Biology subjects

McCauley, J. W.

Publications and source records attributed to McCauley, J. W..

6 recordsLinked to original sources

bioRxiv2025

Immunogenicity and Efficacy of Digitally Immune Optimised H1N1 Vaccine Candidates in Swine and Murine Animal Models

Influenza A virus (IAV) zoonotic transmission and constant evolution in multiple species heightens the risk of emerging novel strains at the human-animal interface. Composite antigens including hemagglutinin (HA), neuraminidase (NA), and matrix-2 (M2) proteins were computationally designed to maximize the breadth of the immune response elicited to human seasonal, pandemic, and zoonotic H1N1 IAVs. Mouse hyperimmune serum raised against these antigens demonstrated broad H1 neutralization and N1 inhibition activity. To enhance immunogenicity, the antigens were combined as a single DNA expression construct (DVX-H1N1). Studies in the well-recognized swine model for human influenza demonstrated that DVX-H1N1 immunization induced broad, neutralizing antibody responses and markedly reduced nasal shedding of viral RNA following challenge with 1A.3.3.2 subclade strain A/swine/England/1353/2009 (H1N1). An effective immune response and reduction in virus shedding was observed in pigs immunized with a whole inactivated virus (WIV) vaccine homologous to the challenge strain but not with a human-origin seasonal WIV vaccine. Overall, we demonstrated broad immunogenicity and efficacy of the DVX-H1N1 vaccine candidate, benchmarked against relevant IAV H1N1 strains in vitro and in vivo in mice and pigs. IMPORTANCEThe zoonotic potential of swine-origin IAVs is a recognized global health threat. Vaccination remains the most effective intervention against influenza; protecting at the population level by preventing nasal shedding and transmission, but also in individuals by limiting clinical disease, particularly by reducing the severity of lung infection. The World Health Organization (WHO) spearheads biannual surveillance efforts to review evolving virus strains and vaccine antigens at Vaccine Candidate Meetings (VCM) to recommend strain updates for the human seasonal influenza vaccine and for pandemic preparedness purposes. However, the strain selection approach is complex and efficaciousness of seasonal influenza vaccines still varies significantly based on the accurate matching of the predicted strains in circulation with the manufactured vaccine antigens. This emphasizes the need for next-generation influenza vaccines that improve the breadth and longevity of immunity. We describe a computationally optimized DNA vaccine with broad immunogenicity and robust efficacy in the pig model.

immunology↗

bioRxiv2022

A Bayesian approach to incorporate structural data into the mapping of genotype to antigenic phenotype of influenza A(H3N2) viruses

Surface antigens of pathogens are commonly targeted by vaccine-elicited antibodies but antigenic variability, notably in RNA viruses such as influenza, HIV and SARS-CoV-2, pose challenges for control by vaccination. For example, influenza A(H3N2) entered the human population in 1968 causing a pandemic and has since been monitored, along with other seasonal influenza viruses, for the emergence of antigenic drift variants through intensive global surveillance and laboratory characterisation. Statistical models of the relationship between genetic differences among viruses and their antigenic similarity provide useful information to inform vaccine development though accurate identification of causative mutations is complicated by highly correlated genetic signals that arise due to the evolutionary process. Here, using a sparse hierarchical Bayesian analogue of an experimentally validated model for integrating genetic and antigenic data, we identify the genetic changes in influenza A(H3N2) virus that underpin antigenic drift. We show that incorporating protein structural data into variable selection helps resolve ambiguities arising due to correlated signals, with the proportion of variables representing haemagglutinin positions decisively included, or excluded, increased from 59.8% to 72.4%. The accuracy of variable selection judged by proximity to experimentally determined antigenic sites was improved simultaneously. Structure-guided variable selection thus improves confidence in the identification of genetic explanations of antigenic variation and we also show that prioritising the identification of causative mutations is not detrimental to the predictive capability of the analysis. Indeed, incorporating structural information into variable selection resulted in a model that could more accurately predict antigenic assay titres for phenotypically-uncharactrised virus from genetic sequence. Combined, these analyses have the potential to inform choices of reference viruses, the targeting of laboratory assays, and predictions of the evolutionary success of different genotypes, and can therefore be used to inform vaccine selection processes.

microbiology↗

bioRxiv2021

Low dose pig anti-influenza virus monoclonal antibodies reduce lung pathology but do not prevent virus shedding

