Plasmid DNA vaccines have many advantages, such as targeting and stimulating both humoral and cellular immune responses; flexible and simple large-scale production and formulation processes over short timescales, making them ideal for rapid responses during pandemics; flexibility for multivalency; and room-temperature storage of the final vaccine. However, there are some crucial drawbacks for this type of vaccines: 1 Low immunogenicity in humans, which requires several doses of the vaccine to achieve optimum protection.
Generally, the development of an mRNA vaccine is a straightforward process. Once the target antigen from the emerging pathogen is identified, the gene is sequenced, chemically synthesized with some modifications, such as the addition of specific signal peptides and transmembrane domains Fig.
The plasmid DNA is then subjected to in vitro transcription, following which the vaccine candidate is ready to be tested in pre-clinical trials. In vivo , mRNA vaccine candidates use the host cell machinery to translate the mRNA to the corresponding antigen, thereby stimulating both humoral and cellular immune responses [40].
These are similar to conventional mRNA, but encode the viral replication machinery necessary for intracellular RNA amplification, stimulating high levels of expression of the GOI. Manufacturing of mRNA vaccines against targets from different viruses only requires the replacement of the sequence encoding the GOI, without affecting the final physicochemical characteristics of the RNA molecule [40].
This kind of vaccine has several advantages, as it targets both humoral and cellular immune responses,. However, there are some drawbacks with this platform: 1 Storage at very low temperatures Table 1 is essential to preserve vaccine stability. Previous studies, such as the Phambili Phase IIb that assessed the Ad5-HIV vaccine candidate inoculated via three vaccinations, revealed an increased risk of HIV-1 acquisition among vaccinated men [43] , [44].
Moreover, the step trial showed that men who had high serum titers for Ad-5 on entry into the trial and were uncircumcised had an elevated risk of HIV-1 acquisition during the first 18 months of follow-up [45]. Moreover, men who were uncircumcised with high serum titers for Ad-5 and who reported unprotected insertive anal sex with a HIVpositive partner with HIV-1 antibody titers had the highest risk rate, suggesting the potential for an increased risk of penile acquisition of HIV Additionally, a similar increased risk of HIV infection was also observed in heterosexual men who were enrolled in the Phambili study [43].
However, this hypothesis needs further investigation. Moreover, the older volunteers exhibited a significantly lower immune response post vaccination, indicating that the SARS-CoV-2 Ad-5 vaccine may not work well in the older population [5] , [6].
Another concern is that antibody titers to Ad-5 vector, which may be long-lasting, vary between different ages of the population, making use of Ad-5 vector less promising. However, Janssen Pharmaceuticals uses Ad, a rarer serotype with a very low seroprevalence among different human populations, which makes this a more promising vector compared with Ad-5 [6]. A chimpanzee adenovirus vector was developed by the University of Oxford [46].
There is very low seroprevalence in humans against this vector; however, using this vector in humans will also generate immunity against it, which may lower the efficacy of any other future vaccines developed using the same vector.
These reactions could be a drawback in countries with large young populations such as India and many Middle Eastern countries [6]. The measles virus MV belongs to the genus Morbillivirus , family Paramyxoviridae , and ranges from to nm in size.
MV is an enveloped negative-sense virus with a non-segmented, single-stranded RNA genome that is between 15, to 16, kb in length and encodes six structural proteins, including nucleoprotein N , phosphoprotein P , matrix M , fusion F , hemagglutinin H , polymerase L , and two nonstructural proteins, V and C Fig. MV vaccine strains have shown a high profile of genetic stability, which facilitated scale-up and distribution at low-cost to several countries [48].
Interestingly, the pre-existing immunity to measles vector acquired by earlier infection in the elderly or vaccination in young people did not dampen responses to a Chikungunya-MV-based vaccine [53] , making the Schwartz measles vector a very promising platform comparable with adenovirus vectors.
B Schematic design of the recombinant measles virus MV vector construct. The GOI is designed according to the rule of six with consideration of sequences as above and is cloned into the full-length viral antigenomic cDNA of the measles such as Schwarz vaccine and cloned at various positions to obtain either high or low protein expression dependent on the insertion site arrows indication.
Recombinant Newcastle disease virus NDV vectors developed with the RG system have displayed highly promising results as safe and potent vectored-vaccines against several avian and human pathogens [54]. NDV could be a very promising vector for human vaccine development because of the lack of pre-existing human immunity. A recent study reported an inactivated SARS-COVNDV-based vaccine candidate elicited high levels of neutralizing antibody titers in both mice and hamsters and significantly protected vaccinated animals from viral challenge [60].
