Artículo de Revisión

COVID-19 vaccines: Development, strategies, types and vaccine usage hesitancy

Vacunas contra la COVID-19: desarrollo, estrategias, tipos y reticencia al uso de la vacunación

Ayisha Shaukat^* ORCID: https://orcid.org/0000-0003-1649-1628

Khalid Hussain ORCID: https://orcid.org/0000-0001-9627-8346

Naureen Shehzadi ORCID: https://orcid.org/0000-0001-6688-3289

Punjab University, College of Pharmacy, Pakistan.

Autor para correspondencia: Ayishashaukat@gmail.com

ABSTRACT

Vaccine development using different platforms is one of the important strategies to address coronavirus disease pandemic. The global need for vaccines requires effective vaccine approaches and collaboration between pharmaceutical and biotechnological companies, governments and the industrial and academic sectors. About 72% of the vaccine candidates are being developed by the private sector, while 28% are carried out by the public sector and different non-profit organizations. COVID-19 vaccines are based on complete viruses (inactivated or attenuated), viral vectors (replicating or not), antigenic subunits (proteins or peptides), nucleic acids (RNA or DNA) or virus-like particles. Important aspects of vaccine development include manufacturing flexibility, speed, cost, safety, cellular and humoral immunogenicity, vaccine stability and cold chain maintenance. Vaccines can be prepared using different manufacturing platforms, computational biology, gene synthesis, structure-based antigen design and protein engineering. Individual confidence, convenience and complacency are factors that affect the attitude towards acceptance of COVID-19 vaccination. This could be complicated by socio-demographic, psychologic, cognitive and cultural factors.

Keywords: COVID-19; SARS-CoV-2; vaccines; immunity.

RESUMEN

El desarrollo de vacunas utilizando diferentes plataformas es una de las estrategias importantes para abordar la pandemia de COVID-19. La necesidad mundial de vacunas requiere enfoques de vacunas eficaces y la colaboración entre las empresas farmacéuticas y biotecnológicas, los gobiernos y los sectores industrial y académico. Alrededor del 72% de los candidatos vacunales están siendo desarrolladas por el sector privado, mientras que el 28%, por el sector público y diferentes organizaciones sin fines de lucro. Las vacunas contra la COVID-19 se basan en virus completos (inactivados o atenuados), vectores virales (replicantes o no), subunidades antigénicas (proteínas o péptidos), ácidos nucleicos (ARN o ADN) o partículas similares a virus. Aspectos importantes del desarrollo de vacunas incluyen la flexibilidad de fabricación, la velocidad, el costo, la seguridad, la inmunogenicidad celular y humoral, la estabilidad de la vacuna y el mantenimiento de la cadena de frío. Las vacunas se pueden preparar con precisión utilizando diferentes plataformas de fabricación, biología computacional, síntesis de genes, diseño de antígenos basado en estructuras e ingeniería de proteínas. La confianza individual, la conveniencia y la complacencia son factores que afectan la actitud hacia la aceptación de la vacunación contra la COVID-19. Esto podría complicarse por factores sociodemográficos, psicológicos, cognitivos y culturales.

Palabras clave: COVID-19; SARS-CoV-2; vacunas; inmunidad.

Recibido: 8 de abril de 2021

Aceptado: 24 de junio de 2021

Introduction

Around 2002 and 2012, two epidemic coronavirus infections (MERS-CoV and SARS-CoV) emerged and caused flu-like symptoms and lethal acute respiratory tract infections.⁽¹⁾ The newly emerged virus causing COVID-19 was named SARS-CoV-2 because it showed similarity to SARS-CoV during isolation and phylogenetic investigation of the strain.⁽²⁾ The genetic sequence of the SARS-CoV-2, published on January 2020, triggered research and development activities worldwide for the development of a vaccine against the disease. The first COVID-19 vaccine candidate against SARS-CoV-2 entered human clinical trial on March 2020.

