Twenty-Eight Years of Poliovirus Replication in an Immunodeficient Individual: Impact on the Global Polio Eradication Initiative.
Twenty-Eight Years of Poliovirus Replication in an Immunodeficient Individual: Impact on the Global Polio Eradication Initiative.
复制标题
DOI：
10.1371/journal.ppat.1005114
复制
发表时间：
2015-08
期刊：
影响因子：
6.7
通讯作者：
Martin J
中科院分区：
文献类型：
--
作者：
Dunn G;Klapsa D;Wilton T;Stone L;Minor PD;Martin J
目前，世界卫生组织和合作伙伴正在为完成全球根除脊髓灰质炎做出巨大努力。近年来，随着野生脊髓灰质炎病毒引起的脊髓灰质炎病例显着下降，与使用口服脊髓灰质炎减毒活疫苗相关的罕见病例变得更加重要。已知口服疫苗中的脊髓灰质炎病毒株在免疫后在人体中复制后会迅速恢复为神经毒力表型。这些菌株可以在人与人之间传播，导致脊髓灰质炎爆发，并且可以在免疫缺陷个体中长时间复制，导致瘫痪或慢性感染，目前没有有效的治疗方法来阻止这些患者的排泄。在这里，我们描述了一个人，根据用系列分离株的 VP1 衣壳基因核苷酸序列建立的分子钟估计，他已经分泌 2 型疫苗衍生的脊髓灰质炎病毒 28 年了。这代表了迄今为止该患者的最长排泄期，该患者是目前已知的唯一已知排泄高度进化的疫苗衍生脊髓灰质炎病毒的个体。通过一系列体内和体外测定，我们发现这些病毒具有很强的毒性、抗原性漂移并以高滴度排泄，这表明这种慢性排泄者对根除计划构成了明显的风险。我们用人血清进行的病毒中和试验以及使用表达人脊髓灰质炎病毒受体的转基因小鼠进行的免疫激发实验的结果表明，虽然保持高免疫覆盖率可能会提供针对这些病毒引起的麻痹性疾病的保护，但可能需要对免疫策略进行重大改变才能有效阻止其发生和潜在的广泛传播。最终，可能需要新的稳定的、无逆转风险的减毒活脊髓灰质炎疫苗来应对根除后时代的任何脊髓灰质炎病毒分离。全球根除脊髓灰质炎行动是历史上针对单一疾病最雄心勃勃、最复杂的公共卫生计划，预计成本达 165 亿美元。在三种血清型中，2 型和 3 型似乎已在野外根除，而 1 型主要局限于巴基斯坦和阿富汗地区。在不久的将来完全消灭的可能性确实存在。使用的主要疫苗是减毒活病毒，我们的论文关注的是这对脊髓灰质炎最后阶段最棘手的重大影响之一。我们描述了对一名体液免疫缺陷患者的病毒学研究，该患者已排泄 2 型疫苗衍生脊髓灰质炎病毒 28 年。我们的研究结果表明，这些病毒以高滴度排出，具有极强的毒力和抗原漂移，并提出了如何最好地保护人群免受病毒感染的问题，特别是考虑到疫苗生产可能发生的变化，正在鼓励提高能力和降低成本。该研究对人类肠道中脊髓灰质炎病毒的生态学具有影响，并强调了此类疫苗衍生分离株在根除后时代对脊髓灰质炎重新出现的风险。
There are currently huge efforts by the World Health Organization and partners to complete global polio eradication. With the significant decline in poliomyelitis cases due to wild poliovirus in recent years, rare cases related to the use of live-attenuated oral polio vaccine assume greater importance. Poliovirus strains in the oral vaccine are known to quickly revert to neurovirulent phenotype following replication in humans after immunisation. These strains can transmit from person to person leading to poliomyelitis outbreaks and can replicate for long periods of time in immunodeficient individuals leading to paralysis or chronic infection, with currently no effective treatment to stop excretion from these patients. Here, we describe an individual who has been excreting type 2 vaccine-derived poliovirus for twenty eight years as estimated by the molecular clock established with VP1 capsid gene nucleotide sequences of serial isolates. This represents by far the longest period of excretion described from such a patient who is the only identified individual known to be excreting highly evolved vaccine-derived poliovirus at present. Using a range of in vivo and in vitro assays we show that the viruses are very virulent, antigenically drifted and excreted at high titre suggesting that such chronic excreters pose an obvious risk to the eradication programme. Our results in virus neutralization assays with human sera and immunisation-challenge experiments using transgenic mice expressing the human poliovirus receptor indicate that while maintaining high immunisation coverage will likely confer protection against paralytic disease caused by these viruses, significant changes in immunisation strategies might be required to effectively stop their occurrence and potential widespread transmission. Eventually, new stable live-attenuated polio vaccines with no risk of reversion might be required to respond to any poliovirus isolation in the post-eradication era. The global polio eradication initiative is the most ambitious and complex public health programme directed at a single disease in history with a projected cost of $16.5 billion. Of the three serotypes types 2 and 3 appear to have been eradicated in the wild and type 1 is mostly confined to a region of Pakistan and Afghanistan. There is a real probability of total eradication in the near future. The main vaccine used is a live attenuated virus, and our paper concerns one of the most intractable significant implications that this has for the polio endgame. We describe virological studies of a patient deficient in humoral immunity who has been excreting type 2 vaccine-derived poliovirus for 28 years. Our results show that the viruses are excreted at high titres, extremely virulent and antigenically drifted and raise questions about how the population may best be protected from them, particularly in the light of possible changes in vaccine production which are being encouraged to increase capability and reduce costs. The study has implications for the ecology of poliovirus in the human gut and highlights the risks that such vaccine-derived isolates pose for polio re-emergence in the post-eradication era.