RESUMEN
The continuous emergence of highly immune-evasive SARS-CoV-2 variants has challenged vaccine efficacy. A vaccine that can provide broad protection is desirable. We evaluated the immunogenicity of a series of monovalent and bivalent adenovirus-vectored vaccines containing the spikes of Wildtype (WT), Beta, Delta, Omicron subvariants BA.1, BA.2, BA.2.12.1, BA.2.13, BA.3, BA.5, BQ.1.1, and XBB. Vaccination in mice using monovalent vaccines elicited the highest neutralizing titers against each self-matched strain, but against other variants were reduced 2- to 73-fold. A bivalent vaccine consisting of WT and BA.5 broadened the neutralizing breadth against pre-Omicron and Omicron subvariants except XBB. Among bivalent vaccines based on the strains before the emergence of XBB, a bivalent vaccine consisting of BA.2 and BA.5 elicited the most potent neutralizing antibodies against Omicron subvariants, including XBB. In mice primed with injected WT vaccine, intranasal booster with a bivalent vaccine containing XBB and BA.5 could elicit broad serum and respiratory mucosal neutralizing antibodies against all late Omicron subvariants, including XBB. In mice that had been sequentially vaccinated with WT and BA.5, intranasal booster with a monovalent XBB vaccine elicited greater serum and mucosal XBB neutralizing antibodies than bivalent vaccines containing XBB. Both monovalent and bivalent XBB vaccines induced neutralizing antibodies against EG.5. Unlike the antibody response, which is highly variant-specific, mice receiving either monovalent or bivalent vaccines elicited comparable T-cell responses against all variants. Furthermore, intranasal but not intramuscular booster induced antigen-specific lung resident T cells. This study provides insights into the design of the COVID-19 vaccine and vaccination strategies.
Asunto(s)
Vacunas contra el Adenovirus , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Vacunas contra la COVID-19 , COVID-19 , Ratones Endogámicos BALB C , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , Animales , SARS-CoV-2/inmunología , SARS-CoV-2/genética , Ratones , Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/administración & dosificación , Anticuerpos Neutralizantes/sangre , Anticuerpos Neutralizantes/inmunología , COVID-19/prevención & control , COVID-19/inmunología , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Glicoproteína de la Espiga del Coronavirus/genética , Vacunas contra el Adenovirus/inmunología , Vacunas contra el Adenovirus/administración & dosificación , Femenino , Humanos , Inmunogenicidad Vacunal , Vacunación , Adenoviridae/genética , Adenoviridae/inmunologíaRESUMEN
Adenoviral and mRNA vaccines encoding the viral spike (S) protein have been deployed globally to contain severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Older individuals are particularly vulnerable to severe infection, probably reflecting age-related changes in the immune system, which can also compromise vaccine efficacy. It is nonetheless unclear to what extent different vaccine platforms are impacted by immunosenescence. Here, we evaluated S protein-specific immune responses elicited by vaccination with two doses of BNT162b2 or ChAdOx1-S and subsequently boosted with a single dose of BNT162b2 or mRNA-1273, comparing age-stratified participants with no evidence of previous infection with SARS-CoV-2. We found that aging profoundly compromised S protein-specific IgG titers and further limited S protein-specific CD4+ and CD8+ T cell immunity as a probable function of progressive erosion of the naive lymphocyte pool in individuals vaccinated initially with BNT162b2. Our results demonstrate that primary vaccination with ChAdOx1-S and subsequent boosting with BNT162b2 or mRNA-1273 promotes sustained immunological memory in older adults and potentially confers optimal protection against coronavirus disease 2019.
