Innovation Delivered
Adjuvanting a subunit SARS-CoV-2 nanoparticle vaccine to induce protective immunity in non-human primates
https://www.biorxiv.org/content/10.1101/2021.02.10.430696v1
Summary
Despite of the success of messenger RNA vaccines against SARS-CoV-2, a wider portfolio of different vaccine candidates would be needed to stop COVID-19 pandemic. In particular, vaccinating infants and the elderly could benefit from the use of subunit vaccine platforms with a demonstrable history of safety and efficacy in such populations.
Subunit vaccines include only a fragment of a pathogen which can still induce the immune system. Although, the production of these types of vaccines are safer than producing attenuated pathogen, they often require adjuvants to enhance the immune response for long term protection.
In this extensive research collaboration, the authors demonstrate the capacity of a subunit vaccine under clinical development, containing the SARS-CoV-2 Spike protein receptor binding domain displayed on a two component protein nanoparticle (RBD-NP). They assessed the immunogenicity and protective efficacy of RBD-NP vaccination using five different clinically relevant adjuvants in non-human primates.
Among the tested adjuvants, AS03, an alpha-tocopherol-containing squalene-based oil-in-water emulsion, and CpG 1018 (with Alum), a Toll-like receptor 9 agonist formulated in Alum, were the most promising adjuvants.
The team concluded that the neutralizing antibody response by the RBD-NP/AS03 vaccination was durable. The study results can also help in the development of subunit vaccines to combat the ongoing pandemic.
Results from MultiScan LFER PET/CT
The researchers in University of Pittsburgh School of Medicine evaluated inflammation in the lung tissues with no adjuvant, AS03 and CpG-Alum on pre and post challenge days using MultiScan LFER PET/CT
- Vaccinated animals showed FDG uptake, to a much lesser extent than the control animals (Fig. 3e and f)
Fig 3 e, Inflammation in the lungs of two animals from each group indicated in the legend, pre-challenge (day 0) and post-challenge (day 4 or 5 after infection), measured using PET-CT scans. f, Representative PET-CT images of lungs from one animal in each group. PET signal is scaled 0 to 15 SUV.
Comparison of SARS-CoV-2 infection in two non-human primate species: rhesus and cynomolgus macaques
Kinga P. Boszormenyi1, Marieke A. Stammes2, Zahra C. Fagrouch1, Gwendoline Kiemenyi-Kayere1, Henk Niphuis1, Daniella Mortier1, Nikki van Driel3, Ivonne Nieuwenhuis2, Ella Zuiderwijk-Sick4, Lisette Meijer2, Petra Mooij1, Ed J. Remarque1, Gerrit Koopman1, Alexis C. R. Hoste5, Patricia Sastre5, Bart L. Haagmans6, Ronald E. Bontrop7,8, Jan A.M. Langermans3,9, Willy M. Bogers1, Ernst J. Verschoor1, and Babs E. Verstrepen1
1Department of Virology, Biomedical Primate Research Centre (BPRC), Rijswijk, The Netherlands
2Department of Parasitology, BPRC, Rijswijk, The Netherlands
3Animal Science Department, BPRC, Rijswijk, The Netherlands
4Alternatives unit, BPRC, Rijswijk, The Netherlands
5Eurofins-Inmunologia y Genetica Aplicada (Eurofins-INGENASA), Madrid, Spain
6Department of Viroscience, Erasmus University Medical Center, Rotterdam, The Netherlands
7Department of Comparative Genetics and Refinement, BPRC, Rijswijk, The Netherlands
8Department of Biology, Theoretical Biology and Bioinformatics, Utrecht University, Utrecht, The Netherlands
9Department of Population Health Sciences, Unit Animals in Science and Society, Veterinary Faculty, Utrecht University, Utrecht, The Netherlands
https://doi.org/10.1101/2020.11.05.369413
Summary
SARS-CoV-2 is a coronavirus that sparked the current COVID-19 pandemic. To stop it, effective and safe vaccines, and antiviral therapies are urgently required. To facilitate the preclinical evaluation of intervention approaches, relevant animal models need to be developed and validated. Rhesus macaques (Macaca mulatta) and cynomolgus macaques (Macaca fascicularis) are widely used in biomedical research and serve as models for SARS-CoV-2 infection, but this is the first controlled comparative study investigating which species of them is best suited to examine specific aspects of COVID-19. This study analysed replication and symptoms for three weeks after infection. Pulmonary lesions were detected on CT images acquired with MultiScan LFER PET/CT. Elevated body temperature and decreased in physical activity was also observed. Results show that both rhesus and cynomolgus macaques represent valid models for COVID-19 prophylactic and therapeutic treatments.
