Background
Influenza infection represents a considerable global burden, affecting 5–15% of the adult population during annual influenza epidemics [
1]. Each year, 3–5 million cases of severe illness and 250,000–500,000 deaths are thought to result from these epidemics worldwide [
1,
2].
South-east Asia is considered to be the global influenza epicentre, with several pandemic and epidemic strains known to have originated from China and Hong Kong since 1957 [
3‐
5]. Furthermore, China is generally acknowledged as an area with a high influenza attack rate, due to the high population density and year-round circulation of the virus in tropical regions [
6,
7]. In China, pneumonia and influenza combined ranks fourth in the leading causes of death in adults (≥ 40 years of age) [
8].
Due to their weakened immune response, the elderly are at increased risk of influenza and its related complications [
9]. In China, the annual mortality rate for pneumonia and influenza has been reported to rise to 227.4/100,000 persons in the elderly (≥ 65 years of age), representing a 5-fold increase from the age-standardised annual mortality rate of 43.9/100,000 persons [
8]. Furthermore, during 1999, the reported number of influenza-associated deaths in Hong Kong from cardiorespiratory disease, pneumonia and influenza, chronic obstructive pulmonary disease and ischaemic heart disease was higher in the elderly (1697 deaths), compared with adults (205 deaths; 40–64 years of age) [
10]. Peaks in influenza circulation have been shown to coincide with increased mortality from these conditions, with the elderly accounting for approximately 70–90% of the associated deaths [
10]. In addition to an increased number of deaths [
10,
11], the hospitalisation rate for pneumonia and influenza is also high in the elderly [
12].
Influenza vaccine effectiveness has been studied extensively, mainly in temperate regions. Conventional influenza vaccines confer protection against laboratory-confirmed influenza in 70–90% of young adults (18–64 years of age) [
13,
14]; however, these vaccines are less effective (17–53%) in the elderly, due in part to the elderly's waning immunity [
15]. When evaluating vaccine response, however, it is important to also consider racial background. For example, among a racially diverse, healthy elderly population in the USA, a reduced response to influenza vaccine was observed among elderly African Americans, compared with elderly Caucasian and Latinos [
16]. Furthermore, racial differences in relation to vaccination have been observed in Taiwan among Han Chinese children compared with Aboriginal children; higher titres against hepatitis B vaccination were reported for Han Chinese children [
17].
In Hong Kong, Taiwan and China, vaccination has been shown to offer protection against influenza [
18‐
20]. Influenza vaccination prevented approximately 69% of influenza-related hospitalisation admissions in Hong Kong during the 2003–2004 winter season [
19] and was strongly associated with a reduction in pneumonia, heart disease, stroke, diabetes mellitus and renal disease in Taiwan in 2001 [
20]. Vaccine effectiveness, however, has also been reported to be lower in elderly Chinese people than in adult Chinese people (68.6% versus 74%, respectively) [
18]. Despite the availability of an effective vaccine, coverage rates are low in China; for example, the general vaccination rate among the urban population of Beijing is only 10.5%, falling to 7.9% for those ≥ 60 years of age [
21]. Thus, because currently available vaccines do not offer optimal protection in the elderly [
14,
15] and vaccine coverage rates are low [
21], elderly Chinese people are at increased risk of influenza and its related complications. As China has the world's largest population of elderly people (>80 million) [
22], influenza represents a considerable health and economic burden.
To meet the global challenge presented by waning immunity in the elderly, vaccines that offer the elderly enhanced immunogenicity and increased clinical protection are required. Addition of the adjuvant MF59™ [
23] to subunit influenza vaccine (MF59™-adjuvanted subunit influenza vaccine; FLUAD
®, Novartis Vaccines) has been shown to enhance the immune response and offer increased clinical protection in elderly subjects, compared with non-adjuvanted subunit influenza vaccine [
24‐
26]. Furthermore, enhanced immunogenicity is observed in elderly subjects with underlying chronic conditions, who are at especially high risk of influenza and its complications [
27]. Vaccination of elderly subjects with the MF59™-adjuvanted subunit influenza vaccine also confers protection against a broader range of influenza virus strains than non-adjuvanted subunit influenza vaccine [
28,
29] and has been associated with a reduced risk of hospitalisation for pneumonia and cerebrovascular disease in non-institutionalised elderly subjects [
30,
31].
