A Comprehensive Clinical and Historical Report on Fluvax and the Evolution of Seasonal Influenza Vaccination in Australia

Executive Summary

This report provides a comprehensive clinical and historical analysis of the Fluvax® influenza vaccine and its pivotal role in shaping Australia's contemporary influenza immunisation strategy. While the Fluvax brand is not part of the 2025 seasonal influenza program, its history, particularly the significant safety incident in 2010, serves as a critical case study in vaccinology, immunology, and public health policy. The 2010 event, characterized by a heightened rate of febrile convulsions in young children, was not a simple manufacturing failure but a complex interplay between highly immunogenic viral strains and specific vaccine characteristics. This incident acted as a powerful catalyst, exposing limitations in the existing pharmacovigilance framework and driving profound changes in vaccine regulation, development, and surveillance.

The aftermath of the Fluvax incident directly informed the sophisticated, multi-platform approach evident in Australia's 2025 influenza immunisation landscape. The current program has moved beyond a one-size-fits-all model to a highly stratified strategy employing a diverse portfolio of quadrivalent influenza vaccines. This includes traditional egg-based vaccines, advanced cell-based technologies that mitigate the risks of egg-adaptive mutations, and enhanced formulations—such as adjuvanted and high-dose vaccines—specifically designed to overcome immunosenescence in older adults. Furthermore, the incident precipitated the development of robust, active post-market surveillance systems like AusVaxSafety, which now provide near-real-time safety data to clinicians and the public, fostering transparency and confidence.

This report will first profile the historical Fluvax vaccine, then conduct an in-depth analysis of the 2010 safety incident, its scientific underpinnings, and the subsequent regulatory response. It will then transition to a detailed examination of the 2025 influenza season, providing a comparative clinical analysis of all seven available vaccine products. This analysis is contextualized within the current public health challenge of record influenza circulation coupled with concerning declines in vaccination coverage. The report concludes with expert recommendations for healthcare providers, synthesizing the lessons learned from the Fluvax era to inform best practices in the current, more complex immunisation environment.

Profile of Fluvax®: A Historical Trivalent Influenza Vaccine

Fluvax® was an inactivated, egg-based, split-virion trivalent influenza vaccine (TIV) that for many years was a cornerstone of Australia's annual influenza prevention strategy.[1] As a TIV, its formulation was designed to protect against three distinct influenza viruses, a composition determined annually by the Australian Influenza Vaccine Committee (AIVC) and the New Zealand Ministry of Health to best match the strains predicted to circulate during the upcoming season.[1]

Formulation and Composition

The vaccine was manufactured by growing selected influenza virus strains in fertilised hens' eggs. The harvested viruses were then killed (inactivated) and chemically disrupted, or "split," into smaller, non-infectious fragments. This process yields a "split virion" vaccine, which contains viral proteins, including the key surface antigens haemagglutinin (HA) and neuraminidase (NA), but not the whole virus.[1]

Each annual formulation of Fluvax contained fragments from two influenza A subtypes (e.g., H1N1 and H3N2) and one influenza B lineage virus. For example, the 2018 formulation contained antigens derived from A/Michigan/45/2015 (H1N1)pdm09–like virus, A/Singapore/INFIMH-16-0019/2016 (H3N2)-like virus, and B/Phuket/3073/2013–like virus.[1] The vaccine was supplied in pre-filled disposable syringes for single use.[1]

Mechanism of Action

Consistent with other inactivated influenza vaccines, Fluvax functioned by introducing viral antigens into the body to stimulate a protective immune response without causing disease.[1] The primary target of this response is the haemagglutinin (HA) protein, a major surface glycoprotein that the influenza virus uses to attach to and enter host cells.[3]

Upon injection, the immune system recognizes the HA fragments in the vaccine as foreign. This triggers the production of specific neutralizing antibodies that bind to the HA protein of the actual virus.[1] If a vaccinated individual is later exposed to one of the influenza strains contained in the vaccine, these pre-existing antibodies can rapidly bind to the live virus, preventing it from infecting cells and thereby preventing or mitigating illness.[1] Because the vaccine contains only killed viral fragments, it is biologically incapable of causing influenza.[1] The development of a fully protective immune response typically takes about two to three weeks following vaccination.[1]

Historical Indications, Dosing, and Administration

Fluvax was indicated for annual vaccination to prevent influenza in adults and children, with specific age recommendations evolving over its product lifetime.[1] The standard dose for adults and children aged 5 years and over was a single $0.5$ mL injection, administered either intramuscularly or subcutaneously.[1]

For children between 5 and under 9 years of age who were receiving an influenza vaccine for the first time, a two-dose primary course was recommended, with the second dose administered at least four weeks after the first.[1] This two-dose schedule for immunologically naive children is a standard practice designed to ensure a robust and durable immune response.[10] While this age-based dosing strategy was consistent with immunological principles, the events of 2010 would dramatically demonstrate that age stratification alone was insufficient to account for the complex and sometimes severe immunological responses of very young children to specific vaccine formulations and novel viral strains. The subsequent investigation revealed that the issue was not the vaccine's efficacy but its reactogenicity profile in a specific, vulnerable paediatric sub-population, a finding that would fundamentally reshape the development of age-specific influenza vaccine products in Australia.