Results from MultiScan LFER PET/CT
CT imaging provides a valuable tool to specifically monitor the progression of COVID-19-related lung pathology during the entire course of the study. Respiratory-gated CT scans were performed on Day0, 2, 4, 6, 8, 10, 12, 14, 16, 22 post-infection to monitor lung pathology. A semi-quantitative scoring system for chest CT evaluation was used to estimate SARS-CoV-2-induced lung disease; maximum score of 35 could be reached per timepoint.
Scans revealed that:
- All macaques show levels of pneumonia
- Detected different types of lesions: A) ground glass opacities, B) consolidations, and C) crazy paving patterns (Figure 1)
- Around days 8 and 10 pi., lesions were manifest in all animals, and in several macaques the coverage had increased
- Cumulative CT scores increased and no difference was observed between rhesus and cynomolgus macaques
Further results showed:
- Both groups of animals, the body temperature was significantly higher during the first two weeks after infection
- Significantly lower activity in all four rhesus macaques during the first period after infection, while this difference in cynomolgus macaques was less obvious
- Antibody response became evident between day 10 and 12 pi., IgG level continued to rise for several days (development of IgM titers was barely detected)
- Certain cytokines increased in the plasma of both macaque species
Southwest National Primate Research Center in Texas Biomedical Research, San Antonio has purchased Mediso’s multiscan LFER PET/CT scanner in early 2020. Mediso USA proudly post that Professor Deepak Kaushal and his co-workers used multiscan LFER PET/CT in their recently reported comprehensive work about the course of SARS-CoV-2 infection in nonhuman primate models.
multiscan LFER PET/CT features a 20 cm axial and 15 cm transaxial field of view with a 26 cm bore opening which allows the researcher to scan non-human primates (NHP) with sub-mm PET and even 150 um CT resolution.
preliminary report title: SARS-CoV-2 infection leads to acute infection with dynamic cellular and inflammatory flux in the lung that varies across nonhuman primate species June 5, 2020. https://doi.org/10.1101/2020.06.05.136481
Summary
The authors compare SARS-CoV-2 infection in three species of experimentally infected NHPs (rhesus macaques, baboons, and marmosets). They used a wide variety of methods to describe the course of disease such as clinical parameters of viral infection, viral RNA and viral protein detection, immune response, X-ray, CXR scoring, CT scanning and pathology.
Their results show all NHPs can be infected with SARS-CoV-2 but exhibit differential progression to COVID-19. Baboons exhibit moderate to severe pathology, macaques exhibit moderate pathology and marmosets exhibit mild pathology. They also summarize that rhesus macaques and baboons develop different, quantifiable disease attributes making them immediately available essential models to test new vaccines and therapies.
Results from multiscan LFER PET/CT
The report shows the importance of state-of-the-art, non-invasive imaging – cone beam CT scanning, and the application of innovative algorithms to identify the extent of lung involvement in pneumonia in developing models of COVID-19. CT image analysis provided a quantifiable metric data which enables testing efficacy of vaccines or the impact of therapeutic intervention. Lung hyperdensity and the CT abnormality score was used as a metric parameter to follow the onset of the disease.
- Each NHP species was infected and followed over a 3-day period to describe the early signs of infection. Cone-beam CT scans showed evidence of moderate pneumonia, which progressed over 3 days (Figure 1). CT images were analyzed using the segmentation tool in VivoQuant (Invicro, Boston,MA). Lung hyperdensity and the CT abnormality score were used as a metric parameter to follow the course of the disease.
Figure 1. a) 3D Reconstruction of ROI volume representing the location of the lesion. b-d) represent images for quantification of the lung lesion with the green area representing normal intensity lung voxels (-850 HU to -500 HU), while red areas represent hyperdense voxels (-490 HU to 500 HU). (Image courtesy of Dr. Deepak Kaushal, Texas Biomedical Research)
- They also performed detailed imaging of macaques in a 12-day longitudinal study. Similar to the acute study. imaging revealed a significant, progressive increase in the volume of lung involved in pneumonia at 6 dpi, which normalized by 12 dpi.
- These results suggest that pneumonia in some older macaques may persist longer than in younger animals. Although there were several smaller changes observed in older animals, old and young animals both resolved the infection.
