DataSheet_1_The evolution of humoral immune responses to past and novel influenza virus strains gives evidence for antigenic seniority.docx

The high genetic and antigenic variability of influenza virus and the repeated exposures of individuals to the virus over time account for the human immune responses toward this pathogen to continuously evolve during the lifespan of an individual. Influenza-specific immune memory to past strains has been shown to affect the immune responses to subsequent influenza strains and in turn to be changed itself through the new virus encounter. However, exactly how and to what extent this happens remains unclear. Here we studied pre-existing immunity against influenza A virus (IAV) by assessing IAV binding (IgG), neutralizing, and neuraminidase-specific antibodies to 5 different IAV strains in 180 subjects from 3 different age cohorts, adolescents, adults, and elderly, over a 5-year time span. In each age cohort, the highest neutralizing antibody titers were seen for a virus strain that circulated early in their life but the highest increase in titer was found for the most recent virus strains. In contrast, the highest IgG titers were seen against recent virus strains but the biggest increase in titer occurred against older strains. Significant increases in neutralizing antibody titers against a newly encountered virus strain were observed in all age cohorts demonstrating that pre-existing immunity did not hamper antibody induction. Our results indicate that the evolution of influenza-specific humoral immunity differs for rather cross-reactive virus-binding antibodies and more strain-specific neutralizing antibodies. Nevertheless, in general, our observations lend support to the antigenic seniority theory according to which the antibody response to influenza is broadened with each virus encounter, with the earliest encountered strain taking in the most senior and thus dominant position.

流感病毒的遗传和抗原多样性及其个体随时间对病毒的反复暴露，导致人类免疫系统在个体生命周期内对这种病原体的免疫反应持续进化。研究表明，针对既往流感株的特异性免疫记忆会影响对后续流感株的免疫反应，而后者又通过新病毒遭遇而自身发生改变。然而，这种变化的具体方式和程度尚不明确。在本研究中，我们通过评估180名来自三个不同年龄段（青少年、成年人和老年人）的受试者对五种不同流感A病毒（IAV）株的IAV结合（IgG）、中和和神经氨酸酶特异性抗体，研究了针对IAV的现有免疫力。在每一个年龄段中，对在早期生命周期中流行的病毒株的中和抗体滴度最高，而对最近流行病毒株的滴度增加最为显著。相反，对近期病毒株的IgG滴度最高，但对较老株的滴度增加最为明显。在所有年龄段中，观察到对新型遭遇病毒株的中和抗体滴度显著增加，表明现有免疫力并未阻碍抗体的诱导。我们的结果表明，流感特异性体液免疫的进化对于交叉反应性病毒结合抗体和更株特异性中和抗体而言，呈现出不同的模式。尽管如此，总体而言，我们的观察结果支持抗原优先级理论，即每次遭遇病毒时，对流感病毒的抗体反应范围都会得到扩展，最早遭遇的株将占据最优先和主导的地位。