A Clinical Trial to Assess the Safety and Immunogenicity of LNP-nCOV saRNA-02, a Self-amplifying Ribonucleic Acid (saRNA) Vaccine, in SARS-CoV-2 Seronegative and Seropositive Uganda Population

Background The ongoing pandemic coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in humans in China sometime between October to November 2019, and the disease coronavirus infectious disease 2019 (COVID-19) was identified in China in December 2019.

By the end of January 2021, SARS-CoV-2 had infected with confirmed diagnosis over 106 million people worldwide, resulting in over 2.3 million deaths and over 59 million people recovered from infection. This yields a nominal infection fatality rate (IFR) of ~2%, and around 10% of infected people have been left with health effects lasting for 6 months or more. As of 8 March 2021, Uganda had reported 40,452 coronavirus cases and 334 deaths. Through COVAX, Uganda started rolling out the AstraZeneca vaccine (adenoviral based) from 10 March 2021.

The developing assessment is that the only way the world can exit from the COVID-19 pandemic is through the deployment of an effective vaccine. A number of vaccines have been developed and received emergency use authorization by the United States Food and Drug Administration and/or the World Health Organization. Examples include Pfizer-BioNTech and Moderna's messenger ribonucleic acid (mRNA)-based vaccines which have both shown efficacy at 95%; Oxford-AstraZeneca's ChAdOx1 nCoV-19 and Johnson and Johnson's adenovirus based vaccines which have demonstrated efficacies of 70% and 66% respectively. The problem comes with the scale needed and the time frame in which vaccines need to be developed and deployed. A self-amplifying RNA (saRNA) vaccine provides a novel, feasible, and time-sensitive solution to contribute to addressing the SARS-CoV-2 problem, either during the current pandemic or for ongoing seasonal epidemics.

Studies have demonstrated that nucleic acid-based vaccination can protect against viral infections in non-human primate (NHP) studies, providing proof of concept that gene-based vaccination can induce protective antibodies. However, DNA vaccines require multiple immunizations with the use of electroporation to induce significant immune responses in humans. Non-replicating mRNA-based therapeutics typically require high doses of RNA (100-600 µg). The requirement for high doses, and associated cost, suggest non-replicating mRNA may struggle to produce the potential hundreds of millions of doses required to rapidly respond to a pandemic. In contrast, small animal and non-human primate (NHP) experiments suggest that saRNA induces significantly enhanced responses in comparison to either DNA vaccines delivered with electroporation or mRNA. Indeed, a single immunization with a saRNA vaccine has shown protection against Ebola virus in animal models. Should a ≤10 µg dose of saRNA provide protection from COVID-19, this would provide critical advantages for manufacturing where 100,000 doses can by synthesized in a one liter reaction volume. In contrast to viral vectors, lack of anti-vector immunity provides the opportunity for repeat immunizations with multiple RNA-encoded immunogens.

The first generation saRNA vaccine (LNP-nCoV-saRNA) is already undergoing safety assessment in humans in the COVAC1 trial in the United Kingdom. The safety of this first generation saRNA vaccine has been assessed initially in healthy young adults i.e., 15 participants aged 18-45 years, given one of three different doses (0.1, 0.3 and 1 µg) by injection into the muscle, going slowly from the lowest to the highest over a period of several weeks. To date, there have been no reported serious adverse events (SAEs) associated with this vaccine and a low frequency of Grade 2 events. An additional 35 volunteers have been randomized across each dose. To date, 105 healthy subjects have received two immunizations across each dose, with few Grade 2 events. All participants have safely received both doses. Initial assessment of the first 15 subjects indicates that although the vaccine shows a good safety profile, the levels of seroconversion (75% for the 1ug dose) and binding antibody are lower than anticipated from preclinical models. Indeed, data generated to date suggest responses are at the lower end of a dose response curve. An additional expansion phase has been initiated to explore three higher doses 2.5, 5 and 10ug. The disconnect between human immune response to the vaccine and preclinical models suggests that the level of saRNA expression in humans is less effective than in small animal models. Current data indicate that 5ug dose administered at 0 and 4 weeks induces an acceptable immune response to most (83%) individuals 4-weeks post 2nd vaccination.