Mumbai: The COVID-19 pandemic is a life-changing, once-in-a-generation event, and the most sustainable way out of this problem is vaccination, says Saad B Omer, director, Yale Institute for Global Health, professor of infectious diseases at Yale School of Medicine and of epidemiology at Yale School of Public Health.

In a short presentation on the “evolution of a resilient vaccine system amidst COVID-19”, as part of a TEDxGateway webinar, he says the current paradigm has compressed the steps it takes to produce a reliable vaccine, not bypassed them. Another innovation: “Manufacturers have decided--on their own, or with investments from governments and philanthropic entities--that it is worth investing in manufacturing as trials are being done.”

With 47 vaccine candidates for COVID-19 between phase 1 and phase 3 clinical trials, and three approved for limited use, here are some questions being posed: What are the risks associated with administering these vaccines? How do countries prepare for delivery, distribution and administration of vaccines? And, what is the implication of all of this on other vaccine-preventable diseases?

Edited excerpts from the discussion:

You said that this is the first time that we are doing an adult vaccination at this scale. Could you elaborate on that?

There are adult vaccines. Certain countries do it, but not at this level. Often, countries do it among healthcare workers and some pregnant women. Influenza is the most common one. There is a vaccine recommended for the elderly and various countries do it in the private sector, etc.

We did that as a world in the smallpox eradication programme, but it was very targeted: You would control outbreaks by looking at people who got the virus and creating a ring of protection around them. But a mass vaccination that covers so many adults is unprecedented, especially in recent history.

Is the potency of vaccines for children lower, and that for adults higher? Is there any trade-off or anything to worry about on that account?

The potency and the effectiveness of vaccines used in--and created for--children is pretty strong. The concern is that the elderly, sometimes, have a lower response due to various reasons such as immune senescence, where certain cells and components of the immune system don’t work as well. That’s one of the things that we are looking for in these trials--and a lot of elderly people are included in the trials, because this virus impacts them disproportionately.

Obviously, there is a race here, and the race is also driven by profits. How do you find a balance between the race that we have to be in and the risks that we are taking? And in some ways, who decides what the balance should be?

It is traditionally the government’s role to decide that. But in the US, the dynamic is interesting because of an upcoming election.

Regulatory agencies rely on well-worn procedures. This is not the first vaccine we have licensed around the world. Regulatory agencies have standard procedures. You have a pre-specified, written protocol in terms of what’s [to be] done. With those regulatory agencies relying on well-worn procedures, even if there is government pressure, others can see and comment on the veracity of the process.

But there is a pedal to the metal--everyone is moving fast. And I am sure this is much faster than any or most other vaccine launches that we have seen in history.

When things have been tried to be accelerated, they have been pushed back. For example, in the US, the Food & Drug Administration (FDA) has come out pretty clearly and vociferously. They've set a meeting, on October 22, of their advisory committee where they expect the data to be presented, one way or another. When the Russians came out saying that they have “approved” or “registered” a vaccine, there was substantial pushback. That vaccine is not being used globally. It’s not being pre-approved by the WHO.

This is how we find the balance. There will be an instinct for certain entities to push forward. And then you have these checks and balances. In face of this call for transparency, [we are] using the same old procedure even though [we are] doing it faster.

There was a story that early next week, major pharmaceutical companies in the US will come out with a pledge that they will stop releasing data from press releases; even if they do release them, they will do it with full disclosure, using, for example, scientific article publication. They will commit to making all the decisions using mainstream processes. That’s a good sign. We should hold them to that.

What are the chances of getting emergency approval for the use of a vaccine?

It depends on the regulatory agency’s paradigm, and on legislation as well. There are pre-specified rules. The full approval and licensure is not only dependent on verifying the efficacy of the vaccine, but also on other steps like manufacturing. That kind of thing is not usually sped up in emergencies, because that’s the baseline solid paradigm. I see most of them--at least in the US (Europeans might do it slightly differently)--even if it’s well accepted by the scientific community, to have some form of emergency-use authorisation.

