Highly pathogenic avian influenza viruses (HPAIs) continue to threaten both agriculture and human health. Recent H5N1 clades have caused zoonotic infections in humans with mortality rates approaching 50%. However, currently licensed H5 vaccines are based on ancestral strains and may provide suboptimal protection against circulating variants. Rapidly adaptable DNA vaccine platforms offer a promising approach for clade-specific protection.
Codon-optimized plasmid DNA vaccines expressing hemagglutinin (HA) from two recently circulating H5N1 clades (2.3.2.1c and 2.3.4.4b) were generated and delivered by either intramuscular electroporation (EP) or a lipid nanoparticle (LNP) formulation. Cellular and humoral responses were evaluated by multiparameter flow cytometry and ELISpot and by ELISA and pseudovirus neutralization, respectively. Protective efficacy was evaluated in lethal H5N1 murine challenge models.
EP delivery of clade 2.3.2.1c HA (pCamb) elicited strong humoral and cellular responses and achieved complete protection against homologous viral challenge, but only partial protection against heterologous 2.3.4.4b challenge. In contrast, vaccination with clade 2.3.4.4b HA (pMich) DNA supported robust immune responses and full protection against contemporary clade challenge. Co-immunization with both plasmids via EP induced broad binding and neutralizing antibodies and conferred complete protection from clade 2.3.4.4b challenge. Moreover, formulation of the pMich plasmid optimized LNPs generated durable, protective immunity following a single dose, effective at both acute and memory timepoints.
These studies demonstrate that antigenic clade-matching is likely critical for protection against H5N1 and suggest that currently stockpiled H5N1 vaccines may not protect against contemporary viruses. Further this data suggests that DNA vaccine platforms including EP or LNP formulations can provide a flexible approach for rapid adaptation to evolving influenza strains.
NIH NIAID CIVICs
Vaccines and Immunotherapy (VAC)
Ebony N. Gary, Nicholas J. Tursi, Casey E. Hojecki et al.· Journal of Immunology· 0 citations
Antibodies against the V1V2 domain of the HIV envelope glycoprotein have been identified as a potential correlate of reduced infection risk in three large HIV vaccine efficacy trials. Although vaccine-elicited anti-V1V2 antibodies do not mediate potent virus-neutralizing activities, they mediate Fc-dependent effector functions. Strategies that enhance the magnitude and quality of these responses may improve HIV vaccine efficacy.
We examined a lipid nanoparticle-encapsulated mRNA (mRNA-LNP) vaccine encoding the V1V2 domain of CRF_01.AE244 on the 2J9C scaffold. Immunogenicity was assessed in three animal models: mice, rabbits, and rhesus macaques, following two or more immunizations. Antibody binding, cross-reactivity, and Fc-mediated functions were quantified using Luminex antigen-binding assays, virion- and cell-surface Env recognition assays, antibody-dependent cellular phagocytosis (ADCP), and Fc receptor binding.
In mice two doses of the V1V2 mRNA-LNP vaccine elicited robust, cross-reactive serum IgG responses that recognized soluble Env and native Env on cells and virions. Importantly, murine IgG2a antibodies were generated that displayed Fc-mediated activities. However, in rabbits the elicited responses were directed mainly against the scaffold, with minimal V1V2-specific antibodies even after four vaccinations. In contrast, rhesus macaques developed high-level V1V2-specific antibodies responses after two vaccinations, comparable to those observed in mice.
The V1V2 mRNA-LNP vaccine is highly immunogenic in mice and rhesus macaques, eliciting cross-clade functional antibodies capable of recognizing native Env. The marked species-dependent differences, most notably the weak V1V2 targeting in rabbits, underscore the importance of selecting appropriate animal models for preclinical HIV vaccine evaluation and may provide insights relevant to vaccine testing against other pathogens.
VA Merit Review I01BX005616, NIH R01 AI148327
Vaccines and Immunotherapy (VAC)
Catarina E. Hioe, Xiaomei Liu, C. Yengo et al.· Journal of Immunology· 0 citations