Protective effects of an mRNA vaccine candidate encoding H5HA clade 2.3.4.4b against the newly emerged dairy cattle H5N1 virus

In April 2024, an unprecedented outbreak of highly pathogenic avian influenza (HPAI) H5N1 virus, which belongs to HA clade 2.3.4.4 b, was reported in dairy cattle and related milk products in the US. As of late September 2024, 15 states have been affected, with confirmed reports of four human cases, all of whom had directly contacted with infected cattle, ten cases with exposure to poultry, and one case without known exposure to infected birds or animals.1–6 Although spillover events from infected avian/mammalian species to humans have been rare, HPAI H5N1 viruses have retained >50% mortality in humans since their first emergence in 1996. Given the risk of adaptation of the virus in human,7 vaccines that induce protective immunity are urgently needed. A previous study analysed the effects of H5HA lipid nanoparticle-based mRNA (LNP-mRNA) vaccine in mice and ferrets.8 Here, we aimed to examine the immunogenicity and protective effects of our H5HA LNP-mRNA vaccine candidate (DS8390) encoding HA from A/chicken/Ghana/AVL-76321VIR7050-39/2021 from clade 2.3.4.4b, against the newly emerged cattle H5N1 virus in a small animal model.

 

BALB/c mice were vaccinated with DS8390 twice with a 2-week (wk) interval (Fig. 1A). In pre-challenge sera collected at 6 wks post-boost immunization, binding IgG titres against HAs of the vaccine homologous virus and a cattle virus were detected (Fig. 1B and C). Neutralizing antibody titres were barely detected with authentic virus (Supplementary Table); however, with pseudotyped virus, in the 10 μg/body administration group, we detected significant neutralizing activity against the vaccine homologous virus-derived pseudotyped virus and an equivalent level of neutralizing activity against a pseudotyped cattle-derived virus (Supplementary Table). Vaccinated animals challenged with cattle H5N1 virus (A/dairy cattle/Texas/24-008749-001-original/2024; clade 2.3.4.4 b) were protected from the lethal virus challenge without any body weight loss or other symptoms with either low- (1 μg) or high- (10 μg) dose vaccination, whereas mock-vaccinated animals required euthanasia due to severe (>25%) weight loss and/or neurological symptoms by day 8 post–challenge (Fig. 1D and E). To analyse virus replication in organs, mock- or DS8390-vaccinated animals were challenged with the cattle H5N1 virus at 3 wks post-boost (Fig. 1F). In lungs, low-dose vaccination reduced the median virus titres by 3 log or 7 log on Days 3 and 5, respectively, compared with the mock-vaccinated group (Fig. 1G). No animals in the high-dose vaccinated groups had detectable infectious virus in their lungs (Fig. 1G). In nasal turbinates and brains, even low-dose vaccination was sufficient to reduce virus replication to below the detection threshold at both timepoints (Fig. 1H and I). These potent protective effects despite barely detectable serum neutralizing antibody titres suggest that the T-cell responses induced by this candidate vaccine are important, consistent with recent studies showing that LNP-mRNA vaccine induces T-cell activation against H5 avian viruses.8–10 Collectively, our findings suggest that the LNP-mRNA vaccine is a promising modality to induce protective immunity and of value in vaccine development.