But how that is done is very important. Is it done based on the recommendations of the advisory committee for the FDA and similarly in other places? Is it done based on data that are readily available and transparent? That would matter.

Inherently, the full licensure process takes time and that will add another six months to a year to the process--not just bureaucratic delay; there are specific steps needed for that. What I foresee is that the initial one is likely to be an emergency-use authorisation. Obviously, it’s not certain; things are evolving.

How long will it take to create a foolproof vaccine and bring it to the common person?

In phase 3 trials, you are looking at safety and efficacy. On efficacy, usually these trials are based on event-based sample sizes. You expect 150 infections to happen, for example. So based on that, you can either wait for a lot of people to get it, or you recruit a tonne of people quickly. There will be a second dose administered to them. And then you have to wait. Some people, unfortunately, will get the infection and the disease in the unvaccinated group and others will be protected (in the double-blind trial). That takes time.

But a couple of months are also needed to look for safety follow-up, because most of the safety events actually happen within the first couple of months.

What could those symptoms be? Let’s say the vaccine is in our hands in a month’s time. If I do get it, what is the likely downside and the likely upside?

These steps [mentioned above] would mean that it is unlikely to be available in a month’s time for mass vaccination or mainstream products, no matter what the politicians say. But a vaccine being available or authorised--either under emergency-use or under full licensure--before the end of the year is not a fantasy. That’s a clear possibility. The more likely scenario is early 2021.

In terms of the kinds of stuff you look out for, there are certain conditions, and people in these trials are followed up very intensively to catch even early signs that they exhibit. First, you see what the disease causes and look at those kinds of syndromes. There are these solicited adverse events. Then there are certain autoimmune conditions like the Guillain-Barré syndrome. Antibody-dependent enhancement is another phenomenon that you look out for. It’s rare, but happens under certain diseases.

There are conditions you look for in a trial. But once a trial is done, you can get the vaccine with a peace of mind. That’s the reason why mainstream entities wait for a period of time before saying that it is safe and efficacious.

Would the vaccine not adversely impact patients with comorbidities, given that the virus is deemed dangerous to such patients?

We have found that even in other viruses that disproportionately impact groups with comorbidities, a vaccine is safe and has a lot of net benefit--because although vaccines and natural infection employ some of the same immune pathways, they are not exactly the same.

Even live attenuated virus vaccines [where a pathogen is weakened, but kept alive] do not have disease potential. You are evoking the immune system without causing even a mild form of the disease. That’s how vaccines work. So right now, that is not one of the concerns.

But again, that’s why we do phase 3 trials in a controlled fashion--so that we identify that [potential adverse effects] and don’t get any surprises after the vaccine is licensed.

Would the adult vaccine be more effective for those who have chronic diseases? Or will there be several clinical trials to make sure they would not be facing severe side effects?

We’ll have data. From other vaccines, we know that usually, vaccines are recommended even for those who have chronic diseases. For example, influenza [vaccines] in certain countries are recommended for people with chronic diseases. They don’t have disproportionate adverse events.

That’s less of my worry. We will not need separate trials. They will be included in post-marketing surveillance. The statistical techniques that are being used for post-marketing surveillance are rapid assessment statistical techniques, meaning that you get a result very quickly.

What side effects could emerge over a longer time?

Most of the severe side effects that we’re concerned about, you identify in the trials. There may be rare side effects that we don’t know [of], but they’re so rare that the risk-benefit is still in favour of benefit.

So, we will be on the lookout for things that resemble some autoimmune events etc. We are on the lookout for some sequelae that look similar to the disease itself, but in a milder form. But once the phase 3 is done, and it goes through proper usual procedures, people can be reasonably confident that the risk-benefit ratio is heavily in favour of vaccination.

And you are saying that not because of what’s happening in COVID, but because of your experience and understanding of vaccines in the past. And those have been decades in development. Is that correct?