The 2010 Fluvax Safety Incident: A Turning Point in Australian Vaccinology

The 2010 Australian influenza season marked a watershed moment for vaccine safety and surveillance in the country. An unexpected and severe safety signal emerged, linked directly to the Fluvax vaccine, which precipitated a national public health response and ultimately led to lasting reforms in how vaccines are monitored and regulated.

Emergence of a Safety Signal

In April 2010, clinicians, particularly in Western Australia, began reporting an alarming increase in the number of young children presenting to hospital emergency departments with high fevers and febrile convulsions shortly after receiving their seasonal influenza vaccination.[11] The signal was most apparent in Western Australia for a specific reason: at the time, it was the only Australian state with a publicly funded program providing free seasonal influenza vaccines to all children aged 6 months to 4 years.[11] This program resulted in significantly higher vaccine uptake within this specific age cohort, creating a concentrated population where a potential safety issue could be detected more rapidly than in other jurisdictions with lower, more diffuse vaccination rates.

Epidemiological Investigation and Risk Quantification

The Therapeutic Goods Administration (TGA) and state health departments launched an immediate investigation. Epidemiological analysis quickly established a strong association between the adverse events and the trivalent influenza vaccines manufactured by CSL Biotherapies (now Seqirus): Fluvax® (for older children and adults) and Fluvax® Junior (for children aged 6 months to 35 months).[2]

The quantitative findings were stark. A retrospective cohort study conducted in Western Australia determined that the rate of febrile convulsions among children under 5 years of age was approximately 4.4 per 1,000 doses of Fluvax or Fluvax Junior administered.[10] This risk was dramatically elevated when compared to the alternative vaccine available in the program, Influvac® (Solvay, now Viatris), for which there were no reported cases of febrile convulsions.[10] The risk associated with the Fluvax formulation was estimated to be over 200 times higher than previously published population-based estimates for influenza vaccines.[12] Nationally, a total of 77 cases of febrile convulsion in children aged 5 or under were reported to the TGA, with the majority—57 cases—originating in Western Australia where the detection was most acute.[11]

Regulatory and Public Health Response

The response from health authorities was swift. On April 23, 2010, Australia's Chief Medical Officer announced a temporary suspension of the use of all seasonal influenza vaccines in healthy children under the age of 5.[2] As investigations confirmed the link specifically to the CSL product, this suspension was refined. Ultimately, the TGA took decisive regulatory action: Fluvax was permanently contraindicated for use in children under 5 years of age.[2] For children aged 5 to under 9 years, a cautionary approach was advised, recommending that clinicians base any decision to vaccinate with Fluvax on a careful risk-benefit assessment for the individual child.[13]

These regulatory decisions were supported by mandated changes to the vaccine's Product Information, including the addition of a prominent "Black Box Warning" against its use in the under-5 age group. Further practical measures included new warning labels on the vaccine packaging and specialized labels for vaccine refrigerators to prevent inadvertent administration to young children.[13]

The 2010 incident also cast a harsh light on the limitations of Australia's vaccine safety monitoring systems at the time. Experts noted that the existing system, which relied heavily on passive reporting, was inadequate for rapid signal detection and response. There was significant criticism regarding the inability of authorities to quickly ascertain fundamental data, such as the total number of vaccine doses administered versus the number of adverse events reported, which hampered the initial response and risk communication.[11] This critical failure created the political and scientific impetus for reform. The subsequent establishment and now-central role of active surveillance programs, most notably AusVaxSafety, is a direct legacy of the 2010 crisis. The Fluvax incident demonstrated unequivocally that a modern immunisation program requires an equally modern, proactive, and transparent safety surveillance infrastructure.

The Scientific Basis of Heightened Reactogenicity

Following the 2010 incident, CSL embarked on a comprehensive, four-year investigation in collaboration with international partners and under the close watch of regulatory bodies like the TGA and the US Food and Drug Administration (FDA).[14] The research concluded that the increased rate of febrile convulsions was not the result of a singular manufacturing defect or contamination, but rather a multifactorial phenomenon—a "perfect storm" of virological properties, manufacturing processes, and host immunological factors.

