Department of Microbiology, Mount Sinai School of Medicine, New York, New York, United States of America.
PLoS Pathog. 2010 Jan 29;6(1):e1000745. doi: 10.1371/journal.ppat.1000745.
The recent 2009 pandemic H1N1 virus infection in humans has resulted in nearly 5,000 deaths worldwide. Early epidemiological findings indicated a low level of infection in the older population (>65 years) with the pandemic virus, and a greater susceptibility in people younger than 35 years of age, a phenomenon correlated with the presence of cross-reactive immunity in the older population. It is unclear what virus(es) might be responsible for this apparent cross-protection against the 2009 pandemic H1N1 virus. We describe a mouse lethal challenge model for the 2009 pandemic H1N1 strain, used together with a panel of inactivated H1N1 virus vaccines and hemagglutinin (HA) monoclonal antibodies to dissect the possible humoral antigenic determinants of pre-existing immunity against this virus in the human population. By hemagglutinination inhibition (HI) assays and vaccination/challenge studies, we demonstrate that the 2009 pandemic H1N1 virus is antigenically similar to human H1N1 viruses that circulated from 1918-1943 and to classical swine H1N1 viruses. Antibodies elicited against 1918-like or classical swine H1N1 vaccines completely protect C57B/6 mice from lethal challenge with the influenza A/Netherlands/602/2009 virus isolate. In contrast, contemporary H1N1 vaccines afforded only partial protection. Passive immunization with cross-reactive monoclonal antibodies (mAbs) raised against either 1918 or A/California/04/2009 HA proteins offered full protection from death. Analysis of mAb antibody escape mutants, generated by selection of 2009 H1N1 virus with these mAbs, indicate that antigenic site Sa is one of the conserved cross-protective epitopes. Our findings in mice agree with serological data showing high prevalence of 2009 H1N1 cross-reactive antibodies only in the older population, indicating that prior infection with 1918-like viruses or vaccination against the 1976 swine H1N1 virus in the USA are likely to provide protection against the 2009 pandemic H1N1 virus. This data provides a mechanistic basis for the protection seen in the older population, and emphasizes a rationale for including vaccination of the younger, naïve population. Our results also support the notion that pigs can act as an animal reservoir where influenza virus HAs become antigenically frozen for long periods of time, facilitating the generation of human pandemic viruses.
最近发生的人感染 2009 年大流行性 H1N1 病毒导致全球近 5000 人死亡。早期的流行病学研究结果表明，大流行性病毒在老年人群（>65 岁）中的感染水平较低，而在 35 岁以下人群中的易感性较高，这与老年人群中存在交叉反应性免疫有关。目前尚不清楚哪些病毒可能对这种对 2009 年大流行 H1N1 病毒的明显交叉保护负责。我们描述了一种用于 2009 年大流行 H1N1 株的小鼠致死性挑战模型，并用一组灭活的 H1N1 病毒疫苗和血凝素（HA）单克隆抗体一起使用，以剖析人群中针对该病毒预先存在的免疫的可能体液抗原决定簇。通过血凝抑制（HI）测定和疫苗/挑战研究，我们证明 2009 年大流行 H1N1 病毒在抗原性上与 1918-1943 年流行的人类 H1N1 病毒和经典猪 H1N1 病毒相似。针对 1918 样或经典猪 H1N1 疫苗产生的抗体可完全保护 C57B/6 小鼠免受流感 A/Netherlands/602/2009 病毒分离株的致死性攻击。相比之下，现代 H1N1 疫苗仅提供部分保护。用针对 1918 年或 A/加利福尼亚/04/2009 HA 蛋白的交叉反应性单克隆抗体（mAb）进行被动免疫可提供完全的死亡保护。通过用这些 mAb 选择 2009 年 H1N1 病毒产生的 mAb 抗体逃逸突变体的分析表明，抗原表位 Sa 是保守的交叉保护表位之一。我们在小鼠中的发现与血清学数据一致，该数据表明，只有在老年人群中才普遍存在对 2009 年 H1N1 病毒的交叉反应性抗体，这表明在美国，1918 年样病毒的既往感染或针对 1976 年猪 H1N1 病毒的疫苗接种可能提供对 2009 年大流行 H1N1 病毒的保护。该数据为在老年人群中观察到的保护提供了机制基础，并强调了对年轻的，未感染人群进行疫苗接种的合理性。我们的结果还支持这样的观点，即猪可以充当流感病毒 HA 长时间处于抗原冻结状态的动物储库，从而促进了人类大流行性病毒的产生。
