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1.
Adv Sci (Weinh) ; : e2202771, 2022 Oct 31.
Article in English | MEDLINE | ID: covidwho-2094138

ABSTRACT

Despite the success of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccines, there remains a clear need for new classes of preventatives for respiratory viral infections due to vaccine hesitancy, lack of sterilizing immunity, and for at-risk patient populations, including the immunocompromised. While many neutralizing antibodies have been identified, and several approved, to treat COVID-19, systemic delivery, large doses, and high costs have the potential to limit their widespread use, especially in low- and middle-income countries. To use these antibodies more efficiently, an inhalable formulation is developed that allows for the expression of mRNA-encoded, membrane-anchored neutralizing antibodies in the lung to mitigate SARS-CoV-2 infections. First, the ability of mRNA-encoded, membrane-anchored, anti-SARS-CoV-2 antibodies to prevent infections in vitro is demonstrated. Next, it is demonstrated that nebulizer-based delivery of these mRNA-expressed neutralizing antibodies potently abrogates disease in the hamster model. Overall, these results support the use of nebulizer-based mRNA expression of neutralizing antibodies as a new paradigm for mitigating respiratory virus infections.

2.
Nat Commun ; 13(1): 6309, 2022 Oct 23.
Article in English | MEDLINE | ID: covidwho-2087203

ABSTRACT

Coronavirus vaccines that are highly effective against current and anticipated SARS-CoV-2 variants are needed to control COVID-19. We previously reported a receptor-binding domain (RBD)-sortase A-conjugated ferritin nanoparticle (scNP) vaccine that induced neutralizing antibodies against SARS-CoV-2 and pre-emergent sarbecoviruses and protected non-human primates (NHPs) from SARS-CoV-2 WA-1 infection. Here, we find the RBD-scNP induced neutralizing antibodies in NHPs against pseudoviruses of SARS-CoV and SARS-CoV-2 variants including 614G, Beta, Delta, Omicron BA.1, BA.2, BA.2.12.1, and BA.4/BA.5, and a designed variant with escape mutations, PMS20. Adjuvant studies demonstrate variant neutralization titers are highest with 3M-052-aqueous formulation (AF). Immunization twice with RBD-scNPs protect NHPs from SARS-CoV-2 WA-1, Beta, and Delta variant challenge, and protect mice from challenges of SARS-CoV-2 Beta variant and two other heterologous sarbecoviruses. These results demonstrate the ability of RBD-scNPs to induce broad neutralization of SARS-CoV-2 variants and to protect animals from multiple different SARS-related viruses. Such a vaccine could provide broad immunity to SARS-CoV-2 variants.


Subject(s)
COVID-19 , Nanoparticles , SARS Virus , Viral Vaccines , Mice , Animals , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus , Antibodies, Viral , Mice, Inbred BALB C , COVID-19/prevention & control , Antibodies, Neutralizing/chemistry , Ferritins
3.
Sci Immunol ; 7(76): eadd5446, 2022 10 28.
Article in English | MEDLINE | ID: covidwho-1992933

