A Replicating Modified Vaccinia Tiantan Strain Expressing an Avian-Derived Influenza H5N1 Hemagglutinin Induce Broadly Neutralizing Antibodies and Cross-Clade Protective Immunity in Mice

Xiao, Haixia; Liu, Li; Zhu, Qingyu; Tan, Zhiwu; Yu, Wenbo; Tang, Xian; Zhan, Dawei; Du, Yanhua; Wang, Haibo; Liu, Di; Li, Zhixin; Yuen, Kwok-Yung; Ho, David D.; Gao, George F.; Chen, Zhiwei

MVTT-based vaccines offer certain advantages over conventional influenza vaccines. With recent technical improvements, the time required for constructing MVTT-based vaccines is becoming significantly shortened. In comparison to adeno-vectored or DNAbased vaccines, vaccinia delivers a high level of foreign gene expression directly without time-consuming gene-optimization procedures [10, 13] . Critically, MVTT HA-QH does not depend on SPF eggs or primary chicken embryo fibroblast [34, 35] . MVTT HA-QH can be produced using WHO-recommended Vero cells with ease and without the requirement of bio-safety level-3 containment, which is necessary for inactivated vaccines. The large-scale production of MVTT HA-QH is, therefore, feasible. Given the large capacity for housing large foreign gene inserts, it is possible to use MVTT to generate a multivalent-H5 vaccine in order to further improve the breath of cross-clade NT and HI antibody responses. When compared to the widely-used modified vaccinia Ankara (MVA) vector [36] [37] [38] [39] [40] [41] , we recently demonstrated that MVTT is superior to MVA for inducing high levels of systemic neutralizing antibodies against SARS coronavirus, especially through mucosal routes of vaccination [24] . To this end, we found that intranasal vaccination with MVTT HA-QH induced consistently high levels of systemic NT and HI antibody responses that are equivalent to the outcomes of intramuscular injection. Moreover, intranasal vaccination can overcome preexisting anti-vector immune responses, which offers advantages for the elderly who previously have received VTT against smallpox [24] . As a non-invasive procedure, intranasal vaccination also has great implications for mass vaccination of human populations, especially in developing countries. Lastly, intranasal vaccination has made it possible to develop MVTT HA-QH as a potential aerosol veterinary vaccine, which, however, would require efficacy testing after being sprayed onto poultry and migratory bird populations. Given these reasons, our findings from this study have important implications in the fight against possible zoonotic HPAIV outbreaks.