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1.
Front Immunol ; 12: 776933, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34917089

RESUMO

The efficacy of COVID-19 vaccines appears to depend in complex ways on the vaccine dosage and the interval between the prime and boost doses. Unexpectedly, lower dose prime and longer prime-boost intervals have yielded higher efficacies in clinical trials. To elucidate the origins of these effects, we developed a stochastic simulation model of the germinal center (GC) reaction and predicted the antibody responses elicited by different vaccination protocols. The simulations predicted that a lower dose prime could increase the selection stringency in GCs due to reduced antigen availability, resulting in the selection of GC B cells with higher affinities for the target antigen. The boost could relax this selection stringency and allow the expansion of the higher affinity GC B cells selected, improving the overall response. With a longer dosing interval, the decay in the antigen with time following the prime could further increase the selection stringency, amplifying this effect. The effect remained in our simulations even when new GCs following the boost had to be seeded by memory B cells formed following the prime. These predictions offer a plausible explanation of the observed paradoxical effects of dosage and dosing interval on vaccine efficacy. Tuning the selection stringency in the GCs using prime-boost dosages and dosing intervals as handles may help improve vaccine efficacies.


Assuntos
Linfócitos B/imunologia , Vacinas contra COVID-19/imunologia , COVID-19/imunologia , Seleção Clonal Mediada por Antígeno/imunologia , Centro Germinativo/imunologia , Interações Hospedeiro-Patógeno/imunologia , SARS-CoV-2/imunologia , Antígenos/imunologia , Linfócitos B/metabolismo , COVID-19/virologia , Vacinas contra COVID-19/administração & dosagem , Relação Dose-Resposta Imunológica , Centro Germinativo/metabolismo , Humanos , Imunização Secundária , Modelos Teóricos , Vacinação
2.
Front Immunol ; 12: 795741, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34925381

RESUMO

Glycan-masking the vaccine antigen by mutating the undesired antigenic sites with an additional N-linked glycosylation motif can refocus B-cell responses to desired epitopes, without affecting the antigen's overall-folded structure. This study examined the impact of glycan-masking mutants of the N-terminal domain (NTD) and receptor-binding domain (RBD) of SARS-CoV-2, and found that the antigenic design of the S protein increases the neutralizing antibody titers against the Wuhan-Hu-1 ancestral strain and the recently emerged SARS-CoV-2 variants Alpha (B.1.1.7), Beta (B.1.351), and Delta (B.1.617.2). Our results demonstrated that the use of glycan-masking Ad-S-R158N/Y160T in the NTD elicited a 2.8-fold, 6.5-fold, and 4.6-fold increase in the IC-50 NT titer against the Alpha (B.1.1.7), Beta (B.1.351) and Delta (B.1.617.2) variants, respectively. Glycan-masking of Ad-S-D428N in the RBD resulted in a 3.0-fold and 2.0-fold increase in the IC-50 neutralization titer against the Alpha (B.1.1.7) and Beta (B.1.351) variants, respectively. The use of glycan-masking in Ad-S-R158N/Y160T and Ad-S-D428N antigen design may help develop universal COVID-19 vaccines against current and future emerging SARS-CoV-2 variants.


Assuntos
Antígenos Virais/imunologia , COVID-19/imunologia , Epitopos/imunologia , Domínios e Motivos de Interação entre Proteínas/imunologia , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Adenoviridae/genética , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Formação de Anticorpos/imunologia , COVID-19/prevenção & controle , COVID-19/virologia , Vacinas contra COVID-19/genética , Vacinas contra COVID-19/imunologia , Modelos Animais de Doenças , Relação Dose-Resposta Imunológica , Feminino , Engenharia Genética , Vetores Genéticos/genética , Humanos , Imunização , Camundongos , Testes de Neutralização , Polissacarídeos , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo , Relação Estrutura-Atividade
3.
Cell ; 184(23): 5699-5714.e11, 2021 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-34735795

RESUMO

Extension of the interval between vaccine doses for the BNT162b2 mRNA vaccine was introduced in the United Kingdom to accelerate population coverage with a single dose. At this time, trial data were lacking, and we addressed this in a study of United Kingdom healthcare workers. The first vaccine dose induced protection from infection from the circulating alpha (B.1.1.7) variant over several weeks. In a substudy of 589 individuals, we show that this single dose induces severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing antibody (NAb) responses and a sustained B and T cell response to the spike protein. NAb levels were higher after the extended dosing interval (6-14 weeks) compared with the conventional 3- to 4-week regimen, accompanied by enrichment of CD4+ T cells expressing interleukin-2 (IL-2). Prior SARS-CoV-2 infection amplified and accelerated the response. These data on dynamic cellular and humoral responses indicate that extension of the dosing interval is an effective immunogenic protocol.


