High-dose quadrivalent influenza vaccine for older populations
A high-dose quadrivalent influenza vaccine (Fluzone High-Dose Quadrivalent) is available on the private market in Australia in 2022 for adults aged 60 years and older. It contains four times the antigen content of standard influenza vaccines and has higher effectiveness in people aged 65 years and older while maintaining an acceptable safety profile. It also has comparable effectiveness and safety to the adjuvanted influenza vaccine in this age group.
Influenza is a seasonal infectious disease that usually circulates in the colder months, between April and October in Australia. Most people recover from influenza without serious illness; however, older adults, young children, pregnant women and people with certain chronic medical conditions are at higher risk of developing serious complications.1 Influenza-associated mortality rates are highest among adults aged 65 years and older.1,2
In Australia, annual influenza vaccination is recommended and funded under the National Immunisation Program (NIP) for all people aged 65 years and older and other susceptible groups. The protection provided by influenza vaccines is lower in older compared with younger adults.3,4 A possible approach to improve the level of protection is to increase the amount of antigen in the vaccine.
Currently in Australia, adults aged 65 years and older can receive a standard quadrivalent influenza vaccine or an adjuvanted quadrivalent influenza vaccine. The adjuvanted influenza vaccine is NIP-funded for adults aged 65 years and older and is recommended in preference to standard influenza vaccines because of evidence of its greater effectiveness against severe disease in this population.3-5
The newly available high-dose quadrivalent influenza vaccine contains more antigen than standard-dose influenza vaccines, to provide greater protection for older adults. It has been approved by the TGA and is available in Australia for the 2022 influenza season. A trivalent version of the high-dose vaccine was available in Australia for the 2018 influenza season. This article discusses the new high-dose quadrivalent vaccine.
What is the high-dose influenza vaccine?
The newly registered high-dose influenza vaccine (Fluzone High-Dose Quadrivalent) is an inactivated split-virus quadrivalent influenza vaccine. It contains 240 micrograms of influenza virus haemagglutinin (60 mcg for each strain), four times as much as standard influenza vaccines. It is prepared using the traditional egg-based method.
The high-dose quadrivalent vaccine contains components of four influenza viruses: two influenza virus A strains (subtypes H1N1 and H3N2) and two influenza virus B strains (one from each of the Victoria and Yamagata lineages). The specific strains included comply with the seasonal recommendation of the Australian Influenza Vaccine Committee, which is based on the WHO recommendation for each annual influenza season.
When and how is the vaccine used?
The high-dose quadrivalent influenza vaccine was registered in Australia in 2021 for use in adults aged 60 years and older to prevent influenza disease.6 It is not recommended or registered for people aged less than 60 years. The vaccine has also been approved for use in the USA, UK and Canada for use in adults aged 65 years and older.
The high-dose vaccine is available on the private Australian market in the 2022 influenza season but is not currently funded under the NIP. It is administered by intramuscular injection in a single 0.7 mL dose.
Common side effects
Side effects may occur after vaccination as with any influenza vaccine. Some of these expected adverse events mimic the symptoms of influenza (e.g. fever and myalgia). The high-dose influenza vaccine does not contain live influenza virus and thus cannot cause influenza. Common, usually mild and temporary adverse events after vaccination with the high-dose vaccine may include:
- pain, redness, swelling or bruising at the injection site
- muscle aches or myalgia
- malaise
- headache.
Fever has also been reported in 2 to 3% of recipients of the high-dose vaccine.7 Adverse events after vaccination were slightly more common with the high-dose vaccine than with standard influenza vaccines but were mostly mild and temporary, resolving within three days.7 Reported adverse events after vaccination with the high-dose vaccine are similar to those with adjuvanted influenza vaccines.8-10
Use in pregnancy and breastfeeding
Pregnant women are strongly recommended to receive influenza vaccine during each pregnancy because of a higher risk of morbidity, mortality and adverse birth outcomes if infected.11-13 However, the high-dose influenza vaccine is not registered for use in people under the age of 60 years. It is currently classified as pregnancy category B2, as data are lacking on use of this vaccine in pregnant women.
