There is significant evidence that adjuvants enhance the immunogenicity of influenza virus vaccines, with a favorable impact on the age-related decline of the immune response in elderly people (5
Few studies, to our knowledge, have been reported on the effects of vaccines with MF59 adjuvant administered to adults and to HIV-1-seropositive patients (9
), for whom there is a great need to improve the immune response to vaccination (17
Similarly, no large data sets exist on the immunological outcome of vaccination, other than the titration of specific antibodies by hemagglutination inhibition, the standard method used for evaluating immunogenicity.
In this study, we investigated two influenza virus vaccines available on the market, one with and one without the adjuvant MF59, administered to uninfected and HIV-1-infected adults.
No AEs of concern were observed during the entire safety follow-up, confirming the excellent safety profiles of both vaccines in both healthy adults and HIV-1-seropositive individuals. In addition, the results clearly show that vaccination affects neither HIV viremia nor the CD4+
T-cell count, as previously reported (24
In agreement with previous studies on elderly people, which showed a higher frequency of local side effects for vaccines with adjuvant than for those without adjuvant (13
), the local and systemic adverse reactions reported in our study were classified as mild and resolved within 48 to 72 h after vaccination. Interestingly, Fluad was better tolerated by HIV-1-seropositive subjects than by seronegative subjects. There were no significant differences in the incidences of either local or systemic adverse reactions between the Fluad and Agrippal groups, except for fever (P
≤ 0.01) and shivering (P
≤ 0.05), which were more frequent after Fluad vaccination (Table ). This could reflect a difference in the activation threshold of the immune response to immunization between HIV-1-infected and uninfected subjects, depending on the deteriorated status induced by the primary infection. Lower secretion of proinflammatory cytokines could be responsible for this phenomenon. With this in mind, we are investigating the functional pattern of the T-cell response after influenza vaccination, both in healthy and in immunocompromised patients.
In a previous study, Frey and colleagues studied the safety, tolerability, and immunogenicity of the influenza virus vaccine with MF59 adjuvant, comparing it with a vaccine without adjuvant in nonelderly subjects. The safety and tolerability profiles were generally favorable for both vaccines, and in terms of immunogenicity, Fluad showed only a modest benefit compared to that for elderly people (16
In our experience, both vaccines showed very good immunogenicity profiles, and the CHMP criteria for the licensure of influenza virus vaccines were fully met for both HIV-1-seronegative and -seropositive subjects (Tables and ). With regard to these serological requirements, no significant differences between vaccine groups were observed, either among infected or among uninfected individuals. The immunogenicity results are only partially in agreement with those of a previous study conducted with HIV-1-seropositive subjects receiving highly active antiretroviral therapy (24
), which showed better immune stimulation with Fluad than with Agrippal vaccination.
In order to take into account the generally high baseline seroprotection rates among the study population, comparative immunogenicity analysis was also conducted using Beyer's method, correcting for the presence of preexisting antibodies. This could represent a more reliable indicator, even if theoretical, of the immunological stimulation by the influenza virus antigens present in the two vaccines. By using this new approach, Fluad demonstrated better immunogenicity than Agrippal in subjects not infected with HIV-1 for all influenza virus strains, especially for the H1N1 and B strains (Table ). A better immunogenicity profile of the vaccine with the adjuvant was also confirmed with HIV-1-infected individuals, mainly for the A/H3N2 influenza virus strain (Table ). No definitive conclusions on the clinical significance of such results can be drawn, however, due to the fact that Beyer's method, which was used to estimate antibody response, though interesting, is currently nonstandard for influenza virus vaccines. Furthermore, due to the fact that significant differences between vaccine groups were observed only after correction for prevaccination status, it is difficult to provide any solid biological explanation of why the vaccine with MF59 adjuvant had a greater effect than Agrippal for some influenza virus strains and not for others. In fact, any attempt to explain the phenomenon by relating the results either to personal vaccination history or to virological data on influenza virus strain circulation during previous years is simply not viable.
In consideration of the matters discussed above, we believe further investigation into the immunogenicity of vaccines with MF59 adjuvant is highly desirable, especially for groups at high risk of influenza virus infection, in order to better focus the benefit of the adjuvant in eliciting immune responsiveness, particularly for potential nonresponders or low responders.
In a recent study monitoring a cohort of intravenous drug users living in a rehabilitation community, we described the impact of an influenza epidemic sustained by a drifted A/H3N2 virus (8
). Data from virological surveillance in the last few years has shown this strain to be the predominant one (30
). Influenza attack rates were higher for HIV-1-infected individuals than for other residents (relative risk, 1.77; 95% confidence interval, 1.32 to 2.37), and those infected with HIV were also more likely to develop complications than non-HIV-infected individuals (relative risk, 5.13; 95% confidence interval, 2.52 to 10.20). This study underlines the need for vaccines with wider protective efficacy for this high-risk group, and particularly for patients with severe immunodeficiency (15
Recent studies have recognized intrinsic limitations of the serological methods currently used as a sole measure to evaluate influenza virus vaccine efficacy, and it has been suggested that evaluation of the cellular immune response could provide additional information to enable better estimation of protection against the disease (29
). We monitored the precursor frequency of the proliferating CD4+
T cells in response to specific antigen stimulations by using the flow dye dilution assay. This test, compared to traditional methods for assaying antigen-specific proliferation, offers the additional ability to evaluate the phenotype of the responding cells and is able to determine their rate of proliferation.
Among immunocompetent HIV-1-seronegative subjects, the frequency of proliferating antigen-specific CD4+ T cells was essentially the same for those immunized with either the vaccine without adjuvant or the vaccine with MF59 adjuvant. In contrast, the presence of the MF59 adjuvant induced an enhanced response in HIV-1-infected patients. In fact, among these subjects, a statistically significant increase in the frequency of proliferating T cells was already detected at day 30 postvaccination for the Fluad recipients, in contrast to what was observed for those immunized with Agrippal. A clear benefit of the formulation with the adjuvant was also observed from the comparison between vaccine groups evaluated 1 month after immunization. It is plausible that the robust expansion of the CD4+ memory T cells in infected subjects treated with the vaccine with MF59 adjuvant may translate into a better ability of this vaccine than of Agrippal to confer protection against influenza. This is of particular importance for individuals with impaired immune competence, as stressed above.
In conclusion, the results of this study show that currently available influenza virus subunit vaccines, both with and without MF59 adjuvant, are safe and immunogenic for healthy adults, whether infected with HIV-1 or not.
Vaccines with MF59 adjuvant could represent a new tool for the prevention of influenza in subjects with reduced immune responsiveness, such as HIV-infected individuals (17
), elderly people (13
), and those with underlying chronic debilitating diseases (3
), as recently demonstrated by other authors. Additional studies with this vaccine are required in order to better evaluate the magnitude and duration of both the humoral and cell-mediated responses driven by MF59 adjuvant in various population groups. These data may then contribute to a better understanding of the immune parameters of protection, which may ultimately lead to a change in the current recommendations for the use of vaccines with MF59 adjuvant for adults at risk, such as those infected with HIV-1.