Exactly. Decades of development, a tonnes of experience--even with a new pathogen. Remember, this coronavirus is new. But we have known about coronaviruses for a while. We don’t commonly use a coronavirus vaccine, but we understand some of those things. There’s a reason why a lot of us anticipated a coronavirus outbreak--there were movies about that as well. It is unfortunate. There are a lot of things that are unknown, but there are several things that are known about how things work. It’s a game of probabilities. And the probabilities tell us that we are likely to catch any untoward events earlier on in the trials.

There are systems being developed for post-marketing surveillance. The US has stood up; the Europeans have done that. I’m working with the World Health Organization (WHO) group to prepare other countries to do that. That would be very essential to do--an ongoing systematic monitoring of adverse events.

How do you prevent any untoward effects to the foetus (teratogenic effects) when you vaccinate pregnant women?

The idea for that would be to do trials in a controlled way in pregnant women. And we have learnt a lot. A lot of the work I do is trials in pregnant women. We have worked on tools to vaccinate pregnant women that there will have to be early trials as they get covered. In the H1N1 pandemic, pregnant women were the top priority group. In here [in the case of COVID-19], they are not [the top priority] because there are other probable groups more disproportionately affected. And we will look at that stuff in trials and that would tell us and then there’s post-marketing surveillance.

But there are certain things, also depending on the type of vaccines: We are more careful about giving live attenuated vaccines to pregnant women, for teratogenic effects. If it’s an mRNA and other vaccines, the likelihood is very small for any teratogenic effects. We also do lab-based reproductive toxicity studies. That will be the other data that will give us confidence to even start the trials in pregnant women.

Are pregnant women signing up for these trials?

Most [trials] are excluding pregnant women at this point, but one way or another, there will have to be separate trials for pregnant women fairly soon.

I’m sure you’re looking at the data and what’s happening in these trials far more closely than most other people. Is a vaccine looking like a reality?

The signs are good. First of all, immunologically, the principle has been established that you can evoke an immune response through vaccination. Whether it’s effective is a question for phase 3 [trials]. There is early-phase-level evidence of safety. We should be ready for the first few vaccines to hurt a little, give a few people some fevers. The good news is that that doesn’t correspond with long-term or major side effects. We are seeing that a few people do get [a fever] after they get a shot, but the other good news is--and this varies from vaccine to vaccine--early trial data suggest that if you take paracetamol with that, those symptoms are reduced. These are immediate, what we call reactogenicity, which are events that do not have long-term sequelae but hurt a little earlier on.

The other thing is that initially, the vaccine programmes were trying out single-dose vaccines. They may come in the future, but the frontline products that are showing promise are likely to need two doses of the vaccine.

The other really good sign that I keep coming back to is the fact that there are so many types of products [being tested]--the recombinant, mRNA or vector-based, old school things like live-attenuated vaccines that have shown promise. Just like a stock portfolio that has a lot of stocks, you hedge your bets. You even out your risk. Though you’ll take one vaccine, in the vaccine development programme, one of them is bound to succeed.

Types Of Vaccines

Source: Neal Halsey, Yale Institute for Global Health

No vaccine has been found for AIDS despite a lot of work that has gone into that. Is COVID-19 different?

AIDS, because of the virus, impacts our immune system. And the nature of the virus is such that the antigen targets for antibodies and your immune system are, in a way, hidden or not easily accessible. And there are other factors. HIV is extremely, exceedingly difficult to develop a vaccine against.

This [COVID-19] is not that kind of a virus. Initial data suggest that those signs are very encouraging. And despite the reinfection news, what we have seen after natural infection is overall very encouraging.

On reinfections, some of them have been reported through a different strain than the first one. Do you think a single vaccine will work? Or do we need multiple vaccines targeting different strains?

This is how immunity works, even after natural infection. If I get the flu, or if I get any other disease, most people would be protected after natural infection. There are certain viruses and bacteria that don’t do that. HIV doesn’t do that. But for most of them, there is protection. But some don’t get it as a natural phenomenon. That’s what we are seeing, that some cases that are coming up are being identified as true reinfections.