The entry of the virus into the host cells induces the immune response with the production of antibodies against the coronavirus surface spike protein. However, data on the type of immunity required to protect individuals from subsequent viral re-infection is not known. In experimental animal models, SARS-CoV immunization with nucleic acid, viral vector vaccines, recombinant subunit proteins and passive immunization has been shown to be effective against the disease.⁽³⁾ However, in animal models or in human coronavirus disease, the role of T cell immunity in preventing disease is not clear.⁽⁴⁾ Vaccine development using different platforms is one of the most important strategies to address the coronavirus disease pandemic.⁽⁴⁾

Vaccine development worldwide

The development and distribution of effective and safe vaccines is crucial to the worldwide community for immunization and protection from morbidity and mortality related to SARS-CoV-2. The geographic distribution of COVID-19 and the global need for vaccines require effective vaccine approaches and collaboration between pharmaceutical and biotechnological companies, governments and the industrial and academic sectors, where each sector adds its individual strength.⁽⁵⁾

About 72% of vaccines are being developed by private sector developers, while 28% of the vaccine development projects are carried out by the public sector and different non-profit organizations.⁽⁶⁾ Along with large multinational companies (GSK, Pfizer, Sanofi and Janssen), different small companies are also involved in vaccine development. Hence, coordination of the COVID-19 vaccine manufacturing and supply capacity will be important to meet worldwide vaccine demand. The coronavirus vaccine development activity is 46% in North America, 18% in Europe, 18% in Asia (excluding China), 18% in China and 18% in Australia.⁽⁶⁾ Although regulatory frameworks and vaccine manufacturing capacity exist in Latin America and Africa, no information regarding vaccine development is available in these globe regions.⁽⁶⁾ However, clinical trials were authorized for Soberana 01 (Cuba’s first vaccine candidate), by the Cuba’s national regulatory agency, the Center for Quality Control of Medicines, Equipment and Medical Devices (CECMED) on August 13, 2020, which was the first from Caribbean and Latin America. On August 24, to evaluate vaccine immunogenicity and safety, parallel phase I and phase II randomized, controlled, double blind clinical trials were launched with phase III clinical trials in pipeline for early 2021.⁽⁷⁾ In the battle against COVID-19, another milestone was achieved by Cuban scientists when clinical evaluations of a second candidate vaccine (Soberana 02) were conducted by approval granted by the CECMED.⁽⁸⁾ On the basis of the results from this vaccine clinical trial, the Finlay Institute director general expects that vaccine to exhibit 80-95% efficacy. Therefore, for immunization of Cuba’s citizens this summer, mass vaccination program was planned.⁽⁹⁾ The epidemiology of the coronavirus can differ geographically, thus greater coordination of different regions will be required in research and development sector to control this pandemic situation.⁽⁶⁾

Strategies and platforms for COVID-19 vaccine development

The development of vaccines against COVID-19 has used several platforms, including: whole virus (inactivated or attenuated), viral vectors (non-replicating or replicating), nucleic acids (RNA or DNA) and subunits (recombinant proteins or synthetic peptides). Critical components for various inactivated and subunits vaccines are adjuvants (aluminum salts, emulsions) which induce specific, long lasting and robust immune responses. Evidence regarding the effects of the adjuvants used in coronavirus vaccines is needed.⁽⁴⁾ There are certain advantages and limitations to each of these vaccine platforms. Important aspects in vaccine development include manufacturing flexibility, speed, safety, cost, cellular and humoral immunogenicity, vaccines stability and maintenance of the cold chain. Multiple strategic approaches are critical to vaccine development, since a single platform is not sufficient to meet the global need. DNA and mRNA based vaccines can be developed based on the viral genomic sequence.⁽¹⁰⁾

Vaccines can be prepared with precision using different manufacturing platforms, computational biology, gene synthesis and structure-based antigen design. Examples are recombinant, nucleic acid and live-virus vaccines. The gene-based vaccines deliver genetic sequences encoding antigenic proteins which are produced by host cells. The protein-based vaccines include viral proteins particles or subdomains and inactivated virus manufactured in vitro. Precision for vaccine development is accomplished by knowledge of the structure of vaccine antigen and preservation of the vaccine targeted epitopes.⁽¹¹⁾

Different companies have developed different vaccines. Strategies based on mRNA sequence have been used by BioNTech and Moderna, and based on DNA sequence, by Inovio.⁽¹⁰⁾ Different adjuvants such us MF-59 by Novartis, CpG 1018 by Dynavax and AS03 (GSK) are accessible to the researchers involved in vaccine development to immunogenicity enhancement.⁽¹²⁾

