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Influenza Researchers Explore Real-World Data for Flu-Vaccine Evaluation and Learnings for COVID-19

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.

MEDICAL FRONTIERS - Canadian Immunization Conference (CIC 2020)

Online / December 1-3, 2020

Online – Although the COVID-19 pandemic dominates the infectious disease headlines, influenza remains a striking public-health problem in Canada, with up to 7 million people sickened during a non-pandemic flu season. The seasonal flu-vaccine coverage has yet to meet the 80-percent Canadian target, even in the vulnerable over-65s. During a COVID-19-dominated flu season, presenters at the Canadian Immunization Conference 2020 discussed strategies to improve flu-vaccine uptake and better evaluate vaccine effectiveness. Speakers also explored commonalities between the two infectious diseases and how flu science could inform COVID-19 medicine.

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

“It’s going to be interesting to watch, but impossible to predict,” said Dr. Allison McGeer, an infectious-disease consultant at Mount Sinai Hospital in Toronto, speaking about the co-circulation of seasonal flu and COVID-19.

Although Dr. McGeer expressed caution about the quality of the supporting data, she suggested several ways in which the two diseases could interact, including the following: COVID-19 public-health interventions reducing influenza transmission; co-infections; flu vaccination impacting COVID-19 incidence; and COVID-19 affecting flu-vaccination uptake.

The Australian (i.e., Southern hemisphere) flu season this year suggested that social distancing and masks are having a beneficial effect on the flu numbers, Dr. McGeer said. However, Dr. McGeer cautioned that “there are going to be some people who end up with both infections and frequently co-infections are more severe” and she praised Canadian public-health messaging. “It’s been solid and steady,” Dr. McGeer said: “‘Yep, you need to get your flu vaccine, there could be an interaction.’” On a positive note, Dr. McGeer
speculated that the pandemic would “break some barriers” to flu shots.

Flu Vaccination in the Setting of COVID-19

Two posters presented at the CIC supported Dr. McGeer’s prediction.

An online survey of 4,501 Canadian adults found that 20 percent of respondents aged 50-64 and 8 percent of people over 65 were more likely to seek a flu shot this season.1 Participants gave reasons such as “COVID-19 has demonstrated the devastating potential of viruses,” and “this would be a particularly risky season,” according to poster authors from the University of Waterloo, Dalhousie University and the Institut national de santé publique du Québec. The study was supported by Sanofi Pasteur.

A Seqirus survey on flu-vaccine uptake during COVID-19 showed a similar trend. Fifty-eight percent of Canadian adults said they would ‘definitely/probably’ get a flu shot this season, including 73 percent of those who typically got the flu shot every 2–3 years and 11 percent who had never had a flu vaccination before (N=1,493).2 Study author Kim Murray Perrault said that this research “indicates a much stronger awareness by the public and perception of the risk of influenza…This kind of growth has never been seen before.” Perrault found it concerning, however, that 38 percent of participants “believed they could tell the difference between flu and COVID-19 infection by symptoms alone” and that one-quarter of people in the survey said they would not self-isolate or inform recent contacts if they developed flu-like symptoms. 

Flu vaccination in Canada is typically sub-optimal according to several conference presenters. For example, Dr. Angel Chu, an infectious disease physician at the University of Calgary, presented data from the Seasonal Influenza Vaccination Coverage Survey for 2018–2019.3 During that season, only 43 percent of people with a chronic medical condition had the flu shot, well short of Canada’s 80-percent target. People over 65 years “did better”, said Dr. Chu, with coverage reaching 70 percent. Dr. Chu said healthcare provider recommendation is key to improving uptake: “Very few patients will come and ask for vaccines. But if we, as healthcare professionals, make that strong recommendation and clearly convey a risk to the patient, then we know that vaccine uptake rates will dramatically skyrocket,” she concluded.

A poster presentation at the CIC provided support for Dr. Chu’s remarks on the power of professional reminders – in this case, from pharmacists.4 (Pharmacists are licensed to give flu shots in every Canadian province except Quebec.) A research team from the University of Exeter, U.K., the University of Western Ontario and Seqirus tested a simple pharmacy-led intervention that involved telephoning people over 65 years old who had not yet been vaccinated based on available records. More than 640 people were contacted in Alberta, British Columbia and Saskatchewan. Individuals on the call who turned down vaccination and were willing to give a reason were taken through a ‘myth-related’ discussion to isolate their concerns. Some seniors, it transpired, had already had a flu shot elsewhere. However, 67 percent of the remaining unvaccinated people (316 individuals) agreed to get vaccinated as a result of the call. Presenter Michael Boivin said: “What we’re most excited about is that…we were able to salvage many of these patients that were at high risk…[using] a very short intervention that fits within the current pharmacy workflow.”