ABSTRACT

SARS-CoV-2 Omicron subvariants have generated a worldwide health crisis due to resistance to most approved SARS-CoV-2 neutralizing antibodies and evasion of vaccination-induced antibodies. To manage Omicron subvariants and prepare for new ones, additional means of isolating broad and potent humanized SARS-CoV-2 neutralizing antibodies are desirable. Here, we describe a mouse model in which the primary B cell receptor (BCR) repertoire is generated solely through V(D)J recombination of a human VH1-2 heavy chain (HC) and, substantially, a human Vκ1-33 light chain (LC). Thus, primary humanized BCR repertoire diversity in these mice derives from immensely diverse HC and LC antigen-contact CDR3 sequences generated by nontemplated junctional modifications during V(D)J recombination. Immunizing this mouse model with SARS-CoV-2 (Wuhan-Hu-1) spike protein immunogens elicited several VH1-2/Vκ1-33-based neutralizing antibodies that bound RBD in a different mode from each other and from those of many prior patient-derived VH1-2-based neutralizing antibodies. Of these, SP1-77 potently and broadly neutralized all SARS-CoV-2 variants through BA.5. Cryo-EM studies revealed that SP1-77 bound RBD away from the receptor-binding motif via a CDR3-dominated recognition mode. Lattice light-sheet microscopy-based studies showed that SP1-77 did not block ACE2-mediated viral attachment or endocytosis but rather blocked viral-host membrane fusion. The broad and potent SP1-77 neutralization activity and nontraditional mechanism of action suggest that it might have therapeutic potential. Likewise, the SP1-77 binding epitope may inform vaccine strategies. Last, the type of humanized mouse models that we have described may contribute to identifying therapeutic antibodies against future SARS-CoV-2 variants and other pathogens.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Mice , Animals , Spike Glycoprotein, Coronavirus/genetics , Angiotensin-Converting Enzyme 2 , Membrane Fusion , Antibodies, Viral , Antibodies, Neutralizing , Epitopes , Receptors, Antigen, B-Cell
4.
Cell Rep ; 39(13): 111009, 2022 06 28.
Article in English | MEDLINE | ID: covidwho-1944463

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron BA.2 sub-lineage has gained in proportion relative to BA.1. Because spike (S) protein variations may underlie differences in their pathobiology, here we determine cryoelectron microscopy (cryo-EM) structures of the BA.2 S ectodomain and compare these with previously determined BA.1 S structures. BA.2 receptor-binding domain (RBD) mutations induce remodeling of the RBD structure, resulting in tighter packing and improved thermostability. Interprotomer RBD interactions are enhanced in the closed (or 3-RBD-down) BA.2 S, while the fusion peptide is less accessible to antibodies than in BA.1. Binding and pseudovirus neutralization assays reveal extensive immune evasion while defining epitopes of two outer RBD face-binding antibodies, DH1044 and DH1193, that neutralize both BA.1 and BA.2. Taken together, our results indicate that stabilization of the closed state through interprotomer RBD-RBD packing is a hallmark of the Omicron variant and show differences in key functional regions in the BA.1 and BA.2 S proteins.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Viral , Cryoelectron Microscopy , Humans , Receptors, Virus/metabolism , Spike Glycoprotein, Coronavirus
5.
Mol Cell ; 82(11): 2050-2068.e6, 2022 06 02.
Article in English | MEDLINE | ID: covidwho-1937002

ABSTRACT

Aided by extensive spike protein mutation, the SARS-CoV-2 Omicron variant overtook the previously dominant Delta variant. Spike conformation plays an essential role in SARS-CoV-2 evolution via changes in receptor-binding domain (RBD) and neutralizing antibody epitope presentation, affecting virus transmissibility and immune evasion. Here, we determine cryo-EM structures of the Omicron and Delta spikes to understand the conformational impacts of mutations in each. The Omicron spike structure revealed an unusually tightly packed RBD organization with long range impacts that were not observed in the Delta spike. Binding and crystallography revealed increased flexibility at the functionally critical fusion peptide site in the Omicron spike. These results reveal a highly evolved Omicron spike architecture with possible impacts on its high levels of immune evasion and transmissibility.


Subject(s)
COVID-19 , SARS-CoV-2 , Angiotensin-Converting Enzyme 2 , Humans , Mutation , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/chemistry
6.
Cell Rep ; 38(11): 110514, 2022 03 15.
Article in English | MEDLINE | ID: covidwho-1739598

