Lessons learned from the COVID-19 pandemic for improved influenza control.

The World Health Organization noted that COVID-19 vaccination programmes could be leveraged to deliver influenza vaccination. In 2008, the International Federation of Pharmaceutical Manufacturers and Associations' (IFPMA) Influenza Vaccine Supply International Task Force (IVS) developed a survey method using the number of influenza vaccine doses distributed globally to estimate vaccination coverage rates. Seven hundred and ninety-seven million doses were distributed in 2021, representing a 205% increase over the 262 million doses distributed in 2004, exceeding the number of doses distributed during and after the 2009-2010 influenza pandemic. The most obvious explanation for the global increase is the enabling of critical elements of the vaccine ecosystem by decision-makers during the COVID-19 pandemic to reinforce implementation of influenza vaccination programs. Most of the improvements in performance of influenza programs during the COVID-19 pandemic can be classified in four categories: 1) promoting vaccination using tailored approaches for specific populations; 2) improving convenient access to influenza vaccines in COVID-safe settings; 3) improving reimbursement of seasonal influenza vaccination for priority groups; 4) maintaining the timing of vaccination to the autumn. In spite of the increase in rates of seasonal influenza vaccines distributed during the COVID-19 pandemic, globally, the rate of influenza dose distribution is sub-optimal, and a considerable proportion of the influenza infections remains preventable. To sustain the benefits from increased uptake of influenza vaccines, governments need to sustain the efforts made during the COVID-19 pandemic, and a number of global policy endeavours should be undertaken, including developing a clear global roadmap for achieving influenza control objectives, adopted by a WHA resolution, in line with the strategic objective 3 of the Global Influenza Strategy 2030, embedded in the Immunization Agenda 2030 (IA2030).

Clinical relevance of increased antibody titres in older adults upon vaccination with squalene-adjuvanted versus non-adjuvanted influenza vaccines.

In older adults, the serum antibody response to inactivated influenza vaccine (IIV) is often lower than in adolescents and non-elderly adults which may translate into suboptimal protection against influenza. To counteract this expression of immunosenescence, the use of adjuvanted IIV formulations has been explored. Four recent studies (three meta-analyses and one clinical trial) found an antibody increase of up to 1.5-fold in older adults, when a squalene-adjuvanted (MF59™) IIV was used. The clinical relevance of this increase may well continue to be a matter of debate. We would favour a threshold of 1.5 to consider an adjuvanted vaccine formulation superior to standard aqueous IIV because it exceeds the inevitable variation of antibody responses to non-adjuvanted IIV. It is also the same as the upper FDA equivalence limit for IIV lot-to-lot consistency. A corresponding threshold for the seroresponse rate difference could then be +5%.

Vaccine complacency and dose distribution inequities limit the benefits of seasonal influenza vaccination, despite a positive trend in use.

Sustainable demand for seasonal influenza vaccines is a component of national security strategies for pandemic preparedness. However, the ongoing COVID-19 pandemic has revealed many weaknesses in the capacity of countries to design and execute sustainable vaccination programs. An influenza pandemic remains a global threat and yet there is no global monitoring system for assessing progress towards influenza vaccination coverage targets. The International Federation of Pharmaceutical Manufacturers and Associations' (IFPMA) Influenza Vaccine Supply International Task Force (IVS) developed a survey method in 2008 to estimate seasonal influenza vaccination coverage rates, which in turn serves as a crude estimate of pandemic preparedness. It provides evidence to guide expanded efforts for pandemic preparedness, specifically for increasing COVID-19 vaccine immunization levels. Furthermore, the results presented herein serve as a proxy for assessing the state of pandemic preparedness at a global and regional level. This paper adds data from 2018 and 2019 to the previous analyses. The current data show an upward or stable global trend in seasonal influenza vaccine dose distributed per 1,000 population with a 7% increase between 2017 and 2018 and 6% increase between 2018 and 2019. However, considerable regional inequities in access to vaccine persist. Three regions, Africa, the Middle-east, and Southeast Asia together account for 50% of the global population but only 6% of distributed seasonal influenza vaccine doses. This is an important finding in the context of the ongoing COVID-19 pandemic, as distribution of influenza vaccine doses in many ways reflects access to COVID-19 vaccines. Moreover, improving seasonal vaccine uptake rates is critical for optimizing the annual benefits by reducing the huge annual influenza-associated societal burdens and by providing protection to vulnerable individuals against serious complications from seasonal influenza infections.