Implementing a “mass flu-immunization program” long before the start of each flu season to reduce pressure on healthcare resources should be a crucial part of COVID-19 strategy, according Professor Jianhong Wu, an NSERC/Sanofi Industrial Research Chair at York University.5 Prof. Wu’s mathematical modelling data calculated that 30-percent flu-vaccine coverage in the general population would halve the number of COVID-19/flu cross-infections within 30 days. At 90-percent flu-vaccine coverage, cross-infection would be reduced 95 percent over the same period.

Complexities of Evaluating Influenza Vaccines

The effectiveness of flu vaccines was a key theme at the conference – specifically, the paucity of data comparing flu vaccines with one another. Lack of comparative data creates a challenge for Canada’s National Advisory Community on Immunization (NACI), said University of Calgary’s Dr. Chu. For example, in adults over the age of 65, data supports the use of high-dose flu vaccine over standard dose, as well as adjuvanted vaccine over standard dose; however, randomized controlled trials (RCTs) comparing high-dose with adjuvanted flu vaccines remain lacking. As a result, said Dr. Chu, the 2020–2021 NACI Influenza Vaccine Recommendations for adults 65+ state that “any of the available influenza vaccines should be used”.

“NACI recommendations are sub-optimal because the data is suboptimal,” said McMaster University immunologist Dr. Matthew Miller (PhD) at an accredited Seqirus co-developed symposium. Dr. Miller reviewed the unique complexities of conducting RCTs of flu vaccines – found in no other disease area –  in which the target flu strains vary from year to year so that a flu vaccine may appear superior one year, only to be less effective in a different season. “The end result is that companies have to spend a lot of money really gambling when they initiate these trials,” Dr. Miller said. “Even though they may have a good product, if they get unlucky they won’t get approval.”

A further complication is egg-based adaptations, Dr. Miller said: “One of the problems with growing virus in eggs is they tend to accumulate mutations to help them grow better in eggs…and that can impact the effectiveness relative to the strains that are circulating in humans.” This has led to the introduction of flu vaccines produced in mammalian cells instead. In Canada, NACI has issued a provisional recommendation that a cell-based flu vaccine, Flucelvax Quad, be considered for adults and children ≥9 years old. 

In the meantime, to overcome the challenges of conventional RCTs in flu-vaccine development, Dr. Miller said real-world evidence (RWE) “may serve as the best alternative to help with decision-making”. RWE relies on epidemiological data from public sources and electronic medical-records systems. Health Canada has started building a framework to incorporate RWE data into drug approvals, concluded Dr. Miller.

The RWE approach appeared at the CIC in the form of a poster from Van Hung Nguyen, a former health-technology advisor to the Government of Quebec, working with the Seqirus medical team.6 Nguyen used publically available data, including influenza-strain circulation data from Flunet; U.S. attack-rate data for the 2013 to 2018 seasons; and published literature on vaccine effectiveness, to compare the benefits of different flu vaccines in the Canadian population. Nguyen found that the most effective regimen was a quadrivalent, cell-based flu vaccine for individuals 9–64 years old plus an adjuvanted trivalent vaccine for adults aged 65 and above. During one flu season, this approach resulted in 2.2-million fewer symptomatic flu cases and almost 3,600 fewer deaths, compared to giving a standard-dose flu vaccine to everyone (Figure 1). (For an interview with Van Hung Nguyen, see Q&A).

Figure 1.

 Another way to gain reliable effectiveness data for a flu vaccine is to extend RCTs over several seasons in both hemispheres. A CIC poster presented the latest results for a cell-culture-derived quadrivalent flu vaccine tested in 4,509 children aged 2 to 18 over three seasons (2017–2019), including one in the Southern hemisphere.7 The international Seqirus-supported RCT, headed by Dr. Terence Nolan of the University of Melbourne, found that a mammalian-cell-based vaccine halved the incidence of laboratory-confirmed flu (7.8% vs 16.2%). It had greatest efficacy against A/H1N1, at 81 percent. The safety profile was similar to the non-flu comparator, meningocococcal vaccine.

Learnings for COVID-19

Several speakers at the CIC expressed a hope that flu science will provide learnings for COVID-19. For example, Dr. Melissa Andrew of Dalhousie University, in an interview with MedNet, drew on her study in the over-65s to remind COVID-19 researchers that vaccine protection not only benefits individuals, but the people for whom those individuals care. “I think we can learn a lot [from flu science], especially given the huge knowledge vacuum that we have around COVID, because it’s so new…One of them, to me, is the real impact of influenza in older people on functional outcomes,” she said. Dr. Andrew’s data showed that approximately one-quarter of seniors provided care for others, which came to a standstill when the carer developed flu or flu-like symptoms (N=3,500).8 (For other flu learnings for COVID-19, see the Q&A.)  