Sometimes, vaccines can do better than nature. There’s no guarantee that vaccines will have the same reinfection rate. They may have lower reinfection. That’s what efficacy means--90% efficacy means that 90% people are protected. 50% means that half of the people are likely to be protected. That’s a simplified version of translating efficacy.

Secondly, the strains we have seen are not different enough for us to be majorly concerned about targeting each strain, but we will watch and see. Right now, the way coronaviruses generally behave, that’s not a major concern. To paraphrase Jay Z, we have 99 problems in vaccinology, that’s not one of them.

If a person gets infected for the second time after getting cured from the first infection, would the effectiveness of the vaccine in such a person vary?

We don’t know. And this is one of the things that I’m also studying. Unfortunately, this is a new virus. It’s a test match; it’s the last inning with a new ball, but there are certain googlies that come in after lunch on the last day as well.

So these are things we are watching out for. It’s not going to upend the whole thing. But what may end up happening is that we will tweak the recommendations based on emerging data. This is not the type of thing that will say whether the vaccine works or not overall. It would say, give these many doses to these people, or do this and that to the vaccine, or maybe comparison between different vaccine products.

Will the vaccine be tailored per region? Or is it a one-size-fits-all, globally?

It depends on the vaccine. Vaccines like [that for] measles or some others, we just take one vaccine for everyone. Vaccines like influenza are tailored--by northern and southern hemisphere, at least, and by season. And that depends on the mutation rate.

So far, [from] what we have seen--and what we know from other coronaviruses--a global vaccine is likely to be the reasonable strategy. If things emerge otherwise, we can rest assured that it will not go unnoticed. So far, the data look encouraging for a single vaccine--you could have different products, but not geographic strains in the vaccine.

Will a vaccine give lifelong immunity to COVID-19? Or will we require an annual administration, such as in the case of influenza?

It is unlikely to be annual because of what we know about coronaviruses themselves and some of these platforms, but we don’t know if it would be lifelong. We’ll have to see and study those vaccines to see if they provide lifelong protection. And these are the things that keep researchers [like] myself employed for the long run.

How objective do you think the vaccine distribution will be? Given that rich countries are buying up vaccines early on, who will fulfil the demand for developing countries?

The developing countries, the low and middle-income countries are not the low- and middle-income countries of 20 years ago. Indian manufacturers are the biggest suppliers in the world in terms of doses. That gives a lot of empowerment to several countries. And so the initial investments in production etc. has changed the balance.

Even at healthy market rates that make sure that manufacturers also see the benefit in developing [countries]--these are the market forces that drive production--several countries do not necessarily have the ability to do that as well.

Therefore, the COVAX initiative, an entity that was developed through a collaboration of Coalition for Epidemic Preparedness Innovations, GAVI [formerly the Global Alliance for Vaccines and Immunisation] and the WHO, said that for research and deployment, $18 billion will be needed. They asked for this, and most countries in the world expressed initial interest. And then they asked for solid commitments.

It’s a Robinhood kind of model: High-income countries pay [a higher, but still] a good price, but not as low a price as low-income countries do. That subsidises low-income countries’ vaccine access. And the gaps are filled through philanthropy and aid into that system. And it’s a system that, again, hedges its bets on nine products [vaccine candidates].

Over 70 high-income countries have come in. Europe has done it, the US has put zero dollars into this. Certain big players haven’t put money into it. And that’s concerning. So the prospects are reasonable, but not perfect there. As a global community, we need to advocate and put pressure on governments and other entities to put money into this kind of thing. That would make things equitable.

Will most countries follow a similar distribution or roll-out of the vaccine?

Every country will have a different priority scale. I’m working on the WHO side. I serve on the group that is deciding from the [perspective of] global considerations.