Asunto(s)
Vacuna nCoV-2019 mRNA-1273 , Inmunidad Adaptativa , Vacuna BNT162 , Vacunas contra la COVID-19 , COVID-19 , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , Vacunas de ARNm , Humanos , COVID-19/inmunología , COVID-19/prevención & control , Vacuna BNT162/inmunología , SARS-CoV-2/inmunología , Anciano , Persona de Mediana Edad , Inmunidad Adaptativa/inmunología , Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/administración & dosificación , Glicoproteína de la Espiga del Coronavirus/inmunología , Vacunas de ARNm/inmunología , Adulto , Masculino , Femenino , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Vacunas contra el Adenovirus/inmunología , Vacunas contra el Adenovirus/administración & dosificación , Linfocitos T CD8-positivos/inmunología , Factores de Edad , ChAdOx1 nCoV-19 , Envejecimiento/inmunología , Linfocitos T CD4-Positivos/inmunología , Vacunas Sintéticas/inmunología , Vacunas Sintéticas/administración & dosificaciónRESUMEN
Non-replicating adenovirus-based vectors have been broadly used for the development of prophylactic vaccines in humans and are licensed for COVID-19 and Ebola virus disease prevention. Adenovirus-based vectored vaccines encode for one or more disease specific transgenes with the aim to induce protective immunity against the target disease. The magnitude and duration of transgene expression of adenovirus 5- based vectors (human type C) in the host are key factors influencing antigen presentation and adaptive immune responses. Here we characterize the magnitude, duration, and organ biodistribution of transgene expression after single intramuscular administration of adenovirus 26-based vector vaccines in mice and evaluate the differences with adenovirus 5-based vector vaccine to understand if this is universally applicable across serotypes. We demonstrate a correlation between peak transgene expression early after adenovirus 26-based vaccination and transgene-specific cellular and humoral immune responses for a model antigen and SARS-CoV-2 spike protein, independent of innate immune activation. Notably, the memory immune response was similar in mice immunized with adenovirus 26-based vaccine and adenovirus 5-based vaccine, despite the latter inducing a higher peak of transgene expression early after immunization and a longer duration of transgene expression. Together these results provide further insights into the mode of action of adenovirus 26-based vector vaccines.
Asunto(s)
Vacunas contra el Adenovirus , Glicoproteína de la Espiga del Coronavirus , Vacunas , Animales , Ratones , Humanos , Inmunidad Humoral , Distribución Tisular , Inmunización , Vacunación , Adenoviridae/genética , Transgenes , Vectores Genéticos/genética , Anticuerpos AntiviralesRESUMEN
In recent years, multivariate data analysis (MVDA) has been widely used for process characterization and fault diagnosis in the biopharmaceutical industry. This study aims to investigate the feasibility of using MVDA for the development and scale-up of a perfusion process for HEK293 cell-based recombinant adenovirus zoster vaccine (Ad-HER) production. The Principal Component Analysis (PCA) results suggested comparable performance among the ATF, PATFP, and BFP perfusion systems in benchtop-scale stirred-tank bioreactor (STR). Then a Batch Evolution Model (BEM) was built using representative data from 10 L STR with a BFP system to assess the Ad-HER perfusion process performance at pilot-scale bioreactor (50 L STR and 50 L wave bioreactor). Furthermore, another BEM model and Batch Level Model (BLM) were built to monitor process parameters over time and predict the final adenovirus titer in 50 L wave bioreactor. The loading plot revealed that lactate dehydrogenase activity, viable cell diameter, and base-added during the virus production phase could be used as preliminary indicators of adenovirus yield. Finally, an adenovirus titer of 2.0±0.3×1010 IFU/mL was achieved in the 50 L wave bioreactor with BFP system, highlighting the robustness of the Ad-HER perfusion process at pilot-scale. Overall, this study emphasizes the effectiveness of MVDA as a tool for advancing the understanding of recombinant adenovirus vaccine perfusion production process development and scale-up.
