Immunology

Interview conducted by April Cashin-Garbutt, BA Hons (Cantab)

Please can you outline the four primary influenza strains that circulate each year?

Influenza is a disease that’s caused by a virus and there are many different strains of influenza that can cause disease in humans. Each year the World Health Organization, and other groups, do surveillance all around the globe to see the types of Influenza Strains that are causing disease in humans.

They meet for the Northern hemisphere vaccine selection every year in February to review all the surveillance data that has been collected over the previous months to look to predict what’s likely to cause disease in the upcoming season.

There are over a 130 influenza centers in 101 countries that collect this type of year-round surveillance. They’re looking at influenza disease trends and information comes in from all these laboratories to the World Health Organization, to the CDC and centers in other parts of the world like United Kingdom, Australia, and Japan, and China.

Up until recently the World Health Organization and the other groups have selected three influenza strains for the influenza vaccine: two strains of the A-type, and one strain of a B-type. Typically there are two A strains that tend to cause disease in humans each year and when they look at the B strains, since the 1980s, two different B strains have been circulating at the same time each year.

These groups select one B strain for including the vaccine based on which B strain is more likely to circulate. But it turns out there are two B strains that circulates around the globe each year and in fact in 6 of the the last 11 years the B strain that was chosen to be put in the annual vaccine was actually not the B strain that was the predominant strain that was circulated.

The B strains are two different lineages: there is Yamagada Lineage and the Victoria Lineage. So, in any given year both the Victoria and the Yamagada are circulating and one of those strains were selected. So, let’s say in one year you might have had, of all the strains circulating, 75% might have been Yamagada and 25% Victoria.

If the strain in the vaccine that year the strain was Yamagada and 75% of those that were circulating were the Yamagada, we would call that a good match. But there was still 25% of the Victoria.

What has happened over the last few years is that vaccine manufacturing has gotten to the point where the number of vaccines doses of seasonal influenza vaccines, which are produced by all the manufacturers, has met demand and in fact perhaps even exceeded demand.

So, given that there have been two B strains circulating, the World Health Organization, the FDA, and the CDC have looked at this and said, “You know, is it possible to put two B strains in the vaccine? So, we don’t have the guess which one is going to be more likely to circulate.”

Given that manufacturing has been meeting demand, this perhaps would not put extra stress on the production process. So, what GlaxoSmithKline did was look at this and this and said, “We think we could do this and not impact on our ability to make vaccine to meet customer demands.”

So, our manufacturing and chemistry process groups began to see if we could add both B strains to the vaccine to make it a four strain, a quadrivalent, vaccine. Back in 2010 we began a series of clinical trials, investigating if we could put two B strains along with two A strains in our vaccine and have these vaccines be safe and effective.

There was a question: if you add an extra B strain will it somehow interfere on the other three strains. So, our studies were done both in children and in adults, with both our now US licensed vaccines called ‘Fluarix’ and ‘FluLaval’. And the results of these studies demonstrated that we could add an extra B strain to the vaccines both in children and adults and not negatively impact the safety or efficacy.

So, our results showed that indeed we could produce a four strain vaccine that would be safe and effective in children and adults and we submitted these applications to the FDA to review and they both now resulted in approvals of the quadrivalent Fluarix and the quadrivalent FlulLaval vaccine for children and adults aged 3 and older.

Why have previous influenza vaccines only covered against three of these strains? Why haven’t they always covered four?

So, it’s was until the 1980s that two B Strains actually began to circulate. At that time there were these three strain vaccines - Trivalent vaccines. There were issues with the ability of the vaccine manufacturers to actually make enough of the three strain vaccines to meet the public demand. In fact, in the early to mid-2000s, there were some shortages of influenza vaccines.

So, vaccine manufacturers began to look really critically to see how we could optimize our manufacturing process and meet customer demand. One way GlaxoSmithKline did this was by actually acquiring another vaccine manufacturer which was called IDB in Canada. We made that acquisition in around 2005 and that’s where our FluLaval vaccine is manufactured.