For example, there is an expectation within the US that over 300 million doses for most of the population will be available within 12 months. Even in an equitable distribution scenario, that’s not a realistic expectation of availability of vaccines for the full world. So there will be changes there.

The initial scenarios are that in the first year, we’ll have vaccines available for 20% [of population]. But the good and unfortunate thing is that the burden of this disease is being borne disproportionately by certain groups. So if you cover those groups, then you can open up the economy, etc.

So, each country will have a different strategy, but the focus would be protecting lives and livelihoods by reducing transmission, and the balance of the two. The healthcare workers are likely to feature prominently in most countries’ programmes.

Those who have IgG antibodies do not need a vaccine, but the cost of IgG test is more than the indicated cost of a vaccine in India--about $3 by the Serum Institute of India. If their vaccine is successful, how do we overcome this?

We haven’t decided, as advisory committees, that people who have IgG positives will be excluded, because just the positivity doesn’t mean that they are protected.

There is this concept of correlative protection, which means a certain type or level of antibody. We haven’t identified it. We will identify it in the trials. Once we establish efficacy, often then we look into what level of immune response was associated with actual protection, and what type of immune response. We study that biomarker and then, we look at the safety aspect of vaccinating people with pre-existing antibodies versus not [vaccinating them]. Some trials will do this secondary analysis, etc.

So the bottom line is, at this point, it’s unlikely that we will be restricting it only to IgG-negative people because we don’t know with certainty that they’re protected. We do that for most vaccines as well. We don’t test people for other vaccines, because there’s natural infection out there. Some people undoubtedly have IgGs against that, but we say the cost-benefit ratio is such that you go out and vaccinate everyone.

How do you know if the announcement about a vaccine is the right one? There are anti-vaxxers, and it’s a big movement.

There’s a lot of noise in the system. And unfortunately, it hasn’t been helped by people becoming overnight experts in vaccinology. We initially said that people became experts overnight in herd immunity, [and] for example, in epidemiology. That is [now] happening with vaccines. Even well-meaning physicians, who are very prominent in their own fields, are now delving into this kind of stuff. I’m talking about experts on TV, etc, who are experts in other fields.

This is very specialised understanding and knowledge. One way for the general public to filter out signal from noise is to look if someone has a history of doing vaccine work before January 2020. Those are the people you should listen to. This is not “amateur hour”. This is the last inning of a test match where a new ball is introduced. The new ball is the new coronavirus. The platforms or technology was being developed for the previous four and a half days. So focus on the expertise that is previously there, not the expertise that is acquired overnight.

On anti-vaxxers etc., broadly, the first step is to have a mainstream process. That’s why scientists have been insisting on governments and regulatory authorities to speed up the process, but follow the mainstream process. The reason why I go out and say vaccines are safe and effective is because I know the scientific data for that.

And then, there are communications approaches that are being developed. I’m engaged with the process at WHO to communicate truly, but effectively, the benefit of vaccines in the context of overall risk, which is usually minor.

Can the vaccine itself, in a way, take us to a path of normalcy? Or do we have to wait for a cure? Or a combination of all?

There will have to be a combination. But vaccines are a major tool in getting life back to normal, and there will be a normal. There’ll be a new normal. Maybe the Western countries will adapt a version of their Namaste for greetings--because people will be more averse to shaking hands. But other than that, there will be a normal. It will be a slightly different normal. But Grandma will be able to attend weddings, and so on and so forth.

So what is the time that you’re instinctively--and based on your understanding of all the work that’s going on--thinking of, for when we may enter the new normal?

I cannot tell you in terms of calendar time, but I can tell you from the start of the first licensed vaccine because that starts a series of events. From the start of the first authorised or licensed vaccine, within 12 months, we will have a pretty substantial level of normalcy globally--especially if COVAX gets the money it needs. It wouldn’t be perfect.

And within two to three years in total--it wouldn’t be a thing of the past, the virus will remain with us, but it is likely to be a well-controlled virus, if things go as we are hoping for them to go, and the signs look good.

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