Viral Vectors: Comparison
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Please note this is a comparison between Version 2 by Vicky Zhou and Version 1 by Kenneth Lundstrom.

Viral vectors can generate high levels of recombinant protein expression providing the basis for modern vaccine development. A large number of different viral vector expression systems have been utilized for targeting viral surface proteins and tumor-associated antigens.

  • Viral Vectors
  • Vaccine Development
  • COVID-19

1. Introduction

The recent coronavirus pandemic (COVID-19) has underlined the importance of vaccine development. It has also become clear to the general public that a number of competing approaches for vaccine candidates need to be developed in parallel to achieve success in the shortest possible time. The same strategy should be applied to any vaccine target albeit the global concern related to COVID-19 has drained resources from other important vaccine development initiatives. It should also be pointed out that vaccine development is not restricted to infectious diseases as quite a few approaches have focused on cancer vaccines as discussed below.

The traditional approach, which is still valid and plays an important role in COVID-19 vaccine development against viral infections, relates to the application of killed and live-attenuated vaccines [1]. Moreover, protein subunit and peptide vaccines have become popular, not least due to the development of efficient recombinant protein expression systems in the 1980s and 1990s [2]. The topic of this review is the utilization of viral vectors for vaccine development. In this context, a variety of viral expression systems have been engineered. Typically, expression vectors have been constructed for adenoviruses (Ads), alphaviruses, flaviviruses, measles viruses (MVs), rhabdoviruses, retroviruses (RVs), lentiviruses (LVs), and poxviruses [3,4][3][4]. Briefly, Ad vectors are non-enveloped double-stranded DNA (dsDNA) viruses with a packaging capacity of 7.5 kb foreign DNA providing transient episomal expression in a broad range of host cells [5]. Alphavirus- and flavivirus-based vectors are enveloped single-stranded RNA (ssRNA) viruses with a positive polarity, characterized for their self-replicating RNA property, which provides substantial amplification of foreign mRNA directly in infected host cells [6,7][6][7]. In contrast, MVs [8] and rhabdoviruses [9] possess an ssRNA genome of negative polarity, which requires reverse genetics to establish appropriate expression vectors. Among these self-amplifying RNA viral vectors, alphaviruses hold a packaging capacity of 8 kb of foreign genes, whereas for the others it is about 6 kb. RVs are ssRNA viruses, characterized by reverse transcription of their genome into DNA, which can be integrated into the host cell genome providing long-term transgene expression [10]. The chromosomal integration of RVs has posed some safety issues especially for gene therapy applications, where insertions in active oncogene loci has triggered the development of leukemia in patients with X-linked severe acute immunodeficiency (SCID-X1) [11]. However, this issue has been addressed by the engineering of self-inactivating RV vectors with targeted integration. Another issue with classic RVs is their inability to transduce non-diving cells. For this reason, many gene therapy and vaccine development activities have switched to LVs, also belonging to the genus of RVs, which otherwise provide the same properties as classic RVs including packaging of up to 8 kb of foreign sequences, but are able to infect both dividing and non-dividing cells [12]. Moreover, integration-defective LV vectors have been engineered based on targeted recombinase-mediated cassette exchange to provide safe episomal status [13]. Poxviruses are large dsDNA viruses with a packaging capacity of over 30 kb of foreign DNA, which have been frequently used for vaccine development [14]. Moreover, the small ssRNA Picornaviruses—especially coxsackieviruses—with the potential to insert 6 kb of foreign nucleic acids, have been engineered as expression vectors [15].

2. Vaccines against COVID-19

Naturally, vaccine development against the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) causing the COVID-19 pandemic has overshadowed any other vaccine initiative [159][16]. The impressive number of 155 vaccine candidates in preclinical and 47 candidates in clinical trials are based on inactivated and live attenuated vaccines, protein subunit and peptide vaccines, nucleic acids and viral vectors [160][17].

