Major findings and recent advances in virus-like particle (VLP)-based vaccines.

We have investigated the immunogenicity in rabbits of native-like, soluble, recombinant SOSIP.664 trimers based on the env genes of four isolates of human immunodeficiency virus type 1 (HIV-1); specifically BG505 (clade A), B41 (clade B), CZA97 (clade C) and DU422 (clade C). The various trimers were delivered either simultaneously (as a mixture of clade A + B trimers) or sequentially over a 73-week period. Autologous, Tier-2 neutralizing antibody (NAb) responses were generated to the clade A and clade B trimers in the bivalent mixture. When delivered as boosting immunogens to rabbits immunized with the clade A and/or clade B trimers, the clade C trimers also generated autologous Tier-2 NAb responses, the CZA97 trimers doing so more strongly and consistently than the DU422 trimers. The clade C trimers also cross-boosted the pre-existing NAb responses to clade A and B trimers. We observed heterologous Tier-2 NAb responses albeit inconsistently, and with limited overall breath. However, cross-neutralization of the clade A BG505.T332N virus was consistently observed in rabbits immunized only with clade B trimers and then boosted with clade C trimers. The autologous NAbs induced by the BG505, B41 and CZA97 trimers predominantly recognized specific holes in the glycan shields of the cognate virus. The shared location of some of these holes may account for the observed cross-boosting effects and the heterologous neutralization of the BG505.T332N virus. These findings will guide the design of further experiments to determine whether and how multiple Env trimers can together induce more broadly neutralizing antibody responses.

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Sequential and Simultaneous Immunization of Rabbits with HIV-1 Envelope Glycoprotein SOSIP.664 Trimers from Clades A, B and C.

Introduction: Although much progress has been made in the last decade(s) toward development of effective cancer vaccines, there are still important obstacles to therapeutic successes. New generatio...

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Current challenges for cancer vaccine adjuvant development

Development of an effective vaccine against Ebola virus is of high priority However, knowledge about potential correlates of protection and the durability of immune response after vaccination is limited Here, we elucidate the human antibody repertoire after administration of vesicular stomatitis virus (VSV)-Ebola vaccine at 3 million, 20 million and 100 million plaque-forming units (PFU) and homologous VSV-Ebola vaccine boost in healthy adult volunteers Whole genome-fragment phage display libraries, expressing linear and conformational epitopes of Ebola glycoprotein (GP), showed higher diversity of antibody epitopes in individuals vaccinated with 20 million PFU than in those vaccinated with 3 million or 100 million PFU Surface plasmon resonance kinetics showed higher levels of GP-binding antibodies after a single vaccination with 20 million or 100 million PFU than with 3 million PFU, and these correlated strongly with neutralization titers A second vaccination did not boost antibody or virus neutralization titers, which declined rapidly, and induced only minimal antibody affinity maturation Isotype analysis revealed a predominant IgM response even after the second vaccination, which contributed substantially to virus neutralization in vitro These findings may help identify new vaccine targets and aid development and evaluation of effective countermeasures against Ebola

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Human antibody repertoire after VSV-Ebola vaccination identifies novel targets and virus-neutralizing IgM antibodies

Adjuvant formulations for virus-like particle (VLP) based vaccines.

ISCOMATRIX™ adjuvant promotes epitope spreading and antibody affinity maturation of influenza A H7N9 virus like particle vaccine that correlate with virus neutralization in humans.

Epitope diversity of SARS-CoV-2 hyperimmune intravenous human immunoglobulins and neutralization of variants of concern.

Background Following the failure of antibody therapies in treating COVID-19 hospitalized patients we investigated the impact of viral replication on the pharmacokinetics (PK) and efficacy of a hyperimmune SARS-CoV-2 Immune Globulin (CoVIG) product in treatment of SARS-CoV-2 infection using the adult Syrian hamster model. Methods The CoVIG was manufactured from plasma donors who had recovered from COVID-19. The dose used (400 mg/kg) was based on the dose given in clinical trials to hospitalized COVID-19 patients. Hamsters were given a single dose of CoVIG two days after challenge with the SARS-CoV-2 virus (isolate NY/PV08410/2020), followed by sampling of blood, nasal, tracheal and lung tissues at different time points. The blood samples were assayed for anti-SARS-CoV-2 spike binding and used to calculate PK parameters. Nasal washes, trachea, and lung samples were assayed for viral replication by PCR (sgRNA). Results CoVIG-treated hamsters showed a reduction in viral replication in the lower respiratory tract, but minimally in the upper respiratory tract, following challenge with SARS-CoV-2. Challenge with SARS-CoV-2 resulted in altered PK parameters proportionate to viral replication, resulting in decreased area under the curve (AUC), accelerated clearance and shorter half-life of CoVIG. Conclusions These data indicate that in the presence of actively replicating SARS-CoV-2 virus, PK parameters are altered and should trigger an adjustment in dosing of CoVIG.

Pharmacokinetics and Efficacy of Human Hyperimmune Intravenous Immunoglobulin Treatment of SARS-CoV-2 Infection in Adult Syrian Hamsters.

This invention provides immunogenic compositions comprising an immune stimulant and an respiratory syncytial virus (RSV) oligopeptide or an unglycosylated RSV polypeptide. The RSV oligopeptides are shown in SEQ ID NO: 3-33. The unglycosylated RSV polypeptide may consist essentially of the ectodomain of an RSV G protein, such as that shown in SEQ ID NO: 2 or the ectodomain of an RSV F protein such as the ectodomain of the F protein shown in SEQ ID NO: 39.

Hana Golding

Papers

ISCOMATRIX™ adjuvant promotes epitope spreading and antibody affinity maturation of influenza A H7N9 virus like particle vaccine that correlate with virus neutralization in humans.

Epitope diversity of SARS-CoV-2 hyperimmune intravenous human immunoglobulins and neutralization of variants of concern.

Pharmacokinetics and Efficacy of Human Hyperimmune Intravenous Immunoglobulin Treatment of SARS-CoV-2 Infection in Adult Syrian Hamsters.

Immunogenic rsv polypeptides