A novel sequence-based antigenic distance measure for H1N1, with application to vaccine effectiveness and the selection of vaccine strains

Abstract

H1N1 influenza causes substantial seasonal illness and was the subtype of the 2009 influenza pandemic. Precise measures of antigenic distance between the vaccine and circulating virus strains help researchers design influenza vaccines with high vaccine effectiveness. We here introduce a sequence-based method to predict vaccine effectiveness in humans. Historical epidemiological data show that this sequence-based method is as predictive of vaccine effectiveness as hemagglutination inhibition assay data from ferret animal model studies. Interestingly, the expected vaccine effectiveness is greater against H1N1 than H3N2, suggesting a stronger immune response against H1N1 than H3N2. The evolution rate of hemagglutinin in H1N1 is also shown to be greater than that in H3N2, presumably due to greater immune selection pressure.

Fig. 1

HA1 domain of the H1 HA in the ribbon format (PDB code: 1RU7). Epitope A (blue), B (red), C (cyan), D (yellow), and E (red) are space filling. These five H1 epitopes are the analogs of the well-defined H3 epitopes (Deem and Pan, 2009).

Fig. 2

Vaccine effectiveness for ILI correlates with p_epitope, R²=0.68 (solid line). Data from Table II. The trend line quantifies vaccine effectiveness as a decreasing linear function of p_epitope. Vaccine effectiveness=–1.19 p_epitope+0.53. Also shown is the vaccine effectiveness to H3N2 (dashed line) (Gupta et al. 2006).

Fig. 3

Vaccine effectiveness for ILI correlates with p_all-epitope with R²=0.70. Data from Table II. The trend line quantifies vaccine effectiveness as a decreasing linear function of p_all-epitope. Vaccine effectiveness=–4.16 p_all-epitope+0.54.

Fig. 4

Vaccine effectiveness for ILI correlates with p_sequence with R²=0.66. Data from Table II. The trend line quantifies vaccine effectiveness as a decreasing linear function of p_sequence. Vaccine effectiveness=−7.37 p_sequence+0.54.

Fig. 5

The correlation with R²=0.53 between vaccine effectiveness for ILI and d₁, the antigenic distance defined by HI assay using ferret antisera. Data from Table II. The d₁ values were averaged if multiple HI assay experimental data were found. The trend line quantifies vaccine effectiveness as a decreasing linear function of d₁. Vaccine effectiveness=–0.085 d₁+0.50.

Fig. 6

The correlation with R²=0.46 between vaccine effectiveness for ILI and d₂, the antigenic distance defined by HI assay using ferret antisera. Data from Table II. The d₂ values were averaged if multiple HI assay experimental data were found. The trend line quantifies vaccine effectiveness as a decreasing linear function of d₂. Vaccine effectiveness=–0.013 d₂+0.51.

Fig. 7

The comparison between H3N2 (triangle up) and H1N1 (triangle down) in regard to the antigenic diversity, the evolutionary rate between 1980 and 2000 (left), the evolutionary rate between 2000 and 2007 (right), and the mutation rate on a short-time scale without fixation. The antigenic diversity is measured with p_epitope, the unit of evolutionary rate is 10^–3 nucleotide substitution/site/year, and the unit of mutation rate is 10^–6 nucleotide substitution/site/day.