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“Flu is Back”: Understanding and Preventing Influenza in the Wake of the COVID-19 Pandemic

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 - OPTIONS XI for the Control of Influenza (ISIRV 2022)

Belfast, Ireland / September 26–29, 2022

Belfast – The International Society for Influenza and other Respiratory Virus Diseases (ISIRV) holds its flagship conference, OPTIONS for the Control of Influenza, every three years. At their previous meeting in September 2019, COVID-19, the disease caused by the coronavirus known as SARS-CoV-2, was not even on the radar yet. Three years later, the OPTIONS XI meeting provided a long-awaited opportunity to meet face-to-face and share the latest research on respiratory viruses and how they can be anticipated, prevented, and controlled. While there were many presentations that explored the biology, epidemiology, and management of SARS-CoV-2, the main focus of the meeting remained on influenza and how it can be prevented and managed in the shadow of the COVID-19 pandemic. This report will focus on the current state of influenza, new insights into current vaccine options and emerging technologies, and advice for the upcoming flu season in the Northern Hemisphere.

Control of Influenza

“Influenza is back,” said Dr. John Paget, Netherlands Institute for Health Services Research in a sponsored symposium at the OPTIONS XI for the Control of Influenza conference in Belfast, Northern Ireland. “And I think we really need to focus both on prevention and on control measures.”

Influenza rates were unusually low in the 2020-2021 flu season worldwide, as countries enacted lockdowns and other public health measures to restrict the spread of SARS-CoV-2. In 2021-2022 rates rose again as public health restrictions lifted in many countries and people returned to more normal patterns of social mixing, but overall incidence was still low compared to a typical pre-pandemic flu season. (Figure 1) However, even this “milder” season had a significant impact, as described by Dr. Vivien Dugan, US Centers for Disease Control and Prevention. “Compared to pre-pandemic seasons it was quite mild, but it was also an extended season that went all the way into mid-June. It also had two peaks, that helped create that extended season,” she said. “And even with that mild season, we estimated that there were millions of illnesses, hundreds of thousands of medical visits and hospitalizations, and thousands of flu deaths.”

Looking ahead, this year’s flu season in the Southern Hemisphere, in the earlier months of the year, may hold clues for what is in store in the North this fall and winter. “Despite the low levels of circulating influenza in 2020 and 2021, the Southern Hemisphere has since seen a very strong re-emergence of seasonal flu with unusual patterns,” said Prof. Teresa Lambe, UK Centre for Clinical Vaccinology and Tropical Medicine.  “We’re seeing it come in fast, and peak high and very rapidly. And that, to me, is something of concern.”

Figure 1. 


The Current State of Flu Vaccination:
Uptake and Opinions

During the first flu season of the COVID-19 pandemic (2020-2021), influenza vaccination rates actually increased in many countries compared to prior years; a poster by Dr. Van Nguyen and colleagues showed that it reached an all-time high 52% in the USA. However, the following year the rate dropped to 45%, well below pre-pandemic levels. The authors estimated that in a high-incidence flu season, this low coverage would lead to more than 180,000 acute hospital admissions and almost 28,000 ICU admissions, placing a significant strain on healthcare resources. The authors said their analysis “shows the need to increase the current flu immunization rate, within a co-circulation scenario, to improve health outcomes and avoid saturation of hospital system resources.”

A study by Dr. Samir Sinha, Director of Geriatrics at Mount Sinai and the University Health Network Hospitals, Toronto, and colleagues surveyed over 1500 Canadian adults to explore intentions and opinions about vaccination. They found that while vaccination rates against SARS-CoV-2 were high, only 48% of respondents received an influenza vaccination in 2021-2022; rates were higher among older adults, but still below the national goal of 80%. However, Dr. Sinha was encouraged by respondents’ opinions. “Despite recent media coverage of anti-vaccine movements and such, the vast majority of Canadians haven't changed their opinion and still think that vaccinations are a reasonable healthcare option,” he said. “For those who've changed their opinions, most have actually swung in favour of vaccination, as opposed to a very small minority who say they think more negatively. And it was even more pronounced amongst the older population, who are most likely to benefit from vaccines. Perhaps it’s because they’ve seen what the COVID-19 vaccination can do, and so they might believe more in the value of other vaccinations as well.” He also highlighted that most respondents – and particularly older adults – were positive toward the idea of co-administering flu vaccines along with a COVID-19 booster, and that older adults were more likely to receive a flu vaccine if enhanced (i.e., high-dose or adjuvanted) options were available.