Immunological and Virological Factors

A primary contributing factor was the specific composition of the 2010 Southern Hemisphere vaccine. The formulation included new viral strains that were inherently more immunogenic than those used in previous years.[13] The investigation identified two strains in particular: the influenza B/Brisbane strain and, to a lesser extent, the A/California/7/2009 (H1N1)pdm09 strain.[2] When combined, these components elicited an unusually strong pro-inflammatory cytokine response, especially in young children who were immunologically naive to these newer antigens.[14]

The Role of the Manufacturing Process

The investigation revealed that CSL's standard manufacturing process for its split-virion vaccine, while meeting all regulatory standards of the time, interacted with these new strains in an unforeseen way. The process was found to preserve certain viral components that acted as potent stimulators of the innate immune system. Specifically, the research identified two key issues:

1. Incomplete Splitting: Electron microscopy revealed a disproportionate number of "unsplit virion aggregates" in the final product.[15] Unlike properly split viral fragments, these larger aggregates present a more complex and potent stimulus to the immune system.
2. Retention of Innate Immune Stimulants: The process also resulted in lipid-mediated delivery of small, degraded viral RNA fragments.[2] Viral RNA is a well-known pathogen-associated molecular pattern (PAMP) that is recognized by Toll-like receptors (TLRs) on innate immune cells, triggering a powerful inflammatory cascade and cytokine release.[14]

In vitro studies confirmed that increasing the concentration of the splitting agent used in manufacturing could attenuate these pro-inflammatory signals, demonstrating a direct link between the manufacturing process and the vaccine's reactogenicity profile.[14]

A Multifactorial Conclusion

The scientific conclusion was that the adverse events stemmed from the convergence of these factors. The highly immunogenic 2010 viral strains, when processed through a manufacturing method that produced an unusually reactogenic formulation (containing unsplit aggregates and viral RNA), resulted in an overstimulation of the innate immune system in a vulnerable population of young, immunologically naive children. This hyper-inflammatory response manifested clinically as a higher incidence of fever and, in susceptible individuals, febrile convulsions.[13]

This detailed scientific explanation provides a crucial lesson for vaccine development and regulation. It highlights that meeting standard quality control metrics, such as antigenic content (i.e., the amount of HA per dose), is not sufficient to guarantee a vaccine's safety profile. The initial batch testing of the 2010 Fluvax vaccine by both CSL and the TGA found it to be "satisfactory" because it met these established criteria.[11] However, these tests failed to capture the subtle but critical physical and immunological characteristics of the final product—such as particle aggregation and the presence of innate immune-stimulating components—that were the true drivers of the adverse reactions. This event compelled regulators and manufacturers worldwide to develop more sophisticated analytical assays to characterize vaccine products more comprehensively, ensuring that both antigenic content and biological reactogenicity are understood and controlled.

The Modern Influenza Immunisation Landscape in Australia (2025)

The legacy of the Fluvax incident is clearly visible in the sophisticated and diversified influenza immunisation strategy employed in Australia today. The 2025 program reflects a move away from a single-product approach towards a tailored strategy that utilizes multiple vaccine technologies to optimize protection across different age groups and risk profiles.

The Strategic Shift to Quadrivalent Influenza Vaccines (QIVs)

A fundamental evolution from the era of the trivalent Fluvax is the universal adoption of quadrivalent influenza vaccines (QIVs) for the 2025 season.[16] All funded and privately available vaccines in Australia are QIVs, formulated to protect against four influenza strains: two influenza A viruses (an H1N1-like virus and an H3N2-like virus) and two distinct influenza B lineages (B/Victoria and B/Yamagata).[16] This provides broader protection than TIVs, which only contain one B lineage virus.

However, the virological landscape is dynamic. Due to the prolonged absence of circulating B/Yamagata lineage virus globally, the World Health Organization (WHO) has recommended its removal from future vaccine formulations. In line with this, the Australian Technical Advisory Group on Immunisation (ATAGI) has signaled a planned transition back to trivalent vaccines in the coming years, demonstrating the program's continuous adaptation to global viral epidemiology.[18]

The 2025 National Immunisation Program (NIP)

The Australian Government, through the National Immunisation Program (NIP), provides free seasonal influenza vaccines to groups identified as being at the highest risk of severe complications from influenza. For 2025, these eligible cohorts include:

• Children aged 6 months to under 5 years.[21]
• All Aboriginal and Torres Strait Islander people aged 6 months and over, recognizing the significantly higher burden of influenza in this population.[17]
• Pregnant women at any stage of pregnancy, to protect both the mother and the infant for the first few months of life.[17]
• All adults aged 65 years and over.[17]
• Individuals aged 6 months and over with specific medical conditions that increase their risk of influenza complications. These include cardiac disease, chronic respiratory or neurological conditions, immunocompromising conditions, and chronic metabolic disorders.[16]

State-Level Programs and Public Health Challenges

In addition to the NIP, some states have implemented broader, state-funded programs to improve vaccine access. For example, between March and September 2025, the Queensland Government funded free influenza vaccines for all Queensland residents aged 6 months and older, effectively removing the cost barrier for those not eligible under the NIP.[20] This approach acknowledges the significant burden that influenza places on the entire community and the healthcare system, not just on high-risk individuals. The existence of these parallel programs reflects an ongoing policy debate regarding the optimal scope of publicly funded preventative health measures—whether to target only the most vulnerable or to aim for broader community-wide coverage to maximize herd effects and reduce overall system strain.

