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 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 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.

Zika virus: a whistle-stop tour

Zika virus (false colour transmission
electron microscope image)

In a recent piece on mRNA vaccines[mRNA vaccine technology: industry is getting the message] , I mentioned Zika virus development as an indication for this emerging technology. only to realise my ignorance of this high profile pathogen (shameful, since I spent my post-doc years working in a school of tropical medicine)

First stop in filling the knowledge gap was a visit to the ever-useful World Health Organisation website which features a comprehensive “Zika timeline”. First discovered in 1947 in monkeys living in a Ugandan forest (which gave its name to the virus), and shortly after in species of Aedes mosquito, epidemiological studies conducted in the 60s and 80s indicated widespread human exposure to the Zika virus in Africa and Asia, with infection largely associated with no, or only mild, symptoms.

The more sinister nature of Zika infection emerged in 2007 and 2008, with the first confirmed large scale outbreak on the Micronesian island of Yap, and evidence that infection could be sexually transmitted. Further outbreaks occurred on various Pacific Islands during 2013 and 2014 and pointed to a link between Zika infection and birth defects and with Guillain–Barré  syndrome, a rare autoimmune disease which affects the nervous system. A year later, an epidemic characterized by a skin rash bit otherwise mild symptoms was reported in north-eastern Brazil, but was not recognised as being due to Zika virus.

By October 2015, an increasing numbers of microcephaly cases (newborns with small heads, indicative of abnormal brain development) were being reported. Further Zika outbreaks occurred in several South American and Caribbean countries over the following year, with the first cases (via sexual transmission) being identified in the continental United States in 2016.

Being generally asymptomatic, the prevalence of Zika infection is not easy to quantify, but mosquito-transmitted infection has been reported in over 80 countries (with transmission ongoing in over 60 of these). Over 1.3 million people are thought to have been infected in Brazil alone during the 2015 outbreak. In common with other vector-borne diseases, the spread of Zika owes something to human mobility, although social factors, principally the inability to afford protection against mosquitoes and high population density have been identified as key drivers.

The Zika virus has several properties that contribute to its ready transmission and to its devastating effect on foetal development. The virus is highly persistent in whole blood (up to 100 days) and in the male reproductive tract, allowing sexual transmission. Zika has a preference for certain cell types that facilitate the passage of infection through the placenta; animal studies suggest that viral preference extends to neural progenitor cells essential for normal cortical development. Whether Zika infection is a direct cause of Guillain–Barré  syndrome  has not been established.

As with malaria, Zika’s vulnerability lies in its dependence on mosquito vectors: and targeted insecticide use, management of standing water and the conscientious use of bed nets and repellents can significantly reduce transmission. Like malaria, control initiatives are vulnerable to political and economic factors, including climate change-related changes in mosquito distribution and abundance. Unlike malaria, Zika has a simple lifecycle; as with other flaviviruses (including the causative agents of yellow fever and Japanese encephalitis), infection should, in theory, be preventable through vaccination.

Vaccine development efforts are almost contemporary with the Zika outbreak itself, beginning in the second half of 2015 with the genetic analysis of Brazilian Zika isolates, with the first clinical study of a Zika vaccine being reported in late 2017. Around 45 candidate vaccines have been developed through academic, governmental and industrial efforts, with nine of these reaching the clinic, representing both established (inactivated virus) and experimental approaches (DNA and mRNA vaccines). The WHO’s initial requirement is for a vaccine that can be deployed in response to outbreaks with the primary goal of preventing congenital Zika syndrome through minimizing virus carriage in the immediate population.

Early clinical studies have established that vaccination can elicit aneutralizing antibody responses, although, while an accepted hallmark of flavivirus vaccine efficacy, the importance of neutralising antibodies, and the minimum levels needed to establish protection have still to be established in the context of Zika infection. Other important unknowns include the duration of effective vaccine-induced immunity and whether the reproductive tract can be protected from infection.

              

Perversely, given the untold misery arising from Zika outbreaks around the globe, the virus’s propensity for neural progenitor cells may offer a new means of treating the most aggressive and intractable form of brain tumour, glioblastoma.

Chinese researchers have found that an experimental live attenuated Zika vaccine functions as an oncolytic virotherapy [Going viral] in an animal model of glioblastoma, specifically infecting and destroying glioma stem cells thought to be responsible for the inevitable recurrence of the tumour. Elimination was also observed using glioma stem cells isolated from individual patients.

Photo credit: Credit: NIH/NIAID

Group B Streptococcus vaccine development: an eighty year old challenge

Group B streptococci 

Group B Streptococcus (GBS) and I go back a long way.  In the late 90s and early 2000s, I worked for several companies with ambitions to develop a GBS vaccine, only for hopes to be abandoned as an appreciation of the technical (and commercial) challenge sunk in.

GBS vaccine development has been kept alive over the last couple of decades largely by academic investigators and the odd small-cap biopharma, so it’s good to see a company the size of Pfizer getting involved, albeit with development being subsidised by the Bill and Melinda Gates Foundation.

GBS is a not uncommon resident of the guts and vaginas of healthy women, and is harmless until it turns up in the wrong place at the wrong time. Transmission of the bug to newborns can result in life-threatening, sometimes fatal, sepsis and meningitis. 

Microbiological screening, along with attention to risk factors such as preterm delivery and rupture of the protective amniotic membrane, can give a heads up as to the risk of delivering and infected infant and direct appropriate prophylactic antibiotic therapy. However, not every GBS case is prevented, even in well-resourced countries.

GBS is well-adapted for evasion of the immune system. Spreading bacteria express a variety of virulence factors which help them to set up house and deflect the unwanted attention of patrolling white cells. One of these factors, “capsular polysaccharide” (CPS) naturally elicits a generally ineffectual antibody response and was first investigated as a possible vaccine candidate during the 1930s. 

The immunogenicity of CPS can be boosted by chemically linking it to tetanus toxoid or other proteins (a strategy that works for Haemophilus Type B, Neisseria meningitidis and Streptococcus pneumoniae vaccines).  Investigational   glycoconjugate vaccines have resulted in reduced GBS carriage rates in healthy volunteers but not to the extent necessary for useful vaccination. A small scale study conducted in pregnant women had no beneficial effect on outcome. 

Over the last 15 years or so, whole genome sequencing and recombinant DNA technology have allowed researchers to identify bacterial surface proteins that might potentially protect against infection from a variety of GBS strains.   

MinerVax, a small Danish biotech which receives funding from the EU “Neostrep” project, reported positive results in a Phase I study of an all-protein vaccine,  with antibody responses in group of 240 healthy women elicited at all dosage levels. Pfizer’s candidate, which has just entered Phase I studies, is more old-school, being a conjugate vaccine designed to mimic multiple GBS serotypes. 

Any (potentially) preventable condition that causes infant death is rightly emotive, but harsh as it may seem, it’s not a certainty that GBS vaccination will actually prove to be universally cost-effective. Deployment may not make economic sense in countries where the incidence of GBS infection is low, but payback will hopefully prove substantial in countries such as South Africa, where the incidence of GBS infection is around five times higher than that of the UK. 

What’s more certain is that the technical challenge of effective GBS vaccination will be resolved well within the next 80 years. 

Image courtesy of James Archer, Medical Illustrator US Centers for Disease Control and Prevention 2013