The COVID-19 pandemic, caused by infection with the SARS-CoV-2 coronavirus, is having a deleterious impact on health services and the global economy, highlighting the urgent need for an effective vaccine. Such a vaccine would need to rapidly confer protection after one or two doses and would need to be manufactured using components suitable for scale-up. Here, we developed an alphavirus-derived replicon RNA vaccine candidate, repRNA-CoV2S, encoding the SARS-CoV-2 spike (S) protein. The RNA replicons were formulated with Lipid InOrganic Nanoparticles (LION) that were designed to enhance vaccine stability, delivery, and immunogenicity. We show that a single intramuscular injection of the LION/repRNA-CoV2S vaccine in mice elicited robust production of anti-SARS-CoV-2 S protein IgG antibody isotypes indicative of a Type 1 T helper cell response. A prime/boost regimen induced potent T cell responses in mice including antigen-specific responses in lung and spleen. Prime-only immunization of aged (17-month old) mice induced smaller immune responses compared to young mice, but this difference was abrogated by booster immunization. Importantly, in nonhuman primates, prime-only immunization in one intramuscular injection site or prime/boost immunizations in 5 intramuscular injection sites elicited modest T cell responses and robust antibody responses. The antibody responses persisted for at least 70 days and neutralized SARS-CoV-2 at titers comparable to those in human serum samples collected from individuals convalescing from COVID-19. These data support further development of LION/repRNA-CoV2S as a vaccine candidate for prophylactic protection against SARS-CoV-2 infection.
The COVID-19 pandemic progresses unabated in many regions of the world. An effective antiviral against SARS-CoV-2 that could be administered orally for use following high-risk exposure would be of substantial benefit in controlling the COVID-19 pandemic. Herein, we show that MK-4482, an orally administered nucleoside analog, inhibits SARS-CoV-2 replication in the Syrian hamster model. The inhibitory effect of MK-4482 on SARS-CoV-2 replication is observed in animals when the drug is administered either beginning 12 h before or 12 h following infection in a high-risk exposure model. These data support the potential utility of MK-4482 to control SARS-CoV-2 infection in humans following high-risk exposure as well as for treatment of COVID-19 patients.
We remain largely without effective prophylactic/therapeutic interventions for COVID-19. Although many human COVID-19 clinical trials are ongoing, there remains a deficiency of supportive preclinical drug efficacy studies to help guide decisions. Here we assessed the prophylactic/therapeutic efficacy of hydroxychloroquine (HCQ), a drug of interest for COVID-19 management, in two animal disease models. The standard human malaria HCQ prophylaxis (6.5 mg/kg given weekly) and treatment (6.5mg/kg) did not significantly benefit clinical outcome nor reduce SARS-CoV-2 replication/shedding in the upper and lower respiratory tract in the rhesus macaque disease model. Similarly, when used for prophylaxis or treatment neither the standard human malaria dose (6.5 mg/kg) nor a high dose (50 mg/kg) of HCQ had any beneficial effect on clinical disease or SARS-CoV-2 kinetics (replication/shedding) in the Syrian hamster disease model. Results from these two preclinical animal models may prove helpful in guiding clinical use of HCQ for prophylaxis/treatment of COVID-19.
One Sentence Summary: Hydroxychloroquine prophylaxis/treatment showed no beneficial 23 effect in SARS-CoV-2 hamster and macaque disease models. 24 25 We remain largely without effective prophylactic/therapeutic interventions for COVID-19.26 Although many human clinical trials are ongoing, there remains a deficiency of supportive 27 preclinical drug efficacy studies. Here we assessed the prophylactic/therapeutic efficacy of 28 hydroxychloroquine (HCQ), a drug of interest for COVID-19 management, in two animal 29 models. When used for prophylaxis or treatment neither the standard human malaria dose 30 (6.5 mg/kg) nor a high dose (50 mg/kg) of HCQ had any beneficial effect on clinical disease 31 or SARS-CoV-2 kinetics (replication/shedding) in the Syrian hamster disease model. 32 Similarly, HCQ prophylaxis/treatment (6.5 mg/kg) did not significantly benefit clinical 33 outcome nor reduce SARS-CoV-2 replication/shedding in the upper and lower respiratory 34 tract in the rhesus macaque disease model. In conclusion, our preclinical animal studies do 35 not support the use of HCQ in prophylaxis/treatment of COVID-19.36 37 Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of 38 coronavirus disease 2019 (COVID-19) (1). SARS-CoV-2 infections were initially reported in 39 China near the beginning of December 2019 (2). Following early spread through Asia, and 40 subsequently to European, American and African countries, the virus is responsible for the third 41 pandemic of the 21 st Century. With currently over 6.6 million confirmed cases and >390,000 42 deaths worldwide, health systems are stretched beyond limit with largely no proven treatment or 43 3 prophylaxis available to reduce the burden (3). Public health measures combined with 44 increasingly severe restrictions on public life have been implemented in many countries to stop 45 SARS-CoV-2 transmission. The goal of current public health strategies is to flatten the 46 epidemiologic SARS-CoV-2/COVID-19 curve to ease the burden on health care systems 47 228 Institutes of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), and 229 partially funded through awards to The Vaccine Group Ltd, and the University of Plymouth. We 230 thank Hillary Marston, Karyl Baron and Steven Holland (all NIAID, NIH) for helpful discussion 231 and access to the drug. We are thankful to the animal caretakers and histopathology group of the 232 Rocky Mountain Veterinary Branch (NIAID, NIH) for their support with animal related work, 233 and Anita Mora (NIAID, NIH) for help with the display items.234 235 Disclaimer. The opinions, conclusions and recommendations in this report are those of the 236 authors and do not necessarily represent the official positions of the National Institute of Allergy
Despite mass public health efforts, the SARS-CoV2 pandemic continues as of late-2021 with resurgent case numbers in many parts of the world. The emergence of SARS-CoV2 variants of concern (VoC) and evidence that existing vaccines that were designed to protect from the original strains of SARS-CoV-2 may have reduced potency for protection from infection against these VoC is driving continued development of second generation vaccines that can protect against multiple VoC. In this report, we evaluated an alphavirus-based replicating RNA vaccine expressing Spike proteins from the original SARS-CoV-2 Alpha strain and recent VoCs delivered in vivo via a lipid inorganic nanoparticle. Vaccination of both mice and Syrian Golden hamsters showed that vaccination induced potent neutralizing titers against each homologous VoC but reduced neutralization against heterologous challenges. Vaccinated hamsters challenged with homologous SARS-CoV2 variants exhibited complete protection from infection. In addition, vaccinated hamsters challenged with heterologous SARS-CoV-2 variants exhibited significantly reduced shedding of infectious virus. Our data demonstrate that this vaccine platform can be updated to target emergent VoCs, elicits significant protective immunity against SARS-CoV2 variants and supports continued development of this platform.
