The global COVID-19 pandemic picture is still unclear as the novel coronavirus outbreak shifts constantly around the world. While the number of cases rise critically in South America’s first wave, the UK and European countries have begun to lift their lockdown measures amidst this COVID-19 pandemic. At the same time, South Korea and China, where coronavirus cases seemed to have disappeared, have seen a second wave of infections. However, a common question emerges among this COVID-19 rollercoaster: Will we have a vaccine soon?
A matter of time
Timing is crucial in vaccine research. More than five months have passed since the genetic sequence of SARS- CoV-2, the virus that causes COVID-19, which was published on 11th January 2020. This discovery sparked an unprecedented global research effort to develop a vaccine against this disease1, involving next-generation technology platforms and novel approaches with a hope to speed up this process. However, vaccine development involves a multi-stage process of research and testing, which typically takes more than ten years to be completed2 (Fig. 1). Therefore, we must remain cautious in light of a new vaccine.
What is the current picture?
A recent overview of the global landscape of COVID-19 vaccines by the World Health Organisation (WHO) included more than 140 vaccine candidates from different research groups and developers around the world3. From those, 129 candidate vaccines are under preclinical evaluation, which means a preliminary laboratory exploration but not yet in human trials. On the other hand, 13 candidate vaccines have entered the clinical evaluation stage, which is a three-phase process involving human subjects (Fig. 2).
OK, but can we speed up this process?
In terms of vaccine research time we are progressing at super-fast speed in this scenario. Just consider that the first set of COVID-19 cases, a new type of viral pneumonia, were reported to WHO on 4th January 2020 (Fig.3). Two months later, the first COVID-19 vaccine entered first-in-human trials within record breaking time on 16th March 2020. Scientists and international organizations around the world are still racing to produce and deliver a safe and effective vaccine within an 18-month period1-3.
So, do we have a vaccine yet?
From the array of advanced COVID-19 candidates under clinical development, only one promising study has started their phase 3 trial in Brazil4 (Fig. 4). This a non-replicative viral vector vaccine developed by the University of Oxford and the British-Swedish company AstraZeneca5. As we previously described, this candidate works as an inactive vaccine by using a different non-live virus to deliver coronavirus genes into our cells. In other terms, it can´t reproduce itself but it can still provoke an immune response.
Currently, this vaccine is also moving to Phase II/III in England and will hopefully deliver positive results by next year. A different approach has been employed by The Murdoch Children’s Research Institute in Australia. The experimental coronavirus vaccine, which is currently in phase 3 trial, utilises the Bacillus Calmette-Guerin vaccine6. The BCG vaccine is made from a weakened strain of tuberculosis bacteria and been widely used since the 1920s to fight TB7.
Researchers expect to observe partial protection against SARS-COV-2 as observed for other diseases7,8. Only data and results will decide if the remaining vaccine candidates could progress to phase 3 human trials and if this global effort could be translated into a successful vaccine by early 2021.
Usher AD. COVID-19 vaccines for all?. Lancet. 2020;395(10240):1822-1823. doi:10.1016/S0140-6736(20)31354-4
Thanh Le T, Andreadakis Z, Kumar A, et al. The COVID-19 vaccine development landscape. Nat Rev Drug Discov. 2020;19(5):305-306. doi:10.1038/d41573-020-00073-5
On May 10th, 2020 the UK Government announced that Secondary Schools, Sixth Forms and Further Education Colleges could provide some face-to-face support for year 10 and year 12 students after June 1st 2020. This was subsequently deferred to start on 15th June (1). Students in these year groups have national exams in Summer 2021. This means this time in year 10 and year 12 is critical as the bulk of the curriculum is delivered.
To reduce the spread of COVID-19 in schools on the return of students, the government has advised the regular cleaning of frequently touched surfaces, changing classroom layouts to reduce student contact and to stagger timetables (2). However, what are the students’ views on returning to school?
It was important to me to get this question answered, so I designed a study in aim to voice the views of students.
Why is this research important?
It is not apparent that the Government has engaged with the school students affected most by this decision. Students have not been given a platform to raise their concerns about returning to education. Their views have not been heard.
This motivated me to conduct a prospective study to collate the views of young people and publicise their concerns. It is important to involve young people in decisions that affect their situation so that they engage with the policy (3). Year 10 and year 12 students are also of an age where their opinions should be taken into account.
Aims of the research project:
This study was conducted to explore the opinions of year 10s and 12s concerning returning to partial school after the first wave of the covid-19 outbreak in June 2020. The aim was to provide a voice to young people on returning to partial schooling in June 2020.
Students were invited to express:
Their preferences on returning to school
Their views about safety with respect to government guidance on return to school
How they feel COVID-19 will impact on their future
How COVID-19 has impacted on their education
This study will inform members of the public and policy makers about the opinions of year 10 and 12 students returning to school in the UK at the end of the first wave of the SARS-CoV-2 outbreak.
How the research was conducted:
The aims of this study were addressed with qualitative research using a prospective survey conducted from the 20th to 27th May 2020. Participants were year 10 (age 14 to 15 years old) and year 12 (age 16 to 17 years old) school students in the United Kingdom.
A 12-question survey was compiled on Google Forms™ with 9 close-ended questions and 3 open-ended questions. The survey was distributed to the students via two online Facebook™ forums specific to their year groups: The A level Forum (6,500 members) and a GCSE forum (36,000 members). The survey was accessible on multiple platforms (computers and smartphones) and multiple web browsers.
The 3 open ended questions were subject to Braun and Clarke themed analysis. Thematic analysis is a method for identifying and interpreting patterns of meaning across qualitative data. This meant recurring themes in the written data could be addressed and the reasons behind students’ answers could be found without influence. Braun and Clarke analysis provides a qualitative six phased method of thematic analysis. Firstly, I familiarised myself with the qualitative data and noted general ideas. NVIVO (v12) software was used to group the qualitative data into codes (similar patterns in the data). Themes were then put together by grouping the codes. I then reviewed and defined each theme in relation to the research measures.
There was a rapid uptake from students with 1534 responses in 7 days.
