Scientifically-informed, data-driven answers to your burning questions about the coronavirus pandemic
Post #2: Testing and Treatment
Welcome to Naturally Speaking’s weekly blog series on COVID-19. This second post about Testing and Treatment comes in two flavours:
Short and sweet – bite size summaryHungry for more? Look no further! This version includes a bit more detail and links to further resources.
If we don’t answer all your most pressing questions, please feel free to ask them in the Comments section below – we’ll do our best to respond. We’ll also aim to provide any updates as advice and knowledge evolves.
Disclaimer: Some of the guidance refers specifically to the situation in the UK, although most of the content is relevant regardless of where you hail from.
Testing
Q. How is diagnosis confirmed?
A. If a patient presents with any COVID-19 symptoms, they are generally treated as infected until proven otherwise. This is to minimise potential transmission. RT-PCR testing uses knowledge about the SARS-CoV-2 genetic code to test whether the sample from a patient (taken from the respiratory tract – a swab from the back of the throat or nose) contains the virus. This is being widely used to confirm cases. If there is a backlog of samples in the laboratories (as samples should be analysed ASAP but this is not always possible) or results are inconclusive , then clinicians are also using CT scans of the lungs to identify signs of the disease in more severe cases.
As with any diagnostic test, the accuracy will not always be 100%. False negatives will be more problematic than false positives, as this could lead to an infected patient not self-isolating, which could increase transmission. This will also make processes such as contact-tracing less effective. False negatives can occur for a variety of reasons, including human error (such as improper lab techniques or improper sample collection); however, there are also circumstances in which the tests themselves are not fully accurate due to the stochastic nature of science. Due to the current volumes of samples being taken, the pressure on diagnostic laboratories is increasing. Although samples should ideally be tested as soon after being taken as possible, the demand for testing can lead to delays, which in turn can reduce test accuracy. The tests are only useful when the patient is infectious, as once recovered, the viral RNA cannot be detected by RT-PCR.
Q. What are the differences between RNA, antigen and antibody testing kits?
A. Using reverse-transcription polymerase chain reaction (RT-PCR), it is possible to test a patient’s respiratory sample and ascertain if they are infected with SARS-CoV-2 within a few hours by detecting RNA (genetic material) from the virus. Nonetheless, lab capacities and the extent of the pandemic has meant that the turnaround time for results is often longer than this. These are currently being used in healthcare settings to confirm whether patients have viral RNA. Antigen testing kits, on the other hand, will soon use blood samples to test for circulating viral proteins, and say whether the person is currently infected with SARS-CoV-2. This has the added advantage over RT-PCR of confirming the presence of live virus.
Antibody kits, on the other hand, test whether the person has previously been infected with the virus. This will be important to help understand whether those who have been infected can be re-infected and for how long immunity lasts. All three tests are important to eventually allow those who are self-isolating to only have to do so when necessary.
Antibody testing kits are currently being validated for their sensitivity (ability to detect the virus when it’s really there) and specificity (doesn’t incorrectly give positive results when the patient isn’t infected). The government states that they will be coming from “a variety of manufacturers” and eventually made available to the public, but the NHS and other key workers will need to be prioritised.
Q. Why are there so many criticisms regarding “lack of testing”?
A. From the beginning, the WHO has emphasised the importance of testing. Testing allows researchers to understand much more about the virus, from possible symptoms to transmissibility. Further, as the COVID-19 burden on the NHS begins to increase, staff shortages become more pronounced as many healthcare professionals are self-isolating. Testing NHS staff would allow those who are healthy to return to work. Currently, only patients in hospital presenting COVID-19 symptoms are being tested. NHS staff and other key workers will be prioritised once testing capacity increases. The public will want access to tests and the WHO advises that the best way to control COVID-19 infection will be to test as much as possible – this will better inform measures such as social distancing and other restrictions.
The amount of testing being carried out by different countries is being reported, and there has been a lot of criticism surrounding the UK’s apparent lack thereof. The government has frequently spoken about “ramping up testing”: at the beginning of March, it was stated that they would soon be capable of carrying out 25,000 tests a day. However, there are constraints on testing: sourcing enough kits and reagents (given that they are in high demand globally), but also the capacity of the laboratories performing the tests. Now it is hoped that this will be achievable by the 25th of April. The University of Glasgow has a number of volunteers on standby to help with these testing efforts as they begin to scale up.
Prophylaxis & Treatment
Q. How do vaccines work?
A. Vaccines are a type of control measure, used to prevent infection. They often contain antigens of a pathogen (surface molecules recognised by the immune system) which are introduced into the body in small doses. This triggers an immune response and can ‘train’ a person’s immune system to recognise a virus, which means that when re-infected with the same pathogen, the body’s immune system will be able to mount an effective defense much more quickly.
The antigens present on the pathogen are recognised by the immune system as hostile, so antibodies are produced to combat the disease. These antibodies attach to the epitopes (binding sites) of the antigens. There are many different types of vaccines, including but not limited to:
· Live attenuated vaccines – these contain a weakened form of the pathogen
· Inactivated vaccines – these contain dead cells of the pathogen, the antigens of which are recognised by the immune system
· Subunit vaccines – these contain a specific protein or carbohydrate from the pathogen that can be introduced without inducing illness
There are also vaccines that are still in experimental stages, but that are showing promise:
· DNA/mRNA vaccines – these will contain only part of the pathogen’s genetic material, from which our cells then synthesise the antigen, thereby eliciting the immune response
· Recombinant vector vaccines – similarly to DNA/RNA vaccines, these will introduce part of the pathogen’s DNA/mRNA, but they will use a weakened virus/bacterium as a vector to do so. Using a harmless pathogen that incorporates the genetic material of a more dangerous pathogen will train the body to fight both – like a sheep in wolf’s clothing!
