Explainer: What’s needed for immunity from Covid-19 – and do Indians stand a better chance?

Recent studies have found that antibodies to the novel coronavirus that causes Covid-19 decline rapidly. In other words, immunity to Covid-19 could likely be lost within months of being infected. This could have implications for vaccine candidates currently undergoing human trials.

Another component of the immune system, T-cells, a type of lymphocyte or white blood cell, is also in focus. Studies have shown evidence of T-cell reactivity against SARS CoV-2 – the novel coronavirus at the centre of the current outbreak – in people unexposed to it.

This has resulted in speculation that these are ‘memory T-cells’, developed after exposure to other coronaviruses that cause the common cold, and could offer protection against SARS CoV-2.

In this interview with Scroll.in, Dr Vineeta Bal, immunologist from the Indian Institute of Science, Education and Research, Pune, explains the complex human immune system, unpacks research on the immune response to SARS CoV-2 and weighs in on claims that Indians have innate immunity against the virus.

What is the difference between innate and adaptive immune systems?
These are the two main components of the immune system. Innate immune system comes into action within minutes of any invasion: be it by a virus or a bacterium or anything. So within minutes of the invader breaking the skin barrier or the gut lining or lung lining – if any of this is breached and the invader is inside the body – the cells and other proteins that respond are part of the innate immune system.

The innate immune system does not recognise, necessarily, one virus as distinct from the other. For example, whether the invader was SARS CoV-2 (the novel coronavirus which has caused Covid-19) or SARS CoV-1 (Severe acute respiratory syndrome coronavirus which caused the SARS outbreak in 2003) or MERS (another coronavirus responsible for the Middle Eastern Respiratory Syndrome) or flu, the innate immune responses would be pretty much similar.

The adaptive immune system, in contrast, does not help at all for a new virus within the first few minutes to hours. In fact, its utility becomes apparent after day 4, 5, 6. Slowly and steadily the adaptive immune system builds up to very specifically recognise the present invader. It is slow but it is specific.

So, we are talking about two things: early and non-specific as innate, specific and late as adaptive.

When we talk about vaccines, we are talking about immunological memory. Because vaccines are supposed to generate a protective immune response for the next encounter to be dealt with. This immunological memory is only contributed to by the adaptive immune system.

What is T-cell immunity? What is the difference between antibody response and T cell response?
Both antibody response and T-cell response are part of the adaptive immune system. Antibodies are the proteins that are synthesised by the body. They are normally called immunoglobulins. You may have heard of the IgG antibody test or the IgM antibody test. These are the antibodies specific to SARS CoV-2 (that causes Covid-19), in the present context.

Their main function is, they tend to block the entry of the virus into the host cells. If the entry is blocked, then the virus cannot get into the cell and hence cannot multiply, hence there are no downstream consequences. This is the ideal situation.

The antibodies which prevent the entry of the virus are called neutralising antibodies. They neutralise the attack of the virus. If the neutralising antibodies are present in sufficient quantity in the host, then the chances are that even if there is infection, which means even if there is a breach in the barrier, the infection will be contained rapidly, effectively and it is very unlikely that the person will come down with disease or illness.

Now, say the neutralising antibodies are not present, in which case the virus would infect the cell and the host cell would support virus replication, resulting in a large number of virus particles. Such cells need to be killed, otherwise not only will they replicate the virus but they will also infect other cells. The ‘killer T-cells’ do this function of culling efficiently. Another subset of T-cells is the ‘helper cells’.

The ‘killer T-cells’ will directly kill the virus-infected cells, while the ‘helper t-cells’ help generate better antibodies. By better antibodies I mean, they bind their target with much more strength, so that even the small numbers of antibodies are more useful than very many antibodies which are low in terms of their binding potential to the virus. In other words, ‘helper T-cells’ are complementary to the B-cell antibody response [B-cells are another type of lymphocyte or white blood cell]. ‘Killer T-cells’ act independently of B-cell.

What are memory T-cells specifically?
To understand this, I want to make a distinction between infection and disease.

Currently, we are referring to cases as anybody who is RT-PCR positive [the reverse transcription polymerase chain reaction test, the gold standard for diagnosing Covid-19 cases]. So people who are asymptomatic, mildly symptomatic, hospitalised, on ventilator or dead – this entire spectrum is inappropriately being referred to as cases.

I want to make a distinction between people who are virus positive, which is RT-PCR test positive, but are completely asymptomatic or have half a day of fever, minor cough and have come out of it like we do with seasonal flu and others.