ABSTRACT

The success of nucleoside-modified mRNAs in lipid nanoparticles (mRNA-LNP) as COVID-19 vaccines heralded a new era of vaccine development. For HIV-1, multivalent envelope (Env) trimer protein nanoparticles are superior immunogens compared with trimers alone for priming of broadly neutralizing antibody (bnAb) B cell lineages. The successful expression of complex multivalent nanoparticle immunogens with mRNAs has not been demonstrated. Here, we show that mRNAs can encode antigenic Env trimers on ferritin nanoparticles that initiate bnAb precursor B cell expansion and induce serum autologous tier 2 neutralizing activity in bnAb precursor VH + VL knock-in mice. Next-generation sequencing demonstrates acquisition of critical mutations, and monoclonal antibodies that neutralize heterologous HIV-1 isolates are isolated. Thus, mRNA-LNP can encode complex immunogens and may be of use in design of germline-targeting and sequential boosting immunogens for HIV-1 vaccine development.


Subject(s)
AIDS Vaccines , COVID-19 , HIV-1 , Nanoparticles , Animals , Antibodies, Monoclonal , Antibodies, Neutralizing , COVID-19 Vaccines , Epitopes , Ferritins/genetics , HIV Antibodies , Humans , Liposomes , Mice , RNA, Messenger , env Gene Products, Human Immunodeficiency Virus/genetics
7.
Transl Res ; 242: 38-55, 2022 04.
Article in English | MEDLINE | ID: covidwho-1550105

ABSTRACT

The remarkable success of SARS CoV-2 mRNA-based vaccines and the ensuing interest in mRNA vaccines and therapeutics have highlighted the need for a scalable clinical-enabling manufacturing process to produce such products, and robust analytical methods to demonstrate safety, potency, and purity. To date, production processes have either not been disclosed or are bench-scale in nature and cannot be readily adapted to clinical and commercial scale production. To address these needs, we have advanced an aqueous-based scalable process that is readily adaptable to GMP-compliant manufacturing, and developed the required analytical methods for product characterization, quality control release, and stability testing. We also have demonstrated the products produced at manufacturing scale under such approaches display good potency and protection in relevant animal models with mRNA products encoding both vaccine immunogens and antibodies. Finally, we discuss continued challenges in raw material identification, sourcing and supply, and the cold chain requirements for mRNA therapeutic and vaccine products. While ultimate solutions have yet to be elucidated, we discuss approaches that can be taken that are aligned with regulatory guidance.


Subject(s)
COVID-19 , Vaccines , Animals , COVID-19/prevention & control , Humans , RNA, Messenger/genetics , SARS-CoV-2/genetics
8.
NPJ Vaccines ; 6(1): 50, 2021 Apr 09.
Article in English | MEDLINE | ID: covidwho-1387358

ABSTRACT

The development of an effective AIDS vaccine remains a challenge. Nucleoside-modified mRNAs formulated in lipid nanoparticles (mRNA-LNP) have proved to be a potent mode of immunization against infectious diseases in preclinical studies, and are being tested for SARS-CoV-2 in humans. A critical question is how mRNA-LNP vaccine immunogenicity compares to that of traditional adjuvanted protein vaccines in primates. Here, we show that mRNA-LNP immunization compared to protein immunization elicits either the same or superior magnitude and breadth of HIV-1 Env-specific polyfunctional antibodies. Immunization with mRNA-LNP encoding Zika premembrane and envelope or HIV-1 Env gp160 induces durable neutralizing antibodies for at least 41 weeks. Doses of mRNA-LNP as low as 5 µg are immunogenic in macaques. Thus, mRNA-LNP can be used to rapidly generate single or multi-component vaccines, such as sequential vaccines needed to protect against HIV-1 infection. Such vaccines would be as or more immunogenic than adjuvanted recombinant protein vaccines in primates.