Assuntos
Vacinas contra COVID-19/imunologia , Vacinas Sintéticas/imunologia , Adulto , Idoso , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , COVID-19/sangue , COVID-19/imunologia , COVID-19/virologia , Apresentação Cruzada/imunologia , Relação Dose-Resposta Imunológica , Feminino , Humanos , Imunidade , Imunoglobulina G/imunologia , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Padrões de Referência , SARS-CoV-2/imunologia , Linfócitos T/imunologia , Resultado do Tratamento , Adulto Jovem
4.
PLoS One ; 16(11): e0259990, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34780553

RESUMO

BACKGROUND: COVID-19 vaccination in many countries, including England, has been prioritised primarily by age. However, people of the same age can have very different health statuses. Frailty is a commonly used metric of health and has been found to be more strongly associated with mortality than age among COVID-19 inpatients. METHODS: We compared the number of first vaccine doses administered across the 135 NHS Clinical Commissioning Groups (CCGs) of England to both the over 50 population and the estimated frail population in each area. Area-based frailty estimates were generated using the English Longitudinal Survey of Ageing (ELSA), a national survey of older people. We also compared the number of doses to the number of people with other risk factors associated with COVID-19: atrial fibrillation, chronic kidney disease, diabetes, learning disabilities, obesity and smoking status. RESULTS: We estimate that after 79 days of the vaccine program, across all Clinical Commissioning Group areas, the number of people who received a first vaccine per frail person ranged from 4.4 (95% CI 4.0-4.8) and 20.1 (95% CI 18.3-21.9). The prevalences of other risk factors were also poorly associated with the prevalence of vaccination across England. CONCLUSIONS: Vaccination with age-based priority created area-based inequities in the number of doses administered relative to the number of people who are frail or have other risk factors associated with COVID-19. As frailty has previously been found to be more strongly associated with mortality than age for COVID-19 inpatients, an age-based priority system may increase the risk of mortality in some areas during the vaccine roll-out period. Authorities planning COVID-19 vaccination programmes should consider the disadvantages of an age-based priority system.


Assuntos
Vacinas contra COVID-19/imunologia , Vacinação , COVID-19/epidemiologia , COVID-19/imunologia , Relação Dose-Resposta Imunológica , Inglaterra/epidemiologia , Geografia , Humanos , Prevalência , Fatores de Risco
5.
Nat Commun ; 12(1): 5861, 2021 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-34615860

RESUMO

Several COVID-19 vaccines have shown good efficacy in clinical trials, but there remains uncertainty about the efficacy of vaccines against different variants. Here, we investigate the efficacy of ChAdOx1 nCoV-19 (AZD1222) against symptomatic COVID-19 in a post-hoc exploratory analysis of a Phase 3 randomised trial in Brazil (trial registration ISRCTN89951424). Nose and throat swabs were tested by PCR in symptomatic participants. Sequencing and genotyping of swabs were performed to determine the lineages of SARS-CoV-2 circulating during the study. Protection against any symptomatic COVID-19 caused by the Zeta (P.2) variant was assessed in 153 cases with vaccine efficacy (VE) of 69% (95% CI 55, 78). 49 cases of B.1.1.28 occurred and VE was 73% (46, 86). The Gamma (P.1) variant arose later in the trial and fewer cases (N = 18) were available for analysis. VE was 64% (-2, 87). ChAdOx1 nCoV-19 provided 95% protection (95% CI 61%, 99%) against hospitalisation due to COVID-19. In summary, we report that ChAdOx1 nCoV-19 protects against emerging variants in Brazil despite the presence of the spike protein mutation E484K.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/imunologia , COVID-19/virologia , Filogenia , SARS-CoV-2/imunologia , Adolescente , Adulto , Idoso , Brasil , Estudos de Coortes , Relação Dose-Resposta Imunológica , Feminino , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Vacinação , Carga Viral/imunologia , Adulto Jovem
6.
PLoS Med ; 18(10): e1003769, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34597298

RESUMO

BACKGROUND: NVX-CoV2373 is a recombinant severe acute respiratory coronavirus 2 (rSARS-CoV-2) nanoparticle vaccine composed of trimeric full-length SARS-CoV-2 spike glycoproteins and Matrix-M1 adjuvant. METHODS AND FINDINGS: The phase 2 component of our randomized, placebo-controlled, phase 1 to 2 trial was designed to identify which dosing regimen of NVX-CoV2373 should move forward into late-phase studies and was based on immunogenicity and safety data through Day 35 (14 days after the second dose). The trial was conducted at 9 sites in Australia and 8 sites in the United States. Participants in 2 age groups (aged 18 to 59 and 60 to 84 years) were randomly assigned to receive either 1 or 2 intramuscular doses of 5-µg or 25-µg NVX-CoV2373 or placebo, 21 days apart. Primary endpoints were immunoglobulin G (IgG) anti-spike protein response, 7-day solicited reactogenicity, and unsolicited adverse events. A key secondary endpoint was wild-type virus neutralizing antibody response. After enrollment, 1,288 participants were randomly assigned to 1 of 4 vaccine groups or placebo, with 1,283 participants administered at least 1 study treatment. Of these, 45% were older participants 60 to 84 years. Reactogenicity was predominantly mild to moderate in severity and of short duration (median <3 days) after first and second vaccination with NVX-CoV2373, with higher frequencies and intensity after second vaccination and with the higher dose. Reactogenicity occurred less frequently and was of lower intensity in older participants. Both 2-dose regimens of 5-µg and 25-µg NVX-CoV2373 induced robust immune responses in younger and older participants. For the 2-dose regimen of 5 µg, geometric mean titers (GMTs) for IgG anti-spike protein were 65,019 (95% confidence interval (CI) 55,485 to 76,192) and 28,137 (95% CI 21,617 to 36,623) EU/mL and for wild-type virus neutralizing antibody (with an inhibitory concentration of 50%-MN50%) were 2,201 (95% CI 1,343 to 3,608) and 981 (95% CI 560 to 1,717) titers for younger and older participants, respectively, with seroconversion rates of 100% in both age groups. Neutralizing antibody responses exceeded those seen in a panel of convalescent sera for both age groups. Study limitations include the relatively short duration of safety follow-up to date and current lack of immune persistence data beyond the primary vaccination regimen time point assessments, but these data will accumulate over time. CONCLUSIONS: The study confirmed the phase 1 findings that the 2-dose regimen of 5-µg NVX-CoV2373 is highly immunogenic and well tolerated in younger adults. In addition, in older adults, the 2-dose regimen of 5 µg was also well tolerated and showed sufficient immunogenicity to support its use in late-phase efficacy studies. TRIAL REGISTRATION: ClinicalTrials.gov NCT04368988.


