Prabakaran Mookkan, Leyrer Sonja, He Fang, Auer Sebastian, Kumar Subaschandrabose R, Kindsmueller Kathrin, Mytle Nutan, Schneider Joerg, Lockhart Stephen, Kwang Jimmy
Animal Health Biotechnology, Temasek Life Sciences Laboratory, National University of Singapore, Singapore, Singapore.
Emergent BioSolutions Inc., Rockville, Maryland, United States of America.
PLoS One. 2014 Sep 17;9(9):e107316. doi: 10.1371/journal.pone.0107316. eCollection 2014.
The rapid evolution of new sublineages of H5N1 influenza poses the greatest challenge in control of H5N1 infection by currently existing vaccines. To overcome this, an MVAtor vector expressing three H5HA antigens A/Vietnam/1203/04, A/Indonesia/669/06 and A/Anhui/01/05 (MVAtor-tri-HA vector) was developed to elicit broad cross-protection against diverse clades by covering amino acid variations in the major neutralizing epitopes of HA among H5N1 subtypes.
BALB/c mice and guinea pigs were immunized i.m. with 8×107 TCID50/animal of MVAtor-tri-HA vector. The immunogenicity and cross-protective immunity of the MVAtor-tri-HA vector was evaluated against diverse clades of H5N1 strains.
The results showed that mice immunized with MVAtor-tri-HA vector induced robust cross-neutralizing immunity to diverse H5N1 clades. In addition, the MVAtor-tri-HA vector completely protected against 10 MLD50 of a divergent clade of H5N1 infection (clade 7). Importantly, the serological surveillance of post-vaccinated guinea pig sera demonstrated that MVAtor-tri-HA vector was able to elicit strong cross-clade neutralizing immunity against twenty different H5N1 strains from six clades that emerged between 1997 and 2012.
The present findings revealed that incorporation of carefully selected HA genes from divergent H5N1 strains within a single vector could be an effective approach in developing a vaccine with broad coverage to prevent infection during a pandemic situation.
H5N1流感新亚谱系的快速演变对现有疫苗控制H5N1感染构成了最大挑战。为克服这一问题，研发了一种表达三种H5HA抗原A/越南/1203/04、A/印度尼西亚/669/06和A/安徽/01/05的MVA载体（MVA载体-tri-HA），通过覆盖H5N1亚型中HA主要中和表位的氨基酸变异来引发针对不同进化枝的广泛交叉保护。
用8×107 TCID50/只动物的MVA载体-tri-HA对BALB/c小鼠和豚鼠进行肌肉注射免疫。评估MVA载体-tri-HA对不同进化枝的H5N1毒株的免疫原性和交叉保护免疫。
结果显示，用MVA载体-tri-HA免疫的小鼠诱导了对不同H5N1进化枝的强大交叉中和免疫。此外，MVA载体-tri-HA完全保护动物抵抗10 MLD50的H5N1不同进化枝感染（进化枝7）。重要的是，对接种疫苗后的豚鼠血清进行的血清学监测表明，MVA载体-tri-HA能够引发针对1997年至2012年间出现的来自六个进化枝的二十种不同H5N1毒株的强大交叉进化枝中和免疫。
目前的研究结果表明，在单个载体中纳入精心挑选的来自不同H5N1毒株的HA基因可能是开发具有广泛覆盖范围的疫苗以预防大流行期间感染的有效方法。