9.
Annu Rev Med ; 73: 1-16, 2022 01 27.
Article in English | MEDLINE | ID: covidwho-1371910

ABSTRACT

Prophylactic and therapeutic drugs are urgently needed to combat coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Over the past year, SARS-CoV-2 neutralizing antibodies have been developed for preventive or therapeutic uses. While neutralizing antibodies target the spike protein, their neutralization potency and breadth vary according to recognition epitopes. Several potent SARS-CoV-2 antibodies have shown degrees of success in preclinical or clinical trials, and the US Food and Drug Administration has issued emergency use authorization for two neutralizing antibody cocktails.Nevertheless, antibody therapy for SARS-CoV-2 still faces potential challenges, including emerging viral variants of concern that have antibody-escape mutations and the potential for antibody-mediated enhancement of infection or inflammation. This review summarizes representative SARS-CoV-2 neutralizing antibodies that have been reported and discusses prospects and challenges for the development of the next generation of COVID-19 preventive or therapeutic antibodies.


Subject(s)
COVID-19 , Antibodies, Monoclonal/therapeutic use , Antibodies, Neutralizing , Humans , SARS-CoV-2 , Spike Glycoprotein, Coronavirus
10.
Science ; 373(6558): 991-998, 2021 08 27.
Article in English | MEDLINE | ID: covidwho-1295160

ABSTRACT

The emergence of severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003 and SARS-CoV-2 in 2019 highlights the need to develop universal vaccination strategies against the broader Sarbecovirus subgenus. Using chimeric spike designs, we demonstrate protection against challenge from SARS-CoV, SARS-CoV-2, SARS-CoV-2 B.1.351, bat CoV (Bt-CoV) RsSHC014, and a heterologous Bt-CoV WIV-1 in vulnerable aged mice. Chimeric spike messenger RNAs (mRNAs) induced high levels of broadly protective neutralizing antibodies against high-risk Sarbecoviruses. By contrast, SARS-CoV-2 mRNA vaccination not only showed a marked reduction in neutralizing titers against heterologous Sarbecoviruses, but SARS-CoV and WIV-1 challenge in mice resulted in breakthrough infections. Chimeric spike mRNA vaccines efficiently neutralized D614G, mink cluster five, and the UK B.1.1.7 and South African B.1.351 variants of concern. Thus, multiplexed-chimeric spikes can prevent SARS-like zoonotic coronavirus infections with pandemic potential.


Subject(s)
Betacoronavirus/immunology , COVID-19 Vaccines/immunology , Coronavirus Infections/prevention & control , Spike Glycoprotein, Coronavirus/immunology , Vaccines, Synthetic/immunology , Viral Vaccines/immunology , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Betacoronavirus/physiology , COVID-19/prevention & control , Coronavirus Infections/immunology , Cross Protection , Cytokines/blood , Female , Immunity, Heterologous , Immunogenicity, Vaccine , Liposomes , Lung/pathology , Lung/virology , Mice , Mice, Inbred BALB C , Nanoparticles , Protein Domains , Recombinant Fusion Proteins , SARS Virus/immunology , SARS Virus/physiology , SARS-CoV-2/immunology , SARS-CoV-2/physiology , Severe Acute Respiratory Syndrome/prevention & control , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Virus Replication
11.
Science ; 373(6555)2021 08 06.
Article in English | MEDLINE | ID: covidwho-1282050

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with multiple spike mutations enable increased transmission and antibody resistance. We combined cryo-electron microscopy (cryo-EM), binding, and computational analyses to study variant spikes, including one that was involved in transmission between minks and humans, and others that originated and spread in human populations. All variants showed increased angiotensin-converting enzyme 2 (ACE2) receptor binding and increased propensity for receptor binding domain (RBD)-up states. While adaptation to mink resulted in spike destabilization, the B.1.1.7 (UK) spike balanced stabilizing and destabilizing mutations. A local destabilizing effect of the RBD E484K mutation was implicated in resistance of the B.1.1.28/P.1 (Brazil) and B.1.351 (South Africa) variants to neutralizing antibodies. Our studies revealed allosteric effects of mutations and mechanistic differences that drive either interspecies transmission or escape from antibody neutralization.


