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1.
Intern Med ; 61(13): 1953-1958, 2022 Jul 01.
Article in English | MEDLINE | ID: covidwho-1993648

ABSTRACT

Objective To investigate the serum total antibody (immunoglobulin M and immunoglobulin G) titre against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein receptor-binding domain following BNT162b2 messenger ribonucleic acid (mRNA) coronavirus disease 2019 (COVID-19) vaccination in Japanese rheumatic disease patients undergoing immunosuppressive therapy. Methods The serum antibody titre against SARS-CoV-2 spike protein was analysed in 123 outpatients with rheumatic diseases at Kagawa University Hospital and 43 healthy volunteers who had received 2 doses of the BNT162b2 mRNA vaccine with at least 14 days elapsing since the second dose. Results The antibody titre in rheumatic disease patients was significantly lower than that in healthy subjects (p<0.0001). The antibody titres of the 41 patients who received biologics or Janus kinase inhibitors and the 47 patients who received conventional immunosuppressive agents were significantly lower than those of the 35 patients who did not receive immunosuppressive agents (p<0.0001 and p<0.0001, respectively). In addition, the mean antibody titre of the 43 patients on methotrexate was significantly lower than that of the 80 patients not on methotrexate (p=0.0017). Conclusion Immunogenicity to the BNT162b2 mRNA COVID-19 vaccine in rheumatic disease patients was found to be reduced under immunosuppressive treatment. In particular, methotrexate seems to be associated with a decreased antibody response.


Subject(s)
BNT162 Vaccine , COVID-19 , Immunogenicity, Vaccine , Rheumatic Diseases , Antibodies, Viral/blood , BNT162 Vaccine/immunology , COVID-19/prevention & control , Humans , Immunosuppression Therapy , Immunosuppressive Agents/therapeutic use , Methotrexate/therapeutic use , Neutralization Tests , Rheumatic Diseases/drug therapy , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/immunology
2.
Proc Natl Acad Sci U S A ; 119(30): e2203659119, 2022 Jul 26.
Article in English | MEDLINE | ID: covidwho-1991766

ABSTRACT

This study analyzed whole blood samples (n = 56) retrieved from 30 patients at 1 to 21 (median 9) mo after verified COVID-19 to determine the polarity and duration of antigen-specific T cell reactivity against severe acute respiratory syndrome coronavirus 2-derived antigens. Multimeric peptides spanning the entire nucleocapsid protein triggered strikingly synchronous formation of interleukin (IL)-4, IL-12, IL-13, and IL-17 ex vivo until ∼70 d after confirmed infection, whereafter this reactivity was no longer inducible. In contrast, levels of nucleocapsid-induced IL-2 and interferon-γ remained stable and highly correlated at 3 to 21 mo after infection. Similar cytokine dynamics were observed in unvaccinated, convalescent patients using whole-blood samples stimulated with peptides spanning the N-terminal portion of the spike 1 protein. These results unravel two phases of T cell reactivity following natural COVID-19: an early, synchronous response indicating transient presence of multipolar, antigen-specific T helper (TH) cells followed by an equally synchronous and durable TH1-like reactivity reflecting long-lasting T cell memory.


Subject(s)
COVID-19 , Cytokines , SARS-CoV-2 , T-Lymphocytes, Helper-Inducer , Antibodies, Viral/blood , Antigens, Viral/immunology , COVID-19/blood , COVID-19/immunology , Convalescence , Cytokines/blood , Humans , Interferon-gamma/blood , Nucleocapsid Proteins/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , T-Lymphocytes, Helper-Inducer/immunology
3.
Euro Surveill ; 27(31)2022 Aug.
Article in English | MEDLINE | ID: covidwho-1987417

ABSTRACT

Functional immunity (defined here as serum neutralising capacity) critically contributes to conferring protection against SARS-CoV-2 infection and severe COVID-19. This cross-sectional analysis of a prospective, population-based cohort study included 1,894 randomly-selected 16 to 99-year-old participants from two Swiss cantons in March 2022. Of these, 97.6% (95% CI: 96.8-98.2%) had anti-spike IgG antibodies, and neutralising capacity was respectively observed for 94%, 92% and 88% against wild-type SARS-CoV-2, Delta and Omicron variants. Studying functional immunity to inform and monitor vaccination campaigns is crucial.