New Data on Current Vaccines - Cell-derived IIVs

Although egg-derived vaccines are currently the most widely used option, their vaccine effectiveness (VE) may be reduced by “egg adaptation,” whereby the human-adapted virus undergoes genetic changes in the bird egg, rendering it less antigenic. In order to improve VE, cell-culture-based systems are now being more widely used for vaccine production.

Prof. Victor Huber, University of South Dakota and colleagues reviewed the published literature and expert opinions on egg adaptation, and concluded that across the USA and Europe, experts agreed that VE was likely to be reduced in egg-based products. “The use of non-egg-based manufacturing that avoids egg adaptations should be common policy due to its benefits of improving influenza VE and reducing the risk of influenza disease in individuals and associated health costs,” they concluded in their poster.

A poster by Dr. Mahrukh Imran, CSL Seqirus and colleagues presented a retrospective comparison of influenza outcomes between adults younger than age 65 vaccinated with a quadrivalent cell-derived vaccine (QIVc) or the equivalent quadrivalent egg-based product (QIVe) in 2019-2020. Across all age groups, QIVc was associated with fewer hospitalizations related to influenza, respiratory causes, or cardio-respiratory causes than QIVe. Additionally, in the 50–65 cohort there was a lower rate of hospitalizations for myocardial infarction among recipients of QIVc.

Enhanced Vaccines for Older Populations

For older adults, “enhanced” IIVs that use either an adjuvant or a higher dose of antigen are available to improve immunogenicity. Several analyses at OPTIONS XI added to our knowledge about the real-world efficacy of these products.

Dr. Mahrukh Imran and colleagues analyzed cardiorespiratory outcomes in older adults vaccinated with adjuvanted trivalent (aTIV), high-dose trivalent (HD-TIV) or QIVe products in 2019-2020. Overall, aTIV was more effective than the others at reducing the rate of adverse cardio-respiratory outcomes, particularly influenza-related hospitalizations. The difference in relative VE was higher for the comparison of aTIV versus QIVe, than for aTIV versus HD-TIV, indicating that enhanced vaccines – irrespective of the type of enhancement – may be generally more effective in this population than standard formulations. (Figure 2)

Figure 2. 


These findings were supported by a systematic review and meta-analysis by Dr. Ian McGovern, CSL Seqirus and colleagues, who showed that aTIV and HD-TIV were similar for reducing the risk of influenza-related outpatient visits (pooled relative VE 8.5%; 95% CI -3.0 to 18.8) and hospital/emergency department visits (pooled relative VE 1.2%; 95% CI: -1.3 to 3.8).

New Technologies and Novel Targets

“The Holy Grail is to have a universal influenza vaccine that will not need to be updated each year, either for seasonal influenza or for the sporadic emergence of a novel virus causing a pandemic,” said Prof. Kanta Subbarao, Director of the WHO Collaborating Centre for Reference and Research on Influenza. Several presentations and posters at OPTIONS XI outlined novel strategies for creating more broadly protective or more effective vaccines.

Current influenza vaccines work by provoking an immune response to the head domain of viral hemagglutinin (HA), which is highly antigenic but subject to genetic drift. Prof. Raul Ortiz de Lejarazu, Valladolid National Influenza Centre, Spain, reviewed another potential viral target for a universal vaccine: neuraminidase (NA), an essential surface glycoprotein that is less susceptible to antigenic drift than HA, but has lower immunogenicity. He described how current HA-focused vaccines provoke an additional response against NA; he said that characterizing this response will be crucial for understanding how NA could be used as an antigen in future vaccines. He concluded by noting that several novel NA-containing vaccines are currently in early development.

The Rise of mRNA

The COVID-19 pandemic marked the first time that mRNA vaccines became commercially available. Several posters and presentations at OPTIONS XI explored how mRNA technology might improve vaccines for seasonal and pandemic influenza.

Dr. Raffael Nachbagauer, Moderna USA, presented an interim analysis of a phase I/II trial of an mRNA-based quadrivalent seasonal influenza vaccine (mRNA-1010) incorporating HA epitopes from two influenza A types and two B lineages. Compared to a marketed QIVe, the mRNA vaccine provided comparable antibody levels at day 29 for influenza B and higher levels against the influenza A strains, with no major safety concerns. mRNA-1010 is currently proceeding into a phase III study.