Association between vaccine adjuvant effect and pre-seasonal immunity. Systematic review and meta-analysis of randomised immunogenicity trials comparing squalene-adjuvanted and aqueous inactivated influenza vaccines.

The immunogenicity benefit of inactivated influenza vaccine (IIV) adjuvanted by squalene over non-adjuvanted aqueous IIV was explored in a meta-analysis involving 49 randomised trials published between 1999 and 2017, and 22,470 eligible persons of all age classes. Most vaccines contained 15 µg viral haemagglutinin per strain. Adjuvanted IIV mostly contained 9.75 mg squalene per dose. Homologous pre- and post-vaccination geometric mean titres (GMTs) of haemagglutination-inhibition (HI) antibody were recorded for 290 single influenza (sub-)type arms. The adjuvant effect was expressed as the ratio of post-vaccination GMTs between squalene-IIV and aqueous IIV (GMTR, 145 estimates). GMTRs > 1.0 favoured squalene-IIV over aqueous IIV. For all influenza (sub-)types, the adjuvant effect proved negatively associated with pre-vaccination GMT and mean age. The adjuvant effect appeared most pronounced in young children (mean age < 2.5 years) showing an average GMTR of 3.7 (95% CI: 2.5 to 5.5). With increasing age, GMTR values gradually decreased towards 1.4 (95% CI: 1.0 to 1.9) in older adults. Heterologous antibody titrations simulating mismatch between vaccine and circulating virus (30 GMTR estimates) again showed a larger adjuvant effect at young age. GMT values and their variances were converted to antibody-predicted protection rates using an evidence-based clinical protection curve. The adjuvant effect was expressed as the protection rate differences, which showed similar age patterns as corresponding GMTR values. However for influenza B, the adjuvant effect lasted longer than for influenza A, possibly due to a generally later influenza B virus exposure. Collectively, this meta-analysis indicates the highest benefit of squalene-IIV over aqueous IIV in young children and decreasing benefit with progressing age. This trend is similar for seasonal influenza (sub-)types and the 2009 pandemic strain, by both homologous and heterologous titration. The impact of pre-seasonal immunity on vaccine effectiveness, and its implications for age-specific vaccination recommendations, are discussed.

Seasonal influenza vaccine dose distribution in 195 countries (2004-2013): Little progress in estimated global vaccination coverage.

Seasonal influenza is an important disease which results in 250,000-500,000 annual deaths worldwide. Global targets for vaccination coverage rates (VCRs) in high-risk groups are at least 75% in adults ≥65 years and increased coverage in other risk groups. The International Federation of Pharmaceutical Manufacturers and Associations Influenza Vaccine Supply (IFPMA IVS) International Task Force developed a survey methodology in 2008, to assess the global distribution of influenza vaccine doses as a proxy for VCRs. This paper updates the previous survey results on absolute numbers of influenza vaccine doses distributed between 2004 and 2013 inclusive, and dose distribution rates per 1000 population, and provides a qualitative assessment of the principal enablers and barriers to seasonal influenza vaccination. The two main findings from the quantitative portion of the survey are the continued negative trend for dose distribution in the EURO region and the perpetuation of appreciable differences in scale of dose distribution between WHO regions, with no observed convergence in the rates of doses distributed per 1000 population over time. The main findings from the qualitative portion of the survey were that actively managing the vaccination program in real-time and ensuring political commitment to vaccination are important enablers of vaccination, whereas insufficient access to vaccination and lack of political commitment to seasonal influenza vaccination programs are likely contributing to vaccination target failures. In all regions of the world, seasonal influenza vaccination is underutilized as a public health tool. The survey provides evidence of lost opportunity to protect populations against potentially serious influenza-associated disease. We call on the national and international public health communities to re-evaluate their political commitment to the prevention of the annual influenza disease burden and to develop a systematic approach to improve vaccine distribution equitably.