Year 10 and 12 school students are evenly divided in opinion about whether they should return to school on 15th June. This uncertainty appears based on the majority of students having concerns about schools’ ability to comply with government guidance, particularly around social distancing and the risk of transmission. Some students recognised a need to return to education despite this perceived risk. This uncertainty could be addressed by better engagement from policy makers with school students. School students expressed desire that their students’ concerns are addressed by the Government and better explanation of the reasoning behind returning certain students to school at this time whilst other members of the community continue to isolate.
Policy makers should standardise remote learning. This will ensure all students receive some educational support during pandemics, ensuring the educational divide caused by a lockdown is minimized.
1. Actions for schools during the coronavirus outbreak [Internet]. GOV.UK. 2020 [cited 2020 Jun 9]. Available from: https://www.gov.uk/government/publications/covid-19-school-closures/guidance-for-schools-about-temporarily-closing
2. Coronavirus (COVID-19): implementing protective measures in education and childcare settings [Internet]. GOV.UK. 2020 [cited 2020 Jun 9]. Available from: https://www.gov.uk/government/publications/coronavirus-covid-19-implementing-protective-measures-in-education-and-childcare-settings/coronavirus-covid-19-implementing-protective-measures-in-education-and-childcare-settings
3. Mitchell C. “The Girl Should Just Clean Up the Mess”: On Studying Audiences in Understanding the Meaningful Engagement of Young People in Policy-Making. Int J Qual Methods [Internet]. 2017 Dec 1 [cited 2020 Jun 6];16(1):1609406917703501. Available from: https://doi.org/10.1177/1609406917703501
Written by Rebekah Penrice-Randal and Lucia Livoti
Features of 20,133 UK patients in hospital with COVID-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study 1 was published in The British Medical Journal (BMJ) this week. This report defines clinical characteristics of patients in hospital in the UK, using the ISARIC WHO Clinical Characterisation Protocol. We have written a brief summary to define what this means, discuss the report itself and highlight the key findings to aid public understanding.
You can follow the study on twitter for more updates: @CCPUKstudy
What is the ISARIC WHO Clinical Characterisation Protocol?
A research protocol is the set of documents that includes the instructions for conducting a study, the participant information sheets and consent forms. A clinical research protocol has to be approved by an independent Research Ethics Committee to ensure patient safety and dignity, and in the UK, by the Health Research Authority to ensure that health care resources are used appropriately.
In other words, the study was set up in advance of an outbreak to ask the “who, what and why” of a new disease. Who is affected means, age, sex, ethnicity and underlying medical problems. What means, what does the disease cause any of: breathing problems, diarrhoea, vomiting, sepsis or bleeding.
The ISARIC WHO CCP allows for the collecting of clinical data and biological samples, and their analysis and processing to be done in a globally-harmonised manner. This protocol has been curated by multidisciplinary experts across the world 2, and employed in response to outbreaks such as:
Middle Eastern Respiratory Virus Syndrome coronavirus (MERS-CoV) in 2012,
Influenza in 2013,
Ebola virus in 2014,
Monkeypox and MERS-CoV in 2018,
Tick-borne encephalitis virus (TBEV) in 2019 and
SARS-CoV-2 in 2020.
The ISARIC WHO CCP has been central to the swift and cohesive research response to COVID-19. As a free, readily available resource it has been instrumental in the standardised collection of samples and data for the COVID-19 outbreak. This in turn has allowed clinical investigation to progress as quickly as possible. Global generic documents can be accessed here. Countries are also encouraged to develop “localised” instructions and seek local research permissions. The documents pertaining to UK protocols are available here.
Cohort: a cohort of patients are a group of individuals affected by a common factor, such as a disease, treatments or environmental factors.
Cohort study: cohort studies are central to the study of epidemiology and are often used in the fields of medicine, nursing, psychology and social sciences.
Comorbidity: presence of one or more medical conditions in addition to the condition being studied.
Epidemiology: the study and analysis of factors contributing to disease and health outcomes. In this case it may refer to the frequency and pattern of COVID-19 infection, risk factors, super-spreader events and study of specific populations.
Median: the median is defined as the ‘middle’ value of a data set, such that other values are equally likely to be above or below.
Risk factor: a factor that increases an individual’s risk or susceptibility to a disease.
Aim of the study:
To rapidly understand the clinical characteristics of people severely affected by COVID-19. Severely affected, meaning those who need hospital care.
Why is this work important?
This work is essential to appreciate the clinical features of patients that present with COVID-19 and identify risk factors associated with poor outcome. It is only through the understanding of such aspects that public policy can be informed, particularly around shielding of vulnerable groups and planning of resources such as oxygen and ventilator provision.
Who took part?
20,133 hospital in-patients with COVID-19 from 208 acute care hospitals across the UK were enrolled into the study. Clinical data was collected from patients admitted to hospital between 6th February and 19th April 2020. Patient outcomes are described as known on 3rd May 2020, as people admitted on the 19th April need at least 14 days to complete their admission or “declare the nature of their illness”.
The ISARIC WHO CCP-UK is a large ongoing study of patients hospitalised with COVID-19. This study found that the mortality rate was high in those admitted to hospital. Certain risk factors were associated with higher mortality rate such as; increasing age, male sex, and chronic comorbidity, including obesity. This report provides the first clinical insight of hospital patients with COVID-19 in the UK. The data gathered throughout this study will assist decision-making in the management of COVID-19, from patient to nation.
This report acknowledges the 2648 frontline NHS clinical and research staff, volunteer medical students and many researchers, who have worked tirelessly to make this study happen. Thank you to all involved and congratulations from The Science Social.
A note on ‘open access’
Open access journal articles are available to everyone and are not behind a pay wall. This article is freely available to all, if you would like to read the original article click here.
1 Docherty, A. B. et al. Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study. BMJ369, m1985, doi:10.1136/bmj.m1985 (2020).
2 Dunning, J. W. et al. Open source clinical science for emerging infections. The Lancet Infectious Diseases14, 8-9, doi:10.1016/S1473-3099(13)70327-X (2014).
Thank you to Professor Calum Semple (@tweediechap), an ISARIC investigator and co-author of the original article for permission to write this blog, and for the valuable comments.
