1. Following infection with one influenza strain, antibodies produced in unvaccinated patients were effective against the strain as well as for a broad range of related strains previously in circulation.
2. Vaccination based on a predicted future strain resulted in robust antibody responses against the advanced strain and current strains.
Evidence Rating Level: 2 (Good)
Study Rundown: The influenza virus rapidly adapts its antigens, or antibody-generating molecules, to avoid recognition by the immune system. A vaccine mismatch can occur because vaccines are designed to work against strains circulating 10 to 14 months before the influenza season, and virus evolution can result in new strains within that time period. In this study, patient antibody responses were measured for influenza strains spanning 43 years of virus evolution to determine the effect of prior immunity on infection and vaccination response. The researchers found that for unvaccinated patients, infection with the H3N2 virus led to a “back-boost” of broad antibody response that provided protection against strains from previous decades. The study then compared antibody response for two vaccines, one that was antigenically similar to circulating strains and one that was targeted to a potential future strain. The back-boost observed following the advanced vaccine was protective for the older circulation strains targeted with the first vaccine.
This was the first study to quantitatively evaluate antibody response across the antigenic evolution of influenza strains. Because the study was limited to retrospectively analyzing patient antibody samples, a prospective trial will be needed to determine the efficacy of the proposed vaccine strategy. The study provided evidence to support such a trial, and demonstrated the potential of using an antigenically advanced vaccine to protect against current and future strains. This technique of vaccinating based on predicted future strains could help avoid the mismatch problem that can arise with current vaccines.
In-Depth [animal study]: The antigenic relationships between 81 influenza viruses were measured using hemagglutination inhibition (HI) assays against ferret sera. After each ferret was infected with a specific strain, serum was tested for antibody inhibition of agglutination between virus and red blood cells. The HI assay was also used to measure the antibody response of patient sera to each strain. Results from HI assays on patient samples were plotted against antigenic distance between strains in order to generate a comprehensive antibody response map, or landscape, for each patient. Antibody landscapes varied among patients (r = 0.28), but remained stable for each individual patient across the sampling time range of 2007 to 2012 (r = 0.86).
Sera from 69 unvaccinated patients were analyzed to determine the effect of infection on antibody response. Infection with H3N2 resulted in back boost protection against a wide range of earlier-evolved viruses, including a 1968 cluster of no longer circulating strains. This range represented 13 major antigen cluster evolutions and 20 vaccine updates. In a separate analysis, sera from a total of 225 patients who were vaccinated before an antigenic cluster transition were analyzed. 102 patients comprised the first group and received a vaccine based on circulating strains. 123 patients in the second group received an antigenically advanced vaccine based on the predicted new cluster. Pre- and post-vaccination antibody landscapes were similar for the two groups. Notably, sera from the second group showed back boost protection for the strains before the antigenic cluster transition.
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