Subject(s)
COVID-19 Vaccines , COVID-19 , SARS-CoV-2 , Adolescent , Adult , Aged , Aged, 80 and over , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/immunology , COVID-19/prevention & control , COVID-19 Vaccines/administration & dosage , Cross-Sectional Studies , Humans , Immunization Programs , Immunization, Secondary , Middle Aged , Prospective Studies , Spike Glycoprotein, Coronavirus/immunology , Switzerland/epidemiology , Young Adult
4.
Allergy ; 77(8): 2431-2445, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1985600

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the ongoing global COVID-19 pandemic. One possibility to control the pandemic is to induce sterilizing immunity through the induction and maintenance of neutralizing antibodies preventing SARS-CoV-2 from entering human cells to replicate in. METHODS: We report the construction and in vitro and in vivo characterization of a SARS-CoV-2 subunit vaccine (PreS-RBD) based on a structurally folded recombinant fusion protein consisting of two SARS-CoV-2 Spike protein receptor-binding domains (RBD) fused to the N- and C-terminus of hepatitis B virus (HBV) surface antigen PreS to enable the two unrelated proteins serving as immunologic carriers for each other. RESULTS: PreS-RBD, but not RBD alone, induced a robust and uniform RBD-specific IgG response in rabbits. Currently available genetic SARS-CoV-2 vaccines induce mainly transient IgG1 responses in vaccinated subjects whereas the PreS-RBD vaccine induced RBD-specific IgG antibodies consisting of an early IgG1 and sustained IgG4 antibody response in a SARS-CoV-2 naive subject. PreS-RBD-specific IgG antibodies were detected in serum and mucosal secretions, reacted with SARS-CoV-2 variants, including the omicron variant of concern and the HBV receptor-binding sites on PreS of currently known HBV genotypes. PreS-RBD-specific antibodies of the immunized subject more potently inhibited the interaction of RBD with its human receptor ACE2 and their virus-neutralizing titers (VNTs) were higher than median VNTs in a random sample of healthy subjects fully immunized with registered SARS-CoV-2 vaccines or in COVID-19 convalescent subjects. CONCLUSION: The PreS-RBD vaccine has the potential to serve as a combination vaccine for inducing sterilizing immunity against SARS-CoV-2 and HBV by stopping viral replication through the inhibition of cellular virus entry.


Subject(s)
COVID-19 Vaccines , COVID-19 , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Animals , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/prevention & control , COVID-19 Vaccines/immunology , Humans , Immunoglobulin G , Pandemics/prevention & control , Rabbits , Spike Glycoprotein, Coronavirus/immunology
5.
Cell Rep ; 36(8): 109591, 2021 08 24.
Article in English | MEDLINE | ID: covidwho-1370154

ABSTRACT

The relationship between B cells and CD4 T cells has been carefully studied, revealing a collaborative effort in which B cells promote the activation, differentiation, and expansion of CD4 T cells while the so-called "helper" cells provide signals to B cells, influencing their class switching and fate. Interactions between B cells and CD8 T cells are not as well studied, although CD8 T cells exhibit an accelerated contraction after certain infections in B-cell-deficient mice. Here, we find that B cells significantly enhance primary CD8 T cell responses after vaccination. Moreover, memory CD8 numbers and function are impaired in B-cell-deficient animals, leading to increased susceptibility to bacterial challenge. We also show that interleukin-27 production by B cells contributes to their impact on primary, but not memory, CD8 responses. Better understanding of the interactions between CD8 T cells and B cells may aid in the design of more effective future vaccine strategies.


Subject(s)
B-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Immunologic Memory , Interleukin-27/immunology , Interleukin-27/metabolism , T-Lymphocytes, Helper-Inducer/immunology , Vaccines, Subunit/immunology , Animals , B-Lymphocytes/metabolism , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , COVID-19/immunology , Humans , Lymphocyte Count , Mice , Mice, Inbred C57BL , Receptors, Virus/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Vaccination
6.
Theranostics ; 12(12): 5522-5536, 2022.
Article in English | MEDLINE | ID: covidwho-1975299

ABSTRACT

Objective: Nobody knows when the COVID-19 pandemic will end or when and where the next coronavirus will outbreak. Therefore, it is still necessary to develop SARS-CoV-2 inhibitors for different variants or even the new coronavirus. Since SARS-CoV-2 uses its surface spike-protein to recognize hACE2, mediating its entry into cells, ligands that can specifically recognize the spike-protein have the potential to prevent infection. Methods: We have recently discovered DNA aptamers against the S2-domain of the WT spike-protein by exploiting the selection process called SELEX. After optimization, among all candidates, the aptamer S2A2C1 has the shortest sequence and the best binding affinity toward the S2-protein. More importantly, the S2A2C1 aptamer does not bind to the RBD of the spike-protein, but it efficiently blocks the spike-protein/hACE2 interaction, suggesting an RBD-independent inhibition approach. To further improve its performance, we conjugated the S2A2C1 aptamer with a reported anti-RBD aptamer, S1B6C3, using various linkers and constructed hetero-bivalent fusion aptamers. Binding affinities of mono and fusion aptamers against the spike-proteins were measured. The inhibition efficacies of mono and fusion aptamers to prevent the hACE2/spike-protein interaction were determined using ELISA. Results: Anti-spike-protein aptamers, including S2A2C1 and S1B6C3-A5-S2A2C1, maintained high binding affinity toward the WT, Delta, and Omicron spike-proteins and high inhibition efficacies to prevent them from binding to hACE2, rendering them well-suited as diagnostic and therapeutic molecular tools to target SARS-CoV-2 and its variants. Conclusions: Overall, we discovered the anti-S2 aptamer, S2A2C1, which inhibits the hACE2/spike-protein interaction via an RBD-independent approach. The anti-S2 and anti-RBD aptamers were conjugated to obtain the fusion aptamer, S1B6C3-A5-S2A2C1, which recognizes the spike-protein by an RBD-dependent approach. Our strategies, which discovered aptamer inhibitors targeting the highly conserved S2-protein, as well as the design of fusion aptamers, can be used to target new coronaviruses as they emerge.