All feedback and comments are welcome, get in touch:
“SARS-COV-2 was already spreading in France in late December 2019” – A Scientific Perspective.
A French study has recently made the claim that SARS-CoV-2, the causative agent of COVID-19, was detected in France on December 27th after re-testing samples from patients diagnosed with unknown pneumonias. A single sample, belonging to a French man, tested positive for SARS-CoV-2 DNA multiple times by PCR.
Figure 1: The original paper published in ‘International Journal of Antimicrobial Agents’.
Does this explicitly mean he had COVID-19?
Not necessarily, however, more evidence is required before drawing any final conclusions. The claim is based on a PCR experiment which suggested segments of the SARS-CoV-2 genome were present in this sample. False positives can occur in this type of experiment. The investigators compensate for this by running the PCR twice. Other methods the investigators could have used to further validate this claim include are viral genome sequencing, use of phylogeny to study how closely related this viral genome is to others that the science community have sequenced and finally serology, to detect antibodies that would have been produced by the immune system during infection.
Sequencing is the process of determining the sequence of nucleotides within DNA or RNA. Knowing this can mean the virus can be compared to ‘reference genomes’ of other viruses to see if there is a match. This sequence can also be used to construct phylogenetic trees which show the evolutionary relationships between organisms, including viruses. The more closely related the virus is the more similar it usually is. These methods would show that the virus was present in the sample and also confirm where the virus belonged on the evolutionary tree, allowing scientists to pinpoint whether this virus was closely related to the viruses observed at the beginning of the outbreak.
Finally, serological evidence would prove that infection had occurred. Serological evidence is based on antibodies, a protein produced during the innate immune response to neutralise pathogens. The presence of RNA doesn’t necessarily mean infection (see the recent stir created by RNA being detected in dogs for example), antibody production does as it proves an immune response was mounted. Scientists would require a blood sample from this patient, many different tests can be performed but for SARS-CoV-2 it’s likely a simple colour change test would be used – similar to a pregnancy test(1).
Figure 2: Methods for validating identities of infectious diseases.
So, should we discount the study?
No, we shouldn’t. A result is still a result and knowledge of this is important. However, when information isn’t communicated well, or an incomplete picture is presented a wave of misinformation can occur. It’s important now more than ever to think critically about information and our sources of information. Ultimately, this is what the Science Social is about – communicating science with non-scientists and encouraging critical thinking.
Have any questions about the content covered today? Drop us a message on any of our platforms.
1. Amanat F, Stadlbauer D, Strohmeier S, Nguyen T, Chromikova V, McMahon M, et al. A serological assay to detect SARS-CoV-2 seroconversion in humans. medRxiv [Internet]. 2020 Jan 1;2020.03.17.20037713. Available from: http://medrxiv.org/content/early/2020/04/16/2020.03.17.20037713.abstract
We discussed the latest updates on drug therapies as countermeasures for COVID-19 here. Instead of treating diseases, vaccines have the capacity to prevent them.
No, really what is a vaccine and how do they work?
Like natural infections, vaccines work by initiating a first line immune response, known as the innate immune response. In turn this allows the body to remember the pathogen, preparing the body to defend itself on the pathogens next attack, known as an adaptive immune response 1. Each pathogen (or vaccine) contains unique and specific shapes that the body’s immune system is able to recognise. Once the pathogen is dealt with, the adaptive immune response establishes what we call immunological memory, which is essentially the main goal of vaccination 1.
There isn’t just one type of vaccine either, scientists have found different ways of getting your immune system ready and prepared for infectious diseases.
Two main types of vaccines
Vaccines can be split into two main categories 2:
Live attenuated vaccines
This is when scientists take the causative agent of the disease, i.e. the virus or the bacteria and weaken it so it can no longer cause disease in healthy people. This is not an appropriate vaccination method for those with an immune system that does not work 1,2.
Live attenuated vaccines tend to be produced for viral diseases, as viruses have fewer genes and weakening these pathogens can be achieved more reliably 1.
Examples of Live Attenuated Vaccines used in the UK are as follows:
Measles Mump and Rubella Vaccine
If you are big on your travelling, you may have had the Yellow Fever Vaccine or the oral typhoid vaccination.
These types of vaccines contain either; the whole bacteria or virus that have been “killed”. OR, small elements of the disease-causing agents such as associated proteins or sugars. All of which cannot cause disease, even in those with severely weakened immune systems. The immune response produced by these vaccines aren’t always as powerful as those observed in a live attenuated vaccine, and because of this may require boosters 1,2.
Adjuvants are often added to inactivated vaccines to help boost the immune response and thus make them more protective.
So, an adjuvant is actually an aluminium salt that is added to vaccines to help produce an immune response, such as aluminium hydroxide, aluminium phosphate or potassium aluminium sulphate.
This is not like injecting an aluminium can into your body, by the way. Aluminium is actually a very natural metal found naturally in water, food and the earth itself. The amount used in vaccines is very tiny and is a vital element for these types of vaccines to protect you2.
“Whole killed” vaccines
Some examples of diseases prevented with inactivated “whole killed” vaccines are; poliovirus, hepatitis A, Rabies and Japanese Encephalitis 2.
There are 3 types of subunit vaccines; toxoid, conjugate and recombinant vaccines. All of which essentially take a subunit of the pathogen and turn this into a vaccine 2. When scientists say subunit, they are referring to only a part, or an element of the pathogen as opposed to the whole thing.
Many bacteria release toxins during an infection. Our bodies are able to recognise these toxins and produce an immune response. Therefore, making these a good target for vaccines. Examples of toxoid vaccines are Diptheria, tetanus and pertussis (whooping cough) 2.
The work “conjugate” means connected or joined. Sometimes, the subunit of a pathogen doesn’t elicit a good enough immune response by itself, so the subunit is joined to something else. Quite often the subunit is joined to the tetanus or diphtheria toxoid. Examples of conjugate vaccines are Haemophilus influenzae B, Meningitis C, Pneumococcal and Meningococcal vaccines 2.