A major advantage of the NDV-based vaccine platform is that the egg-based production of recombinant NDV vaccines can produce millions of doses at low-cost and under BSL2 laboratory conditions, thereby facilitating easy distribution to middle- and low-income countries. Adeno-associated virus vector AAV is the leading platform for gene delivery with three current licensed products Glybera, Luxturna, and Zolgensma.
AAV is a small non-enveloped virus in the genus Dependovirus within the family Parvoviridae [62]. AAV is 4. These genes can be removed and replaced with a cassette expressing a therapeutic GOI along with the necessary rep and cap genes in trans [63].
The first study that documented the capacity of AAV to induce a strong humoral and cellular response against the herpes simplex virus type 1 glycoprotein B was reported in [64] followed by an increasing number of uses of AAV for genetic vaccinations. A recent study showed that recombinant AAV rAAV vectors that expressed influenza virus hemagglutinin HA or chimeric HA protected mice against homologous and heterologous virus challenges.
V1 or variant of concern, and has subsequently spread to other countries [67] , [68] , [69]. Two more variants were reported, known as B. V2 and variant P1 Y. V3 , also known as the South African variant and the Brazilian variant, respectively [70] , [71].
These new SARS-CoV-2 lineages have been suggested to be more transmissible than the original virus, and a recent study has revealed that the B. Therefore, evaluation of the currently approved vaccines should be continued and the inevitable ongoing emergence of new SARS-CoV-2 variants should be monitored. The main challenge of responding to emerging and re-emerging viral diseases is always in low- and middle-income countries where at least half the global population live. Therefore, to combat any emerging viral disease, scale-up manufacture and globally distribution of developed vaccines should be simple and as straightforward as possible, which is an advantage of live-attenuated vaccines such as measles vaccine.
However, the situation is different for SARS-CoV-2 vaccine candidates that have been granted EUA or are currently in Phase III trials as many of these candidates are unlikely to be affordable by low-income countries and will not be cost-effective.
This is very important as it is necessary to vaccinate this large human population to establish herd immunity in a short time before emergence of any virus mutant variants. SARS-CoV-2 inactivated vaccine may be of more value than live-attenuated vaccine because of more favorable safety profile, in particular for vulnerable persons.
However, scale-up of this vaccine will require using large volumes of the propagated virus under BSL3 conditions and few of these laboratories and facilities are located in low- and middle-income countries.
Genetic vaccines DNA- and RNA-based vaccines have a considerable promise; however, they have only recently been developed and their long-term safety and efficacy performance in humans requires further investigation.
There are many viral vectors that showed highly promising results in clinical trials, but pre-existing immunity is the main challenge for most of these. Therefore, having viral vectors that can evade the pre-existing immunity challenge and can be scaled-up at low-cost, such as measles, AAV, certain serotypes of adenovirus chimpanzee or Ad , and NDV vectors, would be ideal platforms for rapid production and distribution of effective vaccines.
AN and BA conceived the project, collected data from the literature, and wrote and edited the manuscript. All authors interpreted and discussed the data and read and approved the final version of the manuscript.
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. National Center for Biotechnology Information , U. Comput Struct Biotechnol J. Published online Apr Author information Article notes Copyright and License information Disclaimer. Bader Alhatlani: as. This article has been cited by other articles in PMC.
Graphical abstract. Open in a separate window. Introduction 1 In late December , China reported cases of idiopathic pneumonia in the city of Wuhan. S e Janssen Pharmaceutical CompaniesAd Inactivated virus vaccine There are six inactivated vaccine candidates currently in Phase III trials as of April 13, [11]. Protein subunit vaccines There are seven protein subunit vaccine candidates currently in Phase III trials as of April 13, [11].
This kind of vaccine has several advantages, as it targets both humoral and cellular immune responses, has a high safety profile, does not result in human genome integration, has no antivector immunity, and has no chance of infectious virus. Concerns about Adenovirus-5 Ad-5 vector use Previous studies, such as the Phambili Phase IIb that assessed the Ad5-HIV vaccine candidate inoculated via three vaccinations, revealed an increased risk of HIV-1 acquisition among vaccinated men [43] , [44].
