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A Multivalent Vaccine Based on Ferritin Nanocage Elicits Potent Protective Immune Responses against SARS-CoV-2 Mutations.

ABSTRACT: The SARS-CoV-2 pandemic has created a global public crisis and heavily affected personal lives, healthcare systems, and global economies. Virus variants are continuously emerging, and, thus, the pandemic has been ongoing for over two years. Vaccines were rapidly developed based on the original SARS-CoV-2 (Wuhan-Hu-1) to build immunity against the coronavirus disease. However, they had a very low effect on the virus' variants due to their low cross-reactivity. In this study, a multivalent SARS-CoV-2 vaccine was developed using ferritin nanocages, which display the spike protein from the Wuhan-Hu-1, B.1.351, or B.1.429 SARS-CoV-2 on their surfaces. We show that the mixture of three SARS-CoV-2 spike-protein-displaying nanocages elicits CD4⁺ and CD8⁺ T cells and B-cell immunity successfully in vivo. Furthermore, they generate a more consistent antibody response against the B.1.351 and B.1.429 variants than a monovalent vaccine. This leads us to believe that the proposed ferritin-nanocage-based multivalent vaccine platform will provide strong protection against emerging SARS-CoV-2 variants of concern (VOCs).

SUBMITTER: Kim SA

PROVIDER: S-EPMC9181758 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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A Multivalent Vaccine Based on Ferritin Nanocage Elicits Potent Protective Immune Responses against SARS-CoV-2 Mutations.

Kim Seong A SA Kim Seohyun S Kim Gi Beom GB Goo Jiyoung J Kim Nayeon N Lee Yeram Y Nam Gi-Hoon GH Lim Seungho S Kim Taeerk T Chang Ki Hwan KH Lee Tae Gyu TG Kim In-San IS Lee Eun Jung EJ

International journal of molecular sciences 20220530 11

The SARS-CoV-2 pandemic has created a global public crisis and heavily affected personal lives, healthcare systems, and global economies. Virus variants are continuously emerging, and, thus, the pandemic has been ongoing for over two years. Vaccines were rapidly developed based on the original SARS-CoV-2 (Wuhan-Hu-1) to build immunity against the coronavirus disease. However, they had a very low effect on the virus' variants due to their low cross-reactivity. In this study, a multivalent SARS-Co ...[more]

PMID: 35682801

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Project description:Since the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) outbreak, several solutions have been proposed to manage the disease. The most viable option for controlling this virus is to produce effective vaccines. Most of the current SARS-CoV-2 vaccines have focused on the infusion spike protein. Spike exists as a trimer and plays a vital role in infecting host cells by binding to the Angiotensin-Converting Enzyme 2 (ACE2) receptor through its Receptor Binding Domain (RBD). Ferritin protein, a naturally occurring iron-storage protein, has gained attention for vaccine production due to its self-assembling property, non-toxic nature, and biocompatibility. Ferritin nanocages have recently been employed in the development of a SARS-CoV-2 vaccination eliciting not only long-term protective memory cells but also a sustained antibody response. In this study, a combination of in silico investigations including molecular docking, molecular dynamics simulations, and immune simulations were carried out to computationally model the monomeric spike protein on the ferritin nanocage as well as to evaluate its stability and interactions for the first time. The structural dynamics of the modeled complex demonstrated noticeable stability. In particular, the Receptor Binding Domain (RBD) and ferritin within the monomeric spike-ferritin complex illustrated significant stability. The lack of alterations in the secondary structure further supported the overall steadiness of the complex. The decline in the distance between ferritin and spike suggests a strong interaction over time. The cross-correlation matrices revealed that the monomeric spike and ferritin move towards each other supporting the stable interaction between spike and ferritin. Further, the orientation of monomeric spike protein within the ferritin unit facilitated the exposure of critical epitopes, specifically upward active Receptor Binding Domain (RBD), enabling effective interactions with the ACE2 receptor. The immune simulations of the model indicated high-level stimulations of both cellular and humoral immunity in the human body. It was also found that the employed model is effective regardless of the mutated spikes in different variants. These findings shed light on the current status of the SARS-CoV-2-ferritin nanoparticle vaccines and could be used as a framework for other similar vaccine designs.

