Next Generation Cell-based Influenza Vaccine Shows Significantly Greater Effectiveness Compared to Standard Egg-based Options in the 2017-18 US Influenza Season

CSL spotlights developments in cell-based vaccine technology at Australian Research and Development briefing

CSL Limited (ASX:CSL; USOTC:CSLLY) subsidiary Seqirus, today presented new real-world data showing that its cell-based quadrivalent influenza vaccine (QIVc) was 36.2 percent more effective than standard* egg-based quadrivalent vaccines (QIVe) in preventing influenza-like illnesses during the 2017/18 influenza season in the United States. This is likely due to the predominance of the H3N2 virus and its propensity for mutation when it is adapted for influenza vaccine production in chicken eggs. These observational data were presented today at the Canadian Immunisation Conference and also shared at CSL’s annual Research and Development briefing in Sydney.

The finding is based on an analysis of over one million (1,353,862) medical records for patients aged four years and above who received either a four-strain egg-based influenza vaccine or a four-strain cell-based influenza vaccine in a primary care setting during the 2017/18 influenza season in the United States. Analysing real-world data from electronic medical records is a new and important approach to understanding the effectiveness of influenza vaccines and their impact on health outcomes. These types of analyses are different from traditional randomised clinical trials which study clinical efficacy.

According to the US Centers for Disease Control1 the 2017/18 influenza season in the US was the worst in recent years with the H3N2 virus being associated with the majority of influenza infections. Research has shown that H3N2 viruses often undergo changes when they are grown in eggs2. When produced completely outside of the egg-based process, cell-based influenza vaccines avoid egg-adapted changes, which means they may offer a closer match and potentially improved protection compared to standard egg-based options in some seasons.3 4 5 6 7

QIVc was first licensed in the US in 2016 based on a study showing non-inferiority immune response to a three-strain cell-based influenza vaccine. Both cell-based products used in this study were produced using egg-based starting viruses8. The 2017/18 season was the first in which QIVc was manufactured using a cell-derived H3N2 starting virus, making this component of the vaccine exclusively cell-based. Seqirus is incorporating other cell-derived starting viruses into the production process for QIVc and has plans to conduct real-world studies over future seasons to help determine the full potential of the cell-based technology in preventing influenza.

“The real-world data, along with other emerging evidence, indicates that cell-based influenza vaccines may result in better influenza-related outcomes compared to standard egg-based vaccine options in some seasons, particularly those seasons characterised by egg-adapted changes,” said Gregg Sylvester, VP Medical Affairs, Seqirus. “We are greatly encouraged by the data and with increasing availability of our vaccine look forward to working with partners to generate additional data in future seasons.”

Developing new and better influenza vaccine technologies is a strategic priority for Seqirus, including further advancing current cell-based technology as well as adjuvants – or ‘immune boosters’ – to enhance the immune response of those particularly vulnerable to influenza such as children and the elderly.

While QIVc is currently only licensed in the US, the European regulatory agency (EMA) recently issued a positive recommendation for the vaccine, indicating formal approval in Europe by the end of 2018. Expansion into other markets is planned after that, including the submission of an application to the TGA in Australia in 2019.

Seqirus’ QIVc is manufactured in the company’s Holly Springs facility in North Carolina. The capacity of the plant to meet anticipated future demand for the vaccine has been greatly enhanced with approval by the FDA earlier in 2018 for important process improvements to the manufacturing process, and by the recently announced US$140 million plant expansion.

"The burden of influenza is a global healthcare concern, and Seqirus is committed to developing new and potentially better vaccines that help reduce the hundreds of thousands of deaths and severe illness caused every year by influenza. Since we acquired the cell-based technology just three years ago, we have increased vaccine production five-fold and introduced cell-derived starting viruses (rather than viruses that have been optimised to grow in eggs). These innovations together with other major investments into the Holly Springs facility will assist us to meet further global demand for the vaccine," said CSL’s Chief Scientific Officer Professor Andrew Cuthbertson.

Influenza is a common, highly contagious infectious disease that can cause severe illness and life-threatening complications in many people. In Australia, the impacts of the 2017 season included high levels of absenteeism and a substantial burden on primary care and hospitals.9

“Vaccination is the best line of defence in reducing deaths and severe illness caused by influenza. Every flu season is different and it’s important that we stay one step ahead of influenza viruses through the development of more effective vaccines, better matched to the strains in circulation. This real-world data on cell-based vaccines is encouraging and will bring another welcome influenza vaccine option to Australia,” said Professor Terry Nolan AO, Head, Melbourne School of Population and Global Health. - ends -

*standard QIVe is non-adjuvanted with standard dose of antigen.


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About the Study: Data from a large U.S. electronic medical record (EMR) provider for primary care practices were obtained between August 1, 2017 and March 31, 2018. This was a retrospective cohort study with the objective of determining the relative vaccine effectiveness (rVE) of cell-based quadrivalent, inactive influenza vaccine (QIVc) compared to that of egg-based, quadrivalent, inactive influenza vaccine (QIVe). The endpoint assessed was influenza-like illness (ILI), as defined by CDC, which is a widely used set of symptoms that serves as an indicator for people who have influenza infection and reflects exposure and outcome experiences during routine clinical practice.