These types of vaccines take the genetic code (DNA) from the virus or bacteria that we want to protect ourselves from. In the case of the Hepatitis B vaccine, the DNA is inserted into yeast cells, which are able to produce surface proteins of the pathogen. This is then purified and used as the active part of the vaccine. Examples of recombinant vaccines: Hepatitis B, Human Papilloma Virus and Meningitis B vaccines 2.
Vaccine trials are essential
Like we discussed in our article about drugs, all medicines have to go through a robust clinical trial. This is to ensure that the vaccine is not only safe, but to test whether the vaccine works and provide sufficient protection.
Phase I: a small-scale trial to assess whether the vaccine is safe in health people.
Phase II: more participants are recruited, and the study assess the efficacy of the vaccine, vaccine safety and the immune response is studied.
Phase III: The vaccine is studied under natural disease conditions, hundreds to thousands will be recruited to the study.
If the vaccine retains safety and works well over a defined period of time, the manufacturer of the vaccine is able to apply for a licence to market the product for human use.
Phase IV: The vaccine has been licensed and approved for use, however, data is still collected to monitor adverse effects and to determine the longevity and effectiveness of the vaccine 3,4.
Eradication of disease
In May 1980, the world was declared free of smallpox 5. The last naturally occurring case of this disease was observed in Somalia in 1977 5. Edward Jenner in 1796 observed that those who contracted cowpox, a disease known to be very mild, developed immunity against smallpox 6. This inspired Jenner to prepare a vaccine containing material from cowpox lesions, where he knew “the annihilation of smallpox must be the final result of this practice”. Despite this ground breaking discovery, it took nearly 200 years to eradicate smallpox 5. Smallpox remains the only human infection eradicated by vaccination.
Of course, it is not only humans that are vaccinated against infectious agents, but our pets and our livestock are also vaccinated. Rinderpest is known as the most devastating infectious disease of cattle, associated with a mortality rate more than 70% 7. Rinderpest is a virus belonging to the same virus family as measles. In 1918, the first vaccine was developed in Korea as an inactivated virus. This later got developed into a live attenuated vaccine until 1989 where the first recombinant rinderpest vaccine was developed 7. However, before the recombinant vaccine got to trial, eradication was achieved with the use of Plowright’s live attenuated vaccine 7.
Vaccines will allow us to prevent the disease, protect vulnerable members of our communities through herd immunity and in turn reduce the pressure on healthcare systems.
There is currently no vaccine for any of the known coronaviruses. Despite massive research efforts, it is not expected that a vaccine against SAR-CoV-2 will be available in less than 18 months 8. Keep an eye out for a break down on SARS-CoV-2 vaccines that are going through trial over the next couple of weeks.
1 Vetter, V., Denizer, G., Friedland, L. R., Krishnan, J. & Shapiro, M. Understanding modern-day vaccines: what you need to know. Annals of Medicine50, 110-120, doi:10.1080/07853890.2017.1407035 (2018).
This is one of our long reads, grab yourself a coffee! 15 min read.
*SPOILER ALERT* At the present time, there is no quick-fix solution to the COVID-19 problem. The good news is, scientists are working on it!
Antibiotics do not work!
Antibiotics are not effective against viruses; they are entirely different microorganisms and therefore require different types of intervention. You may however, have heard of antibiotic use in the context of secondary infection. As the name suggests, this term describes when a patient acquires an infection secondary to the original [figure 1]. This is relatively common in patients with an infection of the lung (pneumonia), due to lowered immunity as a result of the original infection. This secondary infection may be viral or bacterial and so, may be treated with antibiotics (1,2).
A brief word on vaccinations…
Whilst there are several drug treatment options under investigation, the best way of protecting the population is through the development and deployment of a vaccination programme. Vaccines work by introducing a weakened version or fragment of the virus or bacteria to an individual’s immune system. This does not cause infection and instead elicits a mild immune response that allows the body to safely generate antibodies against the antigen. As part of this response, special memory cells that are part of the immune system, are trained to recognise and remember. Should you come across the real thing in future, your memory cells will fire into action and enable the production of antibodies to fight against it. As the immune system has already seen the antigen before, the response is more effective and much faster, making it highly efficient at eliminating the intruder and protecting your health (3,4).
Keep an eye out for our future blog post scratching beneath the surface of vaccination.
So, whatare the other options?
Whilst vaccinations are in the making, there are a number of options to explore to improve patient outcome. The unprecedented global collaboration has accelerated research into these options, from drugs to vaccinations and beyond but here’s the rub… they still need to go through the clinical trials process. Here we discuss several drugs under the scrutiny of clinical trial to identify their safety and efficacy against SARS-CoV-2.
The clinical trials process is of vital importance but remains extremely lengthy. It usually takes 10-15 years for a new drug to make it from start to finish, that is, from conception to approval for use. Clinical trials are essential as they serve to filter out the ineffective and unsafe. Just because a drug has made it to first-in-man (phase I) does not mean it’s a sure-fire win. In fact only 10% of medicines that enter phase I ever make it through to approval – at the cost of tens-to-hundreds of millions of pounds (5).
At present, there is tremendous focus on the repurposing of existing medications as opposed to generating new drugs. Drug repurposing is a crucial initiative, as it may greatly reduce the cost and time spent identifying treatment options for COVID-19. There are 4 treatment options under the investigation of the clinical trial named “Solidarity”, which has been launched by the WHO in collaboration with international partners (6).
What is it?
Remdesivir is a rising star in therapeutics against SARS-CoV-2. It is an investigational drug that was originally developed and trialled a treatment strategy against the Ebola virus. However, other treatment options showed greater efficacy against Ebola and remdesivir was subsequently shelved.
Why is it in trial?
Ongoing research has since demonstrated its broad antiviral activity and highlighted its promise in the fight against COVID-19. In in vitro testing, remdesivir was effective at inhibiting the replication of a range of coronaviruses including those that cause severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). Remdesivir works by targeting and incorporating itself into the genetic material of the virus, so it can no longer replicate (7). Pre-clinical testing has provided strong evidence that intravenous treatment is effective at reducing viral load and preventing progression to severe pneumonia in primates (8).
Where are we now?
