10. Viral vector vaccines
Engineered vectors are a novel generation of vaccines that invoke recombinant DNA technology to insert the encoding gene of pathogen antigens into the genome of bacterial or viral vectors [100]. Following vaccination, the recombinant vector sometimes multiplies in the host body and induces potent B and T cell immune responses by expression and processing of pathogen antigens (Fig. 2) (Table 3). Escherichia coli, adenovirus (Ad) and poxvirus are among the most widely used bacterial and viral vectors, respectively. Manufacturing of vaccines against meningococcus, hepatitis B virus (HBV), human papillomavirus (HPV), haemophilus influenza type b (Hib) and pertussis are the most common examples of vector utilization in vaccine design [27]. Viral vectors based on their ability to propagate in the host cells are divided into two main categories including non-replicating and replicating vectors. The non-replicating vectors have lost their reproductive ability by deleting a certain part of their genome, but retain the capacity of expressing a target gene. These are account for a large share of vaccine production and are primarily designed based on adenovirus as well as adeno-associated virus (AAV), Modified Vaccinia virus Ankara (MVA), influenza, parainfluenza and Sendai viruses [60, 101, 102]. Most of these vectors are injected intramuscularly and induced passable specific cellular and humoral immune responses. Besides, high titers of these vectors can be achieved by the laboratory instruments [101]. On the other hand, replicating vectors compose of attenuated or vaccine type viruses that expressing the foreign antigen and proliferate somewhat in the host cells. Animal viral vectors are more popular in this case because of limited replication in human hosts and significant innate immune induction due to specious heterogenicity. Besides, mucosal administration of these xenogen vectors will significantly stimulate mucosal immunity, which is important in combating mucosal viruses such as SARS-CoV2 [103]. Currently, two human vaccines based on viral vectors have been reported to fight Ebola and cancer maladies. This platform of the Ebola vaccine has been extensively studied and can be used as a model for other infectious diseases, while the safe anti-cancer vector vaccine induced strong T cell responses without the need of adjuvants [104, 105]. Meanwhile, some viral vectors, such as Ad5 and ChAd, are preferred for use in SARS-COV2 researches because they provide acceptable protection with a single dose and demonstrate natural tendency for the respiratory mucosa [49]. In addition, this technology is available for mass production of clinical grade vaccines. Overall, 41 viral vector vaccine candidates against COVID-19 are under preclinical stage and 16 candidates are undergoing clinical trials [52] while only 3 vaccines based on ChAdOx1, vesicular stomatitis virus (VSV) and Ad26 viral vectors have been selected for the public–private Operation Warp Speed (OWS) partnership of the US [106]. Viral vector vaccines with attenuated or defective replication capacity against SARS-CoV2 are Ad5 or MVA-dependent and mainly express the epitopes of S protein and related RBD domain. Although the viral vectors with suitable replicative competency are more common with vaccine type of human (influenza and measles (or zoonotic (VSV) pathogens. It is important to note that in some cases, due to previous exposure of immune system to similar strains during a person’s lifetime or prime-boost regimen, the viral vector is disarmed before any action and does not work as well as it should. This can be overcome by using animal-derived viral vectors such as ChAd or infrequent human vectors, against which the probability of previous immunity is very low or near to zero [49]. Besides, different priming and boosting vectors greatly reduce the risk of previous vector immunity. Also, some viral vectors, such as AAV, are weak stimulant of immune responses and mostly used in human studies [103].
As of February 9, 2021, four adenovirus-based vector vaccines including Ad5-nCoV (replication-defective Ad5 containing S protein) by CanSino Biologics, Sputnik V or Gam-Covid-Vac (combination of Ad5 and Ad26 containing S protein) by Gamaleya Research Institute, Ad26.COV2.S (optimized Ad26 containing S protein) by Johnson & Johnson and AZD1222 (replication-deficient ChAdOx1 containing S protein) by AstraZeneca company and university of Oxford are going through phase ΙΙΙ clinical trials, and the Ad5-nCoV and Sputnik V have received licenses of limited and early use in China and Russia, respectively. Also, intranasal spray of influenza vector-based-RBD vaccine, DelNS1-2019-nCoV-RBD- OPT1, as a phase ΙΙ clinical trial is under investigation. Currently, an innovative COVID-19-artificial antigen presenting cell (aAPC) vaccine was also developed by Shenzhen Geno-Immune Medical Institute using the replication-competent NHP/TYF lentiviral vector system in order to expressing the immunomodulatory and viral genes in modified APCs. By doing so, T cells are likely to be significantly activated, although the efficacy and safety of this vaccine in a phase Ι clinical trial are being investigated. In addition, a similar vaccine, named LV-SMENP-DC, is being evaluated in a phase Ι/ΙΙ trial using non-replicating lentiviral vectors from the same company that express the COVID-19 SMENP mini-gene along with immunomodulatory genes in DC cells. However, other similar researches based on replication-incompetent vectors including simian adenovirus (SAV), MVA, Ad5 are in development [52].