Important precautions and interactions
Precautions to be taken when administering high-dose influenza vaccines are similar to those for standard and adjuvanted influenza vaccines (Box 1). The high-dose influenza vaccine is contraindicated in individuals with a history of severe allergic reaction after previous administration of any influenza vaccine and to any component of the vaccine. Although the high-dose vaccine is egg-based, it can be administered to people with a history of anaphylaxis to egg.14
There are currently no data on the coadministration of the high-dose influenza vaccine with other vaccines. However, the Australian Technical Advisory Group on Immunisation (ATAGI) recommends that people can receive the high-dose influenza vaccine with most other vaccines, including COVID-19 vaccines.6,15
Effectiveness of the high-dose influenza vaccine
Much of the current evidence on relative effectiveness of high-dose compared with standard and adjuvanted influenza vaccines comes from observational studies. These studies indicate that, compared with standard influenza vaccines, high-dose vaccine may slightly reduce influenza- or pneumonia-associated mortality and hospitalisation from influenza or pneumonia in people aged 65 years and older.16-25 Compared with adjuvanted influenza vaccines, studies in people aged 65 years and older also suggest that the rates of influenza-related hospitalisations are similar.18-20,26-28
Based on this evidence, high-dose influenza vaccine can be considered a preferred alternative to standard influenza vaccines and an equivalent alternative to adjuvanted influenza vaccines in older people. Although the adjuvanted influenza vaccine is available under the NIP at no patient cost for people aged 65 years and older, it is not registered for use in people aged 60 to 64 years.
ATAGI recommends that people aged 65 years and older should receive an adjuvanted or high-dose influenza vaccine but may receive standard influenza vaccine if the adjuvanted or high-dose vaccine is unavailable.5 The high-dose influenza vaccine is currently not NIP-funded, whereas the adjuvanted influenza vaccine is funded for use in people aged 65 years and older.
Conclusion
After two years of limited circulation of influenza viruses in Australia during the coronavirus disease 2019 pandemic, as international borders begin to open, seasonal influenza is likely to re-emerge. The newly registered high-dose quadrivalent influenza vaccine offers an alternative vaccine to protect older people against influenza. Key practice points about the vaccine are summarised in Box 2.
The new high-dose vaccine is more effective than standard-dose influenza vaccines for older people and is comparable to adjuvanted influenza vaccine. Adverse events may be slightly more common after vaccination with the high-dose vaccine compared with standard vaccines. However, overall, it has an acceptable safety profile compared with both standard and adjuvanted vaccines. Unlike the adjuvanted vaccine, which is NIP-funded for people aged 65 years and older, the high-dose vaccine is currently available only on the private market. MT
References
1. Coleman BL, Fadel SA, Fitzpatrick T, Thomas SM. Risk factors for serious outcomes associated with influenza illness in high- versus low- and middle-income countries: systematic literature review and meta-analysis. Influenza Other Respir Viruses 2018; 12: 22-29.
2. Li-Kim-Moy J, Yin JK, Patel C, et al. Australian vaccine preventable disease epidemiological review series: Influenza 2006 to 2015. Commun Dis Intell Q Rep 2016; 40: E482-E495.
3. Fielding JE, Levy A, Chilver MB, et al. Effectiveness of seasonal influenza vaccine in Australia, 2015: an epidemiological, antigenic and phylogenetic assessment. Vaccine 2016; 34: 4905-4912.
4. Sullivan SG, Chilver MB, Carville KS, et al. Low interim influenza vaccine effectiveness, Australia, 1 May to 24 September 2017. Euro Surveill 2017; 22: 17-00707.
5. Australian Technical Advisory Group on Immunisation (ATAGI). Statement on the administration of seasonal influenza vaccines in 2022. Canberra: Australian Government Department of Health; 2021. Available online at: https://www.health.gov.au/sites/default/files/documents/2022/02/atagi-advice-on-seasonal-influenza-vaccines-in-2022.pdf (accessed March 2022).
6. Sanofi-Aventis Australia. Australian product information – Fluzone high-dose quadrivalent (influenza virus haemagglutinin [Fluzone HD QIV]). Therapeutic Goods Administration; 2021. Available online at: https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2020-PI-02061-1&d=20220227172310101 (accessed March 2022).
7. Pepin S, Nicolas JF, Szymanski H, et al; QHD00011 study team. Immunogenicity and safety of a quadrivalent high-dose inactivated influenza vaccine compared with a standard-dose quadrivalent influenza vaccine in healthy people aged 60 years or older: a randomized Phase III trial. Hum Vaccin Immunother 2021; 17: 5475-5486.
8. Cowling BJ, Thompson MG, Ng TWY, et al. Comparative reactogenicity of enhanced influenza vaccines in older adults. J Infect Dis 2020; 222: 1383-1391.
9. Pillsbury AJ, Fathima P, Quinn HE, et al. Comparative postmarket safety profile of adjuvanted and high-dose influenza vaccines in individuals 65 years or older. JAMA Netw Open 2020; 3: e204079.
10. Schmader KE, Liu CK, Harrington T, et al. Safety, reactogenicity, and health-related quality of life after trivalent adjuvanted vs trivalent high-dose inactivated influenza vaccines in older adults: a randomized clinical trial. JAMA Netw Open 2021; 4: e2031266.
