Will we need Omicron-specific COVID vaccines? A leading virologist says the global system for flu shots could be a model to help us decide

Many are thinking about that question, but few may be more central to resolving it than Dr. Kanta Subbarao, the virologist who chairs the World Health Organization’s Technical Advisory Group on COVID-19 vaccine composition (TAG-CO-VAC). Subbarao is also currently the director of the WHO Collaborating Centre for Reference and Research on Influenza in Melbourne, and a professor at the Peter Doherty Institute for Infection and Immunity; from 2002 to 2016, she served as chief of the Emerging Respiratory Viruses Section at the National Institute of Allergy and Infectious Diseases in the U.S.

Coins2Day spoke with Subbarao in late January about Omicron, her committee’s work, and what she expects of the virus and COVID vaccines going forward. Among her insights: As new SARS-CoV-2 variants like Omicron continue to emerge, the global system we have for updating influenza vaccines may be the best model for coordinating a global COVID vaccination strategy in the future. While the existing COVID vaccines continue to work well in protecting individuals against severe illness and death, says Subbarao, they are not being used widely enough, a status quo that virtually guarantees there will be more variants.

This interview has been edited lightly for clarity and length.

Coins2Day: You chair the WHO committee focused on COVID vaccine composition. Can you tell us about it?

Subbarao: The committee is new. The hope when we started down this track, when the first SARS-CoV-2 vaccines were made, was that it would be like measles—you make one vaccine, and it lasts for 50 years. Then, of course, we’ve seen the variants emerge. The early variants, the Alpha variant, certainly, and to some extent, the Delta variant, were really covered fairly well with the original vaccines. And yet, certainly with the emergence of the Beta variant, and there was concern even with Delta as to whether the vaccines would need to be updated because as time went along, we were seeing these surges of disease as the new variants emerged. So the WHO recognized the need to have these discussions, and they formed this committee in September. 

This is a committee of 18 people—you can go to the TAG-CO-VAC’s site and read about the committee and what we’re tasked to do, but essentially, we are tasked to advise the WHO about the composition of the SARS-CoV-2 vaccines: When would we recommend a change? And what change would we recommend? 

How’s it going so far?

When we first met, we were still talking about Delta, and then Omicron happened. So we have been meeting pretty frequently. The whole committee has met about once every two weeks if not more frequently than that. But it is a very new committee, and we’re coming to grips with the decisions that we have to make. 

We can think about it in two parts. One is a decision about what factors would take us to the point where we would actually recommend a change to the composition of the vaccine. And then the second part of that is, if we think that we need to update the vaccine, exactly what strain would we recommend using? The model for some of this is influenza. Influenza is the only vaccine that is currently updated regularly, and the influenza vaccine composition—how that advice is given and what it’s based on—has been about 50 years in the making. 

How does the influenza system work? What makes it a good model for COVID?

It’s called the Global Influenza Surveillance Response System, or GISRS. In my position here, I am the director of one of five WHO collaborating centers that work on human influenza. The centers get together twice a year to make recommendations on what the composition of the influenza vaccine should be for the Northern Hemisphere and for the Southern Hemisphere.

Influenza vaccine manufacturers are very used to this. They’re comfortable with it. They know that we will meet in the fourth week of February and the third or fourth week of September, and we make a recommendation at the end of a week of deliberation. It’s on their calendars, they know this, and that’s what they’re looking for. 

This is not the case yet for the SARS-CoV-2 vaccines. The vaccine manufacturers, to date, have been making their own decisions about what should be in their vaccine. Initially it was a no-brainer—Wuhan-like viruses were circulating, and people worked with what they had, which were the prototype or reference viruses that the labs have been working on. Each of the companies have their scientific advisers who have been advising them on what to do, what the composition should be. The WHO’s hope is that we can make this more harmonized and make it a decision that is a recommendation that’s made for global vaccine manufacturers. This is still seen as advice from the WHO, even for flu vaccines: Each country and each country’s regulators meet then to decide whether to take the WHO advice on a strain or not. They are all free not to. It’s not like the WHO mandates something. It’s a recommendation. 

So that is the hope—that we’ll bring some harmonization on this sort of decision-making, because there are so many different vaccine manufacturers, and there are more vaccine platforms for COVID-19 vaccines than there are for flu vaccines. 

I see this committee working very closely with the manufacturers and the regulators. We’re not going to step on the regulators’ toes and make any determination of how a new vaccine would be regulated, what would it take to get that into licensure? But we really want to create some transparency and have some open discussions, because all three parties really have to work together to get this right.

What’s the response been from those other parties?

For COVID-19, these are early days. We’re still socializing this concept with vaccine manufacturers, that this committee exists, and that this is what the committee is tasked to do. Country regulators need to know what’s coming their way, so we have spent quite a bit of the time since we first started meeting regularly to get up to speed in our communications with these groups. It didn’t help that it was Christmas and Omicron and everything all happening at the same time. 

