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Adenovirus vaccines and thrombosis
complex formation with consequent increase of inflam- mation and immunopathology.50 Both ADE pathways can occur when non-neutralizing antibodies or antibodies at sub-neutralizing levels bind to viral antigens without blocking or clearing the infection. ADE has been reported for vaccines against both severe acute respiratory syn- drome corona virus (SARS-CoV) and Middle East respira- tory syndrome corona virus (MERS-CoV) in vitro and in animal models.50 The cytoplasmic tail of FcgRIIa activates the protein-tyrosine kinases Src 51,52 and Syk.53-55 Src- dependent signaling has been shown to be crucial for ADE triggered by Ebola virus, enhancing viral uptake into cells and thus worsening the infection.56
Circulating antibodies activating platelet IgG FcgRIIa may be key determinants of a host response leading to uncontrolled platelet aggregation and thrombosis. Studies in transgenic mice expressing human FcgRIIa on platelets showed that the administration of anti-CD9 antibodies caused thrombosis accompanied by platelet consump- tion, a response that was absent in mice lacking the receptor.57 The clinical relevance of this pathway for thrombotic disorders in humans is confirmed by the observation that FcgRIIa expression is higher in patients with stroke58 and that relatively common FcgRIIa poly- morphisms are associated with increased risk of throm- bosis in patients with heparin-induced thrombocytopenia (HIT).59 Immuno-complex formation, complement depo- sition and local immune activation are likely mechanisms triggered by SARS-CoV-2 vaccine. Furthermore, pre- existing antibodies to coronavirus strains endemic in humans could mediate ADE by facilitating cross-reactive recognition of SARS-CoV-2 in the absence of viral neu- tralization.60
Interestingly, compared to Ad-5 and Ad-6, chimpanzee adenoviruses (ChAd) are much less frequently neutral- ized by pre-existing antibodies present in humans. The prevalence of vector-neutralizing antibodies against Y25, now renamed ChAdOx1, the vector of the Vaxzevria vac- cine, in human sera from British and Gambian adults was found to be 0% (n=100) and 9% (n=57), respectively.61 The presence of these antibodies in rare patients in Europe might theoretically represent one potential mech- anism triggering ADE, and possibly VITT, in vaccine recipients but no data on this are available yet.
Despite the above hypotheses, preliminary in vitro evi- dence suggests that serum from convalescent COVID-19 patients does not induce either enhancement of SARS- CoV-2 infection or innate immunity responses in human macrophages, indicating that ADE may not be involved in the immune-pathological processes associated with COVID-19 infection or immunization.62
Use of adenovirus vectors and thrombotic events
Adenovirus vectors for gene therapy
Ad vectors have been used therapeutically for their ability to transduce and deliver transgenes to different cell types. However, for these indications the clinical use of Ad vectors has been limited to a few tens of patients and the main concerns have been the development of humoral and cellular immunity occurring upon repeated administration and/or the possible neutralization of the vector by pre-existing immunity against the virus, while
little attention had been paid to the possible interactions of Ad vectors with platelets and the blood clotting sys- tem.
The first use of Ad vectors for gene therapy of inherited disorders or to treat neoplasia dates back to the 1990s. An analysis of the risks associated with the use of Ad-vec- tored gene therapies among 90 individuals who received 140 administrations for various diseases (cystic fibrosis, metastatic colorectal cancer, cardiovascular disease), showed that 13 deaths were recorded. The authors con- cluded that none was linked to the Ad vector.63 The reported hematologic abnormalities were decreased hemoglobin, leukocytosis, thrombocytopenia, and pro- longation of the activated partial thromboplastin time (aPTT), with no cases of DIC.63
It is, however, puzzling that a recently European Medicines Agency-licensed Ad-vectored gene therapy for spinal muscular atrophy received a warning about the possible risk of thrombotic microangiopathy based on the reporting of five cases in treated infants (https://www.ema.europa.eu/en/medicines/human/EPAR/zol- gensma).
Adenovirus-vectored vaccines
Beside SARS-CoV-2, Ad vectors have been used for the preparation of other vaccines, including the ChAdOx1- vectored vaccines for MERS-CoV and Chikungunya; with only a few hundred volunteers having received these vac- cines up to June 2020,64 no excess of thrombotic events had been noted.65 Even for the Ebola vaccination campaign, the largest previous example of large-scale vaccination using an Ad vector, a maximum of around 200,000 volunteers were treated, with only one vena cava thrombosis reported (Table 1). However, it may be extremely difficult to prove that adverse events following immunization are caused by the vaccine itself when their occurrence is extremely rare (https://www.nature.com/articles/d41586-021-00880-9. Accessed on April 9, 2021).
Except for common mild/moderate reactome reactions, the most frequently recorded adverse events in clinical trials were hematologic (e.g., mild hemoglobin decrease, thrombocytopenia, leukopenia) the majority of which recovered a few days or weeks after vaccination. The extent and rate of hematologic adverse events associated with Ad-vectored vaccines are summarized in Table 1. Occasional abnormalities of coagulation were reported, with prolongation of the aPTT, possibly due to the devel- opment of transient antiphospholipid antibodies. Thrombotic events were rare both for human and non- human Ad-vectored vaccines. One case of phlebitis was observed among 114 volunteers who received a recombi- nant, replication-defective Ad-5-vectored vaccine expressing human immunodeficiency virus (HIV)-1 anti- genic proteins.66 Another case of deep vein thrombosis was observed among 58 volunteers after administration of a recombinant, replication-defective Ad-35-vectored vaccine expressing HIV-1 antigens.67 Both events were considered unrelated to the vaccine.
A systematic review identified 200 clinical studies on active immunization against SARS-CoV-2. The second most used vaccine platform, after mRNA-based vaccines, was represented by Ad vectors (24%).68 Concerning chimpanzee Ad-vectored vaccines (ChAdOx1 nCoV-19), neutropenia was the most common hematologic abnor- mality (Table 1). Across all studies, vaccines had a good
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