11. ACOG Committee Opinion No. 732: influenza vaccination during pregnancy. Obstet Gynecol 2018; 131: e109-e114.
12. Mertz D, Kim TH, Johnstone J, et al. Populations at risk for severe or complicated influenza illness: systematic review and meta-analysis. BMJ 2013; 347: f5061.
13. Wang R, Yan W, Du M, Tao L, Liu J. The effect of influenza virus infection on pregnancy outcomes: a systematic review and meta-analysis of cohort studies. Int J Infect Dis 2021; 105: 567-578.
14. Australasian Society of Clinical Immunology and Allergy (ASCIA). ASCIA guidelines - vaccination of the egg-allergic individual. ASCIA; 2017. Available online at: https://www.allergy.org.au/hp/papers/vaccination-of-the-egg-allergic-individual (accessed March 2022).
15. Australian Technical Advisory Group on Immunisation (ATAGI). Clinical recommendations for COVID-19 vaccines. Australian Government Department of Health; 2022. Available online at: https://www.health.gov.au/initiatives-and-programs/covid-19-vaccines/advice-for-providers/clinical-guidance/clinical-recommendations (accessed March 2022).
16. Doyle JD, Beacham L, Martin ET, et al. Relative and absolute effectiveness of high-dose and standard-dose influenza vaccine against influenza-related hospitalization among older adults - United States, 2015-2017. Clin Infect Dis 2021; 72: 995-1003.
17. Gravenstein S, Davidson HE, Taljaard M, et al. Comparative effectiveness of high-dose versus standard-dose influenza vaccination on numbers of US nursing home residents admitted to hospital: a cluster-randomised trial. Lancet Respir Med 2017; 5: 738-746.
18. Izurieta HS, Chillarige Y, Kelman J, et al. Relative effectiveness of cell-cultured and egg-based influenza vaccines among elderly persons in the United States, 2017-2018. J Infect Dis 2019; 220: 1255-1264.
19. Izurieta HS, Chillarige Y, Kelman J, et al. Relative effectiveness of influenza vaccines among the United States elderly, 2018-2019. J Infect Dis 2020; 222: 278-287.
20. Izurieta HS, Lu M, Kelman J, et al. Comparative effectiveness of influenza vaccines among US Medicare beneficiaries aged 65 years and older during the 2019-2020 season. Clin Infect Dis 2021; 73: e4251-e4259.
21. Paudel M, Mahmud S, Buikema A, et al. Relative vaccine efficacy of high-dose versus standard-dose influenza vaccines in preventing probable influenza in a Medicare fee-for-service population. Vaccine 2020; 38: 4548-4556.
22. Richardson DM, Medvedeva EL, Roberts CB, Linkin DR. Comparative effectiveness of high-dose versus standard-dose influenza vaccination in community-dwelling veterans. Clin Infect Dis 2015; 61: 171-176.
23. Young-Xu Y, Snider JT, Mahmud SM, et al. Clinical effectiveness of high-dose versus standard-dose influenza vaccination among Veterans Health Administration patients: a crossover study. Pharmacoepidemiology Drug Safety 2018; 27: 392-393.
24. Young-Xu Y, Snider JT, van Aalst R, et al. Analysis of relative effectiveness of high-dose versus standard-dose influenza vaccines using an instrumental variable method. Vaccine 2019; 37: 1484-1490.
25. Young-Xu Y, Van Aalst R, Mahmud SM, et al. Relative vaccine effectiveness of high-dose versus standard-dose influenza vaccines among Veterans Health Administration patients. J Infect Dis 2018; 217: 1718-1727.
26. Boikos C, Fischer L, O’Brien D, et al. Relative effectiveness of adjuvanted trivalent inactivated influenza vaccine versus egg-derived quadrivalent inactivated influenza vaccines and high-dose trivalent influenza vaccine in preventing influenza-related medical encounters in US adults ≥ 65 years during the 2017-2018 and 2018-2019 influenza seasons. Clin Infect Dis 2021; 73: 816-823.
27. Machado MAA, Moura CS, Abrahamowicz M, Ward BJ, Pilote L, Bernatsky S. Relative effectiveness of influenza vaccines in elderly persons in the United States, 2012/2013-2017/2018 seasons. NPJ Vaccines 2021; 6: 108.
28. Pelton SI, Divino V, Shah D, et al. Evaluating the relative vaccine effectiveness of adjuvanted trivalent influenza vaccine compared to high-dose trivalent and other egg-based influenza vaccines among older adults in the US during the 2017-2018 influenza season. Vaccines (Basel) 2020; 8: 446.