Subject(s)
SARS-CoV-2/chemistry , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Amino Acid Substitution , Angiotensin-Converting Enzyme 2/metabolism , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Antigens, Viral/immunology , COVID-19/transmission , COVID-19/veterinary , COVID-19/virology , Cryoelectron Microscopy , Host Adaptation , Humans , Immune Evasion , Mink/virology , Models, Molecular , Mutation , Protein Binding , Protein Conformation , Protein Interaction Domains and Motifs , Protein Structure, Quaternary , Protein Subunits/chemistry , Receptors, Coronavirus/metabolism , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism
12.
Cell ; 184(11): 2955-2972.e25, 2021 05 27.
Article in English | MEDLINE | ID: covidwho-1237636

ABSTRACT

Natural antibodies (Abs) can target host glycans on the surface of pathogens. We studied the evolution of glycan-reactive B cells of rhesus macaques and humans using glycosylated HIV-1 envelope (Env) as a model antigen. 2G12 is a broadly neutralizing Ab (bnAb) that targets a conserved glycan patch on Env of geographically diverse HIV-1 strains using a unique heavy-chain (VH) domain-swapped architecture that results in fragment antigen-binding (Fab) dimerization. Here, we describe HIV-1 Env Fab-dimerized glycan (FDG)-reactive bnAbs without VH-swapped domains from simian-human immunodeficiency virus (SHIV)-infected macaques. FDG Abs also recognized cell-surface glycans on diverse pathogens, including yeast and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike. FDG precursors were expanded by glycan-bearing immunogens in macaques and were abundant in HIV-1-naive humans. Moreover, FDG precursors were predominately mutated IgM+IgD+CD27+, thus suggesting that they originated from a pool of antigen-experienced IgM+ or marginal zone B cells.


Subject(s)
Antibodies, Neutralizing/immunology , HIV-1/immunology , Immunoglobulin Fab Fragments/immunology , Polysaccharides/immunology , SARS-CoV-2/immunology , Simian Immunodeficiency Virus/immunology , Spike Glycoprotein, Coronavirus/immunology , env Gene Products, Human Immunodeficiency Virus/immunology , Animals , B-Lymphocytes/immunology , Broadly Neutralizing Antibodies/immunology , COVID-19/immunology , Dimerization , Epitopes/immunology , Glycosylation , HIV Antibodies/immunology , HIV Infections/immunology , Humans , Immunoglobulin Fab Fragments/chemistry , Macaca mulatta , Polysaccharides/chemistry , Receptors, Antigen, B-Cell/chemistry , Simian Immunodeficiency Virus/genetics , Vaccines/immunology , env Gene Products, Human Immunodeficiency Virus/chemistry , env Gene Products, Human Immunodeficiency Virus/genetics
13.
Nature ; 594(7864): 553-559, 2021 06.
Article in English | MEDLINE | ID: covidwho-1221200

ABSTRACT

Betacoronaviruses caused the outbreaks of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome, as well as the current pandemic of SARS coronavirus 2 (SARS-CoV-2)1-4. Vaccines that elicit protective immunity against SARS-CoV-2 and betacoronaviruses that circulate in animals have the potential to prevent future pandemics. Here we show that the immunization of macaques with nanoparticles conjugated with the receptor-binding domain of SARS-CoV-2, and adjuvanted with 3M-052 and alum, elicits cross-neutralizing antibody responses against bat coronaviruses, SARS-CoV and SARS-CoV-2 (including the B.1.1.7, P.1 and B.1.351 variants). Vaccination of macaques with these nanoparticles resulted in a 50% inhibitory reciprocal serum dilution (ID50) neutralization titre of 47,216 (geometric mean) for SARS-CoV-2, as well as in protection against SARS-CoV-2 in the upper and lower respiratory tracts. Nucleoside-modified mRNAs that encode a stabilized transmembrane spike or monomeric receptor-binding domain also induced cross-neutralizing antibody responses against SARS-CoV and bat coronaviruses, albeit at lower titres than achieved with the nanoparticles. These results demonstrate that current mRNA-based vaccines may provide some protection from future outbreaks of zoonotic betacoronaviruses, and provide a multimeric protein platform for the further development of vaccines against multiple (or all) betacoronaviruses.