What does virus positive mean? The nasal swab testing shows positive as the virus has broken the barrier and the virus has got in. That has initiated an immune response. But here, the host has dominance over the virus and that is why the person is not falling sick. So there is no disease, so to speak. Such people are infected. On the other hand, those that fall sick are patients.

Now, let’s understand memory T-cells. The adaptive immune system stacks away some of its supplies, which is the T-cells that are generated or are triggered by the presence of the virus, for the future. This is called immunological memory or memory T-cells. So, a large number of T-cells, whether helper or killer, will be used up if the infection is severe, a small portion of the ammunition (T-cells) is kept in reserve, so that once this virus attack is over, these extra cells will remain as back up. These will be specific to SARS CoV-2 in this case or if it were a Japanese encephalitis infection, then the memory T-cells will be specific to Japanese encephalitis and are unlikely to provide protection to other viral infections.

A study by King’s college London found a steep drop in patients’ antibody levels three months after infection. Antibody levels fell as much as 23-fold over a three-month period. In some cases, they became undetectable, giving rise to fears that one can be reinfected by the SARS CoV-2 virus, and raising questions on long-term vaccine protection.
I will answer this based on some data and some speculation based on what we know of viral infections in general. Even in such individuals when the T-cells are tested for, T-cells are still present. There are some studies that have only looked at antibodies. T-cell responses are always technically more difficult to test. Hence, many studies ignore T-cells. Because you can simply collect blood, separate serum and test for antibodies. It is not so easy to test for the presence of T-cells.

But there are studies that have recorded that there are T-cell responses, triggered even by asymptomatic infections or mild infections and of course, these responses are even higher if the patient is more severely ill.

The findings of the King’s College study that show antibody responses are dying is not surprising. Antibodies will die over a period of time, because ultimately these are proteins which we are trying to detect in the serum, and proteins have their own decay period or as we call it ‘half-life’.

But in some research papers in which both antibodies as well as T-cells were checked, or independently only T-cells were checked, it was found that even beyond three months, T-cells were present. We must remember that this pandemic is only six or seven months old. So researchers are looking at those that were infected in December 2019, January 2020, and have recovered.

Here is what we can say based on viral infections we know about: most viruses trigger a robust immune response, both antibody and T-cell response, such that the protective response is long lasting. For example, in the case of smallpox, which we have now conquered, booster vaccines used to be given every five years. Persistence of T-cells was the norm. Another example is yellow fever vaccine boosters given only once in five years. So the expectation was that if we are lucky, the SARS CoV-2, will also produce a long lasting T and B cell (antibody) response. It seems, going by the findings of the King’s College study, that the SARS CoV-2 virus is not falling in the category where antibodies last for years on end.

Similar to the King’s College study, a study by Mumbai’s civic body reportedly revealed the level of antibodies in asymptomatic patients as being low. Here, it is being inferred that asymptomatic patients are not producing expected levels of antibodies as they already have protection from memory T-cells derived from earlier common cold infections. Covid-19 is caused by a coronavirus, one of the largest families of viruses that causes common cold. Is this what we call cross reactivity?
We need evidence to say this. Remember, there have been claims earlier that the death rate is low in India because we are generally immune, we are exposed to so many other assaults and so on. That also is incorrect. Just because we have a history of being exposed to other assaults doesn’t mean we have better memory.

But when we talk of cross-reactivity, there is a theoretical possibility that many of us who were exposed to other cough and cold coronaviruses would have some kind of immunity. But this is what one needs to understand: T-cells recognise small peptides derived from proteins. So, if there is a long nucleoprotein, which is say, 300 amino-acid-long, then what the T-cells would recognise is small pieces of eight or ten amino-acid-long peptides.

Now, if you are looking at say, SARS CoV-1 and SARS CoV-2, these are called cousin coronaviruses. Why are they called so? Because they have similarities in terms of the proteins they can produce. If you look at the nucleoprotein sequence of SARS CoV-1 and SARS CoV-2, you will find some peptides that are identical. Many others will not be identical.

So, hypothetically, if I was exposed to SARS CoV-1 or other coronaviruses, and if I had developed T-cell response to say, 30 different peptides, there is a statistical probability that one or two of those T-cells which are specifically recognising, say, peptide A and peptide B are also shared by SARS CoV-2. So, of the T-cell memory component I have for the corona family, there would be some cross reactivity.