In China, the registration of FLUAD® for use in elderly people is currently under consideration. For this reason, a randomised comparative trial was performed in a large cohort of elderly Chinese people to assess the safety and immunogenicity of FLUAD® against a non-adjuvanted subunit influenza vaccine.
Discussion
This study has demonstrated that MF59™-adjuvanted subunit influenza vaccine is as well tolerated as non-adjuvanted subunit influenza vaccine in elderly Chinese subjects. Although the number and incidence of some of the solicited local reactions in the Sub/MF59™ vaccine group was greater than in the Subunit group, they were generally mild or moderate and of short duration, and no subjects withdrew from the study due to safety concerns. Furthermore, the incidence of injection-site pain reported here was lower than has been reported in other studies [
25,
27]. Although the incidence of fever was higher than has been reported previously with MF59™-adjuvanted influenza vaccination [
25,
27], the increased incidence was evident for both vaccines used in this study, rather than for the Sub/MF59™ vaccine only. The increase does not appear to be due to race, as in a previous study in elderly Chinese subjects [
19] the incidence of fever was 0% following vaccination with non-adjuvanted influenza vaccine. These findings are in agreement with the published results of clinical trials conducted in elderly Caucasian populations in Europe [
25]. These trials supported registration of the vaccine in Europe, and concluded that the addition of MF59™ to subunit influenza vaccines does not cause clinically important changes in the safety profile of the influenza vaccine. To date, more than 30 million doses of the MF59™-adjuvanted subunit influenza vaccine have been sold, and it has demonstrated a good safety profile [
32]. Evaluation of post-marketing pharmacovigilance case reports (n = 385; September 1997 to April 2006) confirmed that vaccination with the MF59™-adjuvanted subunit influenza vaccine was associated with a very low frequency of adverse reactions [
33].
Evaluation of the primary (pre- and post-vaccination GMTs and GMT ratio) and secondary (proportion of subjects with protective antibody titres [≥ 40] and those demonstrating seroconversion post-vaccination) immunogenicity parameters showed that both the Sub/MF59™ and Subunit vaccines were able to induce an immune response in elderly Chinese subjects. Significantly (P < 0.05) higher antibody titres were induced by the Sub/MF59™ vaccine compared with the Subunit vaccine. Furthermore, as for the safety profile, the immunogenicity results agree with the results of trials conducted in Europe [
24,
25,
27]. For all three influenza strains tested, both the MF59™-adjuvanted and the non-adjuvanted vaccine met at least one criterion of the European Committee for Medicinal Products for Human Use (CHMP) criteria for the immunogenicity evaluation of seasonal influenza vaccines, as required for vaccine licensure [
34]. For both vaccines, the trend was for higher immunogenicity for the influenza A strains, compared to the B strain. It is of note that very high pre-vaccination titres were recorded in this study, especially for A/H1N1. This could be explained in part by the A/H1N1 vaccine strain (A/New Caledonia/20/99-like H1N1) being included in the vaccine formulation for several influenza seasons previous to the 2005–2006 season. Furthermore, from an epidemiological standpoint, influenza A strains are often the most dominant and the most relevant strains among adults and the elderly, with A/H1N1 having been the predominant circulating strain in the Guangxi region of China during the time before the trial was conducted.
It is well documented that levels of HI antibody titres correlate with seroprotection against influenza [
35], thus it is expected that increased immunogenicity should lead to increased clinical protection from influenza. This approach has been widely used across the clinical trial programme for the MF59™-adjuvanted vaccine [
25]. During field studies in Europe, MF59™-adjuvanted vaccine has been shown to offer greater clinical protection against influenza-like illness compared with non-adjuvanted vaccine [
26]. Therefore, it is anticipated that MF59™-adjuvanted vaccine may also offer greater clinical protection in elderly Chinese subjects.
Results from trials using an MF59™-adjuvanted subunit influenza vaccine suggest that adjuvanted vaccination induces a greater immune response in elderly (≥ 60 years of age) Chinese subjects, and demonstrates a good tolerability profile, compared with a non-adjuvanted subunit influenza vaccine.
Competing interests
The study was funded by Novartis Vaccines, and Michele Pellegrini and Audino Podda are employees of Novartis Vaccines. The remaining authors declare that they have no competing interests.
Authors' contributions
RL and HF were responsible for the design, co-ordination and conduct of the clinical trial and the statistical analysis. RL, HF, YL, YL, MP and AP consulted the clinical results and prepared the manuscript. All authors read and approved the final manuscript.