Assuntos
Vacinas contra COVID-19/administração & dosagem , COVID-19/prevenção & controle , Imunogenicidade da Vacina , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Relação Dose-Resposta Imunológica , Feminino , Humanos , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Adulto Jovem
7.
JAMA Netw Open ; 4(9): e2123622, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34473256

RESUMO

Importance: Patients undergoing hemodialysis have a high mortality rate associated with COVID-19, and this patient population often has a poor response to vaccinations. Randomized clinical trials for COVID-19 vaccines included few patients with kidney disease; therefore, vaccine immunogenicity is uncertain in this population. Objective: To evaluate the SARS-CoV-2 antibody response in patients undergoing chronic hemodialysis following 1 vs 2 doses of BNT162b2 COVID-19 vaccination compared with health care workers serving as controls and convalescent serum. Design, Setting, and Participants: A prospective, single-center cohort study was conducted between February 2 and April 17, 2021, in Toronto, Ontario, Canada. Participants included 142 patients receiving in-center hemodialysis and 35 health care worker controls. Exposures: BNT162b2 (Pfizer-BioNTech) COVID-19 vaccine. Main Outcomes and Measures: SARS-CoV-2 IgG antibodies to the spike protein (anti-spike), receptor binding domain (anti-RBD), and nucleocapsid protein (anti-NP). Results: Among the 142 participants undergoing maintenance hemodialysis, 94 (66%) were men; median age was 72 (interquartile range, 62-79) years. SARS-CoV-2 IgG antibodies were measured in 66 patients receiving 1 vaccine dose following a public health policy change, 76 patients receiving 2 vaccine doses, and 35 health care workers receiving 2 vaccine doses. Detectable anti-NP suggestive of natural SARS-CoV-2 infection was detected in 15 of 142 (11%) patients at baseline, and only 3 patients had prior COVID-19 confirmed by reverse transcriptase polymerase chain reaction testing. Two additional patients contracted COVID-19 after receiving 2 doses of vaccine. In 66 patients receiving a single BNT162b2 dose, seroconversion occurred in 53 (80%) for anti-spike and 36 (55%) for anti-RBD by 28 days postdose, but a robust response, defined by reaching the median levels of antibodies in convalescent serum from COVID-19 survivors, was noted in only 15 patients (23%) for anti-spike and 4 (6%) for anti-RBD in convalescent serum from COVID-19 survivors. In patients receiving 2 doses of BNT162b2 vaccine, seroconversion occurred in 69 of 72 (96%) for anti-spike and 63 of 72 (88%) for anti-RBD by 2 weeks following the second dose and median convalescent serum levels were reached in 52 of 72 patients (72%) for anti-spike and 43 of 72 (60%) for anti-RBD. In contrast, all 35 health care workers exceeded the median level of anti-spike and anti-RBD found in convalescent serum 2 to 4 weeks after the second dose. Conclusions and Relevance: This study suggests poor immunogenicity 28 days following a single dose of BNT162b2 vaccine in the hemodialysis population, supporting adherence to recommended vaccination schedules and avoiding delay of the second dose in these at-risk individuals.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/imunologia , Imunoglobulina G/sangue , SARS-CoV-2/imunologia , Idoso , Idoso de 80 Anos ou mais , COVID-19/epidemiologia , Estudos de Casos e Controles , Relação Dose-Resposta Imunológica , Feminino , Humanos , Imunoglobulina G/biossíntese , Masculino , Pandemias , Estudos Prospectivos , Diálise Renal , Glicoproteína da Espícula de Coronavírus/imunologia
8.
Nat Commun ; 12(1): 5469, 2021 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-34552091

RESUMO

SARS-CoV-2 remains a global threat to human health particularly as escape mutants emerge. There is an unmet need for effective treatments against COVID-19 for which neutralizing single domain antibodies (nanobodies) have significant potential. Their small size and stability mean that nanobodies are compatible with respiratory administration. We report four nanobodies (C5, H3, C1, F2) engineered as homotrimers with pmolar affinity for the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. Crystal structures show C5 and H3 overlap the ACE2 epitope, whilst C1 and F2 bind to a different epitope. Cryo Electron Microscopy shows C5 binding results in an all down arrangement of the Spike protein. C1, H3 and C5 all neutralize the Victoria strain, and the highly transmissible Alpha (B.1.1.7 first identified in Kent, UK) strain and C1 also neutralizes the Beta (B.1.35, first identified in South Africa). Administration of C5-trimer via the respiratory route showed potent therapeutic efficacy in the Syrian hamster model of COVID-19 and separately, effective prophylaxis. The molecule was similarly potent by intraperitoneal injection.