Seasonal influenza vaccine dose distribution in 157 countries (2004-2011).

Globally there are an estimated 3-5 million cases of severe influenza illness every year, resulting in 250,000-500,000 deaths. At the World Health Assembly in 2003, World Health Organization (WHO) resolved to increase influenza vaccine coverage rates (VCR) for high-risk groups, particularly focusing on at least 75% of the elderly by 2010. But systematic worldwide data have not been available to assist public health authorities to monitor vaccine uptake and review progress toward vaccination coverage targets. In 2008, the International Federation of Pharmaceutical Manufacturers and Associations Influenza Vaccine Supply task force (IFPMA IVS) developed a survey methodology to assess global influenza vaccine dose distribution. The current survey results represent 2011 data and demonstrate the evolution of the absolute number distributed between 2004 and 2011 inclusive, and the evolution in the per capita doses distributed in 2008-2011. Global distribution of IFPMA IVS member doses increased approximately 86.9% between 2004 and 2011, but only approximately 12.1% between 2008 and 2011. The WHO's regions in Eastern Mediterranean (EMRO), Southeast Asian (SEARO) and Africa (AFRO) together account for about 47% of the global population, but only 3.7% of all IFPMA IVS doses distributed. While distributed doses have globally increased, they have decreased in EURO and EMRO since 2009. Dose distribution can provide a reasonable proxy of vaccine utilization. Based on the dose distribution, we conclude that seasonal influenza VCR in many countries remains well below the WHA's VCR targets and below the recommendations of the Council of the European Union in EURO. Inter- and intra-regional disparities in dose distribution trends call into question the impact of current vaccine recommendations at achieving coverage targets. Additional policy measures, particularly those that influence patients adherence to vaccination programs, such as reimbursement, healthcare provider knowledge, attitudes, practices, and communications, are required for VCR targets to be met and benefit public health.

Annual public health and economic benefits of seasonal influenza vaccination: a European estimate.

BACKGROUND: Vaccination is currently the most effective means of preventing influenza infection. Yet evidence of vaccine performance, and the impact and value of seasonal influenza vaccination across risk groups and between seasons, continue to generate much discussion. Moreover, vaccination coverage is below recommended levels. METHODS: A model was generated to assess the annual public health benefits and economic importance of influenza vaccination in 5 WHO recommended vaccination target groups (children 6 - 23 months of age; persons with underlying chronic health conditions; pregnant women; health care workers; and, the elderly, 65 years of age) in 27 countries of the European Union. Model estimations were based on standard calculation methods, conservative assumptions, age-based and country-specific data. RESULTS: Out of approximately 180 million Europeans for whom influenza vaccination is recommended, only about 80 million persons are vaccinated. Seasonal influenza vaccination currently prevents an annual average of between 1.6 million and 2.1 million cases of influenza, 45,300 to 65,600 hospitalizations, and 25,200 to 37,200 deaths. To reach the 75% vaccination coverage target set by the EU Council Recommendation in 2009, an additional 57.4 million person would need to be vaccinated in the elderly and other risk groups. By achieving the 75% target rate set in EU-27 countries, average annual influenza- related events averted would increase from current levels to an additional +1.6 to +1.7 million cases, +23,800 to +31,400 hospitalization, +9,800 to +14,300 deaths, +678,500 to +767,800 physician visits, and +883,800 to +1,015,100 lost days of work yearly. Influenza-related costs averted because of vaccination would increase by an additional + €190 to + €226 million yearly, in vaccination target groups. CONCLUSIONS: Full implementation of current influenza vaccination recommendations of 75% vaccination coverage rate (VCR) in Europe by the 2014-2015 influenza season could immediately reduce an important public health and economic burden.

