Vetnews | September 2024 22 « BACK TO CONTENTS One year later, eight (57%) of 14 participants boosted with an 80 μg needle-free intradermal dose of CV7201 achieved titers of 0·5 IU/mL or more. Conversely, intradermal or muscular needle syringe injection was ineffective, with only one participant (who received 320 μg intradermally) showing a detectable immune response. This first-ever demonstration in humans shows that a prophylactic mRNA-based candidate vaccine can induce functional antibodies against a viral antigen when administered with a needle-free device, but not when injected with a needle syringe. The vaccine was generally safe with a reasonable tolerability profile. CV7202 is a novel mRNA-LNP formulation. A Phase I clinical study aimed to evaluate the safety, reactivity, and immunogenicity of different doses of CV7202 administered via intramuscular injection.94 CureVac recruited 55 healthy adolescents aged 18–40 in Belgium and Germany to receive intramuscular injections of 5 μg (n = 10), 1 μg (n = 16), or 2 μg (n = 16) doses of CV7202 on day 1; The subgroups of the 1 μg and the 2 μg (n = 8) received a second dose of CV7202 on day 29. The control group (n = 10) received Rabipur on days 1, 8, and 29. The 5 μg dose of the CV7202 group exhibited unacceptably high reactivity, and a high innate immune response driven by type 1 interferon and cytokines In addition, strong induction of Toll-like receptor signalling pathways was observed in most participants, which may have led to unfavourable reactivity and immunogenicity characteristics. The 1 μg and 2 μg dose groups showed better tolerance. No serious adverse events or vaccine-related discontinuation was observed. Low-dosedependent neutralizing antibody reactions were detected starting from day 15, and low-dose-dependent RVNA reactions were detected. By day 29, 29%, 31%, and 22% of RVNA in the 1, 2, and 5 μg groups, respectively, were 0.5 IU/ mL. After two doses of 1 or 2 μg immunization, all vaccinated individuals had a titer of 0.5 IU/mL on day 43, which was not significantly lower than that in the vaccine control group. However, some difficulties remain in conducting subsequent phase 2 and phase 3 clinical trials in humans. The strength and durability of the immune response, particularly against rabies, an inevitable fatal infection, are not yet fully understood. Discussion Rabies is a preventable but incurable zoonotic infectious disease, and 99% of human cases are transmitted by dogs. The most effective way to prevent rabies is to vaccinate dogs. Currently, effective management of dogs is not possible in many countries; therefore, standardized PEP is the best choice for preventing human rabies. Among these, immunization with a rabies vaccine is one of the core links in PEP. However, many factors, such as high vaccine costs, complex immunization procedures, and the combined use of passive immunization preparations for rabies, have led to a decrease in compliance with rabies vaccines. The main objectives of the development of new rabies vaccines are safety, low cost, good immunogenicity, and simple immunization procedures. First, ensuring that the vaccine has a good safety profile is the key to minimizing adverse reactions and side effects and safeguarding the health and safety of the vaccinated. Second, reducing the cost of vaccine production to make it more affordable will increase vaccination coverage, particularly in less economically developed areas, allowing more people to afford the vaccination. Third, vaccines must be immunogenic, that is capable of inducing a strong and long-lasting immune response that ensures longterm protection. Finally, simplifying the immunization process, including reducing the number and complexity of vaccinations, improves adherence and convenience so that more people are willing and able to complete the full course of vaccination. Achieving these goals will considerably enhance the effectiveness of rabies prevention and contribute to a more effective control of rabies transmission globally, particularly in resource-limited areas. Over the past two decades, researchers have extensively discussed the potential of mRNA as a preventive means for the treatment of various infectious diseases. Particularly since 2020, with the successful application of mRNA vaccines in the COVID-19 epidemic and potential exploration in other diseases, mRNA vaccines have been receiving increasing attention and research investment and are expected to achieve breakthroughs and progress in future vaccine research and development. In this article, we discuss various novel mRNA rabies vaccines that have been studied clinically and preclinically. We found that only the candidate rabies vaccines CV7201 and CV7202 developed by CureVac completed Phase I clinical studies. In preclinical studies, two doses of 80 μg CV7201 vaccine separated by 21 days induced high neutralizing antibody titers in mice and pigs, and triggered antigen-specific CD4+ and CD8+T cell responses62. Subsequently, CureVac used proprietary LNP produced by Acuitas Therapeutics as a delivery vector for the new rabies candidate vaccine, CV7202. In phase I preclinical studies, CV7202 delivered unmodified mRNA encoding RABV-G and Time Vaccine Platform Vaccine Forms Delivery platform Clinical Setting Immunization Methods Immune Response Ref 2017 CureVac CV7201 Non- replicating mRNA Cationic protein protamine Human Volunteers (18–40 y) with no history of rabies vaccination were recruited and received three doses of CV7201 intradermally or intramuscularly via a needle syringe or one of three needleless devices. Subsequent cohorts received incremental doses, with one cohort receiving a booster dose one year later. The mRNA-based prophylactic vaccine candidate induces enhanced functional antibodies against viral antigens when injected using a needleless device, but not when injected via a needle syringe. The vaccine was generally safe and reasonably well tolerated. 92 2021 CureVac CV7202 Non- replicating mRNA LNPs Human Enrolled 55 healthy participants (18–40 y) to receive intramuscular injections of 5 μg (n = 10), 2 μg (n = 16), or 1 μg (n = 16) CV7202 on day 1; subsets (n = 8) of 1 μg and 2 μg groups received second doses on day 29. Controls (n = 10) received rabies vaccine, Rabipur, on days 1, 8 and 29. Two 1 μg or 2 μg doses of CV7202 were well tolerated and elicited rabies neutralizing antibody responses that met WHO criteria in all recipients, but 5 μg had unacceptable reactogenicity for a prophylactic vaccine. 93 Table 3. Clinical trials. Development of mRNA rabies vaccines <<<21
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