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Clinical Medicine (London, England) Mar 2022In the new science emanating from the COVID-19 pandemic, effective vaccine development has made a huge difference and saved countless lives. Vaccine roll-out led to the... (Review)
Review
In the new science emanating from the COVID-19 pandemic, effective vaccine development has made a huge difference and saved countless lives. Vaccine roll-out led to the identification of rare cases of severe thrombotic and thrombocytopenic problems in some recipients. This apparent coupling of thrombosis with haemorrhagic potentiation might seem baffling but the ensuing clinical investigation rapidly shed important light on its molecular mechanism. This review outlines the current understanding on the role of adenovirus-based platforms, the immunogenic triggers and the immunothrombotic response underlying vaccine-induced immune thrombotic thrombocytopenia.
Topics: COVID-19; COVID-19 Vaccines; Humans; Pandemics; SARS-CoV-2; Thrombocytopenia; Thrombosis; Vaccines
PubMed: 35273026
DOI: 10.7861/clinmed.2022-0006 -
Journal of Pharmaceutical Sciences Apr 2023Adenovirus vectors have become an important class of vaccines with the recent approval of Ebola and COVID-19 products. In-process quality attribute data collected during...
Adenovirus vectors have become an important class of vaccines with the recent approval of Ebola and COVID-19 products. In-process quality attribute data collected during Adenovirus vector manufacturing has focused on particle concentration and infectivity ratios (based on viral genome: cell-based infectivity), and data suggest only a fraction of viral particles present in the final vaccine product are efficacious. To better understand this product heterogeneity, lab-scale preparations of two Adenovirus viral vectors, (Chimpanzee adenovirus (ChAdOx1) and Human adenovirus Type 5 (Ad5), were studied using transmission electron microscopy (TEM). Different adenovirus morphologies were characterized, and the proportion of empty and full viral particles were quantified. These proportions showed a qualitative correlation with the sample's infectivity values. Liquid chromatography-mass spectrometry (LC-MS) peptide mapping was used to identify key adenovirus proteins involved in viral maturation. Using peptide abundance analysis, a ∼5-fold change in L1 52/55k abundance was observed between low-(empty) and high-density (full) fractions taken from CsCl ultracentrifugation preparations of ChAdOx1 virus. The L1 52/55k viral protein is associated with DNA packaging and is cleaved during viral maturation, so it may be a marker for infective particles. TEM and LC-MS peptide mapping are promising higher-resolution analytical characterization tools to help differentiate between relative proportions of empty, non-infectious, and infectious viral particles as part of Adenovirus vector in-process monitoring, and these results are an encouraging initial step to better differentiate between the different product-related impurities.
Topics: Humans; Capsid; COVID-19; Viral Proteins; Adenoviridae; Adenoviruses, Human; Genetic Vectors
PubMed: 36563855
DOI: 10.1016/j.xphs.2022.12.012 -
European Journal of Immunology Jun 2023Replication-incompetent adenovirus (Ad) vector and mRNA-lipid nanoparticle (LNP) constructs represent two modular vaccine platforms that have attracted substantial... (Review)
Review
Replication-incompetent adenovirus (Ad) vector and mRNA-lipid nanoparticle (LNP) constructs represent two modular vaccine platforms that have attracted substantial interest over the past two decades. Due to the COVID-19 pandemic and the rapid development of multiple successful vaccines based on these technologies, there is now clear real-world evidence of the utility and efficacy of these platforms. Considerable optimization and refinement efforts underpin the successful application of these technologies. Despite this, our understanding of the specific pathways and processes engaged by these vaccines to stimulate the immune response remains incomplete. This review will synthesize our current knowledge of the specific mechanisms by which CD8 T cell and antibody responses are induced by each of these vaccine platforms, and how this can be impacted by specific vaccine construction techniques. Key gaps in our knowledge are also highlighted, which can hopefully focus future studies.