Subject(s)
Angiotensin-Converting Enzyme 2 , Aptamers, Nucleotide , COVID-19 , Spike Glycoprotein, Coronavirus , Angiotensin-Converting Enzyme 2/immunology , Antibodies, Neutralizing/immunology , Aptamers, Nucleotide/immunology , Aptamers, Nucleotide/pharmacology , COVID-19/immunology , COVID-19/virology , Humans , Pandemics , Peptidyl-Dipeptidase A/metabolism , Protein Binding , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology
7.
Fukushima J Med Sci ; 68(1): 67-70, 2022 Apr 08.
Article in English | MEDLINE | ID: covidwho-1975228

ABSTRACT

This study investigated the immune response and outcome of BNT162b2 vaccination among 12 staff at a hospital in Fukushima, Japan. Blood samples were collected from participants before their first vaccination, with subsequent sampling performed during the participants' work days for six weeks thereafter. Antibody titers peaked 6-13 days after the second vaccination (days 27-34 after the first), followed by a steady decrease. Six males had significantly lower peak antibody titers than six females (p = 0.016 with t-test); the older six (median age 53 years) had lower antibody titers than the younger six (median age 35 years) but without statistical significance (p value=0.24 with t-test).


Subject(s)
Antibodies, Viral , BNT162 Vaccine , COVID-19 , Immunoglobulin G , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Adult , Antibodies, Viral/immunology , BNT162 Vaccine/administration & dosage , BNT162 Vaccine/immunology , COVID-19/prevention & control , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/immunology , Female , Humans , Immunoglobulin G/immunology , Male , Middle Aged , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology
8.
Viruses ; 12(1)2020 01 20.
Article in English | MEDLINE | ID: covidwho-1969491

ABSTRACT

Middle East respiratory syndrome (MERS) is an acute, high-mortality-rate, severe infectious disease caused by an emerging MERS coronavirus (MERS-CoV) that causes severe respiratory diseases. The continuous spread and great pandemic potential of MERS-CoV make it necessarily important to develop effective vaccines. We previously demonstrated that the application of Gram-positive enhancer matrix (GEM) particles as a bacterial vector displaying the MERS-CoV receptor-binding domain (RBD) is a very promising MERS vaccine candidate that is capable of producing potential neutralization antibodies. We have also used the rabies virus (RV) as a viral vector to design a recombinant vaccine by expressing the MERS-CoV S1 (spike) protein on the surface of the RV. In this study, we compared the immunological efficacy of the vaccine candidates in BALB/c mice in terms of the levels of humoral and cellular immune responses. The results show that the rabies virus vector-based vaccine can induce remarkably earlier antibody response and higher levels of cellular immunity than the GEM particles vector. However, the GEM particles vector-based vaccine candidate can induce remarkably higher antibody response, even at a very low dose of 1 µg. These results indicate that vaccines constructed using different vaccine vector platforms for the same pathogen have different rates and trends in humoral and cellular immune responses in the same animal model. This discovery not only provides more alternative vaccine development platforms for MERS-CoV vaccine development, but also provides a theoretical basis for our future selection of vaccine vector platforms for other specific pathogens.


Subject(s)
Coronavirus Infections/immunology , Middle East Respiratory Syndrome Coronavirus/immunology , Viral Vaccines/immunology , Animals , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Antibodies, Viral/blood , Antibodies, Viral/immunology , Cell Line , Coronavirus Infections/prevention & control , Genetic Vectors , Humans , Immunization , Immunoglobulin G/blood , Immunoglobulin G/immunology , Lactococcus lactis/genetics , Mice , Mice, Inbred BALB C , Middle East Respiratory Syndrome Coronavirus/genetics , Rabies virus/genetics , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , T-Lymphocytes/immunology , Vaccines, Synthetic/administration & dosage , Vaccines, Synthetic/immunology , Viral Vaccines/administration & dosage
9.
PLoS One ; 17(7): e0271382, 2022.
Article in English | MEDLINE | ID: covidwho-1963028

