A candidate vaccine based on ferritin nanoparticles for COVID
More than 6 million people have died worldwide as a result of the coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). About 64% of the world’s population has received at least one dose of a COVID-19 vaccine despite the availability of approved vaccines and emergency use authorization (EUA). In the United States, where approximately 64.7% of people are fully immunized and 76.1% have received at least one dose, the vaccination rate has stagnated due to various factors such as concerns about existing vaccinations and the need more testing in young children.
In order to increase immunity and accessibility to vaccines, second generation vaccines are currently being developed to complement or replace existing vaccination strategies. The use of ferritin nanoparticles is a novel method to augment immune responses against a relevant antigen, such as spike (S) glycoprotein.
The SARS-CoV-2 glycoprotein S is located on the surface of the virus with the main functions of binding to angiotensin-converting enzyme 2 (ACE2) and facilitating entry into host cells. Protein S is used in the vast majority of SARS-CoV-2 vaccines, including licensed products BNT162b (Pfizer-BioNTech) and mRNA-1273 (Moderna), as well as EUA Ad26.COV2.S products (Johnson & Johnson/Janssen) and ChAdOx1nCoV-19 (Johnson & Johnson/Janssen) (AstraZeneca).
Study: A SARS-CoV-2 Spike ferritin nanoparticle vaccine is protective and promotes a strong immune response in the Cynomolgus Macaque coronavirus disease 2019 (COVID-19) model. Image credit: NIAID” class=”rounded-img” data-src=”https://d2jx2rerrg6sh3.cloudfront.net/images/news/ImageForNews_708977_16486131242211431.jpg” data-srcset=”https://d2jx2rerrg6sh3.cloudfront.net/image-handler/ts/20220330120528/ri/2000/src/images/news/ImageForNews_708977_16486131242211431.jpg 2000w, https://d2jx2rerrg6sh3.cloudfront.net/image-handler/ts/20220330120528/ri/1950/src/images/news/ImageForNews_708977_16486131242211431.jpg 1950w, https://d2jx2rerrg6sh3.cloudfront.net/image-handler/ts/20220330120528/ri/1750/src/images/news/ImageForNews_708977_16486131242211431.jpg 1750w, https://d2jx2rerrg6sh3.cloudfront.net/image-handler/ts/20220330120528/ri/1550/src/images/news/ImageForNews_708977_16486131242211431.jpg 1550w, https://d2jx2rerrg6sh3.cloudfront.net/image-handler/ts/20220330120528/ri/1350/src/images/news/ImageForNews_708977_16486131242211431.jpg 1350w, https://d2jx2rerrg6sh3.cloudfront.net/image-handler/ts/20220330120528/ri/1150/src/images/news/ImageForNews_708977_16486131242211431.jpg 1150w, https://d2jx2rerrg6sh3.cloudfront.net/image-handler/ts/20220330120528/ri/950/src/images/news/ImageForNews_708977_16486131242211431.jpg 950w, https://d2jx2rerrg6sh3.cloudfront.net/image-handler/ts/20220330120528/ri/750/src/images/news/ImageForNews_708977_16486131242211431.jpg 750w, https://d2jx2rerrg6sh3.cloudfront.net/image-handler/ts/20220330120528/ri/550/src/images/news/ImageForNews_708977_16486131242211431.jpg 550w, https://d2jx2rerrg6sh3.cloudfront.net/image-handler/ts/20220330120528/ri/450/src/images/news/ImageForNews_708977_16486131242211431.jpg 450w” sizes=”(min-width: 1200px) 673px, (min-width: 1090px) 667px, (min-width: 992px) calc(66.6vw – 60px), (min-width: 480px) calc(100vw – 40px), calc(100vw – 30px)” style=”width: 2000px; height: 1496px;” width=”2000″ height=”1496″/>Study: A SARS-CoV-2 Spike ferritin nanoparticle vaccine is protective and promotes a strong immune response in the Cynomolgus Macaque coronavirus disease 2019 (COVID-19) model. Image credit: NIAID
New SARS-CoV-2 vaccine candidate
In a recent study published on the bioRxiv* Preprint Server, Immunogenicity, and Efficacy of SARS-CoV-2 Advanced Ferritin Nanoparticle (SpFN) Adjuvanted with Aluminum Hydroxide (AlOH3) or Army QS-21 Liposomal Formulation (ALFQ) in a cynomolgus macaque (CM) COVID-19 model was evaluated.
The 24 adult CMs in this survey were tested for previous exposure to SARS-CoV-2 and tested negative using three tests: Euroimmun IgG enzyme immunoassay (ELISA), plaque reduction neutralization test (PRNT) and quantitative real-time PCR (RT-qPCR). The study was divided into two parts: the vaccination phase (VP) and the challenge phase (CP).
Vaccinations occurred on study days -56 and -28 as indicated by the syringes in the diagram. Animals were challenged with SARS-CoV-2 (WA-1) on study day 1 as indicated. Physical examination and blood/sample collection days are indicated by red arrows, and euthanasia days are indicated by black arrows.
