Mumbai: Hundreds of millions of Indians--over 250 million school students and hundreds of millions of workers--and billions of people around the world are asking one question: When will life become normal again post-Covid? The answer is only a little clearer now than it was a year and a half ago, but our understanding of the disease and what will effectively put it under control has definitely improved.

The larger questions are: How long will Covid-19 last in the way we know it today? In India, we've gone through a brutal second wave; cases have come down now across the country, quite sharply, except in Kerala where cases are high. But elsewhere, life with masks and other restrictions has come back to some kind of normal.

If we were to look at history, how does Covid-19 compare with other diseases that we have seen in the past, including something like smallpox? Also, what is the combination of vaccine administration, lifestyle changes and a cure--whichever way it might come--that can bring down the spread of this virus, and take us back to life as we know it?

We speak with Monica Gandhi, an infectious diseases specialist and a professor of medicine at the University of California, San Francisco. She is also the director at the same institute's Gladstone Center for AIDS Research. Gandhi has an MD from the Harvard Medical School and a Master's in Public Health from the University of California, Berkeley.

Edited excerpts:

Let me start with that very simple question: What is the endgame looking like for Covid-19?

We have to look at history to understand what's happening with Covid-19. And to look at the history of infectious diseases, we have to also remember our definitions of infectious diseases. There are four levels of what we call containment: One is control, which means that the virus has become endemic. It doesn't cause undue burden of death or suffering or healthcare systems being overburdened. But it's not gone. That is actually the endgame, and that is the hope for Covid-19, and we are getting there in many places.

Why can't we get to the other phases, which we call the elimination (where you take it away from a region), eradication (where it's gone for the whole world) and extinction (where you even destroy lab stocks)? The reason is it doesn't have those features that allow eradication. "Those features" means, no animal reservoirs; Covid-19 has one. "Those features" means, like smallpox, it very clearly looks distinctive and not like other viruses. That's not what Covid-19 is. It looks like a lot of respiratory infections. The third feature is it has a short period of infectiousness, like smallpox had. That's not what Covid-19 is. And then, the fourth feature is that you should be able to interrupt the chain of transmission. Unfortunately, because people can still pass it on before they have symptoms with Covid-19, it's going to be impossible to eradicate it.

You've contrasted Covid-19, in an article for The Washington Post, with measles, where you may see sudden outbreaks, which may be quite big, but do not mean that everyone else is going to be affected. Is that a fair comparison?

Yes. The best comparison is either with measles or even pertussis, which is a bacterial infection that causes whooping cough. And both of these infections, over the world, are in control. You can absolutely see outbreaks. Those outbreaks are more among unvaccinated eligible people. You may even see mild disease in people who have been vaccinated, but you know how to treat it. And we do have treatments for Covid-19. So, it doesn't mean it's gone worldwide. Measles and pertussis are not gone worldwide. But they are at low levels and under control. And that is what we're hoping for with Covid-19, and you can see places that are getting it under control. There are places that are wide open and they are saying that they are done with Covid-19. That's Denmark at 74% vaccination rate; that's Norway, which opened over the weekend, at 67% vaccination rate.

How are you seeing India at this point of time?

India is an interesting example of getting--we are not there yet, but getting--to what we call control, or endemicity. Endemic means low-grade circulating virus that doesn't cause undue burden on the system. Why is India getting there? Very sadly, it is actually what you just said. There was a terrible second wave, and there was a lot of death, a lot of suffering. That actually led to natural immunity in the population. And at the same time, India very quickly started vaccinating very strongly during their second wave, so there was a lot of increase in vaccinations. The population is becoming immune. Before vaccines, remember, that is the only way to get through a pandemic. Measles, pertussis, smallpox, influenza A--unfortunately, before vaccination, the only way to get through them was people getting naturally immune. But in India, there is natural immunity, there is vaccination-induced immunity, and the cases are coming down. And they are lower, except in Kerala like you just said.

Would it be correct to say that, like measles, you could see an outbreak, let's say, 12 or 18 months later, and that would be as deadly or as virulent as it is today, except that it may happen in small pockets? So, in essence, we cannot forget what this disease was like and the harm it could do.

Yes, this disease can do great harm. The thing about measles is it can also do great harm. Measles was first identified in the ninth century, and we actually didn't get a vaccination for measles until 1963. So remember, the way that measles was controlled prior to mass vaccination is that people would be born, they would be non-immune to measles, they'd unfortunately have to get measles to become immune, and that immunity was lifelong. In fact, we actually don't vaccinate people who are born before 1963, because we assume they've had measles.

Covid-19 is more deadly, but we also have better treatments than we've ever had for measles. We actually have true treatments now--monoclonal antibodies, remdesivir, steroids, there's an antiviral coming out named molnupiravir, that we have great hope for: The results are going to be released this week. So hopefully, we'll be able to treat more mild cases. And the question of lifelong immunity is still a debate. But there are good features of immunologic research that show long T-cells and long B-cells that we hope will get lifelong immunity to Covid-19. So, there's a lot of hope that it can become like measles. And if you think about measles, you don't actually think about measles very much in the general population. As an infectious disease doctor, I think about it. But it is gone from the public view that it is actually still a problem. It's not gone. It's called "under control". And that's the hope for Covid.

You talked about T-cells. Could you walk us through what that means, and also in the larger context of vaccine efficacy as we know it at this point?

To put it very simply, there are two arms of the immune system. There are B-cells and there are T-cells. The B-cells are the ones that produce antibodies, but those antibodies are going to come down with time--totally natural, not a glitch of the immune system, you can't keep all those antibodies in your bloodstream, your blood would be too thick. So, they're going to go down with time, but memory B-cells are blueprints to make more antibodies if they see the virus again.

