mRNA-based platform development
In vitro transcribed (IVT) mRNA emerged as a groundbreaking new therapeutic modality that proved its viability as a vaccine platform during the COVID-19 pandemic. Besides vaccination, IVT mRNA can potentially be used for a wide range of clinical applications such as protein replacement, antibody therapy, and genome editing. Our group is interested in further improving the mRNA platform by examining the contribution of mRNA’s structural elements, chemistry, and composition as well as exploring ways to alter its stability, translatability and inflammatory capacity. We believe that a better understanding of these important features of mRNA biology and production will allow for a more precise and optimized mRNA design for various applications.
mRNA vaccine development for infectious diseases
The lipid nanoparticle (LNP)-encapsulated nucleoside-modified mRNA vaccine platform – being utilized in the mRNA-1273 and BNT162b2 vaccines against SARS-CoV-2 – is saving lives every day in the COVID-19 pandemic. The flexibility of mRNA vaccine design and its highly scalable manufacturing enable the rapid development of modified vaccines adjusted to new variants of SARS-CoV-2 and the production of hundreds of millions of vaccine doses in just a few months. These beneficial features of the nucleoside-modified mRNA-LNP technology are critical for successfully battling quickly mutating pathogens and dealing with pandemic outbreaks where rapid development of production of novel vaccines are key for success.
Our lab quickly reacted to the SARS-CoV-2 outbreak by designing, producing and testing novel SARS-CoV-2 mRNA vaccines similar to mRNA-1273 and BNT162b2. As the SARS-CoV-2 pandemic is the third coronavirus outbreak in less than 20 years, we have no doubts that coronaviruses will be responsible for more epidemics and pandemics in the near future. We are committed to contributing to global pandemic preparedness, a pro-active approach that aims at designing, producing, and testing new vaccines against pathogens with high pandemic potential. As part of a team of investigators at various institutions, we are developing mRNA-based pancoronavirus vaccines that can elicit broad protection against multiple coronaviruses and help to significantly decrease the negative impact (morbidity, mortality, economic loss) of future coronavirus outbreaks.
Influenza virus vaccines are also in the main focus of the Pardi Lab. Influenza virus infection causes significant morbidity and mortality every year. Currently used seasonal influenza virus vaccines provide protection from the vaccine-matched circulating strains, but they do not protect from antigenically drifted and shifted viruses and thus need to be updated and manufactured annually. These vaccines primarily induce antibodies against the highly variable and ever-changing head domain of the influenza virus hemagglutinin protein. Taking advantage of the flexibility of mRNA-LNP vaccine design, our group is developing universal/broadly protective mRNA-based influenza vaccines by targeting several antigens of numerous different influenza virus strains with a single, combined vaccine formulation. We hope to develop and evaluate a vaccine that provides protection against a very wide range of influenza A and B viruses.
The Pardi Lab is highly collaborative and is involved in the development of novel vaccines against HIV, HBV, malaria (targeting Plasmodium falciparum and Plasmodium vivax) and various bacterial and fungal targets.
Understanding the mechanism of action of nucleoside-modified mRNA-LNP vaccines
Multiple publications demonstrated that modified mRNA-LNP vaccines can induce protective immune responses against various pathogens in preclinical studies. Recently, it has become clear that this revolutionary vaccine modality induces robust, protective immune responses in humans as well. However, we know very little about innate immune sensing mechanisms of mRNA vaccines. We believe that if we can identify the signaling pathways involved in sensing of mRNA-LNPs, we will likely be able to develop a new generation of vaccines with higher immunogenicity and lower reactogenicity.
mRNA-based monoclonal antibody therapy
The mRNA-LNP platform represents a versatile technology with a wide range of potential clinical applications. Of these areas, one of the most exciting is passive immunotherapy with mRNA-encoded monoclonal antibodies. We established proof-of-concept for the viability of this approach in 2017. Since then, other labs confirmed our findings in animal studies, and promising clinical data has also been generated. We are interested in using this approach to develop broadly protective mRNA-encoded antibodies against coronaviruses and other pathogens.
