Stanford Scientists First to Identify New Cellular Correlates of Protection Against Influenza for an Oral Flu Vaccine Developed by Vaxart
A new Stanford study published in Cell Host and Microbe has demonstrated that VXA-A1.1, an investigational oral tablet flu vaccine under development by Vaxart, Inc., had cellular correlates of protection against influenza infection.
These cellular correlates were found using mass cytometry analysis of vaccine-elicited cellular immune responses in the peripheral blood of participants in a previously reported Phase II H1N1 challenge study of VXA-A1.1.
The US Centers for Disease Control and Prevention (CDC) estimates that, on average, 36,000 people in the US died from the flu in each of the past 10 years. It is estimated that 61,000 people in the US died from the flu in the 2017-2018 season – the highest toll in recent years. The 2019-2020 season, which was shorter than normal, resulted in approximately 22,000 US deaths. Globally, the number of annual flu deaths has been estimated to range from nearly 300,000 to more than 600,000.
“The data show that cellular responses are potentially more relevant for protection for an oral vaccine than circulating antibody responses,” said David McIlwain, PhD, Senior Research Scientist in the Department of Microbiology and Immunology at the Stanford School of Medicine and lead author of the study.
“These results support using early immune response data to predict protection against respiratory pathogens several months later, potentially speeding vaccine development,” added Sean Tucker, PhD, Vaxart’s Founder and Chief Scientific Officer and a co-author of the publication.
Results of a Phase 2 human influenza challenge study following vaccination with VXA-A1.1, which was funded by the US government’s Biomedical Advanced Research and Development Authority (BARDA), have previously been reported. Participants in the Phase 2 study received either VXA-A1.1, an injected quadrivalent, inactivated influenza vaccine (IIV) or a placebo. Participants were challenged with H1N1 influenza virus 90-120 days after vaccination and were monitored for signs and symptoms of infection and viral shedding.
Results of the Phase 2 study were the first to show that VXA-A1.1 offered greater protection against viral shedding than the injected IIV. The results suggested that cellular responses rather than neutralizing antibodies may be especially important in the VXA-A1.1 mechanism of protection.
The study announced today is the first to use mass cytometry to evaluate more than 40 different immune cell parameters in peripheral blood samples collected from 141 participants in the Phase 2 study. Mass cytometry immune cell profiling was performed on samples collected immediately prior to (day 1) and seven days following (day 8) vaccine administration.
Immune profiling tracked levels of multiple cell subsets with similar patterns of markers. The relationship between each subset and virus shedding was determined. Random forest-based machine learning models were used to define high-dimensional cellular correlates between the immune profiling and viral shedding data.
Key findings from the study include:
- Specific B cell and T cell responses contribute to protection from viral shedding with VXA-A1.1 but not with IIV.
- At day 8, vaccine-elicited subsets of plasmablasts (including α4β7+, CD62L-, pSTAT5+ cells) and hemagglutinin (HA+)-specific cells significantly correlated with protection from viral shedding after day 90 in participants vaccinated with VXA-A1.1, but not in participants treated with IIV or placebo.
- At day 8, VXA-A1.1, but not IIV or placebo, elicited subsets of T cells expressing markers (β7 integrin and CCR9) that are indicative of enhanced homing to mucosal tissue.
- Random forest models of the VXA-A1.1-treated group could distinguish those individuals who were later protected versus those who remained susceptible to the virus using datasets from both unsupervised clustering approaches and manual gating (p= 0.00001).
Vaxart is a clinical-stage biotechnology company developing a range of oral recombinant vaccines based on its proprietary delivery platform. Vaxart vaccines are designed to be administered using tablets that can be stored and shipped without refrigeration and eliminate the risk of needle-stick injury. Vaxart believes that its proprietary tablet vaccine delivery platform is suitable to deliver recombinant vaccines, positioning the company to develop oral versions of currently marketed vaccines and to design recombinant vaccines for new indications. Vaxart’s development programs currently include tablet vaccines designed to protect against coronavirus, norovirus, seasonal influenza, and respiratory syncytial virus (RSV), as well as a therapeutic vaccine for human papillomavirus (HPV), Vaxart’s first immune-oncology indication. Vaxart has filed broad domestic and international patent applications covering its proprietary technology and creations for oral vaccination using adenovirus and TLR3 agonists.
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