Whilst remdesivir remains unlicensed and has not yet been approved for safe and effective use, it is in clinical trial to determine its utility. A Chinese study concluded that remdesivir afforded no clinically significant benefit to COVID-19 patients and demonstrated adverse events where the treatment was halted in 12% of patients. However, the authors state a key limitation of this study; the number of patients included was not great enough to detect clinical significance (9).
Recent data has shone a more promising light on remdesivir. An international study recruiting over 1000 patients has reported a 30% faster recovery time for remdesivir vs standard care, which was found to be statistically significant. The data also shows a trend towards reduced mortality rate in those receiving remdesivir however, the difference was not great enough to be significant. Although this is good news, we must still be cautious, the safety data has not yet been published and there are some concerns regarding adverse effects (10,11). Whilst it has been touted by leading scientists that remdesivir will become the new standard of care in the United States, there is still work to be done. There are many questions regarding safety, dosing regimen and patient suitability that need answering but so far so good… watch this space and we’ll keep you posted.
Hydroxychloroquine & chloroquine
What is it?
Hydroxychloroquine and its cousin chloroquine are also in the running having been publicised early on by the American Government for their effectiveness. They are similar in structure and function however hydroxychloroquine is less toxic and so much safer for a patient (12). Both drugs have already made it through to the clinical trial finish line for use in other applications, where they can be used to prevent and treat malaria. Hydroxychloroquine is also known to have anti-inflammatory action and is often prescribed for the treatment of inflammatory conditions like lupus and rheumatoid arthritis (13,14).
Why is it in trial?
Both drugs have been included in the Solidarity trial as there is a wealth of evidence demonstrating both antiviral and anti-inflammatory properties. Following the SARS epidemic in 2002, pre-clinical research demonstrated that chloroquine inhibited the replication of SARS-CoV in cells (15). More recent work has shown there may be a multitude of mechanisms through which SARS-CoV-2 infection in cells can be prevented (16). Although already approved, they must be tested for safety and efficacy in a COVID-19 setting. There are a number of reported side effects and concerns regarding potential toxicity must be carefully assessed and considered before regarding it as a viable treatment option (15).
Where are we now?
The available data from clinical trials is very mixed. A number of early trials have a small sample size and poor study design (17). One paper available on the preprint server MedRxiv found that patients critically ill with COVID-19 benefitted from administration of hydroxychloroquine. Those that received the drug had a significantly lower mortality rate and level of inflammation. However, the drug treatment group included only a small number of people and inflammation levels were reported to be twice as high as the control group at the beginning of the study (18).
In contrast, an American group found no evidence that use of hydroxychloroquine reduced the risk of need for mechanical ventilation. The authors of this study do also discuss its limitations, in that the study cohort only included men over 65 and the patients were not allocated different treatments at random (19).
It is important to remember these articles are still in preprint and have not yet been accepted for publication. Evidently the answer is not clear cut and the ongoing work is essential to better understand the treatments and outcomes.
What is it?
Lopinavir and ritonavir are antiretroviral drugs that have been approved and are prescribed to treat human immunodeficiency virus (HIV). They are often used in combination as ritonavir helps to boost the efficacy of lopinavir. Although HIV and coronaviruses are very different, the known mechanism of action against HIV has propelled the combination into the Solidarity trial. It is accepted that lopinavir/ritonavir work by blocking essential proteins to prevent replication of the virus (20).
Why is it in trial?
In vitro research has demonstrated that lopinavir has an antiviral effect against several coronaviruses in cells, whilst additional in vitro studies have confirmed the same effect against SARS-CoV-2 (21,22). More advanced pre-clinical study evaluating treatment of MERS in primates, revealed improved clinical outcome when lopinavir/ritonavir was combined with interferon-β1b – more on this next (23).
Where are we now?
Studies conducted early in the epidemic demonstrated no benefit to patients that received lopinavir/ritonavir, compared to those receiving the standard of care. Although less than 200 patients participated, there was no improvement in recovery time or mortality rate (24). Other studies have provided similar evidence, whereby there is no difference in ‘viral clearance’ – the time it takes for the virus to no longer be detectable in a patient (25). Alongside having no benefit, side effects involving the gastrointestinal tract and liver have also been reported in several of these trials (25,26).
At present there just isn’t enough evidence to say if this combination is effective in humans, the current clinical trials will present more data to answer this question in the future.
What is it?
Don’t panic! Interferon-β1a is a subclass of chemical messengers that belongs to a family called type I interferons, broadly speaking they help to regulate the immune system. This β1 subclass refers to specialised signals that are produced by cells in response to infection, particularly viral. Once the signals have been released, they are intercepted and interpreted by other cells, which allows them to increase their antiviral activity. Interferons are naturally produced by the body but have also been manufactured for use in a medical setting. Some of the β1 class, like interferon- β1a, are used as a treatment for the autoimmune condition multiple sclerosis (27).
Why is it in trial?
Interferons have proved promising in in vitro and pre-clinical tests against other coronaviruses. One pre-clinical study demonstrated that administration of interferon-β1b significantly reduced viral load in the lung and severity of disease in MERS (23). There is an ongoing human trial in Saudi Arabia, assessing the utility of interferon-1 and lopinavir/ritonavir against MERS however, no clinical data has yet been published (28). The Solidarity trial is testing interferon-β1a in conjunction with the antiviral drugs lopinavir/ritonavir to see if the combination offers any advantage to patient outcome.
Where are we now?
Interferons are being used in combination with a variety of other antiviral drugs in different trials across the world. There is limited data available to say whether or not this strategy is paying off. In China interferon-B1b is being trialled in an inhaled format for direct administration to the lungs (29). One study has shown that inclusion of interferon therapy accelerated viral clearance compared to treatments that did not include interferon. However, the paper has not yet been accepted for publication and is limited by poor design, a small sample size and disproportionate male-female representation (30).
Ongoing trials will aim to assess a much larger and more balanced sample population, so we should hope to draw more firm conclusions about this treatment option in the future.
Are there any other therapeutic options?
What is it?
