Many different influenza viruses circulate in nature and mutate constantly. Influenza types A and B infect humans; type A is responsible for many influenza epidemics and all influenza pandemics. The haemagglutinin (HA) and neuraminidase (NA) proteins on the surface of influenza viruses are the dominant antigens recognised by the immune system. HA consists of a distal “head” and a proximal “stalk” domain. Current vaccines are designed to elicit serum antibodies to the highly variable head of the HA proteins of specific influenza strains and generally lack efficacy against other strains. Neither a universal influenza vaccine that protects against all seasonal (epidemic) influenza strains and potential pandemic strains, nor a broadly cross-protective influenza vaccine is available. The effectiveness of available influenza vaccines depends on a match between the 3 or 4 specific seasonal influenza virus strains (or a single pandemic strain) in the vaccine and the strains in circulation.
The proposed FLUniversal approach has the potential to meet all the characteristics of the desired target product profile for a universal influenza vaccine. We aim for a pan-influenza vaccine providing protection against all influenza A virus subtypes and B virus lineages by prime-boost vaccination. Intranasal administration of our universal influenza vaccine provides convenience and, most importantly, near-immediate protection by inducing interferon and broadly cross-neutralising antibodies in the nasal passages (ref 3,4) and B- and T-cell-mediated systemic immunity.
The FLUniversal consortium unites world-leading experts with the tools and knowledge to develop novel universal influenza vaccine strategies and dissect the underlying protective immunological mechanisms. The parallel use of preclinical models, clinical trial samples, challenge study, and realworld samples enables the FLUniversal team to obtain synergy, de-risk the clinical development pathway, and identify signatures of protection through integrated complex immunological analyses.
Consequently, throughout the FLUniversal lifetime, the DeltaFLU vaccine and platform methodologies will be optimised through iterative, synergistic processes whereby preclinical and clinical data will be united to maximise output.
DeltaFLU serves to diversify the portfolio of vaccine candidates by the following features:
We envision the FLUniversal legacy to last beyond the project in generating a platform network for the expedited clinical development of novel vaccines. It includes a novel human challenge model for influenza with a strain that closely matches circulating strains (i.e., no egg-derived mutations) which will be publicly available, and new, more appropriate correlates of protection for the development and regulatory review of next-generation influenza vaccines.
The objectives of the FLUniversal consortium are aligned with the expected outcomes:
Foto Vivaldi Bioscience
State of the art: Universal influenza vaccines that target conserved regions of the influenza virus, including the HA stalk domain, the ectodomain of the M2 ion channel, or the internal matrix and nucleoproteins, have achieved solid progress recently. Several promising vaccine candidates are in earlyclinical trials, with each candidate exploiting conserved regions of the virus. Among those, different strategies directing the antibody response to the conserved HA stalk were evaluated. The most promising approach appears to be sequential vaccination withchimeric HAs (cHAs) with different head domains but the same stalk domain. In a Phase 1 trial, the safety and immunogenicity of the chimeric HA-based approach were demonstrated. Sequentialvaccination with cHAs with different head domains but the same stalk domain caused high anti-stalkantibody titres in all experimental groups. Vaccination with cHA vaccines was acceptably safe in adultswhile providing strong broad-spectrum functional and long-lasting antibodies. Similar results wereobtained in a subsequent Phase 1/2 trial. These clinical trials focused on proof of concept andonly considered type A/group 1 influenza viruses. However, the researchers are currently developinggroup 2 and B cHAs with the goal of a trivalent vaccine enabling protection for a significantly widerpool of seasonal influenza viruses.
While the FLUniversal consortium partly builds on these observations, it will go far beyond the current state of the art on different levels. A new strategy to direct the antibodies to the stalk region wasdeveloped and combined with a live attenuated approach based on deleting the interferon antagonistNS1. Other objectives of the project are to define new correlates of protection and develop a clinicalchallenge model that closely mimics natural human infection. Finally, the vaccine candidates will beproduced in an innovative production system based on Vero cells.
The core of our project is combining two highly innovative concepts in the field of influenza virus vaccines and testing this combination in preclinical and clinical trials:
We thus propose to use the delNS1 concept in an innovative immunisation regimen for universal protection from influenza. Ultimately, at the end of the project, we envision FLUniversal providing proof-of-concept data for heterologous protection by a universal influenza vaccine in a new human challenge model for influenza, identifying correlates of protection in clinical and preclinical data, and expanding our molecular understanding of cross-strain protection in preclinical animal models.
The safety of delNS1 (deletion of NS1 gene) virus vaccines in healthy adults has already been demonstrated in clinical trials. In the long run, we expect to demonstrate safety in young children, the elderly and high-risk groups due to the replication-deficient phenotype of delNS1 strains. The immunogenicity of delNS1 intranasal vaccines indicates the potential for superior protective efficacy against influenza, as demonstrated in animal models and clinical trials (NCT00724997 and NCT03745274). The novel vaccination strategy proposed here will expand specifications to include protection against all influenza virus strains. Furthermore, FLUniversal will provide the much-needed integrated approach toward vaccine development, uniting world-leading experts to expedite the development of universal influenza vaccines with major global impact. The delNS1 strains used in the aforementioned clinical studies were produced using Vivaldi AG’s earlier Vero-cell process. The DeltaFLU vaccine strains used in FLUniversal will be produced in an improved version of this process; strains produced using these process improvements have not yet been tested in humans. With DeltaFLU in FLUniversal, the heterologous prime-boost administration regimen will be used in humans for the first time. Thus, the proposed programme is at the preclinical stage corresponding to TRL3. The current project aims to conduct all nonclinical and preclinical research studies involving parametric data (TRL5) and a Phase 1 clinical trial to achieve TRL6.