Project description:Current vaccination schedules, including COVID-19 vaccines, require multiple doses to be administered. Single injection vaccines eliciting equivalent immune response are highly desirable. Unfortunately because unconventional release kinetics are difficult to achieve it still remains a huge challenge. Herein a single-injection COVID-19 vaccine was designed using a highly programmable release system based on dynamic layer-by-layer (LBL) films. The antigen, S1 subunit of SARS-CoV-2 spike protein, was loaded in CaCO3 microspheres, which were further coated with tannic acid (TA)/polyethylene glycol (PEG) LBL films. The single-injection vaccine was obtained by mixing the microspheres coated with different thickness of TA/PEG films. Because of the unique constant-rate erosion behavior of the TA/PEG coatings, this system allows for distinct multiple pulsatile release of antigen, closely mimicking the release profile of antigen in conventional multiple dose vaccines. Immunization with the single injection vaccine induces potent and persistent S1-specific humoral and cellular immune responses in mice. The sera from the vaccinated animal exhibit robust in vitro viral neutralization ability. More importantly, the immune response and viral inhibition induced by the single injection vaccine are as strong as that induced by the corresponding multiple dose vaccine, because they share the same antigen release profile. STATEMENT OF SIGNIFICANCE: Vaccines are the most powerful and cost-effective weapons against infectious diseases such as COVID-19. However, current vaccination schedules, including the COVID-19 vaccines, require multiple doses to be administered. Herein a single-injection COVID-19 vaccine is designed using a highly programmable release system. This vaccine releases antigens in a pulsatile manner, closely mimicking the release pattern of antigens in conventional multiple dose vaccines. As a result, one single injection of the new vaccine induces an immune response and viral inhibition similar to that induced by the corresponding multiple-dose vaccine approach.

Project description:IntroductionInfluenza viruses pose a significant threat to global public health. Several influenza pandemic outbreaks have had serious economic and public health implications. Current influenza virus vaccines generally provide strain-specific protection and must be rapidly produced annually to match the circulating viruses. Developing influenza vaccines that confer protection against a broad range of viruses will have a positive impact on public health. In this study, we aimed to develop a ferritin-based influenza nanoparticle vaccine with a broad protective spectrum to enhance the immune response against diverse influenza viruses.ResultsWe generated an adjuvant-free, self-assembling nanoparticle vaccine against diverse influenza A viruses. This nanoparticle vaccine displayed multi-antigen targets on the surface of Helicobacter pylori ferritin, which consists of the ectodomain of hemagglutinin of the H3N2 virus and three tandem highly conserved influenza M1 epitopes fused with the universal helper T-cell epitope PADRE, named HMP-NP. HMP-NPs were expressed in a soluble form in the baculovirus-insect cell system and self-assembled into homogeneous nanoparticles. Animal immunization studies showed that the HMP-NP nanovaccine elicited 4-fold higher haemagglutination inhibition (HAI) titers than inactivated influenza vaccine. And neutralization titers induced by HMP-NPs against the H3N2 virus and heterologous strains of the H1N1 and H9N2 viruses were ~8, 12.4 and 16 times higher than inactivated influenza vaccine, respectively. Meanwhile, we also observed that the number of IFN-γ- and IL-4-secreting cells induced by HMP-NPs were ~2.5 times higher than inactivated influenza vaccine. Importantly, intranasal immunization with HMP-NPs, without any adjuvant, induced efficient mucosal IgA responses and conferred complete protection against the H3N2 virus, as well as partial protection against the H1N1 and H9N2 viruses and significantly reduced lung viral loads.DiscussionOverall, our results indicated that the self-assembled nanovaccines increased the potency and breadth of the immune response against various influenza viruses and are a promising delivery platform for developing vaccines with broader protection against emerging influenza viruses and other pathogens.

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A Multivalent Vaccine Based on Ferritin Nanocage Elicits Potent Protective Immune Responses against SARS-CoV-2 Mutations.

Publications

A Multivalent Vaccine Based on Ferritin Nanocage Elicits Potent Protective Immune Responses against SARS-CoV-2 Mutations.

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