We now have two vaccine manufacturing facilities for influenza one in Germany that’s where the Fluarix vaccines are manufactured and one in Canada, that’s where our FluLaval vaccines are manufactured. In fact the final production process of both of those vaccines takes place in Marietta, Pennsylvania. We acquired a facility in Marietta, Pennsylvania where we do secondary manufacturing of our vaccines.

We have been looking to meet customer demands by increasing our production capabilities and we have now gotten to the place, as have other vaccine manufacturers as well, where the ability to make influenza vaccines can exceed the customer demands which are about 160 million doses a year across all manufacturers.

We have come to the point where we ask ourselves: can we add an extra strain without it interfering with our ability to meet customer demands? We’re at that point now and that’s why we looked at this process. And at the same time, the World Health Organization and the FDA and the CDC began to appreciate that in any given year, the ability to predict which B strains was not always accurate what would be the most likely strain? They also looked at the manufacturing process and said, “Okay, the manufacturers look like they can meet customer demands. Could they actually do this an extra B strain and then it would take this guess work out.” And that’s what happened.

Now one more thing I should tell you about Influenza B is that it is a strain of influenza that can be quite serious across all of the ages: children, adolescents, adults, and the elderly. The ability to have both B strains in the vaccine has the potential to improve the public health impact of the vaccine. In any given year the impact will change and we will see this year, now that two B strains will be in some of the vaccines, we’ll get to see what the potential impact is.

The CDC follows, during influenza seasons weekly, the trends. There are a number of laboratories around the United States that send samples back to the CDC and we’ll get to see the type of disease and the type of protection that’s being provided. But the potential for improved protection of the public is there and it’ll be looked at carefully this year by the CDC.

When the influenza experts were deciding which strains to cover, how frequently did they get it right?

In the last 11 seasons they got it right, as far as which B was more likely to circulate, 5 out of the 11 times.

So about half of the times the actual B strain that was selected was not the strain that was most likely to be circulating in that upcoming season.

It is just very difficult to predict and so by having both the strains that prediction is no longer needed and both B strains will be there.

What made quadrivalent influenza vaccines possible?

It was a concerted effort by our manufacturing facility, our chemistry and process experts, and our executive team to say, “This is something that is really important.”

Influenza is a disease that strikes very hard all around the globe including in the United States every year, some years are worse than others. Even in the mild seasons, there are still hundreds and thousands of people who’re stricken in the United States every year by an average that is thought to be upwards of 40,000 people die from influenza each year in the United States.

Our goal at GSK Vaccines is to improve public health and this was a clear public health needs as enforced by the CDC in their every year focus to get more people vaccinated against influenza. All of our staff at GSK looked at this and thought it was something we really should work at.

As I mentioned there was an acquisition a company in Canada, there was an acquisition of a manufacturing facility in Pennsylvania, and we just put more focus, more efforts, and more resource behind this and our scientists got to work too. They evaluated adding an extra B strain to the vaccine and whether they could do this without interfering with the way that the three strain vaccine works

Through concerted efforts, and always looking at the customer and what the customer wants, we were able to achieve our goal and we’re thrilled to do this.

Demand by the customers in the United States has been very high for the four strain vaccine, the quadrivalent vaccine. We’ve had what we call ‘Pre Booking Orders’ of upwards of 8 million doses of the Fluarix quadrivalent. 4 million of those doses were ordered by the Center for Disease Control.

We expect to have upwards of 2 million doses available, should customers ask for the in-season ordering with our Flulaval quadrivalent vaccine. The demand has been very good and we expect that in the 2014/2015 season between our two vaccines we could produce upwards of 35 million doses. We will know that next year based on the customer orders.

So, customer demand has been high and we feel that we’ve done the right thing here because this is what our customers are asking for.

How safe and effective are quadrivalent influenza vaccines compared to trivalent vaccines?

That’s the question that we ask in our clinical trials. We said to ourselves, we couldn’t bring a four strain vaccine unless our data from clinical trials showed that adding the fourth strain would result in a vaccine that’d be as safe and effective as the three strain vaccine.