Asunto(s)
Vacunas contra el Adenovirus , Vacuna contra el Herpes Zóster , Humanos , Técnicas de Cultivo de Célula/métodos , Adenoviridae , Células HEK293 , Reactores BiológicosRESUMEN
On March 13, 2021, Tunisia started a widespread immunization program against SARS-CoV-2 utilizing different vaccinations that had been given emergency approval. Herein, we followed prospectively a cohort of participant who received COVID-19 vaccine (Pfizer BioNTech and Sputnik-Gameleya V). The goal of this follow-up was to define the humoral and cellular immunological profile after immunization by assessing neutralizing antibodies and IFN- γ release. 26 vaccinated health care workers by Pfizer BioNTech (n=12) and Sputnik-Gameleya V (n=14) were enrolled from June to December 2021 in Military hospital of Tunis. All consenting participants were sampled for peripheral blood after three weeks of vaccination. The humoral response was investigated by the titer of anti-SARS-CoV-2 immunoglobulin G (IgG) antibodies to S1 protein. The CD4 and CD8 T cell responses were evaluated by the QuantiFERON® SARS-CoV-2 (Qiagen® Basel, Switzerland). Regardless the type of vaccine, the assessment of humoral and cellular response following vaccination showed a strong involvement of the later with expression of IFN-γ as compared to antibodies secretion. Moreover, we showed that people with past SARS-CoV-2 infection developed high levels of antibodies than those who are not previously infected. However, no significant difference was detected concerning interferon gamma (IFN-γ) expression by CD4 and CD8 T cells in health care worker (HCW) previously infection or not with COVID-19 infection. Analysis of immune response according to the type of vaccine, we found that Pfizer BioNTech induced high level of humoral response (91.66%) followed by Sputnik-Gameleya V (64.28%). However, adenovirus vaccine gave a better cellular response (57.14%) than mRNA vaccine (41.66%). Regarding the immune response following vaccine doses, we revealed a significant increase of neutralizing antibodies and IFN-γ release by T cells in patients fully vaccinated as compared to those who have received just one vaccine. Collectively, our data revealed a similar immune response between Pfizer BioNTech and Sputnik-Gameleya V vaccine with a slight increase of humoral response by mRNA vaccine and cellular response by adenovirus vaccine. It's evident that past SARS-CoV-2 infection was a factor that contributed to the vaccination's increased immunogenicity. However, the administration of full doses of vaccines (Pfizer BioNTech or Sputnik-Gameleya V) induces better humoral and cellular responses detectable even more than three months following vaccination.
Asunto(s)
Vacunas contra el Adenovirus , Antígenos de Grupos Sanguíneos , COVID-19 , Vacunas , Humanos , SARS-CoV-2 , Vacunas contra la COVID-19 , Vacunas de ARNm , Vacunación , Anticuerpos Neutralizantes , Personal de Salud , Interferón gamma , Anticuerpos Antivirales , Inmunidad HumoralRESUMEN
Feline coronavirus (FCoV) is an unsegmented, single-stranded RNA virus belonging to the Alphacoronavirus genus. It can cause fatal feline infectious peritonitis (FIP) in cats of any ages. Currently, there are no effective prevention and control measures to against FCoV. In this study, we developed a recombinant adenovirus vaccine, AD5-N, based on the nucleocapsid(N) protein of FCoV. The immunogenicity of AD5-N was evaluated through intramuscular immunization in 6-week-old Balb/c mice and 9-12 months old cats. Compared to the control group, AD5-N specifically induced a significant increase in IgG and SIgA levels in the vaccinated mice. Furthermore, AD5-N not only effectively promoted strong cellular immune responses in cats but also induced high levels of specific SIgA, effectively helping cats resist FCoV infection. Our findings suggest that adenovirus vector vaccines based on the N gene have the potential to become candidate vaccines for the prevention and control of FCoV infection.