ABSTRACT

The Lower Austrian Wachau region was an early COVID-19 hotspot of infection. As previously reported, in June 2020, after the first peak of infections, we determined that 8.5% and 9.0% of the participants in Weißenkirchen and surrounding communities in the Wachau region were positive for immunoglobulin G (IgG) and immunoglobulin A (IgA) antibodies against the receptor-binding domain of the spike protein of SARS-CoV-2, respectively. Here, we present novel data obtained eight months later (February 2021) from Weißenkirchen, after the second peak of infection, with 25.0% (138/552) and 23.6% (130/552) of participants that are positive for IgG and IgA, respectively. In participants with previous IgG/IgA positivity (June 2020), we observed a 24% reduction in IgG levels, whereas the IgA levels remained stable in February 2021. This subgroup was further analyzed for SARS-CoV-2 induced T cell activities. Although 76% (34/45) and 76% (34/45) of IgG positive and IgA positive participants, respectively, showed specific T cell activities (upon exposure to SARS-CoV-2 spike protein-derived peptides), those were not significantly correlated with the levels of IgG or IgA. Thus, the analyses of antibodies cannot surrogate the measurement of T cell activities. For a comprehensive view on SARS-CoV-2-triggered immune responses, the measurement of different classes of antibodies should be complemented with the determination of T cell activities.


Subject(s)
Antibody Formation , COVID-19 , Spike Glycoprotein, Coronavirus , Antibodies, Viral , Austria/epidemiology , COVID-19/epidemiology , COVID-19/immunology , Humans , Immunoglobulin A , Immunoglobulin G , Immunoglobulin M , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/immunology
10.
Sci Transl Med ; 14(655): eabn3715, 2022 Jul 27.
Article in English | MEDLINE | ID: covidwho-1962064

ABSTRACT

Several variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have emerged during the current coronavirus disease 2019 (COVID-19) pandemic. Although antibody cross-reactivity with the spike glycoproteins (S) of diverse coronaviruses, including endemic common cold coronaviruses (HCoVs), has been documented, it remains unclear whether such antibody responses, typically targeting the conserved S2 subunit, contribute to protection when induced by infection or through vaccination. Using a mouse model, we found that prior HCoV-OC43 S-targeted immunity primes neutralizing antibody responses to otherwise subimmunogenic SARS-CoV-2 S exposure and promotes S2-targeting antibody responses. Moreover, vaccination with SARS-CoV-2 S2 elicited antibodies in mice that neutralized diverse animal and human alphacoronaviruses and betacoronaviruses in vitro and provided a degree of protection against SARS-CoV-2 challenge in vivo. Last, in mice with a history of SARS-CoV-2 Wuhan-based S vaccination, further S2 vaccination induced broader neutralizing antibody response than booster Wuhan S vaccination, suggesting that it may prevent repertoire focusing caused by repeated homologous vaccination. These data establish the protective value of an S2-targeting vaccine and support the notion that S2 vaccination may better prepare the immune system to respond to the changing nature of the S1 subunit in SARS-CoV-2 variants of concern, as well as to future coronavirus zoonoses.


Subject(s)
COVID-19 Vaccines , COVID-19 , Coronavirus OC43, Human , Spike Glycoprotein, Coronavirus , Animals , Antibodies, Neutralizing , Antibodies, Viral , Broadly Neutralizing Antibodies , COVID-19/prevention & control , COVID-19 Vaccines/immunology , Coronavirus OC43, Human/immunology , Humans , Mice , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/immunology , Vaccination
11.
Proc Natl Acad Sci U S A ; 119(33): e2201616119, 2022 Aug 16.
Article in English | MEDLINE | ID: covidwho-1960617

ABSTRACT

With the rapid increase in SARS-CoV-2 cases in children, a safe and effective vaccine for this population is urgently needed. The MMR (measles/mumps/rubella) vaccine has been one of the safest and most effective human vaccines used in infants and children since the 1960s. Here, we developed live attenuated recombinant mumps virus (rMuV)-based SARS-CoV-2 vaccine candidates using the MuV Jeryl Lynn (JL2) vaccine strain backbone. The soluble prefusion SARS-CoV-2 spike protein (preS) gene, stablized by two prolines (preS-2P) or six prolines (preS-6P), was inserted into the MuV genome at the P-M or F-SH gene junctions in the MuV genome. preS-6P was more efficiently expressed than preS-2P, and preS-6P expression from the P-M gene junction was more efficient than from the F-SH gene junction. In mice, the rMuV-preS-6P vaccine was more immunogenic than the rMuV-preS-2P vaccine, eliciting stronger neutralizing antibodies and mucosal immunity. Sera raised in response to the rMuV-preS-6P vaccine neutralized SARS-CoV-2 variants of concern, including the Delta variant equivalently. Intranasal and/or subcutaneous immunization of IFNAR1-/- mice and golden Syrian hamsters with the rMuV-preS-6P vaccine induced high levels of neutralizing antibodies, mucosal immunoglobulin A antibody, and T cell immune responses, and were completely protected from challenge by both SARS-CoV-2 USA-WA1/2020 and Delta variants. Therefore, rMuV-preS-6P is a highly promising COVID-19 vaccine candidate, warranting further development as a tetravalent MMR vaccine, which may include protection against SARS-CoV-2.