During the VP, the animals were randomized into three groups, each with eight animals. They were vaccinated intramuscularly (IM) with 50 µg of SpFN prepared with the adjuvant ALFQ (group 1) or AlOH3 (group 2) on study days -56 and -28. On days -56 and -28 of the study, group 3 received phosphate buffered saline (PBS) to produce the control group. On Study Day 1, the CM received an intratracheal dose of 2.89×107 plaque-forming units (pfu)/4 mL of SARS-CoV-2 and an intranasal dose of 3.62×106 pfu/0.5 mL of SARS -CoV-2 (WA-1). On days -4, 1, 3, 5, 7, 9, 11 and 15 of the study, physical examinations and blood and sampling [bronchoalveolar lavage (BAL) and swab] samples were taken under anesthesia.
Clinical pathology analyzes
The researchers performed clinical chemistries and complete blood counts on whole blood and serum samples. Excluding creatine kinase, which was elevated above baseline for most animals on at least one VP study day, alterations in clinical pathology during VP were mostly unremarkable. Although the cause of the increased creatine kinase is unclear, it was likely caused by inflammation or stress in the muscle tissue after the injections.
The majority of changes in clinical pathology markers during CP were similar to those observed previously and may be related to an inflammatory response indicative of ongoing viral infection. Elevations in one or more leukocyte markers, as well as creatine kinase and/or C-reactive protein, were among the findings. With two exceptions: C-reactive protein and monocytes, all changes found were identical between groups. Control animals showed significantly greater change from baseline than vaccinated animals in both situations.
CMs vaccinated with SpFN show reduced viral replication in the airways
SARS-CoV-2 subgenomic RNA (sgRNA) was measured in BAL and nasopharyngeal (NP) swabs by RT-PCR to determine the effects of vaccination on virus replication in the respiratory tract. On the third day of the survey, mean sgRNA levels in control animals were 104 copies/mL in BAL and NP swabs, 7/8 animals showing substantial viral replication in BAL, and all animals showing replication virus in the nasopharyngeal tract. Control animals had significantly higher peak BAL and NP swab titers than vaccinated animals. In the BAL of 5/8 and 6/8 vaccinated animals in the ALFQ and AlOH3 groups, respectively, the sgRNA was below the limit of detection (LOD). By day 7, all vaccinated animals had undetectable BAL sgRNA, but 5/8 controls had detectable replication in the lungs. By day 9 of the assay, all but one of the control animal’s BAL sgRNAs had been resolved.
RT-qPCR was used to analyze genomic RNA in BAL and NP swab samples. Trends were mostly comparable to those seen with sgRNA. On day 3 of the assay, BAL genomic RNA levels in vaccinated animals were significantly lower than in control animals. Unlike control animals, where viral RNA was still detectable on day 9, viral RNA in BAL was identified for only one animal in each immunization group after day 3. On day 3 of the assay, all animals had detectable viral RNA in NP swabs, with mean values of 9.57, 8.68, and 9.05 Log10 genomic equivalents (ge)/mL for control, ALFQ, and AlOH3 groups, respectively. In comparison to SpFN+ALFQ vaccinated animals, these peak levels were significantly higher in controls.
A strong SARS-CoV-2 specific antibody response is obtained by SpFN vaccination
On samples collected during VP and CP, the total IgG and IgA response to SARS-CoV-2 was analyzed using the Euroimmun ELISA, and the antigen-specific IgG and IgM response was characterized using the Magpix multiplex immunoassay. Two weeks after the first vaccination, an IgG response was identified in the vaccinated animals, with the ALFQ group having a significantly greater reaction than the AlOH3 group. Both groups reported identical IgG levels at all successive time points after the second vaccination on day 28, which enhanced the antibody response seen on day 14.
After viral challenge, there was no anamnestic reaction for total IgG. Magpix analysis of the antigen-specific IgG response in vaccinated animals demonstrated the highest binding to S1 before and after challenge. Moreover, after viral challenge, S1 binding antibodies increased, indicating an anamnestic response to this antigen. The full peak response was significantly smaller than S1 and equivalent in amplitude to the response produced against RBD, although it was observable.
After CMs were exposed to SARS-CoV-2, SpFN+ALFQ and SpFN+AlOH3 were effective in reducing clinical disease. In small animal models and two non-human primate models of SARS-CoV-2, efficacy and significant immunogenicity have already been proven. In rhesus macaques, the spike protein receptor-binding domain alone, adjuvanted with ALFQ, was found to be highly effective. Although SpFN+ALFQ outperformed SpFN+AlOH3 in these assays in terms of immunology, SpFN+AlOH3 also elicited robust responses.
The ability of SpFN to confer protection confirms the need for further investigations to assess the extent and longevity of protection against SARS-CoV-2 variants and related sarbecoviruses, including split vaccine doses, optimization of the vaccination schedule and the additional comparative adjuvant dosage. These data also support the evaluation of SpFN in ongoing clinical trials (clinical trial number: NCT04784767 https://clinicaltrials.gov/ct2/show/NCT04784767).
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be considered conclusive, guide clinical practice/health-related behaviors, or treated as established information.
- Sara C. Johnston, Keersten M. Ricks, Ines Lakhal-Naouar, Alexandra Jay, et al. (2022). A SARS-CoV-2 Spike ferritin nanoparticle vaccine is protective and promotes a strong immune response in the Cynomolgus Macaque coronavirus disease 2019 (COVID-19) model. bioRxivhttps://doi.org/10.1101/2022.03.25.485832,