Subject(s)
Antibodies, Neutralizing/immunology , Betacoronavirus/immunology , COVID-19/immunology , COVID-19/prevention & control , Common Cold/prevention & control , Cross Reactions/immunology , Pandemics , Viral Vaccines/immunology , Adjuvants, Immunologic , Administration, Intranasal , Animals , COVID-19/epidemiology , COVID-19 Vaccines/immunology , Common Cold/immunology , Common Cold/virology , Disease Models, Animal , Female , Humans , Macaca/immunology , Male , Models, Molecular , Nanoparticles/chemistry , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Trachea , Vaccination
14.
Sci Transl Med ; 13(583)2021 03 03.
Article in English | MEDLINE | ID: covidwho-1117652

ABSTRACT

Seasonal influenza vaccines confer protection against specific viral strains but have restricted breadth that limits their protective efficacy. The H1 and H3 subtypes of influenza A virus cause most of the seasonal epidemics observed in humans and are the major drivers of influenza A virus-associated mortality. The consequences of pandemic spread of COVID-19 underscore the public health importance of prospective vaccine development. Here, we show that headless hemagglutinin (HA) stabilized-stem immunogens presented on ferritin nanoparticles elicit broadly neutralizing antibody (bnAb) responses to diverse H1 and H3 viruses in nonhuman primates (NHPs) when delivered with a squalene-based oil-in-water emulsion adjuvant, AF03. The neutralization potency and breadth of antibodies isolated from NHPs were comparable to human bnAbs and extended to mismatched heterosubtypic influenza viruses. Although NHPs lack the immunoglobulin germline VH1-69 residues associated with the most prevalent human stem-directed bnAbs, other gene families compensated to generate bnAbs. Isolation and structural analyses of vaccine-induced bnAbs revealed extensive interaction with the fusion peptide on the HA stem, which is essential for viral entry. Antibodies elicited by these headless HA stabilized-stem vaccines neutralized diverse H1 and H3 influenza viruses and shared a mode of recognition analogous to human bnAbs, suggesting that these vaccines have the potential to confer broadly protective immunity against diverse viruses responsible for seasonal and pandemic influenza infections in humans.


Subject(s)
Hemagglutinin Glycoproteins, Influenza Virus/immunology , Influenza Vaccines/immunology , Primates/immunology , Animals , Antibodies, Viral/biosynthesis , Antibodies, Viral/chemistry , Antigen-Antibody Complex/chemistry , Broadly Neutralizing Antibodies/biosynthesis , Broadly Neutralizing Antibodies/chemistry , COVID-19 , Ferritins/chemistry , Ferritins/immunology , Hemagglutinin Glycoproteins, Influenza Virus/chemistry , Hemagglutinin Glycoproteins, Influenza Virus/genetics , Humans , Influenza Vaccines/administration & dosage , Influenza Vaccines/chemistry , Influenza, Human/immunology , Influenza, Human/virology , Macaca fascicularis , Models, Molecular , Nanoparticles/chemistry , Pandemics , Primates/virology , Protein Structure, Quaternary , SARS-CoV-2
15.
Nat Struct Mol Biol ; 28(2): 128-131, 2021 02.
Article in English | MEDLINE | ID: covidwho-1010060

ABSTRACT

The SARS-CoV-2 spike (S) protein, a primary target for COVID-19 vaccine development, presents its receptor binding domain in two conformations, the receptor-accessible 'up' or receptor-inaccessible 'down' states. Here we report that the commonly used stabilized S ectodomain construct '2P' is sensitive to cold temperatures, and this cold sensitivity is abrogated in a 'down' state-stabilized ectodomain. Our findings will impact structural, functional and vaccine studies that use the SARS-CoV-2 S ectodomain.