The analysis included data from people 4 years and older in primary care setting, 92,192 who received QIVc and 1,255,983 who received a QIVe. Exposures were derived from recorded immunizations in individual patients EMRs.

The rVE estimated from the study’s primary analysis indicated that QIVc was more effective than standard egg-based QIVs in preventing ILI (rVE of 36.2%, 95% CI (26.1,44.9; P<0.001)). Potential study limitations were minimised using stringent quality control of the data set, cross-referencing the exposure classification step, evaluating two different outcomes code sets for ILI, adjusting for key variables and conducting multiple sensitivity analyses.10 There are currently no head to head clinical trials comparing the efficacy QIVc to QIVe.
Quadrivalent cell-culture influenza vaccine is not approved in Australia.

About Seasonal Influenza: Influenza is a common, highly contagious infectious disease that can cause severe illness and life-threatening complications in many people. To reduce the risk of more serious outcomes, such as hospitalization and death, resulting from influenza, the CDC encourages annual vaccination for all individuals aged 6 months and older.11 Because transmission to others may occur one day before symptoms develop and up to 5 to 7 days after becoming sick, the disease can be easily transmitted to others.12 Influenza can lead to clinical symptoms varying from mild to moderate respiratory illness to severe complications, hospitalization and in some cases death. The CDC estimates that 959,000 people in the United States were hospitalized due to influenza-related complications during the 2017/18 influenza season. Since it takes about 2 weeks after vaccination for antibodies to develop in the body that protect against influenza virus infection, it is best that people get vaccinated to help protect them before influenza begins spreading in their community.9

About CSL: CSL (ASX:CSL) is a leading global biotechnology company with a dynamic portfolio of life-saving medicines, including those that treat haemophilia and immune deficiencies, as well as vaccines to prevent influenza. Since our start in 1916, we have been driven by our promise to save lives using the latest technologies. Today, CSL — including our two businesses, CSL Behring and Seqirus - provides life-saving products to more than 60 countries and employs 22,000 people. Our unique combination of commercial strength, R&D focus and operational excellence enables us to identify, develop and deliver innovations so our patients can live life to the fullest. For more information about CSL Limited, visit www.csl.com.

References

1 Centers for Disease Control and Prevention (CDC). (2018). Estimated influenza illnesses, medical visits, hospitalizations, and deaths in the United States — 2017–2018 influenza season. Retrieved from: https://www.cdc.gov/flu/about/burden/estimates.htm Accessed November 2018.
2 CDC. (2018). Advisory Committee on Immunization Practices (ACIP) Presentation Slides: June 2018 Meeting. Retrieved from https://www.cdc.gov/vaccines/acip/meetings/slides-2018-06.html Accessed November 2018.
3 Rajaram S., Van Boxmeer J., Leav B., et al. (2018). Retrospective evaluation of mismatch from egg-based isolation of influenza strains compared to cell-based isolation and the possible implications for vaccine effectiveness. Presented at IDWeek 2018, October 2018.
4 Zost S.J., Parkhouse K., Gumina M.E., et al. (2017). Contemporary H3N2 influenza viruses have a glycosylation site that alters binding of antibodies elicited by egg-adapted vaccine strains. PNAS, 114(47)12578-12583. doi:10.1073/pnas.1712377114.
5 Wu N.C., Zost S.J., Thompson A.J., et al. (2017). A structural explanation for the low effectiveness of the seasonal influenza H3N2 vaccine. PLOS Pathogens, 13(10): e1006682.
doi:10.1371/journal.ppat.1006682.
6 The Francis Crick Institute. (2018). Worldwide Influenza Centre: Annual and Interim Reports – February 2018 interim report. Retrieved from https://www.crick.ac.uk/research/worldwide-influenza-centre/annual-and-interim-reports/ Accessed November 2018.
7 CDC. (2018). Cell-Based Flu Vaccines. Retrieved from: https://www.cdc.gov/flu/protect/vaccine/cell-based.htm Accessed November 2018.
8 Flucelvax Quadrivalent – Seqirus Inc. 07/2018 (revision 2) Highlights of Prescribing Information: https://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM619588.pdf
9 Australian Government Department of Health. 2017 Influenza Season in Australia – A summary from the National Influenza Surveillance Committee, Information Brief 22 Nov, 2017: http://www.health.gov.au/internet/main/publishing.nsf/Content/097F15A91C05FBE7CA2581E20017F09E/$File/2017-season-summary-22112017.pdf
10 Armed Forces Health Surveillance Center (AFHSC): Influenza-Like Illness (ILI). (2015). Retrieved from https://www.health.mil/Reference-Center/Publications/2015/10/01/Influenza-Like-Illness Accessed November 2018.
11 CDC. (2018). Key facts about seasonal flu vaccine. Retrieved from: http://www.cdc.gov/flu/protect/keyfacts.htm Accessed November 2018.
12 CDC. (2018). How flu spreads. Retrieved from: https://www.cdc.gov/flu/about/disease/spread.htm Accessed November 2018

The Holly Springs facility was built in partnership with the US Biomedical Advanced Research and Development Authority (BARDA) and has been funded in whole or in part with Federal funds from the Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and BARDA, under contract numbers HHSO100200600012C, HHSO100200700030C HHSO100200900101C and HHSO100201200003I.