But have we really been exposed to so many coronaviruses in the past? We don’t test for it. Also, not all common colds are caused by coronaviruses.

What then do we make of atleast four studies, one of them published in Cell and the others pending peer review, that say, T-cell reactivity against SARS-CoV-2 was observed in unexposed people. It is speculated that this reflects T-cell memory from exposure to circulating ‘common cold’ coronaviruses. Can these memory T-cells play a role in protection against Covid-19?
Remember, I described a subset of antibodies as neutralising antibodies. It is this subset that actually prevented virus entry into the cell. And hence they were protective. Again, there are antibodies which are an immune response but they are not protective but there is a subset of antibodies that are neutralising, inhibiting the entry of the virus. These are the antibodies we value.

That is not what is tested by the standard ELISA test, because to test for neutralising antibodies specifically, you need cell based acids which are harder to do. Taking off from there: when we talk of immunological memory, we should be focusing on killer T-cells because they would be more efficient in providing protection.

Say we have 30 peptides specific killer T-cells from an earlier coronavirus infection, then as it is, one or two are bound to be cross reactive to SARS CoV-2. What I am saying is, a small subset will be shared between other coronaviruses and SARS CoV-2. Do we know if the T-cells that are recognising these specific peptides are the most efficient killers? We don’t know that. Because there will be very efficient killer cells and there will be less efficient killer cells. Again, there is a statistical probability that some people may hit it right and they have peptide specific killer T-cells which will provide them with protection against SARS CoV-2. But can we generalise? No.

Look, we are infected by many common cold viruses but common cold is not caused only by coronaviruses. It is also caused by many other viruses. And if we don’t have evidence that much of the common cold infections we see are caused by coronaviruses, then we have to assume that flu viruses and others could also be causing common cold. So the cross reactivity between say, flu and coronaviruses and SARS CoV-1 or 2 is even less. So with hazy, assumed knowledge, we have to interpret what the claim is.

I want to reiterate: one may get protected as an individual but as a whole population, it is not really a guarantee that because I was infected by a cousin of SARS CoV-2, I will get protected.

The learnings from the various studies, particularly those showing a rapidly waning antibody response, what does it portend for Covid-19 vaccines in the works?
We need assurance from vaccines that they will provide long lasting protective antibody responses and long lasting T-cell responses. Because otherwise what use is the vaccine? You would say, there could be booster doses, but remember the example of smallpox booster requirement was every five years.

If the vaccine protective response is going to one year or less, then how are we going to cover the susceptible population every year? We barely handle childhood vaccination. And children are only a subset of society. SARS CoV-2 would be needed for the whole population. It’s impossible. And we are not going to know if the vaccine protective response is going to last five years because we desperately need the vaccine and there will be short cuts implemented. The reason why vaccines take 10-12 years to develop is because you need to check if in a few years the vaccine is still protective to the recipient.

Finally, you spoke briefly about the claims that have been made about Indians having ‘innate immunity’. How would you respond to the claim that because Indians have received BCG vaccine [for tuberculosis], MMR vaccine [for measles, mumps, rubella], vaccines that are not part of the inoculation programme in the West, Indians have better resistance and therefore many are showing milder infections.

I don’t think we have evidence of this. You have to remember that BCG coverage in India is poor. And people getting infected with SARS CoV-2 are of all age groups. Sure, older people in India, like other places are more susceptible to death because of co-morbidities. Now, because it is the case that BCG was not a compulsory childhood vaccine, say 40-50 years ago, it is being inferred that it is these people who didn’t receive the BCG vaccine that are more susceptible in India. But that is not the case. This is an epidemiological loose association which all these studies have come up with.

Even if you were to look at other vaccines, non-BCG, that are part of the western countries’ programmes, they would make the same association, is my guess. Because it is so loose an association.

There is no cross protection likely because BCG and its proteins are very different, it is a bacterium.

People think their innate immunity may be useful. While innate immunity is useful in building a containment zone around the port of entry of these viruses, the innate immune system also produces cytokines. If innate immunity is generally activated, because I had received BCG vaccine 5-10 days ago and now I am actually getting infected by SARS CoV-2, high levels of innate immunity and inflammation as we would call it, might actually be counterproductive.

I know there is a new fashion in immunology over the last six years where innate immunity is spoken about as also providing immune memory, but I think that is a very limited claim and in a disease like Covid-19, I don’t see it as having utility.