Ditching the Egg: An Alien Concept

As many of you will know, the vast majority of influenza vaccines are traditionally made in chicken eggs. . The virus is grown in the chorio-allantoic membrane which surrounds the embryo of a fertilized egg in a well-established process that has been in use for decades. Prior to COVID-19, vaccines were not a hot topic, nor were they frequently seen as a lucrative business prospect. It was well accepted that more modern processes could be used for influenza vaccine production, but innovation in this space has been slow for a variety of reasons, including the old adage: “If it ain’t broke, don’t fix it (especially if the latter needs investment).” 

That said, some companies were starting to evaluate other options, including a shift from egg-based to cell-culture based vaccines. One example of innovation in this field is Flublok – a protein-based vaccine made in insect cells. According to Piergiuseppe Nestola, Manager of Process Technology Consultants at Sartorius, the influenza vaccine has always been a key vaccine to optimize and improve, particularly in terms of the manufacturing process. “Egg-based processes are slow and require huge facility footprints, which are also becoming unfavorable as more attention is paid to sustainability. In terms of development, strain selection is a challenge too. There is a limited window of time from when the yearly influenza strain is detected, which puts pressure on the process. It’s not unusual in influenza for the strain selected to ultimately not end up being the one circulating with high prevalence during the winter seasons.” 

Explaining one of the biggest disadvantages of traditional egg-based processes, Joseph Payne, CEO, President, and Co-Founder of Arcturus Therapeutics, which is developing mRNA-based vaccines and therapeutics, points to another element of speed. “The term in the vaccine industry that is extraordinarily important is ‘clock speed.’ The World Health Organization (WHO) and other non-profit organizations will publicly share the strains of concern – and then vaccine producers design, manufacture, and distribute the vaccine in time for the flu season.”

Recognizing the challenges, some companies were already taking action. The famous Pfizer/BioNTech COVID-19 vaccine actually has its roots in influenza innovation efforts, with the companies agreeing their first partnership in 2018. In 2020, the companies agreed to expand their collaboration to the far more pressing threat of COVID-19. The story of the COVID-19 collaboration is history, but what of influenza? The work continues – with volunteers recruited for a phase III clinical trial last year. Ultimately, they hope that an mRNA-based method will be faster to develop and manufacture, thus achieving more accurate matching against circulating strains. 

Several companies are now keenly exploring the potential of mRNA. One key area of interest is combining influenza and COVID-19 vaccines in a single shot. “Other clinical trials are looking at combining different subtypes of influenza (A and B) to develop a broadly protective vaccine or, in some cases, even a universal flu vaccine, thus avoiding the risk of not having selected the right strain for the next flu season. It could help adoption of this vaccine and facilitate its production, while also reducing the frequency of the booster injections,” says Nestola. “Of course, the industry still needs more data to assess the feasibility of mRNA in terms of immune response and whether re-optimization of LNP formulations is required for influenza. Nevertheless, mRNA vaccines have proven their superiority in terms of manufacturing speed (it takes around 24 hours to manufacture a batch of mRNA, compared to 2–3 weeks for a cell culture based process). These aspects taken together bring a potentially strong competitive advantage for mRNA. Time will tell if the immune response against other disease targets will be as good as what we saw for COVID-19 or if we need a toolbox to work with different disease targets.”

For Payne, the benefit of mRNA lies in its ability to reduce the critical clock speed. “mRNA makes it much faster to design and manufacture the vaccine. At Arcturus, we are finding that next generation mRNA, such as self-amplifying mRNA, may offer even more benefits too – such as lower doses that are much more efficient from a manufacturing perspective because one manufacturing run generates so many more doses.”  

We spoke with companies to find out how they are innovating in influenza – from making monoclonal antibodies, to mRNA – and beyond. Check out the articles below…