Assuntos
Anticorpos Neutralizantes/farmacologia , COVID-19/tratamento farmacológico , Anticorpos de Domínio Único/farmacologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Administração Intranasal , Animais , Anticorpos Neutralizantes/administração & dosagem , Anticorpos Neutralizantes/genética , Anticorpos Neutralizantes/imunologia , Microscopia Crioeletrônica , Cristalografia por Raios X , Modelos Animais de Doenças , Relação Dose-Resposta Imunológica , Epitopos/química , Epitopos/metabolismo , Feminino , Masculino , Mesocricetus , Testes de Neutralização , SARS-CoV-2/efeitos dos fármacos , Anticorpos de Domínio Único/administração & dosagem , Anticorpos de Domínio Único/imunologia , Anticorpos de Domínio Único/metabolismo , Glicoproteína da Espícula de Coronavírus/química
9.
Sci Rep ; 11(1): 15799, 2021 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-34349145

RESUMO

The SARS-CoV-2 virus caused the most severe pandemic around the world, and vaccine development for urgent use became a crucial issue. Inactivated virus formulated vaccines such as Hepatitis A and smallpox proved to be reliable approaches for immunization for prolonged periods. In this study, a gamma-irradiated inactivated virus vaccine does not require an extra purification process, unlike the chemically inactivated vaccines. Hence, the novelty of our vaccine candidate (OZG-38.61.3) is that it is a non-adjuvant added, gamma-irradiated, and intradermally applied inactive viral vaccine. Efficiency and safety dose (either 1013 or 1014 viral RNA copy per dose) of OZG-38.61.3 was initially determined in BALB/c mice. This was followed by testing the immunogenicity and protective efficacy of the vaccine. Human ACE2-encoding transgenic mice were immunized and then infected with the SARS-CoV-2 virus for the challenge test. This study shows that vaccinated mice have lowered SARS-CoV-2 viral RNA copy numbers both in oropharyngeal specimens and in the histological analysis of the lung tissues along with humoral and cellular immune responses, including the neutralizing antibodies similar to those shown in BALB/c mice without substantial toxicity. Subsequently, plans are being made for the commencement of Phase 1 clinical trial of the OZG-38.61.3 vaccine for the COVID-19 pandemic.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , SARS-CoV-2/imunologia , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Chlorocebus aethiops , Citocinas/metabolismo , Relação Dose-Resposta Imunológica , Raios gama , Humanos , Imunidade , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , RNA Viral , SARS-CoV-2/efeitos da radiação , Vacinação , Vacinas de Produtos Inativados/imunologia , Células Vero , Replicação Viral
10.
Front Immunol ; 12: 678318, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34248960

RESUMO

Cervical cancer caused by human papillomavirus (HPV) infections is the fourth most common cancer in women worldwide. Current prophylactic HPV vaccines have achieved promising success in preventing HPV infection. However, still 570,000 new cases were reported in 2018. The current primary treatment for the patient with cervical cancer is either surgery or chemoradiotherapy. Cervical cancer still lacks standard medical therapy. HPV18 induced cervical cancer has the worst prognosis and high mortality compared to other HPV infections. The development of HPV18 related with cervical malignancy requires the persistent infection of cervical-vaginal epithelium by HPV18 subtype, which can take years to transform the epithelium. This period of repeated infection provides a window for therapeutic intervention. Neutralizing antibodies formulated as topical agents that inhibit HPV18 infection should reduce the chance of cervical malignancy. We previously demonstrated that potent neutralizing anti-sera against HPV18 infection were induced by HPV18 viral like particle (VLP) generated in mammalian cells. We, therefore, isolated two potent neutralizing antibodies, 2A12 and 8H4, from over 3,810 hybridomas prepared from mice immunized with HPV18 VLP. 2A12 and 8H4 exhibited excellent potency, with 50% virus-inhibitory concentrations (IC50) of 0.4 and 0.9 ng/ml, respectively. Furthermore, 2A12 and 8H4 recognized distinct and non-overlapping quaternary epitopes and bound specifically with HPV18. Humanized 2A12 (Hu2A12) retained comparable neutralizing activity against HPV18 infection in various acidic pH settings and in hydrogel formulation with IC50 values of 0.04 to 0.77 ng/ml, indicating that Hu2A12 will be a promising candidate for clinical development as a topical vaginal biopharmaceutical agent against HPV18 infection.


Assuntos
Anticorpos Monoclonais/farmacologia , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Papillomavirus Humano 18 , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/imunologia , Neoplasias do Colo do Útero/etiologia , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Gerenciamento Clínico , Modelos Animais de Doenças , Suscetibilidade a Doenças , Relação Dose-Resposta a Droga , Relação Dose-Resposta Imunológica , Feminino , Papillomavirus Humano 18/fisiologia , Humanos , Imunização , Camundongos , Terapia de Alvo Molecular , Testes de Neutralização , Infecções por Papillomavirus/virologia , Vacinas contra Papillomavirus/administração & dosagem , Vacinas contra Papillomavirus/imunologia , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/patologia , Vacinas de Partículas Semelhantes a Vírus/administração & dosagem , Vacinas de Partículas Semelhantes a Vírus/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Nat Commun ; 12(1): 4617, 2021 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-34326317

RESUMO

Several COVID-19 vaccines have received emergency approval. Here we assess the immunogenicity of a single dose of the AZD1222 vaccine, at one month, in a cohort of health care workers (HCWs) (629 naïve and 26 previously infected). 93.4% of naïve HCWs seroconverted, irrespective of age and gender. Haemagglutination test for antibodies to the receptor binding domain (RBD), surrogate neutralization assay (sVNT) and ex vivo IFNγ ELISpot assays were carried out in a sub-cohort. ACE2 blocking antibodies (measured by sVNT) were detected in 67/69 (97.1%) of naïve HCWs. Antibody levels to the RBD of the wild-type virus were higher than to RBD of B.1.1.7, and titres to B.1.351 were very low. Ex vivo T cell responses were observed in 30.8% to 61.7% in naïve HCWs. Previously infected HCWs, developed significantly higher (p < 0.0001) ACE2 blocking antibodies and antibodies to the RBD for the variants B.1.1.7 and B.1.351. This study shows high seroconversion after one vaccine dose, but also suggests that one vaccine dose may be insufficient to protect against emerging variants.