Topics: Humans; mRNA Vaccines; Pandemics; COVID-19; Genetic Vectors; Adenoviridae
PubMed: 36330560
DOI: 10.1002/eji.202250022 -
Frontiers in Microbiology 2021Vaccination is the most effective method to date to prevent viral diseases. It intends to mimic a naturally occurring infection while avoiding the disease, exposing our... (Review)
Review
Vaccination is the most effective method to date to prevent viral diseases. It intends to mimic a naturally occurring infection while avoiding the disease, exposing our bodies to viral antigens to trigger an immune response that will protect us from future infections. Among different strategies for vaccine development, recombinant vaccines are one of the most efficient ones. Recombinant vaccines use safe viral vectors as vehicles and incorporate a transgenic antigen of the pathogen against which we intend to generate an immune response. These vaccines can be based on replication-deficient viruses or replication-competent viruses. While the most effective strategy involves replication-competent viruses, they must be attenuated to prevent any health hazard while guaranteeing a strong humoral and cellular immune response. Several attenuation strategies for adenoviral-based vaccine development have been contemplated over time. In this paper, we will review them and discuss novel approaches based on the principle that protein synthesis from individual genes can be modulated by codon usage bias manipulation. We will summarize vaccine approaches that consider recoding of viral proteins to produce adenoviral attenuation and recoding of the transgene antigens for both viral attenuation and efficient viral epitope expression.
PubMed: 33643266
DOI: 10.3389/fmicb.2021.633946 -
Virologica Sinica Jun 2021Successful vaccines induce specific immune responses and protect against various viral and bacterial infections. Noninactivated vaccines, especially viral vector...
Successful vaccines induce specific immune responses and protect against various viral and bacterial infections. Noninactivated vaccines, especially viral vector vaccines such as adenovirus and poxvirus vaccines, dominate the vaccine market because their viral particles are able to replicate and proliferate in vivo and produce lasting immunity in a manner similar to natural infection. One challenge of human and livestock vaccination is vaccine stability related to the antigenicity and infectivity. Freeze-drying is the typical method to maintain virus vaccine stability, while cold chain transportation is required for temperatures about 2 °C-8 °C. The financial and technological resource requirements hinder vaccine distribution in underdeveloped areas. In this study, we developed a freeze-drying formula consisting of bovine serum albumin (BSA), L-glutamic acid (L-Glu), polyethylene glycol (PEG), and dextran (DEX) to improve the thermal stability and activity of viral vaccines, including vaccinia recombinant vaccine (rTTV-OVA) and adenovirus vaccine (Ad5-ENV). We compared a panel of five different formulations (PEG: DEX: BSA: L-GLU = 50:9:0:0(#1), 50:5:4:0(#2), 50:10:9:0(#3), 50:0:0:9(#4), and 50:1:0:8(#5), respectively) and optimized the freeze-drying formula for rTTV-OVA and Ad5-ENV. We found that the freeze-drying formulations #2 and #3 could maintain rTTV-OVA infectivity at temperatures of 4 °C and 25 °C and that rTTV-OVA immunogenicity was retained during lyophilization. However, formulations #4 and #5 maintained Ad5-ENV infectivity under the same conditions, and Ad5-ENV immunogenicity had maximum retention with freeze-drying formulation #4. In summary, we developed new freeze-drying formulations that increased virus vaccine storage times and retained immunogenicity at an ambient temperature.
Topics: Adenoviridae; Adenovirus Vaccines; Drug Stability; Freeze Drying; Humans; Temperature
PubMed: 32696399
DOI: 10.1007/s12250-020-00250-1 -
Vaccines Nov 2023Respiratory syncytial virus (RSV) infection and shingles are two viral diseases that affect older adults, and a combined vaccine to protect against both could be...
Respiratory syncytial virus (RSV) infection and shingles are two viral diseases that affect older adults, and a combined vaccine to protect against both could be beneficial. RSV infection causes hospitalisations and significant morbidity in both children and adults and can be fatal in the elderly. The RSV fusion (F) envelope glycoprotein induces a strong RSV-neutralising antibody response and is the target of protective immunity in the first RSV vaccine for older adults, recently approved by the FDA. An initial childhood infection with the varicella zoster virus (VZV) results in chickenpox disease, but reactivation in older adults can cause shingles. This reactivation in sensory and autonomic neurons is characterized by a skin-blistering rash that can be accompanied by prolonged pain. The approved protein-in-adjuvant shingles vaccine induces VZV glycoprotein E (gE)-fspecific antibody and CD4 T cell responses and is highly effective. Here we report the evaluation of RSV/shingles combination vaccine candidates based on non-replicating chimpanzee adenovirus (ChAd) vectors. We confirmed the cellular and humoral immunogenicity of the vaccine vectors in mice using T cell and antibody assays. We also carried out an RSV challenge study in cotton rats which demonstrated protective efficacy following a homologous prime-boost regimen with our preferred vaccine candidate.