Q. What progress has been made towards the development of a COVID-19 vaccine?
A. Many companies and academic institutions are working towards a vaccine. Moderna Therapeutics, a Massachusetts-based biotech company, has already produced a vaccine called mRNA-1273. The US National Institutes of Health (NIH) are now set to lead a study of mRNA-1273, in which healthy adult volunteers will be trialed. Nonetheless, it is still expected to be 12 – 18 months before this vaccine, or any other, is made widely available due to the longevity of clinical trials. It is imperative that the vaccine is both effective and safe.
As the virus that causes COVID-19 (SARS-CoV-2) was sequenced so rapidly, work on a vaccine began very quickly. Also, prior to this pandemic, work had already been done on understanding how to develop vaccines for other coronaviruses, primarily by Coalition for Epidemic Preparedness Innovations (Cepi). Following the SARS-CoV outbreak in 2003, much of the information regarding its sequence has been used to give us a head start, because so much of its genetic material is shared with SARS-CoV-2. This has made identifying epitopes for SARS-CoV-2 more efficient. Several companies are taking different approaches to vaccine development, with Moderna opting for using mRNA, whilst Novavax is attempting to produce a recombinant vector vaccine. Nonetheless, due to the importance of conducting clinical trials safely, trials for any drug/treatment/vaccine are split into phases:
Phase 1 has a small number of healthy volunteersPhase 2 usually has up to 100 volunteers and focuses on safety and efficacyPhase 3 can have hundreds to thousands of volunteers, confirms effectiveness and compares the drug to other treatmentsPhase 4 has many thousands of volunteers, comes after formal approval of the treatment and incorporates long-term surveillance
The necessity of this phased approach means that it will be a long time before a vaccine is made widely available.
Q. If there are multiple strains of the virus, is developing a vaccine futile?
A. When we think of diseases such as the flu, we know that there are multiple strains and that vaccines only protect against the strains for which they have been developed. Fortunately, the structure of SARS-CoV-2 is easier to target than that of the flu, as its genetic material is all encoded on a single RNA molecule (whilst influenza consists of 8 segments). Though research is consistently being done on ways to make vaccines more effective at combating multiple strains (i.e. by focusing the immune response on a more stable target than changeable antigens), the truth is that the immediate goal must simply be to develop a COVID-19 vaccine that works.
It seems as though in spite of its worldwide prevalence, SARS-CoV-2 is actually mutating fairly slowly. This is thought to be in part due to the ability of the virus to “proofread” its RNA during replication. Though there is concern that there might be multiple strains of SARS-CoV-2, we could hope to find broadly neutralising antibodies (bNAbs) against the virus, which would act against a wide range of virus strains by binding to conserved regions of the virus surface proteins; these are conserved (less likely to mutate) because they are functionally essential for the virus’ replication. Research on these bNAbs has already been carried out with respect to conditions such as HIV and the Hepatitis C virus. Further, any mutations in SARS-CoV-2 won’t necessarily influence infectiousness, virulence or behaviour in a way that would render a vaccine ineffective. Any vaccine produced now is likely to be immediately useful and will protect against all viral lineages circulating globally in this current pandemic. As mutations give rise to different strains of a virus, these are rarely enough to impact the virus’ function.
Q. Why are antivirals being spoken about alongside vaccines?
A. Antivirals can be used as a treatment for those already suffering from COVID-19, whilst vaccines act more as a control measure, and will seek to immunise people in advance of them contracting the virus.
Generally, scientists are investigating the re-purposing of existing drugs (e.g. chloroquine for malaria and various drugs for Ebola, HIV and TB). The advantage of any existing drug being effective is that the critical but lengthy regulatory processes needed to ensure such drugs are safe could be fast-tracked, so treatments could be rapidly rolled out without extensive safety testing.
SARS-CoV-2 is composed of RNA as its nucleic acid, which must be replicated in order for the virus to propagate. Antivirals are often RNA-polymerase inhibitors, which act to block the RNA genome from being copied. Another way in which antivirals work is to disrupt copying by inserting inauthentic RNA building blocks into the genome of the virus. Due to the aforementioned proofreading ability of SARS-CoV-2, these functional analogues are recognised and removed, so many of these drugs do not work; however, a similar drug, remdesivir, might be effective at stopping coronavirus replication. Another interesting option being explored is the antiparasitic drug ivermectin, which has been shown to prevent the replication of SARS-CoV-2 (so far only in the lab). While still in the very early testing stages, blood plasma from recently recovered patients may also hold some promise.
Various clinical trials are in progress such as this one for remdesivir that was previously tested in humans for Ebola and was promising in mouse models for MERS (another coronavirus). For drugs not yet used in humans, lengthy trials and safety testing will be needed.
Feature image is original artwork by PhD candidate Chiara Crestani, ©2020.