T-cells, which are very long-lasting, not only aid B-cells making more antibodies but [also] prevent severe disease. What we have seen from immunologic research with these vaccines--also with natural infection--is that T-cells look like they're durable, and they have what's called the very long half-life, meaning they don't look like they're coming down, even when people were infected--now we have 20 months of data. And we know that T-cell immunity is durable. People who had their measles vaccines 40 years ago still have strong T-cell immunity. People who had SARS in 2002-03 but recovered still have strong T-cell immunity 17 years later. If this protects us from severe disease and T-cell immunity is long lasting, the hope is we will get long-lasting protection from the vaccinations or from natural infection for a very long time.

Therefore, where do you stand on the booster debate?

In the United States, I did actually stand on the fact that I think older people, immunocompromised people, should get a third shot. Why? Because those are always the populations that we are not sure form the strong B-cell and T-cell immunity, and those are the two arms of the immune system that you need high to get long-lasting immunity. So I approve [for] the immunocompromised, those over 65. However, giving widely third booster shots to everyone, the data do not indicate that. Here in the United States, I would definitely talk to your doctor before you decide on a third shot. If you are younger and healthier, I really just would have that conversation. And I would approve it for [those] over 65, which is what I'm recommending to my patients.

Tell us about the evolution of Covid-19. What could we see happening to this virus as time passes? Is it going to become stronger or weaker, or is it going to be exactly as it was, to again use the measles example? And what can we learn from history or from other infectious diseases, in this context?

The only thing we can look to is history. One thing to remember about measles and pertussis and all of these infections is that they have never evolved to become more virulent. In fact, let's just remember that every pandemic--except for HIV, malaria, tuberculosis, where we don't have an effective vaccine, and [because] HIV of course affects the immune system--every one of these virus pandemics have ended because of immunity. They haven't kept on going and becoming more and more virulent. And, importantly, we have never changed the measles vaccine. We had the same vaccine in 1963 that we use in 2021.

So why do viruses not evolve to become more virulent and keep on going and going? Because when a virus evolves--and this is sort of evolutionary biology--it usually takes a hit in some other function if it wants to gain function in one way. So, what is the Delta variant, for example? The Delta variant has gained the ability to be very transmissible. It transmits very readily, it's very quick to go from person to person. But it hasn't clearly shown that that made it vaccine-evasive or in some way more deadly. We just had a lot more cases because Delta is so transmissible. This is true of HIV itself. It can evolve to evade the HIV drugs that we use, but it takes a hit to do so. It becomes less fit.

So, history will tell us we have never seen a virus that keeps on going and going. Remember, measles was identified in the ninth century. We don't see worse and worse measles now.

That's encouraging to note. Could you throw some light on HIV, and if can we draw inspiration from where HIV is or isn't today?

HIV, which was first described in 1981 but probably entered human populations around the turn of the 20th century, has not evolved in any way to become more virulent. In fact, once we got good HIV medications--which, by the way, the best ones were formed in 1996, and they've just gotten better from there--the virus actually becomes less fit if it actually evolves to evade the antivirals. Though HIV is still clearly a problem--we don't have a vaccine against HIV--it is controllable. Why is it controllable? Because we have antiviral medications that shut down viral replication, and it keeps it a chronic lifelong disease.

So when we think about Covid-19, in the 21st century, we are developing treatments that hopefully are going to be targeted just against Covid-19. For example, mulnupiravir is this antiviral, the phase 3 data will be presented just this Wednesday [September 29] at ID Week. If mulnupiravir looks good, you can imagine a world in which someone comes in, they have a moderate respiratory infection, they get swabbed, it's influenza, they get tamiflu and also tamivir, and it's Covid-19 and they have moderate disease, they get mulnupiravir and they go home. And if they have mild infection, because that's what Covid-19 [vaccines] should do--bring down severe disease to a very mild infection--then they go home; they have a cold. So this is the dream and the hope for what the vaccines have done for Covid.

If you were to now look around the world, how is the fact that we are still vaccinated and better controlled in some parts, and not in other parts of the world, likely to affect the transition or the trajectory of this virus as you see it, particularly in the next year or so?

When I look around the world, there are places that have a 2.2% vaccination rate. In sub-Saharan Africa, for example, only 2% of low-income nations have gotten our vaccine supply. So it really is tragic in terms of global vaccine equity. But there is a combination--in other places like India--of natural immunity and vaccination-induced immunity. And then places like Denmark and Norway have more vaccine-induced immunity because they have high levels of access and uptake of vaccines. At all levels, it's getting to the same point--it's immunity to the virus. And you want immunity, of course, through safe ways like vaccination. But ultimately, they'll all get to the same place, which is endemicity--low levels of virus that we can manage, it's under control, and we can live with it.

What are you working on specifically right now inasmuch as your understanding of where you see this disease going in the coming months maybe or a year? And also, what are your points of optimism and concern?

When I look at history as an infectious disease scholar, the optimism is it will end. It will not end exactly the way we want it. It won't be eradicated from the face of the earth. But it will end, it will be controllable, and we will go back to normal life. I really do believe that. And again, about four countries in this world are completely wide open and going back to normal life with high rates of immunity. So, it does happen. This will happen.

However, I think what happened in this pandemic, we have to learn about what we did as a world--that we have had vaccines since December 2020. India for example appealed to the World Trade Organization in October 2020 asking for vaccine access for waiving of patents and they were denied. And in March of 2021, this terrible second wave happened in India. I think if we do not learn through this pandemic that we are one world, and we have to give vaccines out to the whole world, we could have this happen again. So that's what I'm working on and interested in. And then fundamentally, even with mild disease, it's important to remember that we will have antivirals to work against mild disease. And I'm also interested in that.

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