Immunological memory to SARS-CoV-2 infection and COVID-19 vaccines.

Immunological memory is the basis of protective immunity provided by vaccines and previous infections. Immunological memory can develop from multiple branches of the adaptive immune system, including CD4 T cells, CD8 T cells, B cells, and long-lasting antibody responses. Extraordinary progress has been made in understanding memory to SARS-CoV-2 infection and COVID-19 vaccines, addressing development; quantitative and qualitative features of different cellular and anatomical compartments; and durability of each cellular component and antibodies. Given the sophistication of the measurements; the size of the human studies; the use of longitudinal samples and cross-sectional studies; and head-to-head comparisons between infection and vaccines or between multiple vaccines, the understanding of immune memory for 1 year to SARS-CoV-2 infection and vaccines already supersedes that of any other acute infectious disease. This knowledge may help inform public policies regarding COVID-19 and COVID-19 vaccines, as well as the scientific development of future vaccines against SARS-CoV-2 and other diseases.

A Novel Piggyback Strategy for mRNA Delivery Exploiting Adenovirus Entry Biology.

Molecular therapies exploiting mRNA vectors embody enormous potential, as evidenced by the utility of this technology for the context of the COVID-19 pandemic. Nonetheless, broad implementation of these promising strategies has been restricted by the limited repertoires of delivery vehicles capable of mRNA transport. On this basis, we explored a strategy based on exploiting the well characterized entry biology of adenovirus. To this end, we studied an adenovirus-polylysine (AdpL) that embodied "piggyback" transport of the mRNA on the capsid exterior of adenovirus. We hypothesized that the efficient steps of Ad binding, receptor-mediated entry, and capsid-mediated endosome escape could provide an effective pathway for transport of mRNA to the cellular cytosol for transgene expression. Our studies confirmed that AdpL could mediate effective gene transfer of mRNA vectors in vitro and in vivo. Facets of this method may offer key utilities to actualize the promise of mRNA-based therapeutics.

An Adenoviral Vector as a Versatile Tool for Delivery and Expression of miRNAs.

Only two decades after discovering miRNAs, our understanding of the functional effects of deregulated miRNAs in the development of diseases, particularly cancer, has been rapidly evolving. These observations and functional studies provide the basis for developing miRNA-based diagnostic markers or new therapeutic strategies. Adenoviral (Ad) vectors belong to the most frequently used vector types in gene therapy and are suitable for strong short-term transgene expression in a variety of cells. Here, we report the set-up and functionality of an Ad-based miRNA vector platform that can be employed to deliver and express a high level of miRNAs efficiently. This vector platform allows fast and efficient vector production to high titers and the expression of pri-miRNA precursors under the control of a polymerase II promoter. In contrast to non-viral miRNA delivery systems, this Ad-based miRNA vector platform allows accurate dosing of the delivered miRNAs. Using a two-vector model, we showed that Ad-driven miRNA expression was sufficient in down-regulating the expression of an overexpressed and highly stable protein. Additional data corroborated the downregulation of multiple endogenous target RNAs using the system presented here. Additionally, we report some unanticipated synergistic effects on the transduction efficiencies in vitro when cells were consecutively transduced with two different Ad-vectors. This effect might be taken into consideration for protocols using two or more different Ad vectors simultaneously.

Unusual blood clots with low blood platelets from Covid-19 viral vector vaccines

In providing human immunity from the SARS-CoV-2 virus, AstraZeneca’s ChAdOx1 nCov-19 vaccines have been administered in multiple nations around the world. Throughout this literature review, the background behind derivation of this vaccine from chimpanzees to avoid pre-existing human immunity to this adenoviral vector’s mechanism of interactions will be discussed prior to clinical issues this vaccine brings. Arranged in sections, this discussion concerns the adenovector vaccine’s ability to induce both innate and adaptive immunity, featuring the mucosal route of administration’s ability to stimulate tissue-resident memory T cells (TRM), a crucial part of the adaptive immune system. Despite its solid ability to stimulate immunity with high efficiency and efficacy, a surge in female fatalities following administrations of the ChAdOx1 nCov-19 adenovector vaccines have also occurred. Published articles regarding both hypothesised mechanisms as well as recorded incidences of this rare vaccine-induced blood clots, also known as the Thrombosis and Thrombocytopenia Syndrome (TTS), have been discussed. Despite still lacking a causal relationship between AZ administrations in heparin-free patients and TTS incidences, all of these articles have implied the mechanisms inducing this condition arise from an induction of platelet-activating antibodies against PF4. The most plausible arisal of these antibodies is from free DNA molecules within the ChAdOx nCov-19 vaccine. Additionally, TTS draws similarities to autoimmune heparin-induced thrombocytopenia cases, where a platelet count decline also occurs. © 2018-2022, Rangsit University.

Deciphering the Role of Humoral and Cellular Immune Responses in Different COVID-19 Vaccines-A Comparison of Vaccine Candidate Genes in Roborovski Dwarf Hamsters.