This multi-pronged approach to vaccination is occurring within a deeply concerning public health context. Post-pandemic, Australia has experienced a dramatic resurgence of influenza. The first quarter of 2025 saw the highest number of confirmed influenza cases on record, representing a 54.8% increase compared to the same period in 2024 and continuing a trend of significant year-on-year growth.[26] This surge in disease is paradoxically accompanied by a "dire" and "alarming" decline in vaccination rates across all age groups.[26] In 2024, vaccination coverage for children under five dropped to just 25.8%, and rates for older adults have also fallen.[28] This growing gap between the threat of influenza and the uptake of the primary preventative measure presents a major challenge for Australia's public health system.

Comparative Clinical Analysis of Influenza Vaccines Available in 2025

The 2025 Australian influenza immunisation program features a portfolio of seven distinct vaccine products from three sponsors, utilizing four different technological platforms. This diversity allows for a tailored approach to vaccination, optimizing safety and immunogenicity for specific patient populations. The following table provides a comparative overview of these vaccines.

Table 1: Comparison of Seasonal Influenza Vaccines Registered for Use in Australia, 2025

Tradename	Sponsor	Vaccine Technology	Approved Age Group	NIP Funding & Eligibility	Private Market Availability	Standard Dose Volume
Vaxigrip Tetra	Sanofi	Egg-based, split virion	6 months and over	Yes: Children 6m-<5y; At-risk groups 5-<65y	Yes	$0.5$ mL
FluQuadri	Sanofi	Egg-based, split virion	6 months and over	Yes (Backup for Vaxigrip Tetra)	Yes	$0.5$ mL
Afluria Quad	Seqirus	Egg-based, split virion	5 years and over	Yes: At-risk groups 5-<65y	Yes	$0.5$ mL
Influvac Tetra	Viatris	Egg-based, surface antigen	6 months and over	No	Yes	$0.5$ mL
Flucelvax Quad	Seqirus	Cell-based, surface antigen	6 months and over	Yes: At-risk groups 5-<65y	Yes	$0.5$ mL
Fluad Quad	Seqirus	Egg-based, adjuvanted	65 years and over	Yes: All persons 65y+ (preferred)	No	$0.5$ mL
Fluzone High-Dose Quadrivalent	Sanofi	Egg-based, high-dose	60 years and over	No	Yes	$0.7$ mL
Sources: 18

Detailed Product Profiles

Standard-Dose QIVs

These vaccines form the foundation of the immunisation program for most of the population under 65 years. They are produced using established egg-based manufacturing methods and contain a standard amount of antigen ($15$ micrograms of HA per strain).

• Vaxigrip® Tetra (Sanofi): An egg-based, split-virion vaccine registered for use in individuals from 6 months of age. It is the primary NIP-funded vaccine for the universal program for children aged 6 months to under 5 years, and for NIP-eligible individuals with medical risk factors up to 65 years of age.[18]
• FluQuadri® (Sanofi): Another egg-based, split-virion vaccine with the same age indication as Vaxigrip Tetra. It serves as an alternative or backup supply for NIP-funded programs and is also available on the private market.[19]
• Afluria® Quad (Seqirus): An egg-based, split-virion vaccine registered for use in individuals aged 5 years and over. It is funded under the NIP for eligible at-risk groups in its approved age range and is also available privately.[18]
• Influvac® Tetra (Viatris): An egg-based, surface antigen (subunit) vaccine registered for use from 6 months of age. For the 2025 season, it is available only on the private market.[18]

Cell-Based QIV Technology

Cell-based manufacturing represents a significant innovation in influenza vaccine production, designed to overcome some limitations of the traditional egg-based process.

• Technology Overview: Instead of chicken eggs, this method uses cultured mammalian cells (Madin-Darby Canine Kidney, or MDCK, cells) to grow the vaccine viruses.[42] This process is not dependent on egg supply and, crucially, avoids the potential for "egg-adaptive mutations." These are changes that can occur in the virus's HA protein as it adapts to grow in eggs, which can sometimes lead to a mismatch between the vaccine strain and the circulating human strain, potentially reducing vaccine effectiveness. Cell-based production results in a vaccine virus that is a closer match to the WHO-selected strain.[44]
• Flucelvax® Quad (Seqirus): Australia's only cell-based influenza vaccine, first made available in 2021.[21] It is registered for use in individuals from 6 months of age and is funded under the NIP for at-risk cohorts aged 5 to 64 years.[17] ATAGI has no preferential recommendation between Flucelvax Quad and standard egg-based vaccines for this group.[17]

Enhanced Formulations for Older Adults

The immune systems of older adults often respond less effectively to standard vaccines, a phenomenon known as immunosenescence. To address this, enhanced vaccines have been developed to elicit a more robust and durable immune response in this population. ATAGI preferentially recommends the use of an enhanced vaccine for all adults aged 65 years and over.[10]