Scale up for vaccines development

In order to manufacture large quantities of vaccine doses, the vaccine-manufacturing capacity of the entire globe is needed. Hence, to achieve the target of SARS-CoV-2 vaccines development, global coordination of different health organizations in a dynamic and planned way is required.⁽¹³⁾ Funding is necessary for the entire vaccine development process. The cost of vaccines, the method of distribution and the maintenance of the cold chain are key elements for global vaccine coverage. The vaccine manufacturing capacity is about 2-4 billion doses annually and it will be sufficient by years 2023-2024.⁽¹⁴⁾ The scale-up process for manufacturing of vaccines might be associated with problems in purification of viral vectors. Moreover, biosafety level-3 facilities must be mandatory for the manufacture of whole-inactivated vaccines.⁽¹⁵⁾

Different companies started large-scale production based on the prediction of the vaccine safety and efficacy testing in phase II or III clinical trials. Several companies have partnered with different manufacturers to scale-up vaccine manufacturing to an estimated level of hundreds of millions of vaccine doses. The company AstraZeneca for its SARS-CoV-2 vaccine has made partnership with Serum Institute of India and SK Bioscience (Korea). The Chinese company Sinovac has partnered with Bio Farma (Indonesia) and Butantan (Brazil). Johnson and Johnson has partnered with Indian company Biological E.⁽¹⁶⁾

Types of COVID-19 vaccines

Protein subunit vaccine

They are based on recombinant antigenic proteins or synthetic peptides able to induce a prolonged immune response.⁽¹⁷⁾ Due to its low immunogenicity, these type of vaccines require an adjuvant to enhance vaccine-induced immune responses, immunomodulatory cytokine responses or biological half-life. These types of vaccines use SARS-CoV-2 S protein or its receptor binding domain as an antigenic protein. The viral entry into host cells is via S- protein induced endocytosis, mediated by binding to hACE₂ receptors.⁽¹⁷⁾ Most used structural proteins of coronaviruses are S and N proteins. These vaccines use cost-efficient manufacturing and are comparatively safer than inactivated/killed and live attenuated vaccines.⁽¹⁸⁾ There are already 30 vaccine candidates in the clinical phase.⁽¹⁹⁾ The vaccine candidate in clinical trial phase, Novavax with the saponin-based Matrix-M adjuvant, showed 95.6% efficacy against the original variant of SARS-CoV-2. Moreover, clinical trial data showed that also provides protection against the newer variants B.1.1.7 with 85.6% efficacy and B.1.351 with 60% efficacy.⁽²⁰⁾