Subject(s)
Spike Glycoprotein, Coronavirus/chemistry , Antibodies, Viral/chemistry , COVID-19 Vaccines/chemistry , Cold Temperature , Cryoelectron Microscopy , Enzyme-Linked Immunosorbent Assay , Humans , Protein Denaturation , Protein Domains , Protein Stability , Spike Glycoprotein, Coronavirus/ultrastructure , Surface Plasmon Resonance
16.
Immunity ; 53(4): 724-732.e7, 2020 10 13.
Article in English | MEDLINE | ID: covidwho-710374

ABSTRACT

SARS-CoV-2 infection has emerged as a serious global pandemic. Because of the high transmissibility of the virus and the high rate of morbidity and mortality associated with COVID-19, developing effective and safe vaccines is a top research priority. Here, we provide a detailed evaluation of the immunogenicity of lipid nanoparticle-encapsulated, nucleoside-modified mRNA (mRNA-LNP) vaccines encoding the full-length SARS-CoV-2 spike protein or the spike receptor binding domain in mice. We demonstrate that a single dose of these vaccines induces strong type 1 CD4+ and CD8+ T cell responses, as well as long-lived plasma and memory B cell responses. Additionally, we detect robust and sustained neutralizing antibody responses and the antibodies elicited by nucleoside-modified mRNA vaccines do not show antibody-dependent enhancement of infection in vitro. Our findings suggest that the nucleoside-modified mRNA-LNP vaccine platform can induce robust immune responses and is a promising candidate to combat COVID-19.


Subject(s)
Antibodies, Neutralizing/biosynthesis , Antibodies, Viral/biosynthesis , Betacoronavirus/drug effects , Coronavirus Infections/prevention & control , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , RNA, Messenger/immunology , RNA, Viral/immunology , Viral Vaccines/administration & dosage , Animals , B-Lymphocytes/drug effects , B-Lymphocytes/immunology , B-Lymphocytes/virology , Betacoronavirus/immunology , Betacoronavirus/pathogenicity , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/virology , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/virology , COVID-19 , COVID-19 Vaccines , Coronavirus Infections/genetics , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Disease Models, Animal , Furin/genetics , Furin/immunology , Humans , Immunity, Humoral/drug effects , Immunization/methods , Immunogenicity, Vaccine , Immunologic Memory/drug effects , Lymphocyte Activation/drug effects , Mice , Mice, Inbred BALB C , Nanoparticles/administration & dosage , Nanoparticles/chemistry , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , RNA, Messenger/genetics , RNA, Viral/genetics , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Vaccines, Synthetic , Viral Vaccines/biosynthesis , Viral Vaccines/genetics
17.
Cell ; 181(7): 1458-1463, 2020 06 25.
Article in English | MEDLINE | ID: covidwho-382065

ABSTRACT

The SARS-CoV-2 pandemic that causes COVID-19 respiratory syndrome has caused global public health and economic crises, necessitating rapid development of vaccines and therapeutic countermeasures. The world-wide response to the COVID-19 pandemic has been unprecedented with government, academic, and private partnerships working together to rapidly develop vaccine and antibody countermeasures. Many of the technologies being used are derived from prior government-academic partnerships for response to other emerging infections.


Subject(s)
Coronavirus Infections/drug therapy , Coronavirus Infections/prevention & control , Pandemics/prevention & control , Pneumonia, Viral/drug therapy , Pneumonia, Viral/prevention & control , Viral Vaccines/immunology , AIDS Vaccines/immunology , Animals , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/chemistry , Antibodies, Neutralizing/immunology , Antibodies, Viral/chemistry , Antibodies, Viral/immunology , Betacoronavirus/physiology , COVID-19 , COVID-19 Vaccines , Coronavirus Infections/immunology , Humans , Intersectoral Collaboration , Pneumonia, Viral/immunology , SARS-CoV-2 , Viral Vaccines/chemistry
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