Assuntos
Anticorpos Neutralizantes/imunologia , Vacinas contra COVID-19/uso terapêutico , COVID-19/imunologia , SARS-CoV-2/imunologia , Adulto , Anticorpos Neutralizantes/biossíntese , COVID-19/prevenção & controle , COVID-19/virologia , Relação Dose-Resposta Imunológica , Feminino , Pessoal de Saúde , Humanos , Imunidade , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/isolamento & purificação , Adulto Jovem
12.
Viruses ; 13(6)2021 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-34067349

RESUMO

Europe is experiencing a third wave of COVID-19 due to the spread of highly transmissible SARS-CoV-2 variants. A number of positive and negative factors constantly shape the rates of COVID-19 infections, hospitalization, and mortality. Among these factors, the rise in increasingly transmissible variants on one side and the effect of vaccinations on the other side create a picture deeply different from that of the first pandemic wave. Starting from the observation that in several European countries the number of COVID-19 infections in the second and third pandemic wave increased without a proportional rise in disease severity and mortality, we hypothesize the existence of an additional factor influencing SARS-CoV-2 dynamics. This factor consists of an immune defence against severe COVID-19, provided by SARS-CoV-2-specific T cells progressively developing upon natural exposure to low virus doses present in populated environments. As suggested by recent studies, low-dose viral particles entering the respiratory and intestinal tracts may be able to induce T cell memory in the absence of inflammation, potentially resulting in different degrees of immunization. In this scenario, non-pharmaceutical interventions would play a double role, one in the short term by reducing the detrimental spreading of SARS-CoV-2 particles, and one in the long term by allowing the development of a widespread (although heterogeneous and uncontrollable) form of immune protection.


Assuntos
COVID-19/imunologia , SARS-CoV-2/imunologia , Linfócitos T/imunologia , COVID-19/prevenção & controle , Relação Dose-Resposta Imunológica , Exposição Ambiental , Humanos , Memória Imunológica
13.
Nature ; 595(7869): 718-723, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34082438

RESUMO

Resistance represents a major challenge for antibody-based therapy for COVID-191-4. Here we engineered an immunoglobulin M (IgM) neutralizing antibody (IgM-14) to overcome the resistance encountered by immunoglobulin G (IgG)-based therapeutics. IgM-14 is over 230-fold more potent than its parental IgG-14 in neutralizing SARS-CoV-2. IgM-14 potently neutralizes the resistant virus raised by its corresponding IgG-14, three variants of concern-B.1.1.7 (Alpha, which first emerged in the UK), P.1 (Gamma, which first emerged in Brazil) and B.1.351 (Beta, which first emerged in South Africa)-and 21 other receptor-binding domain mutants, many of which are resistant to the IgG antibodies that have been authorized for emergency use. Although engineering IgG into IgM enhances antibody potency in general, selection of an optimal epitope is critical for identifying the most effective IgM that can overcome resistance. In mice, a single intranasal dose of IgM-14 at 0.044 mg per kg body weight confers prophylactic efficacy and a single dose at 0.4 mg per kg confers therapeutic efficacy against SARS-CoV-2. IgM-14, but not IgG-14, also confers potent therapeutic protection against the P.1 and B.1.351 variants. IgM-14 exhibits desirable pharmacokinetics and safety profiles when administered intranasally in rodents. Our results show that intranasal administration of an engineered IgM can improve efficacy, reduce resistance and simplify the prophylactic and therapeutic treatment of COVID-19.


Assuntos
COVID-19/prevenção & controle , COVID-19/virologia , Imunoglobulina M/administração & dosagem , Imunoglobulina M/imunologia , SARS-CoV-2/classificação , SARS-CoV-2/imunologia , Administração Intranasal , Enzima de Conversão de Angiotensina 2/antagonistas & inibidores , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/genética , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacocinética , Anticorpos Neutralizantes/administração & dosagem , Anticorpos Neutralizantes/efeitos adversos , Anticorpos Neutralizantes/genética , Anticorpos Neutralizantes/imunologia , Proteínas Reguladoras de Apoptose/química , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/imunologia , Proteínas Reguladoras de Apoptose/metabolismo , COVID-19/tratamento farmacológico , COVID-19/imunologia , Relação Dose-Resposta Imunológica , Feminino , Humanos , Imunoglobulina A/genética , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Imunoglobulina M/efeitos adversos , Imunoglobulina M/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Engenharia de Proteínas , Receptores Virais/antagonistas & inibidores , Receptores Virais/metabolismo , SARS-CoV-2/genética
14.
Proc Natl Acad Sci U S A ; 118(28)2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34162739