In 2016, the Bunyavirales order was established by the International Committee on Taxonomy of Viruses (ICTV) to incorporate the increasing number of related viruses across 13 viral families. While diverse, four of the families (Peribunyaviridae, Nairoviridae, Hantaviridae, and Phenuiviridae) contain known human pathogens and share a similar tri-segmented, negative-sense RNA genomic organization. In addition to the nucleoprotein and envelope glycoproteins encoded by the small and medium segments, respectively, many of the viruses in these families also encode for non-structural (NS) NSs and NSm proteins. The NSs of Phenuiviridae is the most extensively studied as a host interferon antagonist, functioning through a variety of mechanisms seen throughout the other three families. In addition, functions impacting cellular apoptosis, chromatin organization, and transcriptional activities, to name a few, are possessed by NSs across the families. Peribunyaviridae, Nairoviridae, and Phenuiviridae also encode an NSm, although less extensively studied than NSs, that has roles in antagonizing immune responses, promoting viral assembly and infectivity, and even maintenance of infection in host mosquito vectors. Overall, the similar and divergent roles of NS proteins of these human pathogenic Bunyavirales are of particular interest in understanding disease progression, viral pathogenesis, and developing strategies for interventions and treatments.
1The ongoing COVID-19 pandemic, caused by infection with SARS-CoV-2, is having a dramatic and 2 deleterious impact on health services and the global economy. Grim public health statistics highlight the 3 need for vaccines that can rapidly confer protection after a single dose and be manufactured using 4 components suitable for scale-up and efficient distribution. In response, we have rapidly developed 5 repRNA-CoV2S, a stable and highly immunogenic vaccine candidate comprised of an RNA replicon 6 formulated with a novel Lipid InOrganic Nanoparticle (LION) designed to enhance vaccine stability, 7 delivery and immunogenicity. We show that intramuscular injection of LION/repRNA-CoV2S elicits 8 robust anti-SARS-CoV-2 spike protein IgG antibody isotypes indicative of a Type 1 T helper response as 9 well as potent T cell responses in mice. Importantly, a single-dose administration in nonhuman primates 10 elicited antibody responses that potently neutralized SARS-CoV-2. These data support further 11 development of LION/repRNA-CoV2S as a vaccine candidate for prophylactic protection from SARS-CoV-Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) first emerged in December 2019 14 and within 3 months, Coronavirus Disease 2019 (COVID-19), caused by SARS-CoV-2 infection, was 15 declared a worldwide pandemic 1-3 . Coronaviruses are enveloped, single-strand positive-sense RNA 16 viruses with a large genome and open reading frames for four major structural proteins: Spike (S), 17 envelope, membrane, and nucleocapsid. The S protein mediates binding of coronaviruses to angiotensin 18 converting enzyme 2 (ACE2) on the surface of various cell types including epithelial cells of 19 the pulmonary alveolus 4-6 . Protection is thought to be mediated by neutralizing antibodies against the S 20 protein 7,8 , as most of the experimental vaccines developed against the related SARS-CoV incorporated 21 the S protein, or its receptor binding domain (RBD), with the goal of inducing robust, neutralizing 22 responses 9-11 . Indeed, previous reports have shown that human neutralizing antibodies protected mice 23 challenged with SARS-CoV 12-14 and Middle East respiratory syndrome (MERS)-CoV 15 suggesting that 24 protection against SARS-CoV-2 can be mediated through anti-S antibodies. Additionally, SARS vaccines 25 that drive Type 2 T helper (Th2) responses have been associated with enhanced lung immunopathology 26 following challenge with SARS-CoV while those with a Type 1 T helper (Th1)-biased immune response 27 are associated with enhanced protection in the absence of immunopathology 16,17 . Therefore, an 28 effective COVID-19 vaccine will likely need to induce, at the very least, Th1-biased immune responses 29 comprised of SARS-CoV-2-specific neutralizing antibodies.30 Nucleic acid vaccines have emerged as ideal modalities for rapid vaccine design, requiring only 31 the target antigen's gene sequence and removing dependence on pathogen culture (inactivated or live 32 attenuated vaccines) or scaled recombinant protein production. In a...
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