Viral vector vaccines

These vaccines are made from a carrier such as poxvirus or adenovirus which after modification contains a gene from the virus of interest.⁽²¹⁾ The commonly used viral vectors include adenovirus, parainfluenza, rabies, Newcastle, Sendai and influenza viruses. For synthesis of these vaccines, the viral vector genomic sequence is grafted with a part of the viral DNA which encodes for immunogenic components, whose expression leads to cellular and humoral immune response activation.⁽²²⁾ These vaccines are characterized by the targeted delivery of genes with high efficiency to evoke gene transduction and immune response.⁽²³⁾ Viral vector vaccines offer prolonged antigenic protein expression, thus can be used prophylactically. Cytotoxic T cells produced in response to these vaccines leads to the elimination of virus-infected cells.⁽⁶⁾ Moreover, data from viral vector-based vaccine development strategies for SARS-CoV and MERS have been shown to be beneficial for the speedy development of the COVID-19 vaccine.⁽²⁴⁾ A total of 17 viral vector-based COVID-19 vaccines are already in clinical trials, among which, 3 are replicating and 14 are non-replicating viral vectors.⁽¹⁹⁾ Adenoviruses are commonly used for the development of SARS-CoV-2 vaccines; clinical studies have proved vaccines based on these vectors reduce the incidence of viral pneumonia. A vaccine candidate, based on adenovirus as viral vector which express full-length S protein (Ad5-nCoV), was studied in a phase I clinical trial by CanSino Biologics.⁽²⁵⁾ Healthy volunteers subject to a randomized, double-blind, placebo-controlled phase II trial, that received two doses of Ad5-SARS-CoV-2 S vaccine, developed strong neutralizing antibodies; the vaccine candidate showed good safety and tolerability profiles with induction of T cell and humoral responses.⁽²⁶⁾ Other vectors like vaccinia virus MVA strain has been engineered for SARS-CoV-2 S protein expression;⁽²⁷⁾ healthy volunteers have been recruited for a phase I clinical trial.⁽²⁸⁾ Four adenovirus-based vaccine candidates entered phase III clinical trials: rAd26 + rAd5-S (Gamaleya Research Institute), adenovirus type 5 vector (Cansino Biological Inc.), ChAdOx1-S (AstraZeneca), and Ad26CoVS1 (Janssen Pharmaceutical).⁽¹⁹⁾ The rAd26-S/rAd5-S vaccine exhibited good tolerability with 91.6% efficacy against COVID-19 in phase III clinical trials.⁽²⁹⁾ A potential option for COVID-19 vaccine delivery comprises intranasal administration taking into account SARS-CoV-2 infections occur intranasally.⁽³⁰⁾ Regarding this aspect, an influenza virus vector expressing the SARS-CoV-2 S RBD (DelNS1-2019-nCoV-RBD-OPT1) has been administered as an intranasal spray; phase I and phase II clinical trials has been registered in China.⁽³¹⁾ The safety of viral vectored vaccines (Ad5 and Ad26) was determined in phase III clinical trials and the results showed acceptable protection by vaccine against COVID-19 after one dose.⁽³²⁾

mRNA vaccines

These vaccines are gaining more attention due to their efficacy, safety and ease in gross scale manufacturing. They can be administered by various methods such as injection needles into muscle tissues, spleen, skin and mucous membranes. These vaccines are non-infectious with almost no risk of mutagenesis.⁽³³⁾ The mRNA vaccines are prepared in the form of lipid nanoparticles. Although they protect and deliver mRNA, the stability and scalability of mRNA lipid nanoparticles are issues that need to be addressed. There are 16 RNA-based vaccines in the clinical phase.⁽¹⁹⁾ Since the outbreak of coronavirus, several biopharmaceutical companies have announced the establishment of mRNA vaccine projects for SARS-CoV-2. To fight the ongoing SARS-CoV-2 pandemic, these vaccines have become an increasingly attractive platform for various reasons. Firstly, to produce a vaccine candidate, the requirement for only a DNA template of the desired antigen results in fast manufacturing time.⁽³⁴⁾ Secondly, potent immune response was evoked by these vaccines in different animal studies and human clinical trials followed by a significant protection from COVID-19 in phase II and III clinical trials.⁽³⁵⁾ The two mRNA vaccine candidates, mRNA-1273 (Moderna) and BNT162 ( BioNTech/Pfizer) entered phase III clinical trials after showing convincing efficacy and safety against SARS-CoV-2 in phase I and II. Although a minimum of 50% efficacy is required by SARS-CoV-2 vaccines to qualify for approval by FDA,⁽³⁶⁾ the aforementioned mRNA vaccines approved for emergency use, reported more than 94% efficacy without any safety concerns except transient and mild local and systemic reactions.⁽³⁵⁾

Modification of these mRNA vaccines can be made if needed. The target immunogenic epitopes can be easily switched in and out of the vaccine candidates, with the antigen DNA sequence as a template. Hence, to target a newly emerged coronavirus strain, a SARS-CoV-2 vaccine can be quickly modified.⁽³⁷⁾ To enhance the stability of these vaccines, modifications that allow their repeated administration can be made, thus the immunogenicity of the mRNA could be minimized.⁽³⁸⁾

One of the major concerns for mRNA vaccine is the need for ultra-cold storage. However, studies have showed the stability of these vaccines at 4°C for one week duration.⁽³⁹⁾ To preserve potency, the storage recommendations of mRNA vaccine (BNT162b2) are -80°C to -60°C for 6 months or 2°C to 8°C for 5 days.⁽⁴⁰⁾ For Moderna vaccine (mRNA-1273), the FDA storage recommendations are 2°C to 8°C for 30 days and at -25°C to -15°C for long-term storage.⁽⁴¹⁾