PubMed: 38006010
DOI: 10.3390/vaccines11111679 -
Cells Oct 2021As of September 2021, twenty-one anti-COVID-19 vaccines have been approved in the world. Their utilization will expedite an end to the current pandemic. Besides the... (Review)
Review
As of September 2021, twenty-one anti-COVID-19 vaccines have been approved in the world. Their utilization will expedite an end to the current pandemic. Besides the usual vaccine formats that include inactivated viruses (eight approved vaccines) and protein-based vaccines (four approved vaccines), three new formats have been validated: recombinant adenovirus (six approved vaccines), DNA (one approved vaccine), and messenger RNA (mRNA, two approved vaccines). The latter was the fastest (authorized in 2020 in the EU, the USA, and Switzerland). Most Western countries have reserved or use the protein vaccines, the adenovirus vaccines, and mRNA vaccines. I describe here the different vaccine formats in the context of COVID-19, detail the three formats that are chiefly reserved or used in Europe, Canada, and the USA, and discuss why the mRNA vaccines appear to be the superior format.
Topics: Adenoviridae; Animals; COVID-19; COVID-19 Vaccines; Canada; DNA; Drug Approval; Europe; Humans; Mice; Patient Safety; RNA, Messenger; SARS-CoV-2; Spike Glycoprotein, Coronavirus; United States
PubMed: 34685696
DOI: 10.3390/cells10102716 -
Infectious Agents and Cancer Feb 2022This study aims to prepare candidate vaccines for cervical cancer immunotherapy by inserting the fused genes of human papillomavirus (HPV)16/18/58 mE6E7 lacking...
OBJECTIVE
This study aims to prepare candidate vaccines for cervical cancer immunotherapy by inserting the fused genes of human papillomavirus (HPV)16/18/58 mE6E7 lacking transforming activity into an adenovirus vector and to verify its efficiency in model mice with tumor expressing the associated HPV genes.
METHODS
The E6/E7 genes of HPV16/18/58 were point-mutated to abolish their transforming activity, and adenovirus (AD)-HPV16/18/58 mE6E7 adenovirus vaccine was constructed. The immune effect of the adenovirus vaccine against HPV16/18/58-type tumors was analyzed by tumor morphology, enzyme linked immunosorbent assay, enzyme-linked immunospot and specific cytotoxic T lymphocyte (CTL) and T lymphocyte subsets.
RESULTS
The HPV16/18/58 mE6E7 plasmid containing point mutations was verified by quantitative real-time polymerase chain reaction (qRT-PCR), enzyme digestion and electrophoresis, and gene sequencing. qRT-PCR and Western blots verified that AD-HPV16/18/58 mE6E7 could express the HPV16 mE6E7, HPV18 mE6E7 and HPV58 mE6E7 fusion genes and proteins in cells. The results of animal experiments were as follows: In the vaccine group, the tumors formed later, the incubation period was longer, the growth was slower, growth was inhibited, and the survival period was significantly prolonged. The immunological results all showed that the vaccine could induce effective humoral and cellular immunity in mice with three types of tumors, compared with the phosphate buffered saline (PBS) group and the adenovirus-negative control (AD-NC) group, the differences were statistically significant (P < 0.05).
CONCLUSION
We successfully constructed the HPV16/18/58 trivalent therapeutic adenovirus vaccine AD-HPV16/18/58 mE6E7. The AD-HPV16/18/58 mE6E7 adenovirus vaccine can protect immunized mice to a certain extent from TC-1, U14/LV-HPV18 E6E7 and U14/LV-HPV58 E6E7 cells, which contain HPV16, 18 and 58 E6 and/or E7 genes, respectively.