There is some exciting research into the usefulness of convalescent plasma. This may sound complicated but the basic premise centres around the plasma of a ‘convalescent’ or recovered individual. Plasma is the liquid part of blood which contains important proteins, salts and crucially, antibodies. It may be isolated through a process called plasmapheresis and for a person donating plasma, it is not dissimilar to giving blood [figure 3]. Instead of donating whole blood, a machine separates it into blood cells and plasma. This allows the plasma to be removed and so returns your blood cells and often a saline solution to replace the lost volume. For patients receiving convalescent plasma, their own will be removed and replaced with the antibody rich plasma of a recovered individual, so conferring passive immunity. This strategy works on the basis that the person donating plasma is now immune and has generated antibodies – which should be around 28 days after recovery. REF.
Why is it in trials?
The concept of convalescent plasma is not new. Use of convalescent blood has been documented as early as 1918 in the prevention and treatment of the Spanish Flu (31). More recent application in several case studies have demonstrated it may be useful against SARS, MERS and even Ebola (32). A study utilising convalescent plasma as a treatment option for SARS reported a clinically significant reduction in mortality rate in those that received it. Early treatment, less than 14 days after symptom onset, also enabled a more positive outcome (33).
Where are we now?
NHS Blood and Transplant is leading a programme to investigate convalescent plasma in clinical trial. The trial will aim to assess if its use can improve patient survival and recovery time. The programme has only just begun but previous case studies are encouraging. A number of these report convalescent plasma use only in severely ill patients but describe clinical improvement and an increase in antibodies against SARS-CoV-2. If you want to more about the convalescent plasma trials and if you could help, click here.
All in all, there is no definite treatment at the moment but there are many options and trials working to gather concrete evidence to make a better judgement.
We hope you enjoyed our first long read! If you need help clarifying some of the jargon or want to know more about the concepts discussed, DM us and we’ll get back to you.
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12. Liu J, Cao R, Xu M, Wang X, Zhang H, Hu H, et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov. 2020 Dec 1;6(1):1–4.
13. Sinha S. Hydroxychloroquine Uses, Dosage & Side Effects – Drugs.com [Internet]. [cited 2020 May 3]. Available from: https://www.drugs.com/hydroxychloroquine.html
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22. Choy KT, Wong AYL, Kaewpreedee P, Sia SF, Chen D, Hui KPY, et al. Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro. Antiviral Res. 2020 Jun 1;178:104786.
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Viral diseases have shaped human history. A sudden emergence has the power to cause huge social changes, like ones we’re currently experiencing. But how do they do this? What causes a virus to jump, or ‘spill over’ into a new species?
What is an emerging virus and how do they emerge?
An emerging virus is a virus which has entered a new population where it previously didn’t exist or is expanding its geographical range. Global disease emergence is increasing for many reasons and we’ll discuss why this is occurring and why most emerging viruses that normally infect animals are now infecting humans.
What’s important to remember is there are no singular reasons for viral disease emergence, and we might never know what occurred to cause a disease to break into new populations. But there’s many ways this can happen, ranging from the virus’s genetics all the way through to human-environment interactions. Here we’re going to focus on RNA viruses as these are the viruses which most commonly cross species barriers1. Let’s start with the genetics first.
RNA viruses contain an enzyme called RdRp. This enzyme replicates RNA. RNA is a form of genetic code like DNA, so it encodes genes. However, RdRp is prone to making mistakes, it might miss a base, it might use the wrong one and its common for this to happen. This means a virus can be produced with different properties, this can range from being able to target a new cell type to replicating faster. One case where this occurred was during the 1918 Spanish Flu, where a mutation allowed the virus to replicate in tissues outside the respiratory tract2.
Reassortment of segmented genomes
Reassortment is the process where genetic material might get ‘mixed up’. When a cell is infected with two different but closely related viruses there’s a chance this might occur. Think of it like mixing your favourite drinks. It could work, and you might have a new flavour, or it might not! It’s easier for segmented genomes, so the genetic code is in multiple segments and is common in viruses like influenza. H1N1 is an influenza virus which is made up of bird, pig and human influenza strains3.
Recombination of RNA genomes
Recombination is a random event which occurs when RdRp, the enzyme which makes new RNA, falls off the genome its copying onto a different one. It ultimately will produce an RNA genome which is a combination of two different viruses. This is another common event and many virus families have evidence of this occurring, including Herpesviruses, HIV and even Coronaviruses4,5.
Changes in weather
Climate change isn’t only impacting our weather, it’s also changing disease distributions through temperature but also causing changes in host territory. Ultimately this changes how we interact with hosts of viruses as well as their biology. For example, Japanese Encephalitis Virus (JEV). This virus is carried by mosquitoes, so a higher temperature alters host territory as well as allowing for mosquito development to occur where it didn’t previously. This is because mosquitos have a minimum temperature where development will occur, and for the mosquito which carries JEV its 22-23 °C. However, viral diseases can have a minimum transmission temperature, and JEV has one of 25-26 °C. If more countries have temperatures above this range, then the virus can be transmitted in new populations. What this all means is as global temperatures rise it’s very likely countries will experience diseases they haven’t previously6.
Bush meat and live animal markets
Consumption of bush meat and live animal markets remove natural barriers in place, meaning that close contact between animals and humans now occurs. Outbreaks may occur due to consumption of an animal which died of a disease, and not of more natural causes. This is how Ebola outbreaks have started before. However, it is important to consider the socio-economic conditions found within regions where consumption of bush meat occurs. Protein sources in these regions can be expensive and the local population may not have the choices we do7. Reducing disease emergence from live animal markets can be done safely by reducing inter-species interactions, essentially handling the animals less and making the markets less crowded. However, it could also be done through limiting the days of operation8.
Changing land use and farming practices
Deforestation of land for farming and urban development is forcing disease hosts to come into closer contact with humans, one example where this is occurring is Australia. Here, horse farms are traditionally where fruit bats reside however urbanisation has resulted in loss of the natural habitat, forcing greater interactions with the human population9.
So, there we have it. Several mechanisms on how viruses can emerge into human populations. But what about SARS-CoV-2? Well, the jury’s still out. Though early cases were linked to a seafood market many weren’t, indicating the source of the virus likely wasn’t here. In the meantime, scientists will be hard at work hoping to solve many puzzles, including this! If you have any questions about what was discussed drop us a message below or on Facebook, Twitter or Instagram and we’ll get back to you.