With the exception of inactivated vaccines, all SARS-CoV-2 vaccines currently used for clinical application focus on the spike envelope glycoprotein as a virus-specific antigen. Compared to other SARS-CoV-2 genes, mutations in the spike protein gene are more rapidly selected and spread within the population, which carries the risk of impairing the efficacy of spike-based vaccines. It is unclear to what extent the loss of neutralizing antibody epitopes can be compensated by cellular immune responses, and whether the use of other SARS-CoV-2 antigens might cause a more diverse immune response and better long-term protection, particularly in light of the continued evolution towards new SARS-CoV-2 variants. To address this question, we explored immunogenicity and protective effects of adenoviral vectors encoding either the full-length spike protein (S), the nucleocapsid protein (N), the receptor binding domain (RBD) or a hybrid construct of RBD and the membrane protein (M) in a highly susceptible COVID-19 hamster model. All adenoviral vaccines provided life-saving protection against SARS-CoV-2-infection. The most efficient protection was achieved after exposure to full-length spike. However, the nucleocapsid protein, which triggered a robust T-cell response but did not facilitate the formation of neutralizing antibodies, controlled early virus replication efficiently and prevented severe pneumonia. Although the full-length spike protein is an excellent target for vaccines, it does not appear to be the only option for future vaccine design.

Pathogenic Mechanisms of Vaccine-Induced Immune Thrombotic Thrombocytopenia in People Receiving Anti-COVID-19 Adenoviral-Based Vaccines: A Proposal.

VITT is a rare, life-threatening syndrome characterized by thrombotic symptoms in combination with thrombocytopenia, which may occur in individuals receiving the first administration of adenoviral non replicating vectors (AVV) anti Covid19 vaccines. Vaccine-induced immune thrombotic thrombocytopenia (VITT) is characterized by high levels of serum IgG that bind PF4/polyanion complexes, thus triggering platelet activation. Therefore, identification of the fine pathophysiological mechanism by which vaccine components trigger platelet activation is mandatory. Herein, we propose a multistep mechanism involving both the AVV and the neo-synthetized Spike protein. The former can: i) spread rapidly into blood stream, ii), promote the early production of high levels of IL-6, iii) interact with erythrocytes, platelets, mast cells and endothelia, iv) favor the presence of extracellular DNA at the site of injection, v) activate platelets and mast cells to release PF4 and heparin. Moreover, AVV infection of mast cells may trigger aberrant inflammatory and immune responses in people affected by the mast cell activation syndrome (MCAS). The pre-existence of natural antibodies binding PF4/heparin complexes may amplify platelet activation and thrombotic events. Finally, neosynthesized Covid 19 Spike protein interacting with its ACE2 receptor on endothelia, platelets and leucocyte may trigger further thrombotic events unleashing the WITT syndrome.

Emergency use of COVID-19 vaccines recommended by the World Health Organization (WHO) as of June 2021.

In December 2019, the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the outbreak of coronavirus disease 2019 (COVID-19), and the resulting pandemic has caused widespread health problems and social and economic disruption. Thus far in 2021, more than 4 million people worldwide have died from COVID-19, so safe and efficacious vaccines are urgently needed to restore normal economic and social activities. According to the official guidance documents of the World Health Organization (WHO), vaccines based on four major strategies including mRNA, adenoviral vectors, inactivated viruses, and recombinant proteins have entered the stage of emergency use authorization and pre-certification evaluation. The current review summarizes these vaccines and it looks ahead to the development of additional COVID-19 vaccines in the future.

SARS-CoV-2 vaccines, where do we stand?

Vaccination against the SARS-CoV-2, the virus responsible for the Covid-19 pandemic, represents a major infection control strategy in the absence of effective treatment of the disease to date. Unprecedented mobilization has led to the development of a large number of projects, some of which have already been in test in humans for several months. The first efficacy and safety data are expected in the coming weeks. New vaccine technologies are being evaluated (RNA, replicating or non-replicating viral vectors), further increasing the chances of success. The criteria for evaluating vaccines-despite the exceptional speed of their development-must remain rigorous enough to ensure their acceptance by the population. Beyond their development, mass production and equitable distribution raise many questions. Finally, vaccination can only be successfully implemented if health professionals and the population are convinced of its validity, which implies particular attention to the quality of the information given and the methods of communication.

La vaccination contre le SARS-CoV-2, virus responsable de la pandémie de Covid-19 représente une stratégie majeure de contrôle de l'infection en l'absence à ce jour de traitement efficace de la maladie. Une mobilisation sans précédent a conduit au développement de très nombreux projets dont certains sont en test chez l'homme depuis déjà quelques mois. Les premières données d'efficacité et de sécurité d'emploi sont attendues dans les prochaines semaines. De nouvelles technologies de vaccin sont évaluées (ARN, vecteurs viraux réplicatifs ou non), élargissant d'autant les chances de succès. Les critères d'évaluation des vaccins ­ malgré la rapidité exceptionnelle de leurs développements ­ doivent garder la rigueur nécessaire à leur acceptation par la population. Au-delà de leur mise au point, la production massive et leur distribution équitable soulèvent de nombreuses questions. Cette vaccination enfin, ne pourra être mise en œuvre avec succès que si les professionnels de santé et la population sont convaincus de son bien-fondé, ce qui implique une attention particulière apportée à la qualité de l'information donnée et aux modalités de communication.