The chimpanzee Ad vector ChAdOx1 nCoV-19 was engineered to express the SARS-CoV-2 S protein and when subjected to immunization of mice and rhesus macaques induced strong humoral and cellular immune responses and prevented pneumonia in macaques [161,162][18][19]. Similarly, Ad5-SARS-COV-2 S elicited strong S-specific antibody and cell-mediated immune responses in mice and rhesus macaques. Moreover, a single intramuscular or intranasal immunization with Ad5-S-nb2 provided protection against challenges with SARS-CoV-2 in macaques [163][20]. Preclinical studies in hamsters demonstrated that a single immunization with an Ad26 vector expressing SARS-CoV-2 S elicited neutralizing antibodies and protected immunized animals against pneumonia and death [164][21]. Immunization of rhesus macaques elicited strong neutralizing antibody responses and protected primates against SARS-CoV-2 [165][22]. In another preclinical approach, the full-length SARS-CoV-2 S gene was inserted into two positions of the MV genome [166][23]. Administration of the vaccine candidates to mice demonstrated efficient Th1-biased antibody and T cell responses after two immunizations. Considering that the lung is a vital organ for SARS-CoV-2 infection, MVA poxviruses have been suggested as potential candidates for COVID-19 vaccine development [167][24]. In this context, a novel vaccine platform was developed for MVA, where a unique three-plasmid system can efficiently generate recombinant MVA vectors from chemically synthesized DNA [168][25]. Using this technology, mice were immunized with fully synthetic MVA (sMVA) vectors co-expressing SARS-CoV-2 S and nucleocapsid, which elicited robust SARS-CoV-2 antigen-specific humoral and cellular immune responses including potent neutralizing antibodies.

Positive results from preclinical studies on COVID-19 vaccine candidates have supported the launch of several clinical trials. The first-in-human phase I dose-escalation, non-randomized clinical trial was conducted with three doses (5 × 1010, 1 × 1011 and 1.5 × 1011) of Ad5-SARS-CoV-2 S particles in 108 healthy volunteers [169][26]. The safety and tolerability of the treatment was good with only some minor pain reactions to the vaccination. Rapid SARS-CoV-2-specific T cell responses were detected 14 days after vaccination and humoral responses against SARS-CoV-2 reached peak levels at day 28 post-immunization. The Ad5-SARS-CoV-2 S vaccine candidate has been subjected to a randomized, double-blind, placebo-controlled phase II trial in 603 healthy volunteers [170][27]. The two doses (1 × 1011 and 5 × 1010 virus particles) elicited significant neutralizing antibodies. Severe adverse reactions were observed in 24 (9%) of vaccinees, but no serious adverse reactions were reported. Overall, the immunization was safe and significant immune responses were induced in the majority of vaccinees after a single vaccination. Moreover, the recruitment of healthy adults 18 years of age and older is in progress for a global double-blind, placebo-controlled phase III trial with an immunization schedule of one intramuscular dose of Ad5-SARS-CoV-2 S [171][28]. Recruitment is in progress for a similar phase III trial for 18 to 85 years old volunteers for a single intramuscular administration of Ad5-SARS-CoV-2 S [172][29]. In another Ad based approach, the Ad26.COV2.S vaccine candidate was subjected to a randomized, double blind, placebo-controlled phase I/II study in 1045 healthy volunteers in Belgium and the USA [173][30]. Interim results demonstrated a good safety profile and immunogenicity after a single immunization [174][31]. A randomized, double-blind, placebo-controlled phase III study enrolling 60,000 participants is in progress [175][32].