Seasonal influenza vaccine provision in 157 countries (2004-2009) and the potential influence of national public health policies.

Seasonal influenza places a major burden on public health. Consequently, the World Health Organization (WHO) and over 40% of national governments recommend vaccination of at-risk groups. However, no systematic global data are available to assess vaccine provision nor the effect of immunization policies. To address this situation, IFPMA IVS surveyed global vaccine supply, covering 157 countries from 2004 to 2009. The study also used UN data and a novel vaccine provision "hurdle" rate (set at 15.9% of the population, based on WHO immunization recommendations for the elderly) to compare vaccine supply with development status. In a sub-group of 26 countries, the level of vaccine provision was also correlated to the presence/absence of specific vaccination policies. Between 2004 and 2009, global annual vaccine provision increased 72% to 449 million doses. Europe and the Americas accounted for 75% to 80% of the total each year, with several countries in these regions, as well as China, Japan and Thailand, achieving notable increases during the study period. However, despite the global growth, only 20% of countries reached the study's modest "hurdle" rate. On a per capita basis, dose distribution did not correlate directly with income, and several less developed countries, particularly in Latin America, outperformed more developed nations (notably in Eastern and Southern Europe). In the sub-group analysis, the presence of official public health authority vaccination recommendations did not correlate well with higher vaccine supply (positive:negative correlation=1.3:1), while reimbursement (4.5:1) and the use of wide-scale communication activities (5.3:1) correlated more strongly than development status (2.7:1). This study shows that globally vaccination levels remain low, and official vaccination recommendations alone are insufficient to drive higher coverage. Rather, policy measures that directly impact patients (i.e. reimbursement and communication) appear more effective, irrespective of countries' development status, and therefore may do more to help protect local populations against influenza.

Cell-mediated immune responses to inactivated trivalent influenza-vaccination are decreased in patients with common variable immunodeficiency.

Influenza-specific cell-mediated immune (CMI) responses can protect from influenza, but may be decreased in CVID-patients since defects in CMI responses have been demonstrated in CVID-patients. Therefore CMI responses were evaluated in 15 CVID-patients and 15 matched healthy controls (HC) by determining frequencies of interferon (IFN)γ-producing PBMC, and frequencies of IFNγ-, interleukin (IL)-2- and tumour necrosis factor (TNF)α-producing CD4+ and CD8+ T-cells before and after influenza vaccination using IFNγ enzyme-linked immunospot (IFNγ-ELISpot) and flow cytometry. Humoral responses were determined using haemagglutination inhibition assay. In CVID-patients the number of spotforming PBMC in the IFNγ-ELISpot did not increase following influenza vaccination, in contrast to HC. In flow cytometry, the frequencies of IFNγ-producing T-cells decreased in CVID-patients after influenza vaccination, while in HC the frequencies of IFNγ-production flow cytometry increased. Concluding, CMI responses following influenza vaccination are hampered in CVID-patients compared to HC. Additional protective strategies against influenza other than vaccination are warranted.

Lessons from pandemic influenza A(H1N1): the research-based vaccine industry's perspective.