• Fluad® Quad (Seqirus - Adjuvanted): This egg-based vaccine is registered for individuals aged 65 years and over (though some materials state 50+).[18] It is the only NIP-funded influenza vaccine for this age group in 2025.[19] Its enhanced effect is achieved through the inclusion of the MF59® adjuvant, an oil-in-water emulsion that stimulates a stronger and broader immune response to the vaccine antigens.[9]
• Fluzone® High-Dose Quadrivalent (Sanofi - High-Dose): This egg-based, split-virion vaccine is registered for individuals aged 60 years and over.[18] It achieves enhanced immunogenicity by containing four times the amount of HA antigen per strain ($60$ micrograms) compared to standard-dose vaccines ($15$ micrograms).[50] For the 2025 season, it is available only on the private market.[18]

The availability of these distinct technologies necessitates careful clinical consideration. The following table summarizes the safety profiles of key vaccines to aid in patient counseling and decision-making.

Table 2: Summary of Safety Profiles and Contraindications for Key 2025 Influenza Vaccines

Vaccine	Common Local Reactions	Common Systemic Reactions	Key Contraindications & Precautions (beyond general anaphylaxis)
Vaxigrip Tetra	Injection site pain (26-57%)	Headache (16-28%), Myalgia (14-23%), Malaise (19-27%)	Caution with bleeding disorders, history of GBS post-influenza vaccine.
Afluria Quad	Pain ($\geq$40% in adults <65; $\geq$20% in adults $\geq$65)	Myalgia & Headache ($\geq$20% in adults <65; Myalgia $\geq$10% in adults $\geq$65)	Contraindicated in children <5 years. Caution with history of GBS.
Flucelvax Quad	Pain (45-61%), Erythema (13-25%)	Headache (16-22%), Fatigue (16-18%), Myalgia (15-16%)	Caution with history of GBS. Some pre-filled syringes may contain natural rubber latex.
Fluad Quad	Pain, tenderness, redness, swelling at injection site.	Fatigue, Headache, Myalgia, Arthralgia.	Registered for ages 65+ (NIP) / 50+ (private). Caution with history of GBS, severe egg allergy. Contains squalene (fish origin).
Fluzone High-Dose Quadrivalent	Pain, redness, swelling, induration at injection site.	Myalgia, Malaise, Headache.	Registered for ages 60+. Caution with bleeding disorders, history of GBS.
Note: Frequencies are derived from clinical trial data and may vary. This table is a summary; refer to full Product Information for complete details. Sources: 31

Vaccine Effectiveness and Contemporary Safety Surveillance

The ultimate value of an annual influenza immunisation program rests on two pillars: the effectiveness of the vaccine in preventing disease and the robustness of the systems in place to monitor its safety. In the post-Fluvax era, Australia has made significant advancements in both measuring effectiveness and ensuring transparent, active safety surveillance.

Effectiveness of the 2025 Southern Hemisphere Formulation

The effectiveness of seasonal influenza vaccines can vary from year to year, depending on the match between the vaccine strains and the circulating viruses, as well as host factors like age and immune status. Generally, in healthy adults and children, the vaccine reduces the likelihood of contracting influenza by approximately 50-60%.[52]

For the current 2025 season, interim data from a multi-country test-negative case-control study, which included Australia, provide specific estimates of vaccine effectiveness (VE) for the Southern Hemisphere formulation. The findings suggest that the 2025 vaccine has provided substantial protection:

• Against Medically Attended Illness: The adjusted VE against influenza-associated outpatient visits (influenza-like illness) was 50.4% for any influenza virus.[53]
• Against Hospitalization: The adjusted VE against influenza-associated hospitalization (severe acute respiratory infection) was 49.7% for any influenza virus.[53]

Effectiveness varied by virus subtype, with an adjusted VE against hospitalization of 41.6% for the predominant A(H1N1)pdm09 subtype and 77.6% for influenza B viruses.[53] These estimates indicate that the 2025 vaccine has reduced the risk of medically attended influenza illness by approximately half, reinforcing its critical role in mitigating disease burden.

The Role of Active Pharmacovigilance: The AusVaxSafety System

A direct and crucial legacy of the 2010 Fluvax incident is the establishment of AusVaxSafety, Australia's national, active vaccine safety surveillance system.[30] The events of 2010 starkly revealed the inadequacies of a passive surveillance system, which relies on spontaneous reports from clinicians and patients and can be slow to detect signals.[11]

AusVaxSafety represents a paradigm shift to active surveillance. The system works by proactively contacting vaccine recipients (or their parents/carers) via SMS or email in the days following vaccination to ask about any adverse events. This near-real-time data collection allows for the rapid detection of any potential safety issues, far more quickly than passive systems would allow.[30]

For the 2025 influenza season, AusVaxSafety commenced its routine surveillance of all available influenza vaccines in March 2025.[30] A key feature of this system is its commitment to transparency. De-identified, aggregated safety data are made publicly available on the AusVaxSafety website, allowing clinicians, policymakers, and the public to monitor the safety profile of the vaccines in use.[30] This approach stands in stark contrast to the information vacuum and uncertainty that characterized the early days of the 2010 crisis. By proactively collecting and disseminating safety data, this modern surveillance infrastructure not only strengthens the public health response capacity but also plays a vital role in building and maintaining public trust in the national immunisation program—a direct and invaluable lesson learned from the Fluvax experience.