Asunto(s)
Infecciones por Adenoviridae , Vacunas contra el Adenovirus , Infecciones por Coronavirus , Coronavirus Felino , Vacunas , Gatos , Animales , Ratones , Adenoviridae/genética , Coronavirus Felino/genética , Inmunoglobulina A Secretora , Ratones Endogámicos BALB C , InmunidadRESUMEN
Influenza virus is a kind of virus that poses several hazards of animal and human health. Therefore, it is important to develop an effective vaccine to prevent influenza. To this end we successfully packaged recombinant adenovirus rAd-NP-M2e-GFP expressing multiple copies of influenza virus conserved antigens NP and M2e and packaged empty vector adenovirus rAd-GFP. The effect of rAd-NP-M2e-GFP on the activation of dendritic cell (DC) in vitro and in vivo was detected by intranasal immunization. The results showed that rAd-NP-M2e-GFP promoted the activation of DC in vitro and in vivo. After the primary immunization and booster immunization of mice through the nasal immune way, the results showed that rAd-NP-M2e-GFP induced enhanced local mucosal-specific T cell responses, increased the content of SIgA in broncho alveolar lavage fluids (BALF) and triggered the differentiation of B cells in the germinal center. It is proved that rAd-NP-M2e-GFP can significantly elicit mucosal immunity and systemic immune response. In addition, rAd-NP-M2e-GFP could effectively protect mice after H1N1 influenza virus challenge. To lay the foundation and provide reference for further development of influenza virus mucosal vaccine in the future.
Asunto(s)
Vacunas contra el Adenovirus , Subtipo H1N1 del Virus de la Influenza A , Vacunas contra la Influenza , Infecciones por Orthomyxoviridae , Animales , Ratones , Humanos , Adenoviridae/genética , Inmunización , Vacunas Sintéticas , Inmunidad Mucosa , Ratones Endogámicos BALB C , Anticuerpos AntiviralesRESUMEN
Several COVID-19 vaccines use adenovirus vectors to deliver the SARS-CoV-2 spike (S) protein. Immunization with these vaccines promotes immunity against the S protein, but against also the adenovirus itself. This could interfere with the entry of the vaccine into the cell, reducing its efficacy. Herein, we evaluate the efficiency of an adenovirus-vectored vaccine (chimpanzee ChAdOx1 adenovirus, AZD1222) in boosting the specific immunity compared to that induced by a recombinant receptor-binding domain (RBD)-based vaccine without viral vector. Mice immunized with the AZD1222 human vaccine were given a booster 6 months later, with either the homologous vaccine or a recombinant vaccine based on RBD of the delta variant, which was prevalent at the start of this study. A significant increase in anti-RBD antibody levels was observed in rRBD-boosted mice (31-61%) compared to those receiving two doses of AZD1222 (0%). Significantly higher rates of PepMix™- or RBD-elicited proliferation were also observed in IFNγ-producing CD4 and CD8 cells from mice boosted with one or two doses of RBD, respectively. The lower efficiency of the ChAdOx1-S vaccine in boosting specific immunity could be the result of a pre-existing anti-vector immunity, induced by increased levels of anti-adenovirus antibodies found both in mice and humans. Taken together, these results point to the importance of avoiding the recurrent use of the same adenovirus vector in individuals with immunity and memory against them. It also illustrates the disadvantages of ChAdOx1 adenovirus-vectored vaccine with respect to recombinant protein vaccines, which can be used without restriction in vaccine-booster programs. KEY POINTS: ⢠ChAdOx1 adenovirus vaccine (AZD1222) may not be effective in boosting anti-SARS-CoV-2 immunity ⢠A recombinant RBD protein vaccine is effective in boosting anti-SARS-CoV-2 immunity in mice ⢠Antibodies elicited by the rRBD-delta vaccine persisted for up to 3 months in mice.