As A(H1N1) influenza enters the post-pandemic phase, health authorities around the world are reviewing the response to the pandemic. To ensure this process enhances future preparations, it is essential that perspectives are included from all relevant stakeholders, including vaccine manufacturers. This paper outlines the contribution of R&D-based influenza vaccine producers to the pandemic response, and explores lessons that can be learned to improve future preparedness. The emergence of 2009 A(H1N1) influenza led to unprecedented collaboration between global health authorities, scientists and manufacturers, resulting in the most comprehensive pandemic response ever undertaken, with a number of vaccines approved for use three months after the pandemic declaration. This response was only possible because of the extensive preparations undertaken during the last decade. During this period, manufacturers greatly increased influenza vaccine production capacity, and estimates suggest a further doubling of capacity by 2014. Producers also introduced cell-culture technology, while adjuvant and whole virion technologies significantly reduced pandemic vaccine antigen content. This substantially increased pandemic vaccine production capacity, which in July 2009 WHO estimated reached 4.9 billion doses per annum. Manufacturers also worked with health authorities to establish risk management plans for robust vaccine surveillance during the pandemic. Individual producers pledged significant donations of vaccine doses and tiered-pricing approaches for developing country supply. Based on the pandemic experience, a number of improvements would strengthen future preparedness. Technical improvements to rapidly select optimal vaccine viruses, and processes to speed up vaccine standardization, could accelerate and extend vaccine availability. Establishing vaccine supply agreements beforehand would avoid the need for complex discussions during a period of intense time pressure. Enhancing international regulatory co-operation and mutual recognition of approvals could accelerate vaccine supply, while maintaining safety standards. Strengthening communications with the public and healthcare workers using new approaches and new channels could help improve vaccine uptake. Finally, increasing seasonal vaccine coverage will be particularly important to extend and sustain pandemic vaccine production capacity.

Cell-mediated immune responses to influenza vaccination in Wegener's granulomatosis.

BACKGROUND: Both antibody and cell-mediated immune responses are involved in the defence against influenza. In Wegener's granulomatosis (WG), antibody responses to influenza vaccination appear to be similar to those in healthy controls, but cell-mediated responses have not been studied. OBJECTIVE: To determine whether cell-mediated responses to influenza vaccination in WG vary from those in controls. METHODS: Twenty-five patients with WG and healthy controls received subunit influenza vaccine. Peripheral blood mononuclear cells were obtained before and 1 month after vaccination. Cell-mediated responses to A/H1N1 and A/H3N2 were assessed using interferon gamma (IFN gamma) ELISpot and intracellular cytokine staining for IFN gamma, tumour necrosis factor and interleukin 2. RESULTS: Before vaccination, patients and controls showed similar recall responses to A/H1N1 and A/H3N2. After vaccination, patients and controls showed similar levels of increase in spot-forming cells against A/H1N1 and A/H3N2. By flow cytometry, upon vaccination, proportions of cytokine-producing CD4 T cells increased in patients and controls for A/H1N1 and A/H3N2. CONCLUSIONS: Cell-mediated responses to influenza vaccination in patients with WG are comparable to those in healthy controls.

Effect of a second, booster, influenza vaccination on antibody responses in quiescent systemic lupus erythematosus: an open, prospective, controlled study.

OBJECTIVE: In SLE, a decreased antibody response on influenza vaccination has been reported. In this study, we assessed whether a booster vaccination could improve antibody responses, as determined by seroprotection rates, in SLE patients. METHODS: SLE patients (n = 52) with quiescent disease (SLEDAI < or =4) and healthy controls (HCs) (n = 28) received subunit influenza vaccine in October-December 2007. After 4 weeks, only SLE patients received a second dose of vaccination. Sera were obtained before both vaccinations, and 4 weeks after the second vaccination. At each visit, SLE disease activity was recorded. The haemagglutination inhibition test was used to measure antibody titres. Seroprotection was defined as a titre > or =40. RESULTS: Following the first vaccination, seroprotection rates and geometric mean titres (GMTs) to each vaccine strain increased in both SLE patients and controls to comparable levels. Seroprotection rates in SLE patients after the first vaccination were 86.5% to A/H1N1, 80.8% to A/H3N2 and 61.5% to the B-strain while GMTs were 92.6, 56.2 and 39.2, respectively. Overall, the booster vaccination did not lead to a further rise of seroprotection rates and GMTs in SLE patients. However, in patients not vaccinated in the previous year, GMT and seroconversion rate to A/H1N1 did rise following the booster vaccination. Both influenza vaccinations did not increase SLEDAI scores. CONCLUSIONS: Additional value of a booster influenza vaccination in SLE is limited to patients who were not vaccinated in the previous year.