Conclusion and Expert Recommendations

The history of the Fluvax vaccine in Australia is a powerful illustration of the dynamic and self-correcting nature of medical science and public health. The 2010 safety incident, while a significant public health challenge, was not a failure of the principles of vaccination but a catalyst for profound and necessary evolution. It forced a deeper understanding of vaccine science, drove regulatory reform, and ultimately resulted in a more sophisticated, safer, and transparent national immunisation program.

Lessons from the Fluvax Incident

The analysis of the Fluvax incident yields several critical lessons that continue to inform best practices in vaccinology today:

1. Manufacturing Consistency and Characterization: The incident demonstrated that antigenic equivalence (the amount of HA) is not synonymous with immunological equivalence. The physical state of viral components and the presence of innate immune stimulants, influenced by the manufacturing process, can dramatically alter a vaccine's reactogenicity. This has led to more rigorous characterization of vaccine products beyond simple antigen quantification.
2. Age-Specific Immunogenicity: The events of 2010 underscored that the immune systems of young, immunologically naive children are distinct and can respond with greater intensity to certain stimuli. This has reinforced the necessity of generating specific safety and efficacy data for paediatric populations and has driven the development of age-specific vaccine formulations.
3. Robust Post-Market Surveillance: The crisis exposed the inherent limitations of passive surveillance systems. The subsequent development of active surveillance infrastructure like AusVaxSafety is a direct and vital legacy, enabling rapid signal detection and transparent communication, which are essential for maintaining public confidence.

Clinical Guidance for Healthcare Providers

Navigating the diverse 2025 influenza vaccine portfolio requires adherence to the evidence-based recommendations from ATAGI and a clear understanding of the available products.

• For Patients Aged 65 Years and Over: An enhanced vaccine is preferentially recommended to overcome immunosenescence. The NIP-funded option is the adjuvanted Fluad® Quad. The privately available alternative is Fluzone® High-Dose Quadrivalent. Clinicians should strongly recommend one of these formulations over standard-dose vaccines for this age group.[10]
• For NIP-Eligible Patients Aged 5 to 64 Years: Both egg-based (e.g., Vaxigrip® Tetra, Afluria® Quad) and cell-based (Flucelvax® Quad) options are funded for at-risk groups. There is no preferential recommendation between these technologies, and the choice may be guided by local availability and patient history.[17]
• Patient Communication: It is essential to manage patient expectations. Clinicians should communicate that the vaccine provides approximately 50% protection against medically attended illness and is highly effective at reducing the severity of disease and preventing complications like hospitalization and death.[53] Explaining that common, mild side effects (such as injection site pain or myalgia) are expected and are a sign of a healthy immune response can improve vaccine acceptance.

Future Outlook

The field of influenza vaccination continues to evolve. The imminent transition from quadrivalent back to trivalent vaccines, driven by the apparent eradication of the B/Yamagata virus lineage, is the next major shift on the horizon.[19] This move exemplifies the core principle of modern public health: continuous adaptation based on the best available global virological and epidemiological data. The journey from the Fluvax crisis to the current era is a testament to this principle—a path of scientific learning, regulatory strengthening, and an unwavering commitment to a more precise, evidence-based, and transparent approach to public immunisation.

