Overcoming Low Influenza Vaccine Effectiveness
This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.
PRIORITY PRESS - The Canadian Immunization Conference (CIC)
Ottawa, Ontario / December 4-6, 2018
Ottawa - Increasing the effectiveness of influenza vaccines is one of the core strategies for dealing with future seasonal influenza outbreaks and pandemics. While egg-based manufacturing processes for influenza vaccines have been in place for 75 years, the Centers for Disease Control and Prevention (CDC) note that growing viruses in eggs can cause adaptive changes and mismatches between the vaccine and the circulating influenza virus. This has been documented particularly with recent influenza A (H3N2) outbreaks. Mammalian cell-based influenza vaccines do not have this problem and represent a promising option for dealing with influenza outbreaks as does the use of adjuvants to enhance the immune response from vaccines. Enhancement of the immune response to a vaccine is particularly important in young children whose immune system is immature as well as in older adults who are subject to immunosenescence, two groups who respond particularly well to adjuvanted vaccines. Older patients also respond better to higher doses of antigens in vaccines such as the high-dose influenza vaccine now used for patients over the age of 65.
Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec
The ongoing challenges of manufacturing effective influenza vaccines to control seasonal and pandemic influenza outbreaks was a topic that emerged repeatedly at this year’s Canadian Immunization Conference which commemorated the centennial of the devastating Spanish Flu pandemic.
Opening plenary speaker, Dr. Nancy Cox, retired Director of the Centers for Disease Control and Prevention Influenza Branch set the tone for the meeting with a comprehensive overview of past and future influenza vaccine and preparedness challenges. Despite many advances in vaccine development and surveillance since the 1918 pandemic, Dr. Cox said significant challenges remain in producing and administering effective vaccines. “If a 1918 flu pandemic were to occur today, there would be an estimated 105-110 million deaths worldwide in spite of all our medical advances,” said Dr. Cox. “A very sobering number.”
One particular issue of concern is the difficulty associated with growing the influenza A (H3N2) strain of influenza viruses in eggs, even though 85% of influenza vaccines are still produced this way. Dr. Cox noted that egg propagation of vaccines results in mutations in hemagglutinin during replication, creating vaccine viruses with lower antigenic similarity to circulating strains which reduces vaccine effectiveness.
In contrast, cell-based vaccines have the potential to more effectively counter pandemics because they can be produced more quickly than egg-based vaccines, as Dr. Cox noted. Dr. Matthew Miller, Assistant Professor of Biochemistry and Biomedical Sciences, McMaster University in Hamilton, noted that relying on egg-based vaccines could completely miss the first wave of a pandemic because of the time it takes to produce them.
Dr. Mark Loeb, Professor of Pathology and Molecular Medicine at McMaster University in Hamilton reaffirmed that there are manufacturing difficulties with egg-based vaccines which have compounded issues of antigenic mismatch.
However, some of the newer vaccines that contain higher-doses of antigens or those that contain adjuvants have shown incremental benefits for some populations.
Cell Culture-Propagated Virus
A comparison between egg-propagated influenza vaccines and those propagated by cell culture presented here, confirmed there is less antigenic mismatch using a cell culture-propagated approach.
Using data from the Worldwide Influenza Centre (WIC), Dr. Sankarasubramanian Rajaram, regional head of medical affairs for Seqirus UK Ltd and colleagues retrospectively compared antigenic similarity of circulating influenza A (H3N2) isolates with egg-propagated versus cell-culture propagated reference viruses for influenza seasons 2003-2018.
The WIC tested the responses of circulating influenza A (H3N2) virus samples to ferret sera raised against egg and cell reference viruses using hemagglutination inhibition (HI) and plaque reduction neutralization assays (PRNA). Researchers further analyzed WIC data to assess the proportion of circulating viruses for each season which showed antigenic similarity to the reference viruses as defined by a fourfold or lower reactivity.
The study found that in HI assays, the circulating influenza A (H3N2) isolates and egg reference viruses were antigenically different in >50% of the seasons analyzed. For more than half of the influenza seasons evaluated, there was little (<25%) or no antigenic similarity between the circulating influenza A (H3N2) virus and the egg-propagated reference viruses. Data from the PRNA assay also showed higher proportions of isolates had antigenic similarity to cell reference viruses compared with egg reference viruses.
As a result of these findings, researchers concluded cell culture-derived reference viruses avoid egg-based viral adaptations which result in vaccine-induced antibody responses of higher specificity for wild-type influenza A (H3N2) hemagglutinin. They also stated that higher levels of antigenic similarity may result in increased influenza A (H3N2)-specific vaccine effectiveness.
Researchers said their findings support the use of cell culture-derived seasonal influenza vaccines against influenza A (H3N2).
