key: cord-1026696-zalk5ul7 authors: Conforti, Antonella; Marra, Emanuele; Roscilli, Giuseppe; Palombo, Fabio; Ciliberto, Gennaro; Aurisicchio, Luigi title: Are genetic vaccines the right weapon against Covid-19? date: 2020-06-10 journal: Mol Ther DOI: 10.1016/j.ymthe.2020.06.007 sha: a9b606693d00e6a1ff9fc7d4316762dc99a9a596 doc_id: 1026696 cord_uid: zalk5ul7 nan infectivity. 2 To this aim, diverse platforms have been set up, but only a few can address these requirements. Conventional vaccines, such as inactivated, attenuated or subunit vaccines have been successful but have drawbacks, such as their strain specificity, and consequently are potentially associated with risks of viral interference and cross-immunity, 3 and can be allergenic in some patient groups. Furthermore, vaccines based on viral proteins tend to elicit immune responses that are limited to the CD4+ T cell response or antibody-dependent mechanisms, and lack a CD8+ T cell response. Besides this, the production of conventional vaccines can be expensive and time-consuming. Safety concerns, commonly associated with the use of whole virus as a vaccine platform, have been overcome by the development of replicationdefective recombinant adenoviruses, which have proven safe for administration in humans and effective in inducing robust innate and adaptive immune responses. Third-generation adenoviral vectors have been employed to prevent or treat life-threatening infectious diseases such as Ebola, Zika, malaria, HCV and HIV 4, 5 and tested in clinical trials for anticancer immunotherapy. 6 However, this vaccination strategy is hampered by issues such as pre-existing immunity in humans and challenges in construction. Therefore, newer vaccination approaches such as genetic vaccines based on naked DNA or RNA have emerged as promising alternatives owing to several beneficial features. First, they have a highly satisfactory safety profile, without potential risk of integration or pathogenicity, and for this reason they are considered an ideal therapeutic strategy in cancer immunotherapy or for vaccinating immunocompromised people. Second, genetic vaccination can elicit both T cell activation and antibody production in response to even small amounts of expressed protein and, unlike whole virus vectors, can be more easily administered in multi-dose regimens without generating pre-existing immunity. Finally, the manufacturing process confers some advantages: both DNA and RNA are inexpensively and easily constructed directly from the genetic sequence of the desired antigen. Once established, the production process can be easily adjusted according to the HLA diversity in the field in order to include the most immunogenic antigens and modulators for a specific population. Hence, the use of nucleic acids in vaccine development programs is growing in a wide range of traditional pharmaceutical markets, such as cancers and allergies, as well as infectious diseases and it is increasingly demonstrating its safety and efficacy in early and mid-stage human clinical trials. 7, 8 Nevertheless, these vaccination strategies still present some drawbacks, and differences between DNA and RNA must be taken into account. As for immunogenicity, a number of factors can increase DNA potency, such as the use of immunostimulants (cytokines and immunostimulatory molecules), tailored delivery routes and devices (with intramuscular injection followed by electroporation having been found to be the most effective in inducing strong immune responses) and different combination strategies (e.g. DNA prime followed by viral vector/peptide/recombinant protein heterologous boosts). Conversely, over the past decade vaccine developers have striven to increase RNA stability, improve its cellular delivery through encapsulation into nanoparticles, and reduce its constitutive reactogenicity, by using modified nucleosides and controlling the onset of eventual toxicities. Challenges remain for RNA-based strategies such as further improving stability, reducing toxicity (due to intrinsic inflammatory activity) and increasing protein translation, necesitating additional clinical studies. Additionally, in order to avoid the use of any animal or cellular materials, researchers are exploring alternative manufacturing strategies, such as the use of PCR-generated linear DNA fragments. 9 As shown in Table 1 , genetic vaccines, DNA-based ones in particular, are an ideal vaccination platform for infectious diseases: both DNA and RNA can be developed and manufactured rapidly, ensuring a reproducible and standard production process, whatever the target disease or gene insert, but still with some intrinsic limitations to overcome such as lower immunogenicity, in comparison to protein-and viral-based conventional vaccines. 10 The last decade has witnessed the outbreak of several new human pathogens including Ebola, Chikungunya, Zika, Severe Acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and more recently the novel coronavirus (SARS-CoV-2). The continuous spread of such diseases at regular intervals poses a significant threat to human health and the economy, and there is an urgent need for a vaccine technology able to protect against rapidly arising or mutating pathogens. Genetic vaccination represents an ideal vaccine target product profile to be developed in response to an unexpected pandemic outbreak, so in the next future every effort must be addressed to develop a vaccine Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia Roadmap to developing a recombinant coronavirus S protein receptor-binding domain vaccine for severe acute respiratory syndrome Interval between infections and viral hierarchies are determinants of viral interference following influenza virus infection in a ferret model Phase 2 placebo-controlled trial of two vaccines to prevent Ebola in Liberia Rational Zika vaccine design via the modulation of antigen membrane anchors in chimpanzee adenoviral vectors The first approved gene therapy product for cancer Ad-p53 (gendicine): 12 years in the clinic Engineering DNA Vaccines Against Infectious Diseases A Comparison of Plasmid DNA and mRNA as Vaccine Technologies. Vaccines (Basel) Linear doggybone DNA vaccine induces similar immunological responses to conventional plasmid DNA independently of immune recognition by TLR9 in a pre-clinical model Developing Covid-19 Vaccines at Pandemic Speed Vitares, Rome, Italy.