Studies of cell-mediated immune responses to influenza vaccination in systemic lupus erythematosus.

OBJECTIVE: Both antibody and cell-mediated responses are involved in the defense against influenza. In patients with systemic lupus erythematosus (SLE), a decreased antibody response to subunit influenza vaccine has been demonstrated, but cell-mediated responses have not yet been assessed. This study was therefore undertaken to assess cell-mediated responses to influenza vaccination in patients with SLE. METHODS: Fifty-four patients with SLE and 54 healthy control subjects received subunit influenza vaccine. Peripheral blood mononuclear cells and sera were obtained before and 1 month after vaccination. Cell-mediated responses to A/H1N1 and A/H3N2 vaccines were evaluated using an interferon-gamma (IFNgamma) enzyme-linked immunospot assay and flow cytometry. Antibody responses were measured using a hemagglutination inhibition test. RESULTS: Prior to vaccination, patients with SLE had fewer IFNgamma spot-forming cells against A/H1N1 compared with control subjects and a lower frequency of IFNgamma-positive CD8+ T cells. After vaccination, the number of IFNgamma spot-forming cells increased in both patients and control subjects, although the number remained lower in patients. In addition, the frequencies of CD4+ T cells producing tumor necrosis factor and interleukin-2 were lower in patients after vaccination compared with healthy control subjects. As expected for a subunit vaccine, vaccination did not induce a CD8+ T cell response. For A/H3N2-specific responses, results were comparable. Diminished cell-mediated responses to influenza vaccination were associated with the use of prednisone and/or azathioprine. The increase in A/H1N1-specific and A/H3N2-specific antibody titers after vaccination was lower in patients compared with control subjects. CONCLUSION: In addition to a decreased antibody response, cell-mediated responses to influenza vaccination are diminished in patients with SLE, which may reflect the effects of the concomitant use of immunosuppressive drugs. This may render these patients more susceptible to (complicated) influenza infections.

Further evidence for favorable cost-effectiveness of elderly influenza vaccination.

Vaccination represents the single most cost-effective strategy to avert influenza-related morbidity, mortality and economic consequences. This review presents an analysis of the pharmacoeconomic aspects of influenza vaccination of the elderly. The methodology of the analysis focuses on the main drivers of the pharmacoeconomic profile of elderly influenza vaccination, in particular the vaccine effectiveness in terms of prevention of hospitalization and mortality, the background incidence of hospitalization and death in unvaccinated individuals and the relative costing of the vaccine compared with the costs of a hospital in-patient day. The variation in outcomes between different studies could partly be explained by differences in the main drivers defined above. This review demonstrates that the pharmacoeconomic profile of elderly influenza vaccination is highly favorable. From the vast majority of studies it appears that financial benefits of elderly influenza vaccination surpass the costs and that, when this is not the case, cost-effectiveness in terms of net costs per life-year gained is acceptable.

The virosome concept for influenza vaccines.