Subject(s)
COVID-19 Vaccines , COVID-19 , Measles-Mumps-Rubella Vaccine , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Vaccine Efficacy , Animals , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19/prevention & control , COVID-19 Vaccines/genetics , COVID-19 Vaccines/immunology , Immunogenicity, Vaccine , Measles-Mumps-Rubella Vaccine/genetics , Measles-Mumps-Rubella Vaccine/immunology , Mesocricetus , Mice , Mumps virus/genetics , Mumps virus/immunology , Proline/genetics , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Vaccines, Attenuated/genetics , Vaccines, Attenuated/immunology
12.
PLoS Pathog ; 18(7): e1010686, 2022 07.
Article in English | MEDLINE | ID: covidwho-1951569

ABSTRACT

Successful control of the COVID-19 pandemic depends on vaccines that prevent transmission. The full-length Spike protein is highly immunogenic but the majority of antibodies do not target the virus: ACE2 interface. In an effort to affect the quality of the antibody response focusing it to the receptor-binding motif (RBM) we generated a series of conformationally-constrained immunogens by inserting solvent-exposed RBM amino acid residues into hypervariable loops of an immunoglobulin molecule. Priming C57BL/6 mice with plasmid (p)DNA encoding these constructs yielded a rapid memory response to booster immunization with recombinant Spike protein. Immune sera antibodies bound strongly to the purified receptor-binding domain (RBD) and Spike proteins. pDNA primed for a consistent response with antibodies efficient at neutralizing authentic WA1 virus and three variants of concern (VOC), B.1.351, B.1.617.2, and BA.1. We demonstrate that immunogens built on structure selection can be used to influence the quality of the antibody response by focusing it to a conserved site of vulnerability shared between wildtype virus and VOCs, resulting in neutralizing antibodies across variants.


Subject(s)
Antibodies, Neutralizing , COVID-19 , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral , COVID-19/prevention & control , Mice , Mice, Inbred C57BL , Pandemics/prevention & control , Spike Glycoprotein, Coronavirus/immunology
13.
Proc Natl Acad Sci U S A ; 119(31): e2205412119, 2022 Aug 02.
Article in English | MEDLINE | ID: covidwho-1947766

ABSTRACT

Camelid single-domain antibodies, also known as nanobodies, can be readily isolated from naïve libraries for specific targets but often bind too weakly to their targets to be immediately useful. Laboratory-based genetic engineering methods to enhance their affinity, termed maturation, can deliver useful reagents for different areas of biology and potentially medicine. Using the receptor binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein and a naïve library, we generated closely related nanobodies with micromolar to nanomolar binding affinities. By analyzing the structure-activity relationship using X-ray crystallography, cryoelectron microscopy, and biophysical methods, we observed that higher conformational entropy losses in the formation of the spike protein-nanobody complex are associated with tighter binding. To investigate this, we generated structural ensembles of the different complexes from electron microscopy maps and correlated the conformational fluctuations with binding affinity. This insight guided the engineering of a nanobody with improved affinity for the spike protein.


Subject(s)
Antibodies, Neutralizing , Antibodies, Viral , Antibody Affinity , SARS-CoV-2 , Single-Domain Antibodies , Spike Glycoprotein, Coronavirus , Antibodies, Neutralizing/chemistry , Antibodies, Neutralizing/genetics , Antibodies, Viral/chemistry , Antibodies, Viral/genetics , Antibody Affinity/genetics , Cryoelectron Microscopy , Entropy , Genetic Engineering , Humans , Protein Binding , Protein Domains , SARS-CoV-2/immunology , Single-Domain Antibodies/chemistry , Single-Domain Antibodies/genetics , Spike Glycoprotein, Coronavirus/immunology
14.
Proc Natl Acad Sci U S A ; 119(31): e2204336119, 2022 Aug 02.
Article in English | MEDLINE | ID: covidwho-1947765

ABSTRACT

The durability of vaccine-mediated immunity to SARS-CoV-2, the durations to breakthrough infection, and the optimal timings of booster vaccination are crucial knowledge for pandemic response. Here, we applied comparative evolutionary analyses to estimate the durability of immunity and the likelihood of breakthrough infections over time following vaccination by BNT162b2 (Pfizer-BioNTech), mRNA-1273 (Moderna), ChAdOx1 (Oxford-AstraZeneca), and Ad26.COV2.S (Johnson & Johnson/Janssen). We evaluated anti-Spike (S) immunoglobulin G (IgG) antibody levels elicited by each vaccine relative to natural infection. We estimated typical trajectories of waning and corresponding infection probabilities, providing the distribution of times to breakthrough infection for each vaccine under endemic conditions. Peak antibody levels elicited by messenger RNA (mRNA) vaccines mRNA-1273 and BNT1262b2 exceeded that of natural infection and are expected to typically yield more durable protection against breakthrough infections (median 29.6 mo; 5 to 95% quantiles 10.9 mo to 7.9 y) than natural infection (median 21.5 mo; 5 to 95% quantiles 3.5 mo to 7.1 y). Relative to mRNA-1273 and BNT1262b2, viral vector vaccines ChAdOx1 and Ad26.COV2.S exhibit similar peak anti-S IgG antibody responses to that from natural infection and are projected to yield lower, shorter-term protection against breakthrough infection (median 22.4 mo and 5 to 95% quantiles 4.3 mo to 7.2 y; and median 20.5 mo and 5 to 95% quantiles 2.6 mo to 7.0 y; respectively). These results leverage the tools from evolutionary biology to provide a quantitative basis for otherwise unknown parameters that are fundamental to public health policy decision-making.