Questions and Answers

Questions and answers on how flu science could inform COVID-19 medicine with Dr. Melissa Andrew of Dalhousie University’s Division of Geriatric Medicine and VHN Consulting’s Van Hung Nguyen, a former health-technology advisor to the Government of Quebec.

Q: Why is frailty more important than biological age when it comes to respiratory viruses?

Dr. Melissa Andrew: There’s this idea that older people have immunosenescence that goes up with age and therefore they don’t respond to vaccines as well. But we know it’s much more complicated than that. It’s not just a function of your chronological age. It’s really biological age, frailty, immune profiles that differ between subgroups. So it’s not a blanket issue; we still need to understand the variance or variability in responses.

Q: What are the clinical implications of frailty for infections such as flu and COVID-19?

Dr. Melissa Andrew: Older people who are frail tend to present atypically with anything. So if the first case of COVID in a nursing home is someone who’s delirious, and not someone who’s got a fever and cough, and you don’t get on that right away, then that can spread quite quickly to other people.

Q: How might this affect vaccine effectiveness?

Dr. Melissa Andrew: We’re going to go use [the COVID vaccine] in our first target population, which is older people in nursing homes, [but] we didn’t test it in that population. My concern is that if we don’t start considering frailty in those studies of COVID-19 vaccines, then we will miss opportunities to best protect our vulnerable populations. [Dr. Andrew recently wrote a commentary on this topic in The Lancet.9]

Q: Your poster at the CIC used ‘dynamic modelling’ to estimate the overall population benefit of using different combinations of flu vaccines in Canada.6 Why this approach?

Van Hung Nguyen: It’s important to use the dynamic model when you want to reflect the full benefits of vaccination, which is not only the direct effect of the vaccine, but also the indirect effect provided by lowering viral transmission through herd immunity.

Q: What did your analysis find?

Van Hung Nguyen: Our model predicted improved health benefits to the Canadian population as a whole when a quadrivalent, cell-based flu vaccine was used for individuals 9–64 years old and an adjuvanted trivalent vaccine was used for adults aged 65 and above, versus standard-dose flu vaccine for everyone.

Q: What are the implications of your work for flu policymakers?

Van Hung Nguyen: Using a cell-based flu vaccine and an adjuvant-enhanced trivalent vaccine provides a better direct benefit to the people vaccinated and also provides a greater benefit to the whole Canadian population, given that the vaccinee interacts with non-vaccinees.

Q: What lessons can we draw out for COVID-19?

Van Hung Nguyen: If we don’t use the dynamic model we will not be able to educate the policymakers and say, “don’t focus only on a high vaccine efficacy for the vaccinee: with the current COVID circulation, even a moderately effective vaccine, but with a high coverage rate, would have a huge impact on transmission. That’s the full benefit.”

 

References:

1. Waite N, Andrew MK, Gilca V et al. Impact of COVID-19 on Canadian older adults’ willingness to be vaccinated against influenza during the 2020/2021 season. CIC 2020 poster presentation.
2. Perrault KM, Beauchamp P. COVID-19 pandemic impact on patient attitudes about the influenza season and vaccination. CIC 2020 oral presentation.
3. Government of Canada. Vaccine Uptake in Canadian adults 2019: 2018–2019 Seasonal Influenza Coverage Survey. https://www.canada.ca/en/public-health/services/publications/healthy-living/2018-2019-influenza-flu-vaccine-coverage-survey-results.html Accessed Dec 9, 2020.
4. Strain WD, Boivin M, Mansi J et al. Meeting the Canadian influenza vaccine uptake benchmark using a simple pharmacy phone call during the 2019–2020 influenza season. CIC 2020 oral presentation.
5. Wu J. The benefits of mass influenza vaccination campaign in the time of COVID-19. CIC 2020 poster presentation.
6. Nguyen VH, Roy B, Boikos C et al. The epidemiological impact of a cell-based quadrivalent and MF59-adjuvanted trivalent influenza vaccine in Canada: A dynamic modelling approach. CIC 2020 poster presentation.
7. Nolan T, Fortanier AC, Leav B et al. Efficacy of cell culture-derived quadrivalent influenza vaccine in prevention of clinical influenza in children 2 to <18 years of age: results of a randomized controlled trial. CIC 2020 poster presentation.
8. Andrew MK, Waite N, Pereira JA et al. Impact of influenza and influenza-like illness on Canadian adults aged 65+ during the 2018/2019 and 2019/2020 seasons. CIC 2020 poster presentation.
9. Andrew MK, McElhaney JE. Age and frailty in COVID-19 vaccine development. Lancet; published online November 19, 2020. DOI: https://doi.org/10.1016/S0141-6736(20)32481-8

 

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