Dr. Yingxia Wen, CSL Seqirus outlined her company’s approach to mRNA vaccines, which involves a “selfamplifying” mRNA (sa-mRNA) that encodes its own replicase and can rapidly produce antigens within the host cell, yielding a stronger overall immune response with less mRNA input. In mice, a quadrivalent sa-mRNA expressing both HA and NA antigens raised robust, cross-reactive neutralizing antibodies and a cellular response. In ferrets, it was effective at protecting against influenza infection in the upper and lower respiratory tracts. Based on these preclinical findings, the company intends to pursue a phase I clinical trial.

Looking to the 2022-2023 Northern Hemisphere
Flu Season and Beyond

Presentations at the conference also provided guidance on how to approach the upcoming seasonal flu months in the Northern Hemisphere. “With influenza, we’re now in a different era, but really the risk remains the same. And the risk, to my mind, remains in older adults and in young children,” said Prof. Teresa Lambe. “And vaccination remains the mainstay of protection against influenza.” Several presenters highlighted the recent guidance of the Advisory Committee on Immunization Practices (ACIP) of the US CDC, which recommends that:

• Adults aged ≥65 years preferentially receive any one of the following higher-dose or adjuvanted influenza vaccines: quadrivalent high-dose inactivated influenza vaccine, quadrivalent recombinant influenza vaccine, or quadrivalent adjuvanted inactivated influenza vaccine.

• If none of these three vaccines is available at an opportunity for vaccine administration, then any other age-appropriate influenza vaccine should be used.

When asked about his advice for Canadian HCPs and patients, Dr. Samir Sinha replied, “I want HCPs and the public to know that vaccines are still the most effective thing to protect us against severe illness from influenza or COVID-19. While there's concern that with each successive round of vaccination, people are getting less motivated to do so, in my view there is a strong motivation to get vaccinated ahead of this fall flu season. And consider doing it through co-administration, because it's better to be safe than sorry.”


Questions and Answers

Questions and answers with Dr. Samir Sinha, Director of Geriatrics at Mount Sinai and the University Health Network Hospitals in Toronto, Ontario.

Q: What inspired you to do this survey?

Dr. Sinha:  Before the pandemic, we were looking at vaccination uptake in older adults for the “Big Three”: influenza, pneumonia, and shingles. We know that nearly 100% of children are getting their recommended vaccines routinely, but we wanted to understand why we aren’t meeting our Public Health Agency of Canada targets around influenza or pneumonia for older adults, who are a highly vulnerable population that would really benefit from these vaccinations. Then we had the COVID-19 pandemic, where older adults are also by far the most vulnerable. Seeing how well we've done with COVID-19 vaccination made us wonder whether that was helping us improve or change our attitudes towards vaccination for influenza.

Q: What topics did you focus on?

Dr. Sinha: First, we wanted to understand what proportion of our respondents have been vaccinated over the previous year against influenza and COVID-19. Then we asked how their intentions and opinions around vaccination may have changed, in light of what they've been through. And finally, we wanted to understand different options, such as co-administration [of influenza vaccine along with a COVID-19 booster] and the option of receiving an enhanced influenza vaccination.

Q: Was there anything that really surprised you in the results?

Dr. Sinha: The main thing that really stood out is that even though there has been a bit of a stagnation over the last few years, we still probably have more Canadians getting vaccinated in a given year than we previously understood. So that was good news that was a bit surprising.

Q: Based on your survey results, is there any strategy that you think could help us improve influenza vaccination rates?

Dr. Sinha:  In the past year, there's been much more definitive evidence that there are no concerns giving the COVID-19 vaccination at the same time as a seasonal influenza vaccination. That's really important because when flu season hits every year, it will probably also be time to give an annual booster against COVID-19, so there might be an opportunity do both at the same time. We know that when it’s inconvenient for people to get vaccinated – for example, if there has to be a delay between different vaccinations – they might choose to only get the one vaccine for the disease that they think is a bigger threat. So co-administration would improve convenience and give people peace of mind, since now they can better protect themselves against the two most dominant things that could kill them during the fall-winter respiratory disease season. And the majority of Canadians of all ages in our survey felt very positive about co-administration, but more so among older adults.

Q: What would you like to see happen on a public policy level, based on your survey results?

Dr. Sinha:  I think our study helps to give people making public health policies more definitive evidence that making enhanced vaccines available would help with influenza vaccination uptake. And co-administering it with the COVID-19 boosters is probably another good policy option to improve uptake. If we can do that, we're going to better protect the health of Canadians and the stability of our healthcare system as well.


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