Subject(s)
COVID-19 Vaccines , COVID-19 , Immunogenicity, Vaccine , SARS-CoV-2 , Antibodies, Viral/blood , Antibodies, Viral/immunology , Antibody Formation , COVID-19/immunology , COVID-19/prevention & control , COVID-19/virology , COVID-19 Vaccines/immunology , COVID-19 Vaccines/therapeutic use , Humans , Immunoglobulin G/blood , Immunoglobulin G/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Time Factors
15.
Ann Allergy Asthma Immunol ; 129(2): 189-193, 2022 08.
Article in English | MEDLINE | ID: covidwho-1944163

ABSTRACT

BACKGROUND: Vaccine nonresponse during the coronavirus disease 2019 (COVID-19) pandemic has considerable individual and societal risks. OBJECTIVE: To investigate the clinical characteristics of patients with lack of seroconversion after vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: Demographic and clinical data were collected from 805 patients who had validated antibody assays against the SARS-CoV-2 spike protein at least 14 days after completion of their COVID-19 vaccination. Clinical characteristics from patients with a negative (< 0.4 U/mL) antibody response were assessed and summarized. RESULTS: A total of 622 (77.3%) patients attained seroconversion as defined by a titer of greater than or equal to 0.4 U/mL, whereas 183 out of 805 (22.7%) patients exhibited no seroconversion after vaccination against SARS-CoV-2. Univariately, older age (P = .02) and male sex were associated with a lower likelihood of seroconversion (P = .003). Therapy with immunosuppressive drugs was noted in 93 (50.8%) of seronegative patients with most (n = 83/93, 89.2%) receiving ongoing immunosuppressive therapy at the time of vaccination. Among the 134 (73.2%) seronegative patients with immunodeficiency, 110 (82.1%) had primary immunodeficiency. Cancer (n = 128, 69.9%), B cell depletion therapy (n = 90/115, 78.3%), and immunosuppressant steroid use (n = 71/93 on immunosuppressants, 76.3%) were the other common characteristics among the vaccine nonresponders. More importantly, our study did not evaluate the actual efficacy of COVID-19 vaccination. CONCLUSION: Vaccine responses vary by age and sex, with men showing lower rates of seroconversion as compared with women. Primary immunodeficiency along with active malignancy and ongoing immunosuppression with steroids or B cell depletion therapy appeared to be the most common characteristics for those with a lack of vaccine seroconversion after COVID-19 vaccination.


Subject(s)
COVID-19 Vaccines , COVID-19 , Seroconversion , Antibodies, Viral , COVID-19/immunology , COVID-19/prevention & control , COVID-19 Vaccines/immunology , Female , Humans , Male , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/immunology , Vaccination
16.
PLoS One ; 17(7): e0271463, 2022.
Article in English | MEDLINE | ID: covidwho-1933390

ABSTRACT

γδ T cells are thought to contribute to immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but the mechanisms by which they are activated by the virus are unknown. Using flow cytometry, we investigated if the two most abundant viral structural proteins, spike and nucleocapsid, can activate human γδ T cell subsets, directly or in the presence of dendritic cells (DC). Both proteins failed to induce interferon-γ production by Vδ1 or Vδ2 T cells within fresh mononuclear cells or lines of expanded γδ T cells generated from healthy donors, but the same proteins stimulated CD3+ cells from COVID-19 patients. The nucleocapsid protein stimulated interleukin-12 production by DC and downstream interferon-γ production by co-cultured Vδ1 and Vδ2 T cells, but protease digestion and use of an alternative nucleocapsid preparation indicated that this activity was due to contaminating non-protein material. Thus, SARS-CoV-2 spike and nucleocapsid proteins do not have stimulatory activity for DC or γδ T cells. We propose that γδ T cell activation in COVID-19 patients is mediated by immune recognition of viral RNA or other structural proteins by γδ T cells, or by other immune cells, such as DC, that produce γδ T cell-stimulatory ligands or cytokines.


