Humoral immune response after seasonal influenza vaccination

Laburpena

Introduction: Seasonal vaccination provides short-lasting and strain specific protection. Different factors influence efficacy and effectiveness and are related to the vaccine and the receptor. Those include adjuvants and strains contained, and age and sex of the receptor. The major target of antibodies after vaccination and infection is the hemagglutinin(HA) head with a limited number of immunodominant classically defined antigenic sites(Sb, Sa, Cb, Ca1 and Ca2) leading to strain-specific protection. In contrast, the HA stalk is subdominant and more conserved, and anti-stalk antibodies are cross-reactive among strains of the same phylogenetic group. Objective: To evaluate the humoral response after seasonal influenza vaccination considering vaccine composition, age and sex; and determine specific humoral responses against classically defined antigenic sites of the HA head and the stalk domain of influenza A virus. Methods: A total of 4,818 patients were recruited yearly during 28 seasons(1990-2018) from the Sentinel Surveillance Network of Castile and Leon (Spain). Three retrospective and two prospective designs were used. Serological analyses were conducted in samples obtained before and 28 days after seasonal vaccination by the National Influenza Centre of Valladolid (Spain) and the Mount Sinai Hospital of New York(US). Antibody levels against the HA head and stalk were measured by hemagglutination inhibition assay(HAI) and ELISAs. This research was approved by an Ethics Committee(PI 21-2314). Statistical analysis was performed taking significance at p<0.05. Results: Manuscript 1: Higher humoral response was found in the elderly against the A(H3N2) subtype with the adjuvanted influenza vaccine(FI 3.4, SCR 46%) compared to non-adjuvanted vaccine(FI 2.7,SCR 38.8%). However, the non-adjuvanted vaccine induced a better response against A(H1N1)pdm09(FI 4.5, SCR 57.3%) compared to the adjuvanted one(FI 3.2, SCR 45.8%) in the same group. Manuscript 2: Higher humoral response in terms of SCR against classical influenza A (H1N1), A(H1N1)pdm09 subtype and B/Victoria lineage(40.6%, 52.4% and 23.2%) were found in elderly women compared to elderly men(30.2%, 42.0% and 18.9%); and in FI(3.7 vs. 3.0) against A(H1N1)pdm09 in the same comparison. Manuscript 3: Significant heterotypic humoral responses were found between both influenza B lineages, but always lower than the homotypic response. Young adults showed higher homotypic(GMTi 3.2, SCR 41.6%) and heterotypic responses(GMTi 1.7, SCR 18.6%) with B/Victoria vaccine compared to the elderly while similar responses were found with B/Yamagata vaccine. Manuscript 4: Antibodies before vaccination were significantly reduced against all antigenic sites in the elderly and only against Sb and Ca2 in young adults compared to the Wt. Response to vaccination was reduced against all viruses compared to the Wt for the adjuvanted vaccine and only against Sb and Ca2 for the non-adjuvanted vaccine. The strongest reduction was observed against Sb followed by Ca2. Manuscript 5: All age groups elicited a significant increase of anti-stalk antibodies after seasonal influenza vaccination except for ≥ 80-year-old cohort. Additionally, < 65-year-old vaccinees had higher titers against phylogenetic group 1 HAs vs. group 2. Similarly, <50-year-old showed higher increase of anti-stalk antibody titers(GMFR 1.69) compared to ≥ 80-year-old(GMFR 1.08) for group 1. Conclusions: Age and sex play a role in vaccine responses with higher responses in elderly women compared to men against A(H1N1)pdm09. Better responses against this subtype were found with non-adjuvanted vaccines, while adjuvanted vaccines responded better against the A(H3N2) subtype in the elderly. However, seasonal vaccination can boost the induction of cross-reactive anti-stalk antibodies against phylogenetic groups 1 and 2 of HAs, with higher responses in younger populations. The immunodominance hierarchy of antigenic sites of HA head of the A(H1)pdm09 viruses is dominated by Sb followed by Ca2, but age and adjuvants can broaden responses towards subdominant epitopes. Finally, vaccination with a trivalent influenza vaccine provides cross-reactive protection against the B/lineage not contained.