Works cited

1. www.nps.org.au, accessed October 26, 2025, https://www.nps.org.au/assets/medicines/4ef5e689-0d0b-4949-91f8-a53300ff0ad0.pdf
2. Febrile seizures following seasonal influenza vaccination - World Health Organization (WHO), accessed October 26, 2025, https://www.who.int/groups/global-advisory-committee-on-vaccine-safety/topics/influenza-vaccines/febrile-seizures
3. Full article: Inactivated recombinant influenza vaccine: the promising direction for the next generation of influenza vaccine, accessed October 26, 2025, https://www.tandfonline.com/doi/full/10.1080/14760584.2024.2333338
4. Influenza Vaccination Strategies: Comparing Inactivated and Live ..., accessed October 26, 2025, https://www.mdpi.com/2076-393X/3/2/373
5. Seasonal Inactivated Influenza Virus Vaccines - PMC - NIH, accessed October 26, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC2643340/
6. Flu Shot | Flu | Influenza - MedlinePlus, accessed October 26, 2025, https://medlineplus.gov/flushot.html
7. Key Facts About Seasonal Flu Vaccine | Influenza (Flu) - CDC, accessed October 26, 2025, https://www.cdc.gov/flu/vaccines/keyfacts.html
8. Flu vaccine FAQs | healthdirect, accessed October 26, 2025, https://www.healthdirect.gov.au/flu-vaccine-faqs
9. Fluad QUAD - Advanced Flu Vaccines, accessed October 26, 2025, https://www.fluvaccine.co.nz/fluad-quad-full
10. Influenza (flu) | The Australian Immunisation Handbook, accessed October 26, 2025, https://immunisationhandbook.health.gov.au/contents/vaccine-preventable-diseases/influenza-flu
11. Australia suspends seasonal flu vaccination of young children - The BMJ, accessed October 26, 2025, https://www.bmj.com/content/340/bmj.c2419
12. Epidemiological study of severe febrile reactions in young children in Western Australia caused by a 2010 trivalent inactivated influenza vaccine - PMC - PubMed Central, accessed October 26, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC3191393/
13. BioCSL Fluvax - investigations into the cause of fevers in children ..., accessed October 26, 2025, https://www.tga.gov.au/news/media-releases/biocsl-fluvax-investigations-cause-fevers-children-under-5-years
14. CSL studies shed light on 2010 flu vaccine seizures - CIDRAP - University of Minnesota, accessed October 26, 2025, https://www.cidrap.umn.edu/h1n1-2009-pandemic-influenza/csl-studies-shed-light-2010-flu-vaccine-seizures
15. Adverse events associated with 2010 CSL and other inactivated influenza vaccines, accessed October 26, 2025, https://www.mja.com.au/journal/2011/195/6/adverse-events-associated-2010-csl-and-other-inactivated-influenza-vaccines
16. 2025 Flu Vaccination 'what you need to know' | SA Health, accessed October 26, 2025, https://www.sahealth.sa.gov.au/wps/wcm/connect/public+content/sa+health+internet/resources/2025+influenza+program+what+you+need+to+know
17. National Immunisation Program - 2025 Influenza Vaccination - Department of Health, Disability and Ageing, accessed October 26, 2025, https://www.health.gov.au/sites/default/files/2025-03/2025-influenza-vaccination-program-advice-for-health-professionals_0.pdf
18. 2025 Seasonal influenza vaccines | Therapeutic Goods Administration (TGA), accessed October 26, 2025, https://www.tga.gov.au/resources/publication/publications/2025-seasonal-influenza-vaccines
19. Influenza vaccine information - NSW Health, accessed October 26, 2025, https://www.health.nsw.gov.au/immunisation/Pages/flu-providers-vaccine-information.aspx
20. Queensland Health 2025 Influenza vaccination advice, accessed October 26, 2025, https://www.health.qld.gov.au/clinical-practice/guidelines-procedures/diseases-infection/immunisation/service-providers/influenza
21. Influenza vaccines – frequently asked questions (FAQs) - NCIRS, accessed October 26, 2025, https://ncirs.org.au/influenza/influenza-vaccines-frequently-asked-questions-faqs
22. Influenza (flu) vaccine | Australian Government Department of Health, Disability and Ageing, accessed October 26, 2025, https://www.health.gov.au/topics/immunisation/vaccines/influenza-flu-vaccine
23. Seasonal influenza vaccine - Health.vic, accessed October 26, 2025, https://www.health.vic.gov.au/immunisation/seasonal-influenza-vaccine
24. Influenza immunisation - WA Health, accessed October 26, 2025, https://www.health.wa.gov.au/articles/f_i/influenza-immunisation-program
25. 2025 Free Flu Vaccination Program | Queensland Health, accessed October 26, 2025, https://www.health.qld.gov.au/clinical-practice/guidelines-procedures/diseases-infection/immunisation/service-providers/2025-free-flu-vaccination-program
26. Free Flu Vaccination Day Returns in 2025 as Australia Faces Highest Ever Q1 Influenza Cases - Immunisation Coalition, accessed October 26, 2025, https://www.immunisationcoalition.org.au/free-flu-vaccination-day-returns-in-2025-as-australia-faces-highest-ever-q1-influenza-cases/