Subject(s)
COVID-19 , Dendritic Cells , Nucleocapsid Proteins , Receptors, Antigen, T-Cell, gamma-delta , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , COVID-19/immunology , COVID-19/virology , Dendritic Cells/immunology , Humans , Interferon-gamma/immunology , Nucleocapsid Proteins/immunology , Receptors, Antigen, T-Cell, gamma-delta/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology
17.
Sci Rep ; 12(1): 5999, 2022 04 09.
Article in English | MEDLINE | ID: covidwho-1921692

ABSTRACT

The newly identified coronavirus SARS-CoV-2 is responsible for the worldwide pandemic COVID-19. Considerable efforts have been devoted for the development of effective vaccine strategies against COVID-19. The SARS-CoV-2 spike protein has been identified as the major antigen candidate for the development of COVID-19 vaccines. The Pfizer-BioNTech COVID-19 vaccine COMIRNATY is a lipid nanoparticle-encapsulated mRNA encoding a full-length and prefusion-stabilized SARS-CoV-2 spike protein. In the present study, synthetic peptide-based ELISA assays were performed to identify linear B-cell epitopes into the spike protein that contribute to elicitation of antibody response in COMIRNATY-vaccinated individuals. The synthetic S2P6 peptide containing the spike residues 1138/1169 and to a lesser extent, the synthetic S1P4 peptide containing the spike residues 616/644 were recognized by the immune sera from COMIRNATY vaccine recipients but not COVID-19 recovered patients. We assume that the synthetic S2P6 peptide and to a lesser extent the synthetic S1P4 peptide, could be of interest to measure the dynamic of antibody response to COVID-19 mRNA vaccines. The S2P6 peptide has been identified as immunogenic in adult BALB/c mice that received protein-peptide conjugates in a prime-boost schedule. This raises the question on the role of the B-cell epitope peptide containing the SARS-CoV-2 spike residues 1138/1169 in protective efficacy of the Pfizer-BioNTech COVID-19 vaccine COMIRNATY.


Subject(s)
Antibodies, Viral , COVID-19 Vaccines , COVID-19 , Epitopes, B-Lymphocyte , Spike Glycoprotein, Coronavirus , Animals , Antibodies, Viral/immunology , BNT162 Vaccine , COVID-19/prevention & control , COVID-19 Vaccines/immunology , Humans , Liposomes , Mice , Nanoparticles , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/immunology
18.
Lancet ; 398(10295): 121-130, 2021 07 10.
Article in English | MEDLINE | ID: covidwho-1915103

ABSTRACT

BACKGROUND: To date, no immunological data on COVID-19 heterologous vaccination schedules in humans have been reported. We assessed the immunogenicity and reactogenicity of BNT162b2 (Comirnaty, BioNTech, Mainz, Germany) administered as second dose in participants primed with ChAdOx1-S (Vaxzevria, AstraZeneca, Oxford, UK). METHODS: We did a phase 2, open-label, randomised, controlled trial on adults aged 18-60 years, vaccinated with a single dose of ChAdOx1-S 8-12 weeks before screening, and no history of SARS-CoV-2 infection. Participants were randomly assigned (2:1) to receive either BNT162b2 (0·3 mL) via a single intramuscular injection (intervention group) or continue observation (control group). The primary outcome was 14-day immunogenicity, measured by immunoassays for SARS-CoV-2 trimeric spike protein and receptor binding domain (RBD). Antibody functionality was assessed using a pseudovirus neutralisation assay, and cellular immune response using an interferon-γ immunoassay. The safety outcome was 7-day reactogenicity, measured as solicited local and systemic adverse events. The primary analysis included all participants who received at least one dose of BNT162b2 and who had at least one efficacy evaluation after baseline. The safety analysis included all participants who received BNT162b2. This study is registered with EudraCT (2021-001978-37) and ClinicalTrials.gov (NCT04860739), and is ongoing. FINDINGS: Between April 24 and 30, 2021, 676 individuals were enrolled and randomly assigned to either the intervention group (n=450) or control group (n=226) at five university hospitals in Spain (mean age 44 years [SD 9]; 382 [57%] women and 294 [43%] men). 663 (98%) participants (n=441 intervention, n=222 control) completed the study up to day 14. In the intervention group, geometric mean titres of RBD antibodies increased from 71·46 BAU/mL (95% CI 59·84-85·33) at baseline to 7756·68 BAU/mL (7371·53-8161·96) at day 14 (p<0·0001). IgG against trimeric spike protein increased from 98·40 BAU/mL (95% CI 85·69-112·99) to 3684·87 BAU/mL (3429·87-3958·83). The interventional:control ratio was 77·69 (95% CI 59·57-101·32) for RBD protein and 36·41 (29·31-45·23) for trimeric spike protein IgG. Reactions were mild (n=1210 [68%]) or moderate (n=530 [30%]), with injection site pain (n=395 [88%]), induration (n=159 [35%]), headache (n=199 [44%]), and myalgia (n=194 [43%]) the most commonly reported adverse events. No serious adverse events were reported. INTERPRETATION: BNT162b2 given as a second dose in individuals prime vaccinated with ChAdOx1-S induced a robust immune response, with an acceptable and manageable reactogenicity profile. FUNDING: Instituto de Salud Carlos III. TRANSLATIONS: For the French and Spanish translations of the abstract see Supplementary Materials section.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/immunology , COVID-19/prevention & control , Immunization, Secondary , Immunogenicity, Vaccine/immunology , Spike Glycoprotein, Coronavirus/drug effects , Adolescent , Adult , COVID-19/epidemiology , Female , Humans , Male , Middle Aged , Spain/epidemiology , Spike Glycoprotein, Coronavirus/immunology , Young Adult
19.
Biosci Rep ; 41(9)2021 09 30.
Article in English | MEDLINE | ID: covidwho-1915305