RESUMO

Severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2) has emerged as the infectious agent causing the pandemic coronavirus disease 2019 (COVID-19) with dramatic consequences for global human health and economics. Previously, we reached clinical evaluation with our vector vaccine based on modified vaccinia virus Ankara (MVA) against the Middle East respiratory syndrome coronavirus (MERS-CoV), which causes an infection in humans similar to SARS and COVID-19. Here, we describe the construction and preclinical characterization of a recombinant MVA expressing full-length SARS-CoV-2 spike (S) protein (MVA-SARS-2-S). Genetic stability and growth characteristics of MVA-SARS-2-S, plus its robust expression of S protein as antigen, make it a suitable candidate vaccine for industrial-scale production. Vaccinated mice produced S-specific CD8+ T cells and serum antibodies binding to S protein that neutralized SARS-CoV-2. Prime-boost vaccination with MVA-SARS-2-S protected mice sensitized with a human ACE2-expressing adenovirus from SARS-CoV-2 infection. MVA-SARS-2-S is currently being investigated in a phase I clinical trial as aspirant for developing a safe and efficacious vaccine against COVID-19.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , Glicoproteína da Espícula de Coronavírus/imunologia , Animais , Vacinas contra COVID-19/normas , Relação Dose-Resposta Imunológica , Humanos , Camundongos , Camundongos Endogâmicos BALB C , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/genética , Linfócitos T , Vacinação , Vírus Vaccinia
15.
Nat Commun ; 12(1): 3449, 2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34103510

RESUMO

Most COVID-19 vaccines require two doses, however with limited vaccine supply, policymakers are considering single-dose vaccination as an alternative strategy. Using a mathematical model combined with optimization algorithms, we determined optimal allocation strategies with one and two doses of vaccine under various degrees of viral transmission. Under low transmission, we show that the optimal allocation of vaccine vitally depends on the single-dose efficacy. With high single-dose efficacy, single-dose vaccination is optimal, preventing up to 22% more deaths than a strategy prioritizing two-dose vaccination for older adults. With low or moderate single-dose efficacy, mixed vaccination campaigns with complete coverage of older adults are optimal. However, with modest or high transmission, vaccinating older adults first with two doses is best, preventing up to 41% more deaths than a single-dose vaccination given across all adult populations. Our work suggests that it is imperative to determine the efficacy and durability of single-dose vaccines, as mixed or single-dose vaccination campaigns may have the potential to contain the pandemic much more quickly.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/imunologia , Vacinação , Número Básico de Reprodução , COVID-19/transmissão , COVID-19/virologia , Relação Dose-Resposta Imunológica , Hospitalização , Humanos , Imunidade , Unidades de Terapia Intensiva , SARS-CoV-2/imunologia
16.
Ann Hematol ; 100(7): 1837-1847, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33948721

RESUMO

Despite the widespread use of rabbit anti-thymocyte globulin (ATG) to prevent acute and chronic graft-versus-host disease (aGVHD, cGVHD) after allogeneic hematopoietic cell transplantation (allo-HCT), convincing evidence about an optimal dose is lacking. We retrospectively evaluated the clinical impact of two different ATG doses (5 vs 6-7.5 mg/kg) in 395 adult patients undergoing HSCT from matched unrelated donors (MUD) at 3 Italian centers. Cumulative incidence of aGVHD and moderate-severe cGVHD did not differ in the 2 groups. We observed a trend toward prolonged overall survival (OS) and disease-free survival (DFS) with lower ATG dose (5-year OS and DFS 56.6% vs. 46.3%, p=0.052, and 46.8% vs. 38.6%, p=0.051, respectively) and no differences in relapse incidence and non-relapse mortality. However, a significantly increased infection-related mortality (IRM) was observed in patients who received a higher ATG dose (16.7% vs. 8.8% in the lower ATG group, p=0.019). Besides, graft and relapse-free survival (GRFS) was superior in the lower ATG group (5-year GRFS 43.1% vs. 32.4%, p=0.014). The negative impact of higher ATG dose on IRM and GRFS was confirmed by multivariate analysis. Our results suggest that ATG doses higher than 5 mg/kg are not required for MUD allo-HCT and seem associated with worse outcomes.


Assuntos
Soro Antilinfocitário/uso terapêutico , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Adulto , Aloenxertos , Soro Antilinfocitário/administração & dosagem , Soro Antilinfocitário/efeitos adversos , Ciclosporina/uso terapêutico , Intervalo Livre de Doença , Relação Dose-Resposta Imunológica , Feminino , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/etiologia , Neoplasias Hematológicas/terapia , Histocompatibilidade , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Incidência , Infecções/etiologia , Infecções/mortalidade , Estimativa de Kaplan-Meier , Masculino , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Ácido Micofenólico/uso terapêutico , Modelos de Riscos Proporcionais , Recidiva , Estudos Retrospectivos , Linfócitos T/imunologia , Doadores não Relacionados
17.
Lancet Infect Dis ; 21(8): 1161-1174, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33939958