PubMed: 35197089
DOI: 10.1186/s13027-022-00417-3 -
Human Vaccines & Immunotherapeutics Dec 2023Herpes zoster (HZ) results from waning immunity following childhood infection with varicella zoster virus (VZV) but is preventable by vaccination with recombinant HZ...
Herpes zoster (HZ) results from waning immunity following childhood infection with varicella zoster virus (VZV) but is preventable by vaccination with recombinant HZ vaccine or live HZ vaccine (two doses or one dose, respectively). Vaccine efficacy declines with age, live HZ vaccine is contraindicated in immunosuppressed individuals, and severe local reactogenicity of recombinant HZ vaccine is seen in up to 20% of older adults, indicating a potential need for new vaccines. Nonreplicating chimpanzee adenovirus (ChAd) vectors combine potent immunogenicity with well-established reactogenicity and safety profiles. We evaluated the cellular and humoral immunogenicity of ChAdOx1 encoding VZV envelope glycoprotein E (ChAdOx1-VZVgE) in mice using IFN-γ ELISpot, flow cytometry with intracellular cytokine staining, and ELISA. In outbred CD-1 mice, one dose of ChAdOx1-VZVgE (1 × 10 infectious units) elicited higher gE-specific T cell responses than two doses of recombinant HZ vaccine (1 µg) or one dose of live HZ vaccine (1.3 × 10 plaque-forming units). Antibody responses were higher with two doses of recombinant HZ vaccine than with two doses of ChAdOx1-VZVgE or one dose of live HZ vaccine. ChAdOx1-VZVgE boosted T cell and antibody responses following live HZ vaccine priming. The frequencies of polyfunctional CD4+ and CD8+ T cells expressing more than one cytokine (IFN-γ, TNF-α and IL-2) were higher with ChAdOx1-VZVgE than with the conventional vaccines. Results were similar in young and aged BALB/c mice. These findings support the clinical development of ChAdOx1-VZVgE for prevention of HZ in adults aged 50 years or over, including those who have already received conventional vaccines.
Topics: Animals; Mice; Herpesvirus 3, Human; Adenovirus Vaccines; Adenoviridae; Antibodies, Viral; Herpes Zoster; Herpes Zoster Vaccine; Vaccination; Cytokines; Immunogenicity, Vaccine
PubMed: 36785938
DOI: 10.1080/21645515.2023.2175558 -
Human Vaccines & Immunotherapeutics 2015Influenza virus (IFV) infection causes serious health problems and heavy financial burdens each year worldwide. The classical inactivated influenza virus vaccine (IIVV)... (Review)
Review
Influenza virus (IFV) infection causes serious health problems and heavy financial burdens each year worldwide. The classical inactivated influenza virus vaccine (IIVV) and live attenuated influenza vaccine (LAIV) must be updated regularly to match the new strains that evolve due to antigenic drift and antigenic shift. However, with the discovery of broadly neutralizing antibodies that recognize conserved antigens, and the CD8(+) T cell responses targeting viral internal proteins nucleoprotein (NP), matrix protein 1 (M1) and polymerase basic 1 (PB1), it is possible to develop a universal influenza vaccine based on the conserved hemagglutinin (HA) stem, NP, and matrix proteins. Recombinant adenovirus (rAd) is an ideal influenza vaccine vector because it has an ideal stability and safety profile, induces balanced humoral and cell-mediated immune responses due to activation of innate immunity, provides 'self-adjuvanting' activity, can mimic natural IFV infection, and confers seamless protection against mucosal pathogens. Moreover, this vector can be developed as a low-cost, rapid-response vaccine that can be quickly manufactured. Therefore, an adenovirus vector encoding conserved influenza antigens holds promise in the development of a universal influenza vaccine. This review will summarize the progress in adenovirus-vectored universal flu vaccines and discuss future novel approaches.
Topics: Adenoviridae; Animals; Drug Carriers; Drug Discovery; Genetic Vectors; Hemagglutinin Glycoproteins, Influenza Virus; Humans; Influenza Vaccines; Nucleocapsid Proteins; Orthomyxoviridae; RNA-Binding Proteins; Vaccines, Synthetic; Viral Core Proteins; Viral Matrix Proteins
PubMed: 25876176
DOI: 10.1080/21645515.2015.1016674