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the global pandemic of the Coronavirus disease in late 2019 (COVID-19). Vaccine development efforts have predominantly been aimed at 'Extra-viral' Spike (S) protein as vaccine vehicles, but there are concerns regarding 'viral immune escape' since multiple mutations may enable the mutated virus strains to escape from immunity against S protein. The 'Intra-viral' Nucleocapsid (N-protein) is relatively conserved among mutant strains of coronaviruses during spread and evolution. Herein, we demonstrate novel vaccine candidates against SARS-CoV-2 by using the whole conserved N-protein or its fragment/peptides. Using ELISA assay, we showed that high titers of specific anti-N antibodies (IgG, IgG1, IgG2a, IgM) were maintained for a reasonably long duration (> 5 months), suggesting that N-protein is an excellent immunogen to stimulate host immune system and robust B-cell activation. We synthesized three peptides located at the conserved regions of N-protein among CoVs. One peptide showed as a good immunogen for vaccination as well. Cytokine arrays on post-vaccination mouse sera showed progressive up-regulation of various cytokines such as IFN-γ and CCL5, suggesting that TH1 associated responses are also stimulated. Furthermore, vaccinated mice exhibited an elevated memory T cells population. Here, we propose an unconventional vaccine strategy targeting the conserved N-protein as an alternative vaccine target for coronaviruses. Moreover, we generated a mouse monoclonal antibody specifically against an epitope shared between SARS-CoV and SARS-CoV-2, and we are currently developing the First-in-Class humanized anti-N-protein antibody to potentially treat patients infected by various CoVs in the future.


Subject(s)
Antibodies, Viral/blood , COVID-19 Vaccines/immunology , COVID-19/prevention & control , Coronavirus Nucleocapsid Proteins/immunology , Animals , Antibodies, Monoclonal, Murine-Derived , Antibodies, Viral/immunology , COVID-19/immunology , COVID-19/virology , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/genetics , Coronavirus Nucleocapsid Proteins/genetics , Epitopes/immunology , Humans , Immune Evasion , Immunogenicity, Vaccine , Mice , Models, Animal , Pandemics/prevention & control , SARS Virus/genetics , SARS Virus/immunology , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Sequence Homology, Amino Acid , Spike Glycoprotein, Coronavirus/immunology , Th1 Cells/immunology , Vaccines, Subunit/administration & dosage , Vaccines, Subunit/genetics , Vaccines, Subunit/immunology
20.
Front Immunol ; 12: 803647, 2021.
Article in English | MEDLINE | ID: covidwho-1911034

ABSTRACT

The newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is causing a spread of coronavirus disease 2019 (COVID-19) globally. In order to end the COVID-19 pandemic, an effective vaccine against SARS-CoV-2 must be produced at low cost and disseminated worldwide. The spike (S) protein of coronaviruses plays a pivotal role in the infection to host cells. Therefore, targeting the S protein is one of the most rational approaches in developing vaccines and therapeutic agents. In this study, we optimized the expression of secreted trimerized S protein of SARS-CoV-2 using a silkworm-baculovirus expression vector system and evaluated its immunogenicity in mice. The results showed that the S protein forming the trimeric structure was the most stable when the chicken cartilage matrix protein was used as the trimeric motif and could be purified in large amounts from the serum of silkworm larvae. The purified S protein efficiently induced antigen-specific antibodies in mouse serum without adjuvant, but its ability to induce neutralizing antibodies was low. After examining several adjuvants, the use of Alum adjuvant was the most effective in inducing strong neutralizing antibody induction. We also examined the adjuvant effect of paramylon from Euglena gracilis when administered with the S protein. Our results highlight the effectiveness and suitable construct design of the S protein produced in silkworms for the subunit vaccine development against SARS-CoV-2.


Subject(s)
Alum Compounds/pharmacology , Aluminum Hydroxide/pharmacology , Bombyx/genetics , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Adjuvants, Immunologic/pharmacology , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/immunology , COVID-19 Vaccines/immunology , Cell Line , Chickens/genetics , Chickens/immunology , Chlorocebus aethiops , Euglena gracilis/immunology , Euglenozoa Infections/immunology , Female , Humans , Mice , Mice, Inbred BALB C , Pandemics/prevention & control , SARS-CoV-2/immunology , Vaccination/methods , Vero Cells
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