Developing an infection-blocking pan-coronavirus vaccine

Viruses run a highly competitive race to outpace our immune system and establish infection. Our immune responses can't usually expand fast enough to win the race so are unable to prevent viruses spreading amongst our cells and being transmitted on to others. Therefore, it is essential to train our immune systems with more effective vaccines to allow them to shutdown viruses before they gain a foothold, both within an individual and at a population level. In the last 20 years, there have been 3 global pandemics caused by coronaviruses passing from animals to humans: SARS, MERS and COVID-19. Even the accelerated development of vaccines against SARS-CoV-2 was not fast enough to prevent worldwide spread of the virus, with devastating morbidity and mortality. Existing vaccines have become less effective at preventing infection because they target the spike protein that rapidly mutated to escape immunity; making new vaccines against the latest variant means we will always be a step behind the virus. As a crucial component of proactive pandemic preparedness, we are therefore developing a pan-coronavirus vaccine with the capacity to provide broad protection against new animal coronaviruses spreading into humans, as well as against current and future, potentially more lethal, SARS-CoV-2 variants. Our vaccine, 'PanCoVax', will generate immunity that targets regions that are essential for virus replication. We found these regions to be highly conserved across all variants and also all versions of coronaviruses in the animal kingdom. Our vaccine will therefore be 'future variant proof' and offer protection against pandemics from new coronaviruses transmitted from animals. Another limitation of existing SARS-CoV-2 vaccines is that they do not induce immunity able to shut down the virus before it multiplies and can be transmitted on to others. However, PanCoVax mimics a type of immune response we observed in a subset of individuals who were able to 'abort' SARS-CoV-2 so rapidly that the virus never became detectable. To achieve this, we will target the first proteins produced in the viral lifecycle and deliver the vaccine directly into the airways (nose and lungs), the site where the race between the immune system and the virus starts. By delivering the vaccine into the airways, we can expand local immune responses that are specialised to provide very rapid 'frontline defence'. Because our vaccine is designed to stimulate T-cells as well as antibodies, it will provide longer-lasting protection. It should, therefore, be well-suited to boost protection in vulnerable individuals whose antibody production is impaired because of immunosuppressive medication or chronic liver or kidney diseases, for example. To test and select the optimal version of PanCoVax, we have assembled a highly synergistic team of viral immunologists with world-leading expertise in SARS-CoV-2 and vaccine development. We have already constructed our vaccines and generated promising initial results showing that they can generate excellent immune responses. Our preliminary data show that delivering vaccine directly into the airways potently stimulates local immunity, ideally positioned to provide enhanced frontline protection at the site of infection. Funding from this DPFS application will be crucial to allow us to progress PanCoVax by selecting the optimal design and delivery method and confirming it generates durable, infection-blocking immunity. We will investigate the anticipated ability of PanCoVax to provide protection against different coronaviruses by testing whether induced T-cells and antibodies cross-react with a range of different SARS-CoV-2 variants and other coronaviruses, including with cells from human donors and in state-of-the-art models. At the end of this grant funding, we will have assembled a package of data to allow rapid progression of PanCoVax into human testing.

This proposal addresses the pressing unmet need for a vaccine generating durable, frontline mucosal immunity to mediate infection blockade of current and future SARS-CoV-2 variants of concern (VOC), as well as cross-protection against other human and animal coronaviruses (CoV). Our vaccine design ('PanCoVax') is based on T-cell correlates of protection we found enriched in adults who abort SARS-CoV-2 before virus detection and without requirement for antibodies (Swadling, Nature 2022, and unpublished human challenge study data). T-cells targeted the first proteins expressed upon SARS-CoV-2 infection, the replication transcription complex (RTC), highly conserved across all VOC and other CoV, and were enriched in human airways (Diniz, Mitsi, Nature Immunol. 2022). In addition to the RTC-based immunogen, we will test the inclusion of additional SARS-COV-2 genome segments to enhance protection against multiple coronaviruses through additional cross-reactive T cells and antibodies not generated by vaccination with full spike.
MRC accelerator and TAS grants have funded synthesis of PanCoVax constructs and initial demonstration of immunogenicity. DPFS will allow thorough preclinical testing of the cross-protective potential of PanCoVax. Durability and breadth of vaccine-induced T-cell and antibody responses in the periphery and mucosa will be analysed in the setting of prior SARS-CoV-2 immunity and with a homologous or heterologous boost. Cross-reactive immunogenicity and cross protection to heterologous live virus challenge will be compared following intramuscular, intranasal or aerosolised vaccination in state-of-the-art models including one lacking antibodies. This body of pre-clinical data on the induction of sentinel cross-protective immunity with potential to protect against new VOC and zoonoses will allow progression to testing in humans (Phase I followed by controlled human infection model).