Do antibodies hold the key to tackling pandemics? In the case of the novel coronavirus, many look at immunity testing as the way forward and the vital element in reopening society. But as with any new disease, there are many unknowns when it comes to immunity and next steps.
Timothy Tellinghuisen, PhD, is no stranger to antibodies and how they could affect our response to infectious diseases like COVID-19. As Head of Virology Discovery of Roche Pharma Research and Early Development, he explains all about immunological memory, how antibody tests differ from other testing types, what antibodies do against COVID-19 and his predictions on what our future might hold.
The fundamental job of an antibody is to recognise foreign things in and on the body and block them from causing harm. Antibodies do this in several different ways, but the overall theme is the same: they recognise foreign invaders and help eliminate them.
Antibodies provide a number of unique properties that make them excellent drugs. They are very specific to a target and they are things that are already in your body, which tends to make them very safe treatments. We know a lot about inducing them, making them, testing for them, and turning them into medicines.
If a new infectious disease comes along that we know very little about, the fastest way science can respond is with antibody-based approaches. We can make vaccines to induce protective antibodies, or we can make antibodies in a lab and deliver them to patients to inhibit viruses. We can also even simply transfer human plasma from a person that recovered from the viral infection to a sick person to improve their ability to fight the virus. So, all the interest in COVID-19 is because antibodies are the fastest way to get a protective and therapeutic drug.
The other reason antibodies are of interest is that they are excellent diagnostic tools. They can be used to determine who has been infected with a virus and who has not. This can be done many months, or even years, after an infection has ended. The gold standard PCR (polymerase chain reaction) based diagnostic tests provide the most accurate method to detect the genetic signature of the virus in a patient's body.
Antibody tests by contrast can tell you if you were ever infected, but they typically cannot detect infections early in the clinical course of disease as the body takes time to make antibodies. They tend to be seen much later in the infection than when one sees viral genetic material in the case of viruses like SARS-CoV-2. Therefore, tests looking at viral RNA and antibodies are different, but complementary. One can tell you if you are infected now (RNA PCR tests), and the other can tell you if you have ever been infected (antibody tests).
Yes, there are people who had SARS, MERS, and Ebola and have recovered. These people carry antibodies that recognise the virus with which they were infected. On the other hand, billions of others have not been exposed to these viruses. They are what we call “immunologically naïve”. They have no existing protection from these infections, beyond their own immune system’s ability to fight the infections. Vaccination of people would provide some protection from infections by producing an antibody response, and “immunological memory” of the virus.
Immunological memory develops when the body is exposed to an infection, and some of the cells that produce antibodies during the infection become specialised cells called memory cells. These cells survive for a very long time and carry the information needed to fight a future infection with the virus. When an infection happens, these cells become active again, expand quickly, and make many protective antibodies.
A vaccine tricks the body into thinking it is encountering a virus infection and the body responds by producing antibodies and memory cells. This allows the body to respond much faster when exposed to a real infection from the virus targeted by the vaccine in the future.
Existing antibodies in a person can help to cope with similar diseases in the future, at least sometimes. How well this works depends on how similar the new infecting virus and the one that generated antibodies previously are, and how much of the antibodies generated from the memory response recognise the new virus.
Sometimes this works, and sometimes it does not. A great example where it works is something like cowpox and smallpox. Infection of humans with cowpox generates a mild, non-life threatening infection that resolves. This generates antibodies and memory cells that then can recognise and protect from infection with the related and much deadlier smallpox virus. This is the basis of the first vaccination programme in human history. Of course, other times it does not work so well.
For instance, getting infected with last year’s flu does not mean you will be protected from this year’s flu. Even if you get the vaccine this year, there might be some diversity in circulating strains and you will still get the flu, despite numerous prior infections and vaccinations. You should still get the flu shot though, as it is still beneficial in many years. For SARS-CoV-2, there is a lot of evidence emerging that some neutralising antibodies identified from the 2003 SARS outbreak can neutralise SARS-CoV-2 in COVID-19 patients.
A neutralising antibody is an antibody that binds to a virus particle in a very special way and prevents that virus particle from productively infecting a cell. It can block the ability of the virus particle from binding to a cell surface protein, called a receptor, to allow the virus to enter the cell. It can also block the ability of the virus to fuse with a cell membrane; block the disassembly of the virus particle; or block the infection in other ways. The key is that it blocks the virus from infecting a cell.
The virus is effectively neutralised by the antibody binding. Only a very small subset of antibodies generated in an infection are neutralising antibodies. Scientists put a huge amount of effort into finding these neutralising antibodies as they have incredible therapeutic potential as treatments for those who are infected. This is certainly the case for COVID-19, where there is a race to identify new neutralising antibodies, and try to repurpose neutralising antibodies identified after the 2003 SARS outbreak.