We put out our first statement, and I think that really tells you quite a bit about what the committee’s thinking is. We’re going to be working on a document that explains the sort of framework that we will consider, but as you can imagine, we are learning a lot about this virus as we go. And Omicron is quite significantly different from the previous variants, and so there’s a lot to learn about what those differences are and what the implications of those differences are, and what the implications might be for vaccines.

How well does the influenza model translate to SARS-CoV-2?

It took 70 years to develop the flu system to where we are. It’s not going to happen overnight. We also don’t want to just make a carbon copy of the flu system. We want to make something that’s suitable for SARS-CoV-2, that takes elements and lessons from what we do for flu, but then make it specific for SARS-CoV-2. A good example is that we don’t know what the seasonality of COVID-19 is or will be, so we’re not in a position to say we’ll make two decisions a year. 

We have a lot of genetic sequence data for SARS-CoV-2, but at the end of the day, these vaccines work by inducing immunity, and so we need antigenic characterization, we need to know which of these amino acid changes in the spike protein are important for evasion of the immune response. We can talk about Omicron today, but it’ll be another variant tomorrow or six months from now. So, in principle, we need to develop an infrastructure, we need to have a set of assays and labs and shared assays, shared reagents, looking at some of the same viruses so that we can actually link the genetic sequence changes that we’re aware of to phenotypic changes that have an influence on vaccine-induced responses. 

What we do for influenza, we’ve got this global influenza surveillance system with over 140 national Influenza centers that collect viruses. They do some initial characterization and then they forward those viruses on to one of the five WHO collaborating centers: [They’re] in Atlanta; one is in London, Beijing, Tokyo, and Melbourne. And we characterize thousands of viruses a year in the lead-up to figuring out which strain should go into the vaccine. At this point, a similar infrastructure does not yet exist for COVID-19. There are labs that are doing similar work, but they’re not in a cohesive network nor are they using shared reagents or shared assays. That is some of what I think will happen as time goes on. 

As a committee we’re looking at what data we need. We may be able to get those data for Omicron by calling the right people [right now], but down the road, are we going to want to have a similar structure where there are designated labs that do this, that share information on a regular basis? You want labs to independently test viruses and generate their own information and compare it. We don’t want to rely on a single lab providing some insights, we want to see reproducibility. And SARS-CoV-2 is around the world so we need to figure out whether we’re going to have regional information and get good coverage of what’s happening in regions, or are we going to have a global recommendation. I hate to leave you with more questions than answers, but I really feel we’re at the beginning.

I think we’re making really good progress in getting our heads around what the issues are and how we can solve them. We won’t solve the infrastructure, the planning [of] how it is going to look a year from now, tomorrow. In the interim, we know who’s doing what—the WHO has a good feel for that. And the world has been sharing scientific information really, really well. So it’s a matter of connecting the dots between what we know of the genetic sequence data and identifying what implications those changes have for vaccines.

There’s lots of discussion of Omicron-specific vaccines right now. Do you think your committee will recommend updating vaccines to target Omicron?

I can’t say yet what the decision will be. Omicron certainly has us meeting regularly and looking hard at what the vaccine should look like in 2022. In our statement, we have encouraged manufacturers that are already developing Omicron-specific vaccines to share the information that they get so that can inform some of our decision-making. 

From the 30,000-foot view, essentially you could say, “Well, shouldn’t you just make a vaccine against what’s prevalent?” In which case, we would have at least Alpha, Delta, and now Omicron vaccines. But the issue is also how much immune escape had happened, and how well the [current] vaccines are performing. Certainly, the Wuhan virus–containing vaccines have performed very well in preventing severe illness, hospitalizations, and deaths. In any of this discussion, we really want to call out the fact that we still have a lot of confidence in the currently available vaccines to achieve what they were set out to do, which is to try to protect the health care system. 

Now, what we want in the ideal world is that we all want vaccines that will not just prevent severe illness and hospitalization and death, but also prevent infection and reduce transmission. Second generation, third generation vaccines may give us that, but we do want to call out that the currently available vaccines are performing well and they’re not being utilized as widely as we would like. We really want that to be recognized. We will be in the situation of new variants emerging as long as there’s this tremendous burden of infection. And we know that vaccinating more widely will reduce that burden of infection globally and will help reduce the risk of emergence of new variants.

I’m glad you mentioned that. There’s been some discussion in the U.S. About the need to better define the goal of the vaccines. Is the goal to prevent serious illness and death, or is it to prevent all infections? Some argue the latter isn’t realistic with this virus.