Using U.S. data, other researchers assessed the effectiveness of the cell culture-derived seasonal influenza vaccine versus the egg-derived vaccine during the 2017-2018 Northern Hemisphere influenza season in a retrospective cohort study.
“The theory behind the cell-based production platform is that it will circumvent mutations that occur during the propagation of vaccine strain viruses in eggs that are documented and known to happen,” reported study author Dr. Constantina Boikos, an infectious disease epidemiologist and medical science liaison for Seqirus in Canada.
Dr. Boikos noted that the 2017-2018 influenza season was considered an ideal opportunity to measure the effectiveness of the cell-based vaccine “because it was characterized by the widespread circulation of an H3N2 strain that we know to be mutated because of egg-based propagation.” The overall interim influenza vaccine effectiveness during this season in the U.S. was estimated to be 40% because of this.
Using a primary-care electronic medical record (EMR) dataset with a catchment population of 55 million people, the research team evaluated 92,192 individuals who received the quadrivalent, inactive cell-based influenza vaccine and 1,255,983 who received an egg-based quadrivalent vaccine. The study period was between August 1, 2017 and March 30, 2018.
When adjusted for demographic variables, the cell-based vaccine was estimated to be 36.2% (P<0.001) more effective than the egg-based vaccine in preventing influenza-like symptoms as reported during primary care visits. When the data were evaluated using a more conservative propensity score analysis, the cell-based vaccine was still19.3% more effective – a statistically significant difference between the 2 vaccines.
“This is the first season whereby we were able to evaluate the clinical benefit of the cell-based vaccine,” Dr. Boikos concluded. “Theoretically these results would be generalizable to an analogous or similar (influenza) season characterized by H3N2 strains that differed from the vaccine-strain viruses propagated in eggs.”
Cost Effectiveness of Adjuvanted Vaccines
The cost effectiveness of other approaches to influenza vaccination – use of an adjuvanted or a high-dose vaccine – was also discussed at the meeting. One analysis, for example, focused on the public health impact of using enhanced influenza vaccines in several provinces as well as in Canada as a whole.
A Canadian dynamic influenza transmission model formed the basis of the analysis to assess the impact of using enhanced flu vaccines compared to standard of care. Seven age groups were modeled in the analysis, including a high-risk group in long-term care. Each province’s influenza vaccine program for the 2017-2018 influenza season was used as the reference scenario.
Three alternative programs were evaluated for individuals aged 6-24 months, 2-64 years and those older than 65 years of age. Conservative vaccine efficacy and effectiveness estimates and public health costs were taken from published literature.
Vaccines included in the analysis were the standard dose trivalent influenza vaccine, the high-dose trivalent influenza vaccine, the MF-59 adjuvanted trivalent influenza vaccine (aTIV), and the quadrivalent influenza vaccine.
The analysis found that for all provinces, inclusion of aTIV saved costs by reducing the number of cases and hospitalizations from influenza compared to that province’s current program. With an Incremental Cost Effectiveness Ratio (ICER) threshold of $56,000 for each Quality Adjusted Life Years (QALY) gained, using the aTIV in the oldest population group compared most favorably to existing programs.
Findings from this study are similar to other evaluations conducted in the Germany and the US.
Dr. James Mansi, Global Medical Lead at Seqirus and one of the authors of the study, said that while Quebec has a recommendation for using aTIV in long-term care home residents over the age of 65 other provinces currently do not have recommendations for use of the same adjuvanted vaccine.
“The overall message is that by having an enhanced influenza vaccination program for those aged 65 plus, you are going to get the most benefit,” Dr. Mansi said. For enhanced vaccines at their current cost, the biggest cost savings come from using the adjuvanted vaccine, he added.
Two studies presented at the Canadian Immunization Conference confirmed the mismatch between egg-based reference viruses and wild influenza A (H3N2) vaccines and also significantly better vaccine efficacy from cell-based vaccines. Cell-based influenza vaccines avoid problems associated with egg-based vaccine production and potentially have a higher vaccine efficacy. The cost-effectiveness of incorporating the MF-59 adjuvanted trivalent influenza vaccine (aTIV) into Canadian influenza vaccine programs was also demonstrated.
Based on data presented at CIC 2018: An enhanced vaccination program with the adjuvanted seasonal influenza vaccine is highly cost-effective at the programmatic level in Manitoba, Alberta and Nova Scotia: Nguyen V, Boikos C, Mansi J.; Retrospective evaluation of mismatch from egg-based isolation of influenza strains compared to cell-based isolation and the possible implications for vaccine effectiveness: Boikos C, Rajaram (Raja) S, van Boxmeer J, Leav B, Suphaphiphat P, Iheanacho I, Kistler K.; Effectiveness of the cell culture-based and egg-based, seasonal influenza vaccines during the 2017-2018 Northern Hemisphere influenza season Boikos C, Sylvester G, Sampalis J, Mansi J.