Asunto(s)
Vacunas contra el Adenovirus , COVID-19 , Vacunas , Humanos , Animales , Ratones , Pan troglodytes , ChAdOx1 nCoV-19 , Vacunas contra la COVID-19/genética , SARS-CoV-2 , COVID-19/prevención & control , Adenoviridae/genética , Vacunación , Anticuerpos Antivirales , Anticuerpos NeutralizantesAsunto(s)
Vacunas contra el Adenovirus , Vacunas , Humanos , Adenoviridae , Heparina , TromboinflamaciónRESUMEN
Os efeitos generalizados exercidos pela pandemia da doença do Coronavírus 2019 (COVID-19) obrigaram governos e instituições de saúde mundiais a deslocar recursos para a contenção da crise sanitária e a desenvolver métodos para reduzi-los. As vacinas foram elencadas como principal método para conter a pandemia, com mais de um bilhão de doses administradas em todo o mundo. Entre as vacinas produzidas até o momento para combate ao vírus causador, SARS-CoV-2, estão as vacinas de vetores de adenovírus da Oxford-AstraZeneca (AZD1222) e a da Johnson & Johnson (Ad26.COV2.S). Após a implementação da vacinação em massa da população mundial, relatou-se um distúrbio pró-trombótico extremamente raro associado a ambas vacinas com trombocitopenia concomitante e desenvolvimento de anticorpos antiplaquetários fator 4 (anti-PF4). Esta desordem foi denominada inicialmente como Síndrome da Trombose com Trombocitopenia (STT) e posteriormente como Trombose Trombocitopênica Imune induzida por Vacina (TTIV). Os primeiros casos de trombose relacionados à vacinação para o SARS-CoV-2 começaram a ser reportados no final de fevereiro de 2021. Os relatos levaram à abertura de uma investigação pelas Agências do Reino Unido de Regulação de Produtos de Saúde e Medicina (MHRA) e Europeia de Medicina (EMA), as quais anunciaram em 11 de março de 2021 que não havia uma associação identificada. Entretanto, três grupos de cientistas da Noruega, Alemanha e Reino Unido reportaram, na semana seguinte, um caso de trombose localizada no seio venoso cerebral com trombocitopenia e anticorpos antiplaquetários fator 4 em um indivíduo que havia recebido a vacina da Oxford-AstraZeneca. Após maiores investigações, em 7 de abril de 2021, MHRA e EMA anunciaram a nova Síndrome de Trombose com Trombocitopenia e anticorpos antiplaquetários fator 4. Em 11 de novembro de 2021, houve a elaboração de uma definição de caso para STT, realizada pelo Brighton Collaboration, a qual engloba 5 critérios: (1) evidência de trombocitopenia sem exposição recente à heparina; (2) presença de trombose ou tromboembolismo confirmado por exame de imagem, procedimento cirúrgico, exame patológico ou dor de cabeça persistente com elevação de D-dímero (sugerindo trombose de seio venoso cerebral); (3) sintomas clínicos de trombose (Quadro 1); (4) exames de imagem e achados laboratoriais que confirmem o diagnóstico de trombose ou tromboembolismo; (5) achados laboratoriais que confirmem o diagnóstico de anticorpos de ativação plaquetária mediados por trombose, como enzima-imunoensaio (EIA) positivo para anti-PF4 e teste funcional positivo de ativação plaquetária com adição de PF4.
Asunto(s)
Humanos , Trombocitopenia/inducido químicamente , Trombosis/inducido químicamente , Vacunas contra el Adenovirus/efectos adversos , COVID-19/prevención & control , Síndrome , Trombocitopenia/diagnóstico , Trombosis/tratamiento farmacológicoRESUMEN
Se describe la situación global de las infecciones por SARS-CoV-2 y los cuadros clínicos de COVID-19. Se presentan datos epidemiológicos de Centro América y de Guatemala, para ejemplificar algunos factores de riesgo de infección y morbilidad. Se revisa la función y estructura del sistema respiratorio, sus mecanismos de defensa innata -captura y remoción de agentes extraños, reconocimiento e inactivación de agentes potencialmente nocivos, reparación del daño y prevención de futuras incursiones por agentes identificados-, los de defensa adaptativa en las vías respiratorias y el microbioma. Se describen los tejidos linfoides nasal y bronquio-alveolar y la contribución de citoquinas, células especializadas y anticuerpos del tipo IgA secretoria a la protección antiviral, a la respuesta inflamatoria asociada a la infección y a la reparación del daño tisular. Se discuten las interacciones de SARS-CoV-2 con los mecanismos de defensa. Se presentan consideraciones para las medidas preventivas de infecciones, incluyendo la aplicación de vacunas, y para evitar enfermedad severa.