RESUMO

BACKGROUND: Since WHO recommended introduction of at least a single dose of inactivated poliovirus vaccine (IPV) in routine immunisation schedules, there have been global IPV shortages. Fractional-dose IPV (fIPV) administration is one of the strategies to ensure IPV availability. We reviewed studies comparing the effects of fractional with full-dose IPV vaccination to determine when seroconversion proportions with each strategy become similar in children aged 5 years and younger. METHOD: In this systematic review and meta-analysis, we searched 16 databases in July, 2019, for trials and observational studies, including ongoing studies that compare immunogenicity and adverse events of fractional-dose (0·1 mL) to full-dose (0·5 mL) IPV in healthy children aged 5 years or younger regardless of study design, number of doses, and route of administration. Screening, selection of articles, data extraction, and risk of bias assessment were done in duplicate, and conflicts were resolved by discussion or arbitration by a third author. We assessed immunogenicity, the main outcome, as proportion of seroconverted participants and changes in geometric mean titres of anti-poliovirus antibodies. Timepoints were eligible for analysis if measurements were done at least 4 weeks after vaccination. Summary estimates were pooled by use of random-effects meta-analysis. Analysis was stratified by study design, type of outcome measure, type of poliovirus, and number of doses given. We assessed heterogeneity using the χ2 test of homogeneity and quantified it using the I2 statistic. We assessed risk of bias using the Cochrane risk of bias tool, and the certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation approach. The study is registered with PROSPERO, CRD42018092647. FINDINGS: 860 records were screened for eligibility, of which 36 potentially eligible full-text articles were assessed and 14 articles were included in the final analysis: two ongoing trials and 12 articles reporting on ten completed studies. For poliovirus type 2, there were no significant differences in the proportions of seroconversions between fractional and full doses of IPV for two or three doses: the risk ratio for serconversion at one dose was 0·61 (95% CI 0·51-0·72), at two doses was 0·90 (0·82-1·00), and at three doses was 0·95 (0·91-1·00). Geometric mean titres (GMTs) for poliovirus type 2 were lower for fIPV than for full-dose IPV: -0·51 (95% CI -0·87 to -0·14) at one dose, -0·49 (-0·70 to -0·28) at two doses, and -0·98 (-1·46 to -0·51) at three doses. The seroconversion meta-analysis for the three-dose comparison was homogeneous (p=0·45; I2=0%), whereas heterogeneity was observed in the two-dose (p<0·00001; I2=88%) and one-dose (p=0·0004; I2=74%) comparisons. Heterogeneity was observed in meta-analyses of GMTs for one-dose (p<0·00001; I2=92%), two-dose (p=0·002; I2=80%), and three-dose (p<0·00001; I2=93%) comparisons. Findings for types 1 and 3 were similar to those for type 2. The certainty of the evidence was high for the three-dose comparisons and moderate for the rest of the comparisons. INTERPRETATION: There is no substantial difference in seroconversion between three doses of fIPV and three doses of full-dose IPV, although the full dose gives higher titres of antibodies for poliovirus type 1, 2, and 3. Use of fractional IPV instead of the full dose can stretch supplies and possibly lower the cost of vaccination. FUNDING: South African Medical Research Council and the National Research Foundation of South Africa.


Assuntos
Anticorpos Antivirais/sangue , Esquemas de Imunização , Imunogenicidade da Vacina , Vacina Antipólio de Vírus Inativado/administração & dosagem , Administração Oral , Pré-Escolar , Relação Dose-Resposta Imunológica , Humanos , Injeções Intradérmicas , Poliomielite/prevenção & controle , Poliovirus , Vacina Antipólio de Vírus Inativado/imunologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Soroconversão
18.
Pediatr Rheumatol Online J ; 19(1): 62, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33933127

RESUMO

BACKGROUND: Inadequate systemic exposure to infliximab (IFX) is associated with treatment failure. This work evaluated factors associated with reduced IFX exposure in children with autoimmune disorders requiring IFX therapy. METHODS: In this single-center cross-sectional prospective study IFX trough concentrations and anti-drug antibodies (ADAs) were measured in serum from children diagnosed with inflammatory bowel disease (IBD) (n = 73), juvenile idiopathic arthritis (JIA) (n = 16), or uveitis (n = 8) receiving maintenance IFX infusions at an outpatient infusion clinic in a tertiary academic pediatric hospital. IFX concentrations in combination with population pharmacokinetic modeling were used to estimate IFX clearance. Patient demographic and clinical data were collected by chart review and evaluated for their relationship with IFX clearance. RESULTS: IFX trough concentrations ranged from 0 to > 40 µg/mL and were 3-fold lower in children with IBD compared to children with JIA (p = 0.0002) or uveitis (p = 0.001). Children with IBD were found to receive lower IFX doses with longer dosing intervals, resulting in dose intensities (mg/kg/day) that were 2-fold lower compared to children with JIA (p = 0.0002) or uveitis (p = 0.02). Use of population pharmacokinetic analysis to normalize for variation in dosing practices demonstrated that increased IFX clearance was associated with ADA positivity (p = 0.004), male gender (p = 0.02), elevated erythrocyte sedimentation rate (ESR) (p = 0.02), elevated c-reactive protein (CRP) (p = 0.001), reduced serum albumin concentrations (p = 0.0005), and increased disease activity in JIA (p = 0.009) and IBD (p ≤ 0.08). No significant relationship between diagnosis and underlying differences in IFX clearance was observed. Multivariable analysis by covariate population pharmacokinetic modeling confirmed increased IFX clearance to be associated with anti-IFX antibody positivity, increased ESR, and reduced serum albumin concentrations. CONCLUSIONS: Enhanced IFX clearance is associated with immunogenicity and inflammatory burden across autoimmune disorders. Higher systemic IFX exposures observed in children with rheumatologic disorders are driven primarily by provider drug dose and interval selection, rather than differences in IFX pharmacokinetics across diagnoses. Despite maintenance IFX dosing at or above the standard recommended range for IBD (i.e., 5 mg/kg every 8 weeks), the dosing intensity used in the treatment of IBD is notably lower than dosing intensities used to treat JIA and uveitis, and may place some children with IBD at risk for suboptimal maintenance IFX exposures necessary for treatment response.


