Wobble Vaccines: Eliminating Immunodominance and Promoting Cross-Strain Protection Through Flexible mRNA Vaccine Library Encoding
Abstract
The COVID-19 pandemic has placed renewed focus on vaccination as our most effective tool in the control and prevention of emerging viral diseases. In 2020, vaccination technology developed over the past decades, fueled by significant investment and governmental support, allowed for the development and licensing of two mRNA-based vaccines – the first of their kind. These vaccines are easy to design and manufacture, display excellent safety profiles, and have outperformed other vaccines rooted in more traditional approaches. However, despite their success, worldwide emergence of new SARS-CoV-2 variants has injected uncertainty into the ongoing effectiveness of these first-wave vaccines. Mitigation strategies are being rapidly investigated, but the potential loss of vaccine potency highlights an ongoing issue in vaccine design that has not been effectively addressed. While we have progressed greatly in stimulating robust immune responses through vaccination, our ability to guide those responses towards specific viral targets that provide broad variant protection has lagged. Lacking innovative tools in this area we are in a constant state of catch-up – vaccinating against current variants and hoping for durable efficacy. Our lack of knowledge in this area also prevents exploitation of known pathogen vulnerabilities. Decades of research have failed to direct antibodies against targets known to neutralize HIV, provide cross-seasonal influenza protection, or neutralize multiple strains of dengue virus. However, a completely new technology based on advanced mRNA vaccination, WobbleVax, offers a new way forward. Recent immunological studies have revealed a new principle in the selection of antibody responses – the strong preference of an immune system to produce antibodies against conserved targets. When presented with multiple versions of the same pathogen (i.e., SARS-CoV-2 variants), antibody responses prefer to target the similarities between those pathogens and ignore their differences. These antibodies are more likely to be broadly protective and resist future mutations. This approach has shown promise in a limited manner in influenza – simultaneously vaccination against multiple influenza variants results in increased production of cross-protective antibodies. However, current approaches are difficult to formulate and extremely limited in their potential to capitalize on this new principle of immune targeting. mRNA vaccines offer a solution. Leveraging published libraries of naturally occurring viral mutations, we have designed massively diverse pools of mRNA vaccines capable of introducing a huge spectrum of viral diversity within a single vaccine. These vaccines, wobble vaccines (WobbleVax), will allow antibody responses to sift through the mutational tendencies of any given viral protein, and identify targets most likely to result in stable, long-term protection across both existing and emerging viral strains. As a completely new technology, this project proposes the creation of the first-generation WobbleVax platform to be tested in mice against well-characterized vaccine targets. We will document the potential of these vaccines to elicit strong immune responses, and importantly, redirect them towards desired targets, or away from undesired targets. In parallel, we propose the design and development of a WobbleVax library against the SARS-CoV-2 spike protein, both demonstrating the feasibility of the WobbleVax platform and laying the groundwork for future studies to rapidly develop and deploy similar vaccines to critical human pathogens such as influenza and HIV. These libraries will capitalize on the wealth of variant data that has been generated throughout the COVID-19 pandemic, directly target the mutations identified by the Centers for Disease Control and Prevention (CDC) as variants of concern, and are immediately translatable. In all, this program will pave the way for a new generation of vaccines that
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210572
Entities
People
- Matthew C Woodruff
Organizations
- Emory University
- United States Army