That’s what the results of our clinical trial showed and that’s the results the FDA reviewed in their licensing approval for the quadrivalent vaccines.

Now, that’s from clinical trials, but what we also will do, along with the CDC and other public health officials, is follow the actual clinical behavior of the vaccine we’ve given to the public this year in the United States.

From the clinical trial perspective the vaccines were as safe and effective as our three strain vaccine and of course thus the extra four strain. But the actual performance will be accessed this year and in future years as the vaccines used in the United States across all population age.

What impact do you think quadrivalent influenza vaccines will have on reducing the number of cases of severe illness and deaths from seasonal influenza?

The impact is of great potential but we need to see this year the type of the disease that is occurring in the United States. I can’t give you an actual number until the vaccine is out there and we see what the season is like. But the potential is excellent for improved protection as the four strain vaccines provides broader coverage than the three strain vaccine.

Further information can be found in the following paper where Dr. Reed, a staff member of CDC, and her colleagues looked to model the potential impact of a quadrivalent vaccine compared to the Trivalent vaccine: http://www.ncbi.nlm.nih.gov/pubmed/22226861

Please can you explain how the recently FDA-approved FluLaval® Quadrivalent differs from GSK’s Fluarix Quadrivalent?

They’re very similar vaccines but they do have slight differences in their manufacturing process. All of the seasonal influenza vaccines are very similar in that they look to provide protection against the Influenza A and Influenza B. Yet the actual manufacturing process is slightly different in different facilities.

The end result is that both our Fluarix Quadrivalent and FluLaval Quadrivalent are both licensed by the FDA, and from a public health prospective, whatever vaccine the health care provider has available, it makes no difference to the individual patients. They’re all judged to be safe and effective.

Are they made at different places?

Yes they are. The Fluarix Vaccine is made in Dresden, Germany. The FluLaval Vaccine is manufactured just outside of Quebec in Canada.

Both of those vaccines that’s the primary manufacturing process and then their secondary manufacturing, which is where the vaccines are labelled and packaged, is in Marietta, Pennsylvania.

The labelling and packaging on our Fluarix influenza vaccine now includes 2D bar codes. It’s really exciting to see the new technology being added to our influenza vaccines and the public can take advantage of that now.

Do the two vaccines contain the same strains?

Yes, the strains come from influenza virus seeds that are provided to the manufacturers by the FDA. These seeds are provided to the manufacturers and manufacturers look to optimize the growth of the virus from these seeds. So, yes the seeds are the same and it’s just sort of a downstream process that is different between the two vaccines - the way they’re inactivated and so forth - but the end results are two vaccines that are safe and effective and licensed by the FDA.

What do you think the future holds for flu protection?

I think the future is really bright for flu protection. This is an innovation right now by adding the fourth strain, the 2^nd B strain that makes the 4 strain quadrivalent vaccines. So, that’s a new innovation.

The future holds a view to see how vaccines could become even more effective than they currently are. A lot of different technologies that are potentially available for that and then ultimately one of the goals of influenza research is to create a process where vaccines don’t need to be given every year. The vaccines don’t need to be specific to any one strain or another that’s so called universal. So, that day is not here today but that is certainly an avenue of active investigation at GSK.

Where can readers find more information?

Additional information can be found at:

About Dr. Leonard Friedland

Leonard Friedland, MD, is a pediatrician and pediatric emergency medicine trained physician, and vaccine research scientist. 

Leonard is a graduate of Vassar College and Mount Sinai School of Medicine. His residency and fellowship training was in Philadelphia at Children’s Hospital of Philadelphia and St. Christopher’s Hospital for Children.

He was on staff at Cincinnati Children’s Hospital Medical Center (Assistant Professor) and Temple University Children’s Hospital (Associate Professor) before joining GlaxoSmithKline Biologicals in 2003. 

Leonard currently is Vice President and Director of Scientific Affairs and Public Health, Vaccines in North America at GSK.  He has been involved with the development of many vaccines currently recommended for use in infants, children, adolescents, adults and the elderly.