There’s no doubt that that would be the ideal solution, but it is very, very difficult to prevent upper respiratory tract infections of respiratory viruses using an injectable vaccine. What works to prevent upper respiratory infection and transmission is to get a lot of mucosal immunity—you need immunity at the site where the virus initially infects and replicates, which is your nose and throat. It’s very hard to achieve good immunity that lasts a long time in your upper respiratory tract by injecting a vaccine into your arm. The vaccines that we inject into people’s arms, they make an immune response that circulates in the blood and it protects the lungs very well.

Even with influenza, we don’t prevent influenza infection, we prevent complications of influenza; we prevent severe disease that ends up in complications that require hospitalization, or cause death, because it’s so hard to do this. Really, you have to consider administering a vaccine to the mucosal surface, and that’s where the live attenuated vaccines were designed to do that.

I would say our current platforms provide some protection from asymptomatic and mild infection, and they do help prevent transmission. The mRNA vaccines [like those from Pfizer/BioNTech and Moderna], when they did studies in families where people were vaccinated, and there was an introduction of a virus into a family, there was less spread when people had been vaccinated with the mRNA vaccine, so it’s not as if they don’t do any of that. With Omicron we’re not seeing very robust protection of the upper respiratory tract, but that’s because it is really a very high bar. It may be that it will be next generation vaccines that will achieve that. 

I think our expectations of the vaccines have changed over the two years. When we started, we were all absolutely delighted to have vaccines that would prevent severe illness, hospitalization, and death. We should remain very grateful that we have such vaccines, but certainly everybody would really much rather have a vaccine that prevents infection and prevents even milder asymptomatic infection and transmission. That’s why it’s an aspirational goal. It’d be great if we had it, but I would still call out the current vaccines for what an incredible job they’re doing with preventing severe illness and hospitalization.

Does the number of different COVID vaccine platforms make decisions about changing vaccine composition more difficult?

I don’t think that it necessarily complicates things—each of the manufacturers are comfortable with their platforms. What it does is say to us as a committee that we can’t just assume that we pick out a sequence and say, “This is the spike gene sequence that people should be using.” I think the complication will be something that is probably more a discussion for the manufacturers and regulators as to whether the final product will be a vaccine containing a single strain, or whether regulators and manufacturers together may choose to consider a vaccine that contains more than one strain. The reason I say that’s a regulatory issue is because the regulators will then have to give the advice on how such a product will be evaluated for licensure. It’s an issue for manufacturers because their platforms actually have to be compatible with the multivalent vaccine. We do this for flu: We recommend four strains each year, and all the manufacturers make multivalent—quadrivalent and trivalent vaccines. But this is going to be something new for SARS-CoV-2, so whether it will be monovalent or beyond monovalent is something that’s going to be a topic for discussion.

How do you think manufacturers have done in communicating around this?

I think they’re doing really well. This is a new committee, and it’s a new way of doing business. The WHO has reached out to them, and they are having regular discussions while maintaining confidentiality [around business practices]. It’s not as if we can bring 18 manufacturers into the room and say, “Tell us everything.” They play a very, very significant role in the public health response to COVID-19.

As a virologist who has studied emerging respiratory viruses throughout your career, what have you made of the SARS-CoV-2’s evolution? Did Omicron surprise you?

Like I said, at the beginning, we were hopeful that we’d get away with a single vaccine that would cover us for years to come. Coronaviruses actually have an enzyme that proofreads, and so it doesn’t make as many mistakes [in replicating] as influenza does. But the virus has taught us a lot over the course of two years, and there have been surprises.

To me, the surprise with Omicron was not so much that the variant emerged, because we’ve been seeing variants emerge on a somewhat regular basis. To me, the surprise was that a virus with so many changes was fit enough still to become the dominant strain around the world. Normally, when a virus undergoes a huge number of mutations, some of those mutations end up debilitating the virus, in a way that it can survive in a small setting but may not actually come to dominate over the previously very successful Delta variant. That’s what we were looking for, to see whether the Omicron virus, carrying so many mutations would actually be fit enough to become epidemiologically successful. And it has.

What implications does that have for the virus’ future evolution?

We don’t know enough about the variants of SARS-CoV-2 to know whether the next variant will emerge from Omicron or if it will emerge from some other part of the phylogenetic tree. With influenza, with our 70 years of experience, we can track it, and it usually doesn’t go backwards. There’s a continued evolution in a certain direction. We don’t know that yet with SARS-CoV-2, so we have to continue to monitor to see where a new variant with the properties that make it successful will emerge.

Anything else you would add that we haven’t talked about?

I want to highlight these couple of issues that we’ve talked about: We really have a lot of confidence in the existing vaccines, and what we’re trying to do is create a framework to follow SARS-CoV-2 as it evolves and see what the implications are for vaccines. This new committee’s role is to try to get some global harmonization, but there are many questions still that we’re dealing with in terms of how to go about doing this. But it is a step in the right direction.