Protective antibody is a broader term that typically describes the immune response induced by an infection or vaccine. If this treatment induces antibodies that prevents infections, it is called a protective antibody response. All neutralising antibodies are by definition protective, but not all protective antibodies are neutralising. Several neutralising antibodies have been identified from COVID-19 patients, so they do exist. There are many drug development programmes on these antibodies right now, as they represent a very fast way to develop a therapeutic.
I think we already have those two tiers of society right now, with essential and non-essential workers either working from home or risking infection by working outside of the home. I suspect this will continue, but more and more people will have to be essential as things are going to have to be made, built, farmed, cooked, and transported, and all the industries that support these activities will have to go back to work. Eventually, we will have large parts of the economy running again.
I do not see a world where immune people are working while everyone else shelters at home. I think with personal protective equipment, social distancing protocols and hand hygiene we can likely all start to work in the near future. The important thing is to carefully monitor new infections and maintain vigilance while we start to go back to work and let science drive the timing at which this happens.
As for what I see in our future, I see us “returning to normal” fairly soon. I think we have done reasonably well at limiting the spread of the virus. We have seen that virus infections resolve, which is to be expected from this type of RNA virus; and there are no long-term infections or carriers that have been observed. If we can get to a point where very few people are actively infected and limit their contact with the uninfected, we can get to a point where the virus can no longer maintain a productive reservoir in the human population.
In short, it would burn itself out. No new infections means this ends, like SARS, and we go back to normal. The activities we are all working on are to try to speed this along by limiting infections and spread of the virus.
I think they tell us that we are dramatically altering the biosphere. As humans expand into new geographic areas and have enhanced contact with animal species we used to only see sporadically, we have an increased chance of zoonotic infections. Add to this our impact on the global climate, and you have the potential for the expanded geographic range of many disease vector insects placing us all at risk of new infections. As we alter the world around us we come into contact with many new infectious agents, and this can be rather catastrophic in some cases like Ebola or SARS-CoV-2.
I think the greatest impact of the virus is not going to be the infection and mortality numbers, but what it taught us about our society, politicians, the news infotainment complex, economy, employers, culture and us. I know I see the world in a very different way than I did a few months ago, and I suspect I am not alone. We were incredibly lucky the mortality of this virus seems low, but even with that luck, many people have died because of bad policies, poor planning, poor communication, and slow responses. We need to do better in the future.
Antibody testing gives us an idea of who was infected with the virus. This is important in understanding the spread of infections, how deadly infections are, whether preventative measures are working, and what the actual risks of disease in different populations might be. If we see 100 infected people come to a hospital with an infection and 10 die, that is a 10 percent mortality rate. That seems very bad. If we use antibody testing and learn that 100,000 people in the community have had the virus, and only 100 were sick enough to go to the hospital, and those same 10 died, that is an overall mortality rate of 0.01%. These data are incredibly important from a public health perspective. There are also additional benefits in knowing if people have been infected previously or if they have developed protective immunity and therefore cannot be infected again, as we try to get back to work across the globe. In the case of COVID-19, we do not yet know if protective immunity exists and to what extent.
So far, no one really knows what returning to work will look like, as the question of immunity to the virus is not so well defined yet. There are certainly case reports of people who show signs of re-infection. I think this was seen first in South Korea, but now also in Italy and France as well. The number of these patients seems to be rather low so far, suggesting that most recovered patients do not get re-infected. We do not know what is different about patients who seem to show signs of resolution, only to appear with the virus again.
Perhaps this is a case of viral suppression followed by re-emergence, or replication in a different compartment of the body that is not sampled followed by re-emergence into the respiratory tract. It could also be authentic clearance of a first infection followed by a second infection. I think we are just too early in this pandemic to know the answer.
The interaction of the immune system with coronaviruses is incredibly complex, and these viruses have evolved many ways of escaping our immune system, so it is not impossible that an infection with SARS-CoV-2 could result in no protective immunity. Based on the small numbers of these unusual “re-infection” patients, it seems most people do develop some protective immunity. We have also seen plenty of evidence from SARS that animal infections lead to the development of protective immunity. So I am hopeful that will be the case for most, if not all, SARS-CoV-2 patients.
We have active programmes in hepatitis B virus and several respiratory viruses, including coronaviruses. We are defining the way SARS-CoV-2 interacts with host cells, identifying novel targets we can use as future drug targets for the broader problem of emerging coronaviruses.
We also are very active with Roche Partnering, looking for industry partners and collaborators for drugs and antibodies to treat SARS-CoV-2, as well as thinking more broadly about future emerging virus infections. Our vision is to develop broad-spectrum antiviral drugs that can treat many different viruses so that in future pandemics we will have a treatment in hand.
Timothy Tellinghuisen, PhD is the Head of Virology for Roche Pharma Research and Early Development in Basel. A biochemist by training with more than 27 years of academic and industry experience, Timothy drives Roche's early discovery virology efforts in Basel, Switzerland.