing hyperimmune globulin approaches (Takeda, Vir Biotech, Lilly, Celltrion), with others, including Regeneron, looking to monoclonal therapies. 

Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma
Shen C et al. JAMA. Published online March 27, 2020. https://tinyurl.com/tj52h3j 

More on US plans for the use of convalescent plasma here: 

How blood from coronavirus survivors might save lives. Maxmen A. Nature online 23rd March 2020 https://tinyurl.com/s6e9ndy 

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.