CORRELATES OF PROTECTION AND HOST-RELATED MODIFIERS OF THE IMMUNOGENICITY OF INFLUENZA VACCINES: EVIDENCE MAPS AND EVIDENCE GAPS

Seasonal influenza is the leading infectious disease in terms of its health and socioeconomic impact. Annual immunization is the most efficient way to reduce this burden. To be clinically effective, influenza vaccines must be immunogenic, and several immunological assays to test their immunogenicity have been developed. The overall aim of this PhD thesis is to provide the principal stakeholders (including scientists, healthcare professionals, policy-makers, pharmaceutical industry, etc.) with stateof-the-art knowledge and practices related to influenza vaccine-induced immunogenicity. To achieve this aim, we developed a novel empirical approach that incorporated some modern techniques, including, for example, evidence mapping. Basically, this thesis is composed of three main domains. In the introductory part, we will briefly cover the topics of influenza disease, influenza vaccination, the immunogenicity measurements of influenza vaccines and their correlates of protection. The second part, which is the core of the present project, is composed of two original case studies. The first study aimed to describe the patterns of use of the various immunological assays available to measure the influenza vaccine-induced adaptive immune response and to determine its correlates of protection. For this purpose, we analyzed 1,164 phase I–IV studies that enrolled a total of 754,935 subjects. Of the studies included in our analysis, 76.5% measured only the humoral immune response. Among these, the hemagglutination-inhibition assay was by far the most widely used. Other, less common, humoral immune response assays were: virus neutralization (21.7%), enzyme-linked immunosorbent (10.1%), single radial hemolysis (4.6%) and assays able to quantify antineuraminidase antibodies (1.7%). By contrast, cell-mediated immunity was quantified in only 23.5% of studies. Several variables were significantly (P < .05) associated with the use of single assays. Specifically, some influenza vaccine types (e.g. adjuvanted, live attenuated and cell culture-derived or recombinant), study phase and study sponsorship pattern were usually found to be statistically significant predictors. In the second study, we went further by systematically analyzing host-related factors able to modify influenza vaccine-induced immunogenicity. To this end, a total of 28 systematic reviews/meta-analyses (with thousands of participants) were analyzed. These covered the following domains: intravenous drug use, psychological stress, acute and chronic physical exercise, genetic polymorphisms, use of pre-/pro-/symbiotics, previous Bacillus Calmette–Guérin vaccination, diabetes mellitus, vitamin D supplementation/deficiency, latent cytomegalovirus infection and various forms of immunosuppression. In order to present effect sizes on the same scale, all meta-analyses were re-performed, whenever possible, and cumulative evidence synthesis ranking was carried out. Meta-analysis was conducted separately on each health condition category and virus (sub)type. A total of 295 meta-analyses were re-performed/performed ex novo; of these, 97 pooled estimates were used in order to construct an evidence-based stakeholder-friendly map. Finally, we discussed the principal findings, made some suggestions from the point of view of the various stakeholders and proposed a novel immunogenicity pathway.