The global situation of SARS-CoV-2 infections and the clinical picture of COVID-19 are described. Epidemiological data from Central America and Guatemala are presented to exemplify some risk factors for infection and morbidity. The function and structure of the respiratory system and its innate defense mechanisms - capture and removal of foreign agents, recognition and inactivation of potentially harmful agents, repair of damage, and prevention of future incursions by identified agents are reviewed, as are those of the adaptive defense in the airways and of the respiratory microbiome. The nasal and bronchioalveolar lymphoid tissues are described. The contributions of cytokines, of specialized cells and of secretory IgA-type antibodies to antiviral protection, to the inflammatory response associated with infection, and to the repair of tissue damage are explained. SARS-CoV-2 interactions with defense mechanisms are discussed. Considerations are presented for the preventive measures of infections, including the application of vaccines, and those designed to avoid severe disease.
Asunto(s)
Humanos , Sistema Respiratorio , SARS-CoV-2 , COVID-19/prevención & control , Antivirales , Morbilidad , Mecanismos de Defensa , Vacunas contra el Adenovirus , AnticuerposAsunto(s)
Humanos , Resfriado Común/prevención & control , Vacunas contra el Adenovirus/administración & dosificación , Literatura de Revisión como Asunto , Vacunas Atenuadas/administración & dosificación , Ensayos Clínicos Controlados Aleatorios como Asunto , Estado de Salud , Revisiones Sistemáticas como AsuntoRESUMEN
Abstract Human adenovirus species F (HAdV-F) type 40 and 41 are commonly associated with acute diarrheal disease (ADD) across the world. Despite being the largest state in southeastern Brazil and having the second largest number of inhabitants, there is no information in the State of Minas Gerais regarding the role of HAdV-F in the etiology of ADD. This study was performed to determine the prevalence, to verify the epidemiological aspects of infection, and to characterize the strains of human adenoviruses (HAdV) detected. A total of 377 diarrheal fecal samples were obtained between January 2007 and August 2011 from inpatient and outpatient children of age ranging from 0 to 12 years. All samples were previously tested for rotavirus, norovirus, and astrovirus, and 314 of 377 were negative. The viral DNA was extracted, amplified using the polymerase chain reaction and the HAdV-positive samples were sequenced and phylogenetically analyzed. Statistical analyses were performed using the Chi-square test (p < 0.05), considering two conditions: the total of samples tested (377) and the total of negative samples for the remaining viruses tested (314). The overall prevalence of HAdV was 12.47% (47/377); and in 76.60% (36/47) of the positive samples, this virus was the only infectious agent detected. The phylogenetic analysis of partial sequences of 32 positive samples revealed that they all clustered with the HAdV-F type 41. The statistical analysis showed that there was no correlation between the onset of the HAdV infection and the origin of the samples (inpatients or outpatients) in the two conditions tested: the total of samples tested (p = 0.598) and the total of negative samples for the remaining viruses tested (p = 0.614). There was a significant association in the occurrence of infection in children aged 0–12 months for the condition 1 (p = 0.030) as well as condition 2 (p = 0.019). The occurrence of infections due to HAdV did not coincide with a pattern of seasonal distribution. These data indicate the significant involvement of HAdV-F type 41 in the etiology of ADD in Minas Gerais, which demonstrates the importance of other viral agents in the development of the disease after the introduction of rotavirus vaccine immunization.