27. Fresh push to turn around 'dire' flu vaccination rate - RACGP, accessed October 26, 2025, https://www1.racgp.org.au/newsgp/clinical/fresh-push-to-turn-around-dire-flu-vaccination-rat
28. What is stopping kids getting a flu vaccination? - RACGP, accessed October 26, 2025, https://www1.racgp.org.au/newsgp/clinical/what-is-stopping-kids-getting-the-flu-vaccine
29. Europe, Australia report low flu vaccine uptake as flu activity soars Down Under | CIDRAP, accessed October 26, 2025, https://www.cidrap.umn.edu/influenza-general/europe-australia-report-low-flu-vaccine-uptake-flu-activity-soars-down-under
30. Influenza vaccines - AusVaxSafety, accessed October 26, 2025, https://ausvaxsafety.org.au/safety-data/influenza-vaccine
31. DOMASYS Standard - Immunisations, accessed October 26, 2025, https://www.vaxiplace.com.au/sites/default/files/2022-01/Australia%20Vaxigrip%20Tetra%20PI%20approved%2003dec21.pdf
32. VAXIGRIP TETRA (Sanofi-Aventis Australia Pty Ltd), accessed October 26, 2025, https://www.tga.gov.au/resources/prescription-medicines-registrations/vaxigrip-tetra-sanofi-aventis-australia-pty-ltd
33. 2025 seasonal influenza vaccination information for immunisation providers - NSW Health, accessed October 26, 2025, https://www.health.nsw.gov.au/immunisation/Pages/flu.aspx
34. FluQuadri | The Australian Immunisation Handbook, accessed October 26, 2025, https://immunisationhandbook.health.gov.au/vaccines/fluquadri
35. FluQuadri Inactivated Quadrivalent Influenza Vaccine (Split Virion), Influenza virus haemagglutinin 60mcg, 0.5mL suspension for injection (213963) | Therapeutic Goods Administration (TGA), accessed October 26, 2025, https://www.tga.gov.au/resources/artg/213963
36. AUSTRALIAN PRODUCT INFORMATION - FLUQUADRI ..., accessed October 26, 2025, https://apps.medicines.org.au/files/swpfluqu.pdf
37. Afluria Quad | The Australian Immunisation Handbook, accessed October 26, 2025, https://immunisationhandbook.health.gov.au/vaccines/afluria-quad
38. Afluria Quad - NPS MedicineWise, accessed October 26, 2025, https://www.nps.org.au/medicine-finder/afluria-quad-suspension-for-injection
39. Product Information - QUT Medical Centre, accessed October 26, 2025, https://www.medical-centre.qut.edu.au/__data/assets/pdf_file/0003/1212645/Afluria-Quad-2023-PI.pdf
40. Influvac Tetra | The Australian Immunisation Handbook, accessed October 26, 2025, https://immunisationhandbook.health.gov.au/vaccines/influvac-tetra
41. AusPAR - Influvac Tetra - influenza virus haemagglutinin, accessed October 26, 2025, https://www.tga.gov.au/sites/default/files/auspar-influenza-virus-haemagglutinin-220325-pi.pdf
42. Flucelvax Quad | Therapeutic Goods Administration (TGA), accessed October 26, 2025, https://www.tga.gov.au/resources/auspmd/flucelvax-quad
43. AUSTRALIAN PRODUCT INFORMATION Flucelvax® Quad ..., accessed October 26, 2025, https://labeling.seqirus.com/PI/AU/Flucelvax/EN/Flucelvax-Product-Information.pdf
44. Cell-based Flucelvax® Quad influenza vaccine now approved for Australian children aged two years and older - CSL Seqirus, accessed October 26, 2025, https://www.cslseqirus.com.au/news/cell-based-flucelvax-quad-influenza-vaccine-now-approved-for-au-children-aged-2-years-and-older
45. New type of flu vax arrives - MedNews, accessed October 26, 2025, https://mednews.com.au/new-flu-vax-arrives-but-not-on-nip/
46. Flucelvax Quad | The Australian Immunisation Handbook, accessed October 26, 2025, https://immunisationhandbook.health.gov.au/vaccines/flucelvax-quad
47. Fluad® Quad - Consumer Medicine Information (CMI) summary, accessed October 26, 2025, https://labeling.seqirus.com/CMI/AU/Fluad/EN/Fluad-Consumer-Medicine-Information.pdf
48. Fluad Quad - NPS MedicineWise, accessed October 26, 2025, https://www.nps.org.au/medicine-finder/fluad-quad
49. Fluzone High-Dose 2024 - Healthdirect, accessed October 26, 2025, https://www.healthdirect.gov.au/medicines/brand/amt,1731121000168100/fluzone-high-dose-2024
50. High-dose quadrivalent influenza vaccine for older populations | Medicine Today, accessed October 26, 2025, https://medicinetoday.com.au/mt/2022/april/regular-series/highdose-quadrivalent-influenza-vaccine-older-populations
51. Fluzone® High-Dose Quadrivalent, accessed October 26, 2025, https://www.nps.org.au/assets/medicines/4bd4a920-9366-49a0-b3fe-ae2400f36c77.pdf
52. Influenza vaccines – frequently asked questions (FAQs) | NCIRS, accessed October 26, 2025, https://ncirs.org.au/influenza/influenza-vaccines-frequently-asked-questions-faqs#:~:text=In%20young%20children%20and%20healthy,varies%20from%20year%20to%20year.
53. Interim Effectiveness Estimates of 2025 Southern Hemisphere ..., accessed October 26, 2025, https://www.cdc.gov/mmwr/volumes/74/wr/mm7436a3.htm
54. Protection from flu vaccine around 50% for Southern Hemisphere, data reveal - CIDRAP, accessed October 26, 2025, https://www.cidrap.umn.edu/influenza-vaccines/protection-flu-vaccine-around-50-southern-hemisphere-data-reveal