The Ad-based Sputnik V vaccine developed at the Gamaleya Research Institute of Epidemiology and Microbiology in Russia caused some controversy due to its premature approval prior to the completion of any clinical phase III trials and even before the publication of findings from any preclinical or clinical studies with only a preliminary evaluation in 76 volunteers [176][33]. The rAd26-S/rAd5-S vaccine regimen is based on a prime vaccination with the Ad26-based SARS-CoV-2 S, followed by a booster vaccination with Ad5-SARS-Cov-2 S. Several weeks after the approval, the results from a phase I/II trial were published [177][34]. The results indicated a good safety profile with only mild and no serious adverse events. The intramuscular administration elicited strong SARS-CoV-2-specific antibodies in all vaccinated individuals. Despite being approved weeks earlier, the following statement was made in the publication: “further investigation is needed of the effectiveness of this vaccine for prevention of COVID-19” [177][34]. Recently, recruiting for two randomized, double-blind, placebo-controlled, multicenter phase III clinical trials in adult volunteers has started [178,179][35][36]. The simian ChAdOx1 nCoV-19 vaccine candidate showed promising preliminary results in a phase I/II trial [180][37]. The safety was good with no serious adverse events registered after a single intramuscular injection. The immune response was also promising with 32 out 35 vaccinees generating SARS-CoV-2-specific neutralizing antibodies. After a booster immunization, both humoral and cellular immune responses were detected in all vaccinees. The ChAdOx1 nCoV-19 vaccine candidate entered a randomized, double-blind, placebo-controlled multicenter phase III trial in 30,000 adults in August 2020 [181][38]. However, due to some suspect adverse events in patients, the phase III trial was put on hold in early September [182][39]. After an investigation into the issue, the trial resumed in the UK, but it remained on hold in the US until the FDA authorized the restart on 23 October 2020 [183][40].

Recently, the first-in-human phase I clinical trial with the MVA-SARS-2-S vaccine candidate in healthy volunteers was approved [184][41]. The study aims at assessing the safety and tolerability of the vaccine candidate and the enrolment of patients is in progress. An LV vector vaccine candidate based on minigenes of multiple conserved regions of SARS-CoV-2 is planned for a phase I/II clinical trial in 100 healthy volunteers [185][42]. Subcutaneous administration of 5 × 106 dendritic cells (DCs) transduced with the LV vector (LV-DC) in combination with intravenously injected 1 × 108 antigen-specific CTLs will be evaluated for safety and immunogenicity. Very recently, the MV-SARS-CoV-2 vaccine candidate TMV-083 was subjected to a randomized, placebo-controlled, two-center phase I clinical trial to evaluate the safety, tolerability and immunogenicity in 90 volunteers [186][43]. As it has been previously demonstrated that the replication-competent VSV-based SARS-CoV-2 S vaccine candidate (V590) can protect mice from SARS-CoV-2 pathogenesis [187][44], a phase I trial on the safety and tolerability is planned for 252 participants [188][45]. In another approach, a replication-competent VSV-ΔG vaccine, where the VSV G protein was replaced by SARS-CoV-2 S, resulted in potent SARS-CoV-2-specific neutralizing antibody responses in immunized golden Syrian hamsters [189][46]. Moreover, a single dose of 5 × 106  pfu of VSV-ΔG vaccine provided protection of hamsters against challenges with lethal doses of SARS-CoV-2. Additionally, the lung damage in immunized animals was minor and no viral load was detected. Next, the VSV- ΔG vaccine will be evaluated in humans in two phases [190][47]. In a phase I dose-escalation study, 18–55 years old volunteers will receive a single dose of 5 × 105, 5 × 106 and 5 × 107 pfu, respectively. In phase II, elderly subjects will receive a single dose as used in phase I or two immunization with 5 × 105 pfu 28 days apart. Finally, intranasal SARS-CoV-2 vaccine delivery is a potential option [191][48]. For instance, intranasal administration of an Ad5-based vector expressing the SARS-CoV-2 S receptor binding domain (RBD) elicited strong neutralizing antibody responses [192][49].

More recently, the ChAdOx1 nCoV-19, the Ad26.COV2.S and the rAd26-S/rAd5-S vaccines have been approved for emergency use and mass vaccinations are in progress globally. The Ad-based vaccines have demonstrated good efficacy although slightly lower rates have been obtained against novel SARS-CoV-2 variants. Very recently, in rare cases Ad-based COVID-19 vaccines have been associated with thrombosis and thrombocytopenia. This issue is currently under investigation, but regulatory authorities have indicated that the benefits of these vaccines are superior to the risks they cause. 

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