Immuno-epidemiologic correlates of pandemic H1N1 surveillance observations: higher antibody and lower cell-mediated immune responses with advanced age

Abstract

Background: Pandemic H1N1 (pH1N1) surveillance data showed lower attack rates but higher risk of severe outcomes with advanced age. We explored immuno-epidemiologic correlates of surveillance findings including humoral and cell-mediated immunity (CMI).

Methods: In an age-based design, ∼100 banked/residual sera per 10-year age stratum were assessed by hemagglutination inhibition (HI) and microneutralization (MN) assays for preexisting antibody to pH1N1 and recent seasonal H1N1 and H3N2 strains. In a separate birth cohort design defined by childhood influenza A/subtype priming (1919-1929: H1N1; 1945-1949: H1N1; 1958-1960: H2N2; 1969-1970: H3N2; 1978-1989: H3N2/H1N1), whole blood was collected from up to 50 volunteers per birth cohort. The ratio of Th1(IFN-γ):Th2(IL-10) cytokine responses was evaluated in vitro.

Results: Antibody to seasonal viruses was highest in school-age children. Cross-reactive HI/MN antibody to pH1N1 was low among participants <70 years of age (yoa; 6%/4% ≥ 40), but seroprevalence increased at 70-79 yoa (27%/6%), increased even more at 80-89 yoa (65%/47%), and was highest at ≥90 yoa (88%/76%). CMI to pH1N1 was evident in all 5 birth cohorts but was lower compared with seasonal strains. There was little differentiation by subtype priming, but the Th1:Th2 ratio for all viruses dropped significantly in the 2 oldest cohorts.

Conclusions: Preexisting antibody may have protected the very old from pH1N1 infection, while diminished CMI may have contributed to greater severity once infected. In the young, cross-reactive pH1N1 antibody was mostly absent, while more intact CMI may have protected against severe outcomes.

Figure 1.

Antibody titers to A/California/7/2009(pH1N1), seasonal A/Brisbane/59/2007(H1N1), and seasonal A/Brisbane/10/2007(H3N2) viruses, age-based serosurvey. (A) Geometric mean titers (95% confidence intervals). (B) Percentage with titers ≥40 and 95% confidence intervals. HI, hemagglutination inhibition assay; MN, microneutralization assa. NOTE. HI= hemagglutination inhibition assay; MN = microneutralization assay.

Figure 2.

Antibody titers to A/California/7/2009(pH1N1), seasonal A/Brisbane/59/2007(H1N1), and seasonal A/Brisbane/10/2007(H3N2) viruses, birth cohort study. (A) Geometric mean titers and 95% confidence intervals. (B) Percentage with titers ≥40 and 95% confidence intervals. HI, hemagglutination inhibition assay; MN, microneutralization assay; yoa, years of age NOTE. HI= hemagglutination inhibition assay; MN = microneutralization assay; yoa= years of age.

Figure 3.

Log-transformed interferon-γ, interleukin-10, and their ratio for pH1N1, seasonal H1N1, and H3N2 viruses, birth cohort study. (a) Interferon-γ (natural log-transformed). (b) Interleukin-10 (natural log-transformed). (c) Interferon-γ:interleukin-10 ratio (natural log-transformed). yoa, years of age.