For more information on the origins of SARS-CoV-2 read our blogpost breaking down a Nature paper by Dr Jordan Clark here.
For more information on viral disease emergence check out ‘Spillover’ by David Quammen.
1.J Woolhouse, M. E., Adair, K. & Brierley, L. RNA Viruses: A Case Study of the Biology of Emerging Infectious Diseases. Microbiol. Spectr.1, 10.1128/microbiolspec.OH-0001–2012 (2013).
2.Taubenberger, J. K. The origin and virulence of the 1918 ‘Spanish’ influenza virus. Proc. Am. Philos. Soc.150, 86–112 (2006).
3.Vijaykrishna, D. et al. Reassortment of pandemic H1N1/2009 influenza A virus in swine. Science328, 1529 (2010).
4.Fleischmann, W. J. Medical Microbiology. (University of Texas Medical Branch, 1996).
5.Su, S. et al. Epidemiology , Genetic Recombination , and Pathogenesis of Coronaviruses. Trends Microbiol.24, 490–502 (2016).
6.Wu, X., Lu, Y., Zhou, S., Chen, L. & Xu, B. Impact of climate change on human infectious diseases : Empirical evidence and human adaptation. Environ. Int.86, 14–23 (2016).
7.Kurpiers, L. A., Schulte-Herbrüggen, B., Ejotre, I. & Reeder, D. M. Bushmeat and Emerging Infectious Diseases: Lessons from Africa BT – Problematic Wildlife: A Cross-Disciplinary Approach. in (ed. Angelici, F. M.) 507–551 (Springer International Publishing, 2016). doi:10.1007/978-3-319-22246-2_24
8.Karesh, W. B., Cook, R. A., Bennett, E. L. & Newcomb, J. Wildlife trade and global disease emergence. Emerg. Infect. Dis.11, 1000–1002 (2005).
9.Plowright, R. K. et al. Urban habituation, ecological connectivity and epidemic dampening: the emergence of Hendra virus from flying foxes (Pteropus spp.). Proceedings. Biol. Sci.278, 3703–3712 (2011).
Humans are naturally social animals so it’s no surprise that Isolation is linked to lower mood and poor mental health. It can be hard to maintain relationships during a lockdown but they’re very important for our wellbeing.
Take time out of your day to talk to the people in your household, try using video call software to reach out to friends and colleagues or even just send a good old fashioned e-mail or text. Now could be a good time to join an online community too, if you have a hobby, chances are there are lots of other people who do too, why not join a forum or discussion group and make some new friends?
Exercise has been shown to increase mood and feelings of wellbeing in both the short and long-term. Getting the blood flowing releases feel-good chemicals called endorphins for a natural boost. Think how great you’ll look and feel when this is all over.
You are allowed one outside exercise session per day, it can be a great chance to get out of the house and see some nature (which also boosts mental wellbeing!). If you’re self-isolating and can’t leave the house, there are plenty of workouts you can do from your bedroom, your home gym or even your armchair!
Learning a new skill is a great way to boost your self-esteem and can give a sense of direction and purpose. Learning new skills also helps to keep your brain healthy and your mind active, fighting off those lockdown blues.
There are lots of free and accessible online courses for nearly anything you could be interested in. Learn a language, an instrument, a new recipe or a DIY job. It doesn’t matter what it is you learn, that’s up to you, just that you’re interested enough to keep it up and that it’s challenging enough to keep you engaged without being so difficult you give up. Don’t worry about earning certificates unless you want to, it should be fun, not a chore!
Acts of giving and simple kindness can increase your mood and give you a sense of purpose and self-worth. Plus, it makes someone else feel good too as an added bonus!
You can start small and reach out to help colleagues or friends who might just want someone to talk to. There are also plenty of volunteer schemes to get involved with if you’re symptom free and want to help with the crisis.
GoodSAM can help you find volunteering opportunities during the coronavirus outbreak.
Mindfulness is paying attention in the present moment: to your body, your thoughts, the world around you and how you’re feeling. It can boost mood and make you appreciate life more.
The lockdown will affect us all differently, pay attention to how you feel and take time each day to check in with yourself.
Connect, Get Active, Learn, Give and Pay Attention
If you do notice your mental health suffering, don’t feel like there’s nothing you can do. There are still plenty of services that are remaining open during this lockdown because mental health is just as important as physical health. If you don’t feel right, don’t feel like you have to suffer alone.
A final note: self-care is incredibly personal, and you should take these only as suggestions alongside things you know work well for you. None of us are obligated to come out of the end of this with new skills, a summer body, or anything else. If you keep yourself feeling well and functioning, you are doing well in this stressful time.
Often during virus outbreaks, conspiracy theories arise which purportedly explain the emergence of the virus. These range from deliberate government release as an agent of population control to Illuminati concocted plagues designed to disrupt our way of life in order to usher in the New World Order. The Covid-19 pandemic is no exception and there has been a wave of conspiracy theories relating to SARS-COV-19, the virus behind Covid-19. Writing in Nature, Kristian G. Andersen, Andrew Rambaut , Ian Lipkin, Edward C. Holmes and Robert F. Garry sought to investigate the origins of SARS-COV-2, not only in order to dispel some of these theories, but also because during a pandemic it’s important to know where the virus came from as this may inform future preventative strategies.
The authors first start by analysing the receptor binding domain (RBD) of the SARS-COV-2 spike protein. This protein is present on the outside of the SARS-COV-2 virus particle and is responsible for the binding of the virus to the receptor ACE2, which is found on the surface of cells. It’s this protein which the virus exploits to enter our cells, and it’s been shown to be very important for coronavirus host range and pathogenicity.
