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Beating the flu

pharmafile | February 18, 2019 | Feature | Business Services, Manufacturing and Production, Medical Communications, Research and Development, Sales and Marketing | flu, influenza, pharma, seqirus

On 14 January, the European Commission issued marketing approval for Flucelvax Tetra, the first cell-based, quadrivalent influenza vaccine. Pharmafocus spoke to Seqirus’ Dr Rajaram on the challenges of tackling the H3N2 influenza virus, as well as threats to vaccination in general.

What advantages does Flucelvax offer compared to similar products?

Traditionally, influenza vaccines have been manufactured using egg-based technology. This approach has worked very well and we have gained a lot of benefits from routine use of influenza vaccines over a number of decades. The challenge with the egg based vaccine – which we are starting to understand a bit more – is that some of these strains, particularly a strain called H3N2, goes through a series of mutations. It has been shown in literature that one of those mutations is due to isolating the strain and growing them in eggs – that can also cause mutations. In that scenario, when you use cell-based technology – so you use the seed strain from start to finish in a purely cell-based process – you can avoid the mutation. That’s the scientific rationale.

What we have seen for the first time in the last season, 2017/18, in the US is by supplying the cell-based quadrivalent vaccine is that it appears to be of benefit. The numbers are small; however, there is positive data that indicates there is a difference. That is the main reason why we believe this cell-based technology offers additional benefit.

What are the advantages of quadrivalent vaccines?

Traditionally, you have a dominance of either an A strain or a B strain in one season. Or you will have an A strain and a B strain, but we used to have recommendations for only three strains to be included, known as trivalent influenza vaccines (TIV). The benefit of the quadrivalent vaccine is you have more strains than a trivalent vaccine, which gives you more certainty that whichever strains circulate, you have coverage or protection against that virus. In terms of effectiveness, the cell-based, quadrivalent vaccine was 36.2% more effective than standard egg-based quadrivalent influenza vaccines (QIV) in preventing influenza-like illness. The numbers are important, but on the other hand it is important to note that this is from a single season, so we have to be aware of the limitations of interpreting data from a single season.

Did the European regulatory environment present any additional challenges for the approval of the vaccine compared to the US?

The regulatory processes are quite similar between the European Union and the United States. The US has the FDA and in the EU you have the EMA; we still have to file all the randomised controlled trial evidence. The licenses are based on Phase 3 studies where we compared immunogenicity of QIVc versus TIVc; we had all the studies already available to us so we submitted them again. So I wouldn’t say there were more challenges; it’s just a slightly different process, but it’s very similar. The one difference I would say is that in the US they are able to approve vaccines with immunogenicity data alone, and sometimes they will allow you to do a post-marketing trial to confirm the efficacy – in the US we are already doing the post marketing trial. That’s the only difference, but otherwise it’s more or less the same.

Vaccine hesitancy was listed as one of the ten major health threats of 2019 by the World Health Organization (WHO). Do you agree with the WHO’s position?

We absolutely, as a company along with other vaccine manufacturers, completely agreed with the WHO’s statement. Particularly in Europe, vaccine hesitancy is becoming more of a problem. In terms of vaccines uptake, the UK is doing relatively well in comparison to other countries. Rates tend to be very low in eastern European countries, and then as you move further to the west they tend to get better. The UK and the Netherlands used to be on the top of the list and I think that’s still the case for influenza vaccine uptake. Countries like Germany and France are still struggling to bring it up; Germany has an uptake of around 35% and France is around 50%. The same is true for Italy and Spain, so most of the countries are struggling to go above 50% influenza vaccine uptake. Uptake of influenza vaccines is a good indicator of how other vaccines will perform.

What factors do you think contribute towards vaccine hesitancy? How can these be tackled?

There are several factors. I think one of them is a bit of complacency in the public. There are factors to do with accessibility of vaccines; if you have centrally conducted policy making – such as in the UK where you have the Joint Committee on Vaccination and Immunisation (JCVI), the Department of Health and the NHS, who roll out the vaccine programmes – you have increased uptake compared to some other countries where you have disparate bodies involved in broad policy making and implementing vaccine uptake.

Another factor has to do with confidence in vaccines. There isn’t a single solution, I don’t think one organisation can work on their own. I think you need public-private partnership to make sure that you work on all those things and governments definitely have a big role to play, along with scientific bodies, in reinforcing the message that vaccines are important. After water, the next best thing which has improved public health was vaccines, so that message needs to be reinforced to the public. It’s an important issue to solve. Seqirus participates as part of a wider network to ensure that as vaccine manufacturers we are part of the voice through the industry body. Sometimes people forget how bad even a minor disease like influenza can get.

In the US they monitor the number of paediatric deaths. It feels a bit scare-mongering but it’s important to realise that 120-130 children die from influenza in the US each year, most of whom are unvaccinated. It could be prevented. That is the information that in Europe isn’t available. So we work with public health partners and industry partners to improve public uptake.

What role did real-world evidence have in bringing Seqirus to market? How did you collect and analyse this real world evidence?

Real-world evidence is important for policy makers. In the UK the body is called JCVI, which is equivalent to NICE. The methodology was not something completely new; we have seen this kind of data come out even in influenza. We use this kind of methodology which has been used for collection of patient outcomes from electronic medical records and we used a huge electronic medical records database in the US.

If you have enough population exposed to a therapy – in this case vaccines – you can compare outcomes with other vaccines that they received, and that is essentially how we do these studies. We work with academic partners based at McGill University in Canada; we review the outcomes and are able to compare the outcomes between the egg-based and cell-based vaccines.

What are Seqirus’ ambitions for the future of Flucelvax? What’s next for the product, or for the company’s efforts to combat influenza?

Seqirus is the only vaccine manufacturer that is focused on influenza and we have two fundamental platforms which are trying to innovate and also deliver cell-based influenza vaccines. We’ll continue to play our part in protecting public health by making sure we innovate, making sure we bring vaccines such as Flucelvax, and by making sure we continue to generate new data.