There is a need for more efficacious inactivated influenza vaccines, since current formulations show suboptimal immunogenicity in at-risk populations, like the elderly. More effective vaccines are also urgently needed for an improved influenza pandemic preparedness. In this context, there is considerable interest in virosomes. Virosomes are virus-like particles, consisting of reconstituted influenza virus envelopes, lacking the genetic material of the native virus. Virosomes are produced from influenza virus through a detergent solubilization and removal procedure. Properly reconstituted virosomes retain the cell binding and membrane fusion properties of the native virus, mediated by the viral envelope glycoprotein haemagglutinin. These functional characteristics of virosomes form the basis for their enhanced immunogenicity. First, the repetitive arrangement of haemagglutinin molecules on the virosomal surface mediates a cooperative interaction of the antigen with Ig receptors on B lymphocytes, stimulating strong antibody responses. In addition, virosomes interact efficiently with antigen-presenting cells, such as dendritic cells, resulting in activation of T lymphocytes. In a murine model system, virosomes, as compared to conventional subunit vaccine, which consists of isolated influenza envelope glycoproteins, induce a more balanced T helper 1 versus T helper 2 response, virosomes in particular eliciting stronger T helper 1 responses than subunit vaccine. Also, as a result of fusion of the virosomes with the endosomal membrane, part of the virosomal antigen gains access to the major histocompatibility class I presentation pathway, thus priming cytotoxic T lymphocyte activity. Finally, virosomes represent an excellent platform for inclusion of lipophilic adjuvants for further stimulation of vaccine immunogenicity. By virtue of these characteristics, virosomes represent a promising novel class of inactivated influenza vaccines, which not only induce high virus-neutralizing antibody titres, but also prime the cellular arm of the immune system.

Modeling pandemic preparedness scenarios: health economic implications of enhanced pandemic vaccine supply.

Influenza pandemic planning is a complex, multifactorial process, which involves public health authorities, regulatory authorities, academia and industry. It is further complicated by the unpredictability of the time of emergence and severity of the next pandemic and the effectiveness of influenza epidemic interventions. The complexity and uncertainties surrounding pandemic preparedness have so far kept the various stakeholders from joining forces and tackling the problem from its roots. We developed a mathematical model, which shows the tangible consequences of conceptual plans by linking possible pandemic scenarios to health economic outcomes of possible intervention strategies. This model helps to structure the discussion on pandemic preparedness and facilitates the translation of pandemic planning concepts to concrete plans. The case study for which the model has been used shows the current level of global pandemic preparedness in an assumed pandemic scenario, the health economic implications of enhanced pandemic vaccine supply and the importance of cell culture-based influenza vaccine manufacturing technologies as a tool for pandemic control.

Safety and antigenicity of whole virus and subunit influenza A/Hong Kong/1073/99 (H9N2) vaccine in healthy adults: phase I randomised trial.

BACKGROUND: In 1999, avian influenza A/Hong Kong/1073/99 (H9N2) virus emerged as a pandemic threat to human beings. We aimed to assess safety, tolerability, and antigenicity of whole virus and subunit H9N2 vaccines in healthy volunteers. METHODS: In a phase I randomised trial we randomly assigned 60 participants to whole virus or subunit H9N2 vaccine. Two doses of 7.5 microg, 15 microg, or 30 microg haemagglutinin influenza A H9N2 vaccine, were given 3 weeks apart. We measured antibody responses by haemagglutination-inhibition and microneutralisation. The primary outcome was geometric mean antibody titre 21 days after vaccination. Analysis was per protocol. FINDINGS: Both vaccines were safe and well tolerated. The antibody titres after vaccination did not differ significantly between subunit and whole virus vaccine. 24 of 60 prevaccination serum samples had unexpected reactivity to H9N2, but only in participants older than 32 years, in whom one dose of either vaccine evoked antibody responses associated with protection. In participants aged 32 years or younger, antibody responses to one dose of whole virus or subunit vaccine were poor, fulfilling none of the criteria used for yearly relicensing of interpandemic vaccines. Whole virus vaccine produced a significantly higher probability of seroconversion compared with subunit virus for this age-group. INTERPRETATION: In immunologically naive patients whole-virus vaccine produced better responses than subunit vaccine. Two doses of subunit or whole virus vaccine would leave a large proportion of the naive population (< or =32 years) unprotected against A/Hong Kong/1073/99 (H9N2). Primed patients should be protected with a single dose of either vaccine.