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Here is what the experts are predicting for property prices in Chappell K. Joyce M. Carmen J. Ward B. Support Center Support Center. External link. Please review our privacy policy. Sinovac Research and Development Co. Phase IV Not yet recruiting. Efficacy from clinical trials: Brazil : Phase IV Recruiting. Phase III Completed. Phase III Enrolling by invitation.
Not yet approved in any country. Phase III Active, not recruiting. Republic of Kazakhstan. Bharat Biotech International Limited. Efficacy from clinical trials: Shenzhen Kangtai Biological Products Co. Phase III Not yet recruiting. Phase III Recruiting. COVID inactivated vaccine.
Shifa Pharmed Industrial Co. Organization of Defensive Innovation and Research. Phase II Recruiting. Inactivated NDV-based chimeric vaccine. KM Biologics Co. Kocak Farma, Turkey. Phase I Recruiting. Adjuvanted inactivated vaccine.
Inactivated virus. Live recombinant rNDV vector vaccine. IM or IN. Laboratorio Avi-Mex. Live-attenuated virus. Phase I Active, not recruiting. Day 0. Meissa Vaccines, Inc. Viral vector non-replicating.
Chimpanzee adenovirus-vectored vaccine ChAdOx1 expressing S protein. Convidicea Ad5-nCoV. CanSino Biological Inc.
Recombinant replication-defective human type 5 adenovirus Ad5 expressing S protein. Phase IV Active, not recruiting. Janssen Pharmaceutical. Recombinant replication-incompetent adenovirus serotype 26 Ad26 vector encoding full-length and stabilized S protein. Shenzhen Geno-Immune Medical Institute. Phase I—II Recruiting. ImmunityBio, Inc. Human second-generation adenovirus 5 hAd5 encoding S and N antigens. Phase I—II Not yet recruiting.
Institute of Vaccines and Medical Biologicals, Vietnam. MVA vector expressing stabilized S protein. University of Munich Ludwig-Maximilians. MVA vector expressing S protein. Non-replicating adenovirus vector expressing viral antigens and dsRNA adjuvant. Adenovirus expressing the RBD of S protein. Tetherex Pharmaceuticals Corporation. Adenovirus vector vaccine.
Phase I Not yet recruiting. Viral vector replicating. Genetically engineered live attenuated influenza virus vector expressing the RBD of S protein. Institute for Biological Research. Aivita Biomedical, Inc. Lentivirus vector system expressing viral minigenes to the artificial antigen-presenting cells aAPCs. Phase III Not recruiting. Efficacy from clinical trials in India : Genexine Consortium. Entos Pharmaceuticals Inc. Full-length S protein.
GeneOne Life Science, Inc. Providence Health and Services. Symvivo Corporation. DNA based vaccine. IM or ID. University of Sydney, Bionet Co. S protein. Full-length S protein with proline substitutions. Efficacy from clinical trials in the U.
Phase II Active, not recruiting. Arcturus Therapeutics. Phase II Two trials: one is recruiting, and the other is active, not recruiting. Sanofi Pasteur and Translate Bio. Daiichi Sankyo Co. Phase I—II Active, not recruiting. Elixirgen Therapeutics, Inc.
Imperial College London. Phase I No longer recruiting. ChulaCov19 mRNA vaccine. Chulalongkorn University. Providence Therapeutics. Full-length membrane-anchored S protein. RNA vaccine.
S protein with Matrix-M adjuvant. Efficacy from clinical trials: UK : RBD-Dimer with alum adjuvant. China EUA , Uzbekistan. Monovalent and bivalent S protein with adjuvant. Instituto Finlay de Vacunas. Phase III Pending. RBD with alum adjuvant. Russia, Turkmenistan. RBD with aluminum hydroxide adjuvant. Nanogen Pharmaceutical Biotechnology. Recombinant S protein with alum adjuvant. Clover Biopharmaceuticals Inc. Trimeric S protein with CpG and Alum adjuvants.
Vaxxinity, Inc. Vaxine Pty Ltd. Recombinant S protein with Advax-CpG adjuvant. Recombinant S protein with CpG and alum adjuvants. Phase II Active, not recruiting for adults, recruiting for elderly. Razi Vaccine and Serum Research Institute. Recombinant S protein. Phase II Complete. Phase II Not yet recruiting. Phase I—II Pending. Kentucky Bioprocessing Inc. Biological E. Phase I—II Closed. RBD-Fc fusion protein.
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