Assuntos
Artrite Juvenil , Doenças Autoimunes , Monitoramento de Medicamentos , Doenças Inflamatórias Intestinais , Infliximab , Uveíte , Adolescente , Anticorpos Anti-Idiotípicos/sangue , Artrite Juvenil/sangue , Artrite Juvenil/diagnóstico , Artrite Juvenil/tratamento farmacológico , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/epidemiologia , Estudos Transversais , Relação Dose-Resposta Imunológica , Monitoramento de Medicamentos/métodos , Monitoramento de Medicamentos/normas , Monitoramento de Medicamentos/estatística & dados numéricos , Feminino , Humanos , Doenças Inflamatórias Intestinais/sangue , Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Infliximab/administração & dosagem , Infliximab/imunologia , Infliximab/farmacocinética , Masculino , Taxa de Depuração Metabólica/fisiologia , Pediatria/métodos , Inibidores do Fator de Necrose Tumoral/administração & dosagem , Inibidores do Fator de Necrose Tumoral/imunologia , Inibidores do Fator de Necrose Tumoral/farmacocinética , Estados Unidos/epidemiologia , Uveíte/sangue , Uveíte/diagnóstico , Uveíte/tratamento farmacológico
19.
Int J Mol Sci ; 22(5)2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33806315

RESUMO

Systemic injection of a nerve growth factor (NGF) antibody has been proven to have a significant relevance in relieving osteoarthritis (OA) pain, while its adverse effects remain a safety concern for patients. A local low-dose injection is thought to minimize adverse effects. In this study, OA was induced in an 8-week-old male Sprague-Dawley (SD) rat joint by monoiodoacetate (MIA) injection for 2 weeks, and the effect of weekly injections of low-dose (1, 10, and 100 µg) NGF antibody or saline (control) was evaluated. Behavioral tests were performed, and at the end of week 6, all rats were sacrificed and their knee joints were collected for macroscopic and histological evaluations. Results showed that 100 µg NGF antibody injection relieved pain in OA rats, as evidenced from improved weight-bearing performance but not allodynia. In contrast, no significant differences were observed in macroscopic and histological scores between rats from different groups, demonstrating that intra-articular treatment does not worsen OA progression. These results suggest that local administration yielded a low effective NGF antibody dose that may serve as an alternative approach to systemic injection for the treatment of patients with OA.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Artrite Experimental/terapia , Fator de Crescimento Neural/antagonistas & inibidores , Osteoartrite/terapia , Manejo da Dor/métodos , Animais , Artrite Experimental/patologia , Artrite Experimental/fisiopatologia , Cartilagem Articular/patologia , Relação Dose-Resposta Imunológica , Hiperalgesia/fisiopatologia , Hiperalgesia/terapia , Injeções Intra-Articulares , Ácido Iodoacético/toxicidade , Masculino , Fator de Crescimento Neural/imunologia , Osteoartrite/patologia , Osteoartrite/fisiopatologia , Ratos , Ratos Sprague-Dawley , Suporte de Carga/fisiologia
20.
Int J Mol Sci ; 22(5)2021 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-33800950

RESUMO

Male patients with Fabry disease (FD) are at high risk for the formation of antibodies to recombinant α-galactosidase A (AGAL), used for enzyme replacement therapy. Due to the rapid disease progression, the identification of patients at risk is highly warranted. However, currently suitable references and standardized protocols for anti-drug antibodies (ADA) determination do not exist. Here we generate a comprehensive patient-derived antibody mixture as a reference, allowing ELISA-based quantification of antibody titers from individual blood samples. Serum samples of 22 male patients with FD and ADAs against AGAL were pooled and purified by immune adsorption. ADA-affinities against agalsidase-α, agalsidase-ß and Moss-AGAL were measured by quartz crystal microbalance with dissipation monitoring (QCM-D). AGAL-specific immune adsorption generated a polyclonal ADA mixture showing a concentration-dependent binding and inhibition of AGAL. Titers in raw sera and from purified total IgGs (r2 = 0.9063 and r2 = 0.8952, both p < 0.0001) correlated with the individual inhibitory capacities of ADAs. QCM-D measurements demonstrated comparable affinities of the reference antibody for agalsidase-α, agalsidase-ß and Moss-AGAL (KD: 1.94 ± 0.11 µM, 2.46 ± 0.21 µM, and 1.33 ± 0.09 µM, respectively). The reference antibody allows the ELISA-based ADA titer determination and quantification of absolute concentrations. Furthermore, ADAs from patients with FD have comparable affinities to agalsidase-α, agalsidase-ß and Moss-AGAL.


Assuntos
Anticorpos Neutralizantes/imunologia , Terapia de Reposição de Enzimas , Ensaio de Imunoadsorção Enzimática , Doença de Fabry/imunologia , alfa-Galactosidase/imunologia , alfa-N-Acetilgalactosaminidase/imunologia , Anticorpos Neutralizantes/biossíntese , Afinidade de Anticorpos , Relação Dose-Resposta Imunológica , Doença de Fabry/sangue , Doença de Fabry/tratamento farmacológico , Humanos , Imunoglobulina G/biossíntese , Imunoglobulina G/imunologia , Masculino , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/uso terapêutico , Padrões de Referência , alfa-Galactosidase/sangue , alfa-Galactosidase/uso terapêutico , alfa-N-Acetilgalactosaminidase/sangue , alfa-N-Acetilgalactosaminidase/uso terapêutico
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