While it’s clear the SARS-COV-2 RBD is able to successfully bind the ACE2 receptor found in human, ferret and other similar species, this interaction is not exactly perfect. In fact, SARS-COV-2 binds with less efficiency than SARS. If a super plague was generated in a lab, computational studies could have been carried out to formulate better binding of ACE2, therefore improving the infectivity of the pathogen. Pretty sloppy work, Illuminati. It’s much more likely that the RBD of SARS-COV-2 evolved to bind a human-like ACE2 and has been acted upon by natural selection. What do I mean by a human-like ACE2? Remember that we share about 98.5% of our DNA with chimps and around 85% with mice, so its highly likely that SARS-COV-2 evolved to infect a similar, but different species, which provided it with some limited ability to infect humans. Once this human transmission was set up natural selection can allow the virus to adjust to humans in order to infect us more efficiently – more on that later.
There’s also good evidence that SARS-COV-2 wasn’t generated in a lab due to the fact it doesn’t appear to have been designed according to other viral “reverse genetics” systems. Reverse genetics systems are what scientists use to produce genetically manipulated viruses in the lab. These techniques employ the use of the virus genetic material which has been probed and packaged through a variety of molecular techniques which allows infectious virus to be generated. The authors make it quite clear that SARS-COV-2 shows no evidence of being generated by the use of these existing virus reverse genetics systems. So, if SARS-COV-2 is naturally occurring, how did it infect humans in the first place and start the whole pandemic off?
The authors provide two hypotheses:
1) The virus arose in animals and, through natural selection, acquired the necessary genetic changes needed to infect humans, whereupon it jumped the species barrier and infected people.
2) The virus jumped from an animal species into humans, whereupon it spread through the human population and, through natural selection, acquired the genetic changes needed to successfully cause a pandemic.
By comparing the genetic material of SARS-COV-2 and other coronaviruses which have been sampled from different species, it has been shown that SARS-COV-2 shares high sequence similarity with those coronaviruses found in bats. The Huanan market in Wuhan is considered to be ground zero for this pandemic and it is known that bats were stored and sold here, in addition to a myriad of other species. It is therefore highly probable that one of these species was host to the progenitor of SARS-COV-2, which then found its way into the human population.
Interestingly, the RBD of SARS-COV-2 is unlike those found in bats but shares high homology with those found in pangolins. Pangolins are an endangered, and very cute, little species of mammal which are the most illegally trafficked animals in the world. Coronaviruses isolated from these creatures exhibit RBDs with high similarity to those found in SARS-COV-2. Pangolins are also thought to have been present at the Huanan market in Wuhan.
Coronaviruses are also known to undergo genetic recombination, in which they swap genetic material. This happens when two different coronaviruses find themselves infecting the same host. It’s therefore highly likely that SARS-COV-2 arose from a recombination event between two coronaviruses, possibly from bats and pangolins, which was then able to jump into humans.
There’s one more feature of SARS-COV-2 that the authors draw attention to: the addition of a polybasic cleavage site which sits between the two subunits of the spike protein. This site is unique to SARS-COV-2 and may result in efficient cleavage by cellular proteases such as furin. This sounds quite complicated. Simply, the virus has evolved a site in the portion of the virus which is responsible for invading our cells which improves its ability to function, therefore making it more infectious.
We see such adaptations in avian influenza all the time – they arise through natural selection when flu spreads through chicken populations. Such adaptations result in the generation of highly pathogenic bird flu strains and are a major public health concern. Mutations of this type which affect the spike protein subunit junction have also been found in nature many times before. These inserted residues also change the structure of the spike protein slightly in a way that the authors hypothesise may help the virus evade the host immune response.
“OK, so where did this genetic change come from? Is it possible for this to happen in the lab? Can it happen in nature?”
Simply, both are possible, but one is less likely. Looking at our two theories it’s entirely possible that this mutation, which likely allows for increased pathogenicity, arose during repeated human to human transmission, similar to what we see in birds with flu. This would mean that, after making the jump from bats/pangolins/unknown species to human, SARS-COV-2 spread through the human populace, acquiring this mutation, and then setting off the chain of events which led to the pandemic. We see this in SARS often, in which the virus jumps from camels to humans and then spreads from human to human for a short period. Crucially SARS has not yet been able to sustain its human-human transmission, whereas SARS-COV-2 has. It’s also possible that this mutation arose in the progenitor to SARS-COV-2 in an animal host. To have arisen this would require sustained transmission between hosts that are in high density and have human-like ACE2 receptors.
Both theories are plausible…
…What isn’t as likely is that the virus gained this adaptation in a laboratory setting. In labs around the world viruses are routinely grown in cell culture. Viruses are introduced to cells in culture, allowed to grow, and eventually harvested. This is known as “passage”. For this mutation to arise in cell culture the virus must have been serially passaged through cells which contain a human-like ACE2 receptor. While these passages take place, the virus is continually evolving, so much so that serial passage in cells eventually leads to viruses getting so good at infecting cells in culture they become worse at infecting whole animals. It’s theoretically possible that the virus could have been serially passaged through an animal, one which contains sufficiently human-like ACE2, however this has never been documented.
It is very unlikely that SARS-COV-2 originated in a laboratory setting
…and it doesn’t exhibit the genetic fingerprints we’d expect a genetically modified super plague to exhibit. Unfortunately, at the moment all we can do is theorise about its origins until the exact host, or progenitor virus, is found. There are a staggering number of viruses present in nature which we simply haven’t discovered yet (think of a tip of the iceberg kind of thing) which are currently quietly circulating in animals, and possibly humans, throughout the world. The conditions which we saw at the Huanan market in Wuhan in which various different exotic animals are stacked, live and dead, in cages in close proximity to each other, and humans, makes the perfect melting pot for these pandemics to arise. Furthermore, as humans clear more habitat, and as global temperature rise allowing vector species such as mosquitos and midges to extend into higher latitudes, it’s a matter of time until this happens again. While this pandemic is ongoing, the next one in line is lurking out there and it’s vitally important that we learn what we can from SARS-COV-2 so that we are prepared when it finally emerges.
Coronavirus: A natural phenomenon or a man-made weapon? Read a lay summary of @NatureMedicine article: The proximal origin of SARS-CoV-2 by @K_G_Andersen, @arambaut and @edwardcholmes and co. Written by @jordandoesflu with @thescisocial #covid19 #sarscov2 #mythbusters https://thesciencesocial694680041.wordpress.com/?p=104