We have established the pig, a large natural host animal for influenza, with many physiological similarities to humans, as a robust model for testing the therapeutic potential of monoclonal antibodies (mAbs). In this study we demonstrated that prophylactic intravenous administration of 15mg/kg of porcine mAb pb18, against the K160-163 site of the haemagglutinin, significantly reduced lung pathology and nasal virus shedding and eliminated virus from the lung of pigs following H1N1pdm09 challenge. When given at 1mg/kg, pb18 significantly reduced lung pathology and lung and BAL virus loads, but not nasal shedding. Similarly, when pb18 was given in combination with pb27, which recognised the K130 site, at 1mg/kg each, lung virus load and pathology were reduced, although without an apparent additive or synergistic effect. No evidence for mAb driven virus evolution was detected. These data indicate that intravenous administration of high doses was required to reduce nasal virus shedding, although this was inconsistent and seldom complete. In contrast the effect on lung pathology and lung virus load is consistent and is also seen at one log lower doses, strongly indicating that a lower dose might be sufficient to reduce severity of disease, but for prevention of transmission other measures would be needed.

immunology↗

bioRxiv2020

Protective porcine influenza virus-specific monoclonal antibodies recognize similar haemagglutinin epitopes as humans

Pigs are natural hosts for the same subtypes of influenza A viruses as humans and integrally involved in virus evolution with frequent interspecies transmissions in both directions. The emergence of the 2009 pandemic H1N1 virus illustrates the importance of pigs in evolution of zoonotic strains. Here we generated pig influenza-specific monoclonal antibodies (mAbs) from H1N1pdm09 infected pigs. The mAbs recognized the same two major immunodominant haemagglutinin (HA) epitopes targeted by humans, one of which is not recognized by post-infection ferret antisera that are commonly used to monitor virus evolution. Neutralizing activity of the pig mAbs was comparable to that of potent human anti-HA mAbs. Further, prophylactic administration of a selected porcine mAb to pigs abolished lung viral load and greatly reduced lung pathology but did not eliminate nasal shedding of virus after H1N1pdm09 challenge. Hence mAbs from pigs, which target HA can significantly reduce disease severity. These results, together with the comparable sizes of pigs and humans, indicate that the pig is a valuable model for understanding how best to apply mAbs as therapy in humans and for monitoring antigenic drift of influenza viruses in humans, thereby providing information highly relevant to making influenza vaccine recommendations.

immunology↗

bioRxiv2020

Integrating genotypes and phenotypes improves long-term forecasts of seasonal influenza A/H3N2 evolution

Seasonal influenza virus A/H3N2 is a major cause of death globally. Vaccination remains the most effective preventative. Rapid mutation of hemagglutinin allows viruses to escape adaptive immunity. This antigenic drift necessitates regular vaccine updates. Effective vaccine strains need to represent H3N2 populations circulating one year after strain selection. Experts select strains based on experimental measurements of antigenic drift and predictions made by models from hemagglutinin sequences. We developed a novel influenza forecasting framework that integrates phenotypic measures of antigenic drift and functional constraint with previously published sequence-only fitness estimates. Forecasts informed by phenotypic measures of antigenic drift consistently outperformed previous sequence-only estimates, while sequence-only estimates of functional constraint surpassed more comprehensive experimentally-informed estimates. Importantly, the best models integrated estimates of both functional constraint and either antigenic drift phenotypes or recent population growth.

evolutionary biology↗

bioRxiv2019

Segment 2 from influenza A(H1N1)pdm09 viruses confers temperature sensitive HA yield on candidate vaccine virus growth in eggs that is complemented by PB2 701D

Candidate vaccine viruses (CVVs) for seasonal influenza A virus are made by reassortment of the antigenic virus with a high-yielding egg-adapted strain, typically A/Puerto Rico/8/34 (PR8). Many 2009 H1N1 pandemic (pdm09) high-growth reassortants (HGRs) selected by this process contain pdm09 segment 2 in addition to the antigenic genes. To investigate this, we made CVV mimics by reverse genetics (RG) that were either 6:2 or 5:3 reassortants between PR8 and two pdm09 strains, A/California/7/2009 (Cal7) and A/England/195/2009, differing in the source of segment 2. The 5:3 viruses replicated better in MDCK-SIAT1 cells than the 6:2 viruses, but the 6:2 CVVs gave higher HA antigen yields from eggs. This unexpected phenomenon reflected temperature sensitivity conferred by pdm09 segment 2, as HA yields from eggs for the 5:3 viruses improved substantially when viruses were grown at 35{degrees}C compared with 37.5{degrees}C, whereas 6:2 virus yield did not. Authentic 5:3 pdm09 HGRs, X-179A and X-181, were not markedly temperature-sensitive however, despite their PB1 sequences being identical to that of Cal7, suggestive of compensatory mutations elsewhere in the genome. Sequence comparisons of the PR8-derived backbone genes identified single changes in PB2 and NP, 5 in NS1, and 1 in NS2. PB2 N701D but not NP T130A affected the temperature dependency of viral transcription. Furthermore, introducing the PB2 701D change into a 5:3 CVV mimic improved and drastically reduced the temperature sensitivity of HA yield. We conclude that RG PR8 backbones used for vaccine manufacture in eggs should contain PB2 701D to maximise virus yield.

microbiology↗