DNA-based vaccines

Introduction of DNA vaccine is the most comprehensive approach in vaccination which utilizes adjuvant to evoke immune response. For DNA-based vaccines, an injection delivery device or electroporation is required to facilitate entry of DNA into cells. Transfection of myocytes or keratinocytes results in expression of transgene (DNA segment containing a gene sequence) and release of derived protein/peptide via exosomes. Moreover, cell mediated and humoral immune responses are enhanced by endocytosis of antigenic material by immature dendritic cells, which in association with MHC₂ and MHC₁ antigens, ultimately present these cells to the CD⁸⁺ and CD⁴⁺ T cells.⁽⁴²⁾ On January 11, 2020, after the public release of the genomic sequence of SARS-CoV-2, the design and synthesis of synthetic DNA-based vaccine was initiated immediately. A synthetic DNA vaccine candidate (INO-4800), by competitive inhibition of SARS-CoV-2 spike protein expression, evoked humoral and T cell immunity in different animal models. In lung washes of INO-4800-immunized guinea pigs and mice, anti-SARS-CoV-2 binding antibodies were detected; these antibodies had the potential to protect against severe infections of lung tissues by SARS-CoV-2. T cell response against SARS-CoV-2 was induced after 7 days of vaccine administration whith lower viral load and could potentially reduce the spread of SARS-CoV-2.⁽⁴³⁾

Vaccine usage hesitancy

Vaccine hesitancy is the term described as refusal of vaccination or delay in the acceptance of vaccines.⁽⁴⁴⁾ Individual confidence, convenience and complacency are factors that affect the individual attitude towards acceptance of vaccination.^(44,45) Confidence refers to trust in safe vaccination and effectiveness, along with healthcare competence. Convenience refers to affordability, easy availability and delivery of vaccines in a comfortable service. Complacency refers to the lack of understanding of the disease risk; hence, vaccination is perceived inessential by this group of people. Governments may first consider building public trust before imposing vaccination. Fairness, competence, consistency, sincerity, objectivity and faith are six determinants of trust identified by WHO that must be transformed to general public, thus makes people to develop more confidence in vaccination and government.⁽⁴⁶⁾ WHO has encouraged all people to promote the vaccination process.⁽⁴⁷⁾

Religious prohibitions, questioning of dosing recommendations, poor quality of vaccines, myths and rumors related to the presence of active virus in vaccines are some of the misleading claims causing hindrance in vaccination.⁽⁴⁸⁾ One of the major factors which lead to non-compliance to vaccination includes distrust of vaccine safety, vaccine novelty concerns about side effects and the long term effects on health. Moreover, inappropriate risk messages from public health experts may also reduce vaccine usage.⁽⁴⁹⁾ Various socio-demographic, psychologic, cognitive and cultural factors also contribute to vaccine hesitancy.^(44,50,51) Analysis of these factors is required to address the hesitancy of COVID-19 vaccine usage, followed by the evaluation of the magnitude and scope of the pandemic.⁽⁵²⁾ Consequently, this may help in planning interventional measures aimed to tackle this global pandemic.⁽⁵³⁾

The acceptance rates of COVID-19 vaccine were found to be highest in Malaysia (94.3%),⁽⁵⁴⁾ Ecuador (97.0%),⁽⁵⁵⁾ China (91.3%)⁽⁵⁶⁾ and Indonesia (93.3%),⁽⁵⁷⁾ while the acceptance of these vaccines was low in France (58.9%),⁽⁵⁸⁾ Poland (56.3%),⁽⁵⁵⁾ Russia (54.9%),⁽⁵⁵⁾ Jordan (28.4%),⁽⁴⁵⁾ Italy (53.7%),⁽⁵⁵⁾ US (56.9%)⁽⁵⁵⁾ and Kuwait (23.6%).⁽⁴⁵⁾ In a survey conducted among the general public, there is an acceptance rate of more than 70% of the use of coronavirus vaccine with low acceptance rates in Africa, Russia, the Middle East and different European countries. However, how speedily the majority of the population gets vaccinated will have a major impact on the death toll. The coming few months are important to overcome vaccine hesitancy.⁽⁵⁹⁾

As warned by the World Health Organization, the world is facing another type of epidemic called ‘infodemics’ that spreads wrong information and misleading scientific claims.⁽⁶⁰⁾ With the advent of vaccine against COVID-19, there is a high hope of ending the pandemic that has disturbed the lives of people around the globe. It is recommended to address the scope and issue of COVID-19 vaccine hesitancy in various nations as an initial step for building trust among the community.⁽⁴⁵⁾

Conclusion

Since the need for vaccine development is a worldwide challenge, it requires collaboration between pharmaceutical and biotechnological companies, governments and the industrial and academic sectors. Significant aspects in vaccine development include flexibility and speed of manufacture, safety, cellular and humoral immunogenicity, scale of manufacture and cost and stability. Along with them, individual confidence, convenience and complacency are factors which need to be addressed.

References

1. Badgujar KC, Badgujar VC, Badgujar SB. Vaccine development against coronavirus (2003 to present): An overview, recent advances, current scenario, opportunities and challenges. Diabetes Metab Syndr.2020;14(5):1361-76. doi: https://10.1016/j.dsx.2020.07.022.

2. Salvatori G, Luberto L, Maffei M, Aurisicchio L, Roscilli G, Palombo F, et al. SARS-CoV-2 spike protein: an optimal immunological target for vaccines. J Transl Med 2020; 18:222. doi: https://10.1186/s12967-020-02392

3. Bisht H, Roberts A, Vogel L, Bukreyev A, Collins PL, Murphy BR, et al. Severe acute respiratory syndrome coronavirus spike protein expressed by attenuated vaccinia virus protectively immunizes mice. Proc Natl Acad Sci 2004;101(17): 6641-6.

4. Liang Z, Zhu H, Wang X, Jing B, Li Z, Xia X, et al. Adjuvants for coronavirus vaccines. Front Immunol 2020;11: 589833. doi: https://10.3389/fimmu.2020.589833.

5. Lurie N, Saville M, Hatchett R, Halton J. Developing Covid-19 vaccines at pandemic speed. N Engl J Med.2020;382(21):1969-73. doi: https://10.1056/NEJMp2005630.

6. Le TT, Andreadakis Z, Kumar A, Román RG, Tollefsen S, Saville M, et al. The COVID-19 vaccine development landscape. Nat Rev Drug Discov 2020;19(5):305-6. doi: https://10.1038/d41573-020-00073-5.

7. Gorry C. SOBERANA, Cuba’s COVID-19 vaccine candidates: Dagmar García-Rivera PhD, Director of Research, Finlay Vaccine Institute. MEDICC Rev;2020:22(4):10-5. https://10.37757/MR2020.V22.N4.11.

8. Vérez-Bencomo V. Soberana: Clinical trials coming soon. Guardian.2020;1939:12. Available at: https://search.informit.org/toc/10.3316/guasyd.2020_n1939.

9. Burki T. Behind Cuba's successful pandemic response. Lancet Infect Dis.2021;21(4): 465-6. doi:https://10.1016/S1473-3099(21)00159-6.

10. Pardi N, Hogan MJ, Pelc RS, Muramatsu H, Andersen H, DeMaso CR, et al. Zika virus protection by a single low-dose nucleoside-modified mRNA vaccination. Nature 2017;543(7644): 248-51. doi: https://10.1038/nature21428.

11. Graham BS. Rapid COVID-19 vaccine development. Science.2020; 368(6494): 945-6.

12. Lee, J. These 23 companies are working on coronavirus treatments or vaccines — here’s where things stand. New York: Market watch; 2020. Available at: https://www.marketwatch.com/story/these-nine-companies-are-working-on-coronavirus-treatments-or-vaccines-heres-where-things-stand-2020-03-06.

13. World Health Organization. List of stringent regulatory authorities (SRAs). Geneva: World Health Organization; 2020. Available at: https://www.who.int/medicines/regulation/sras/en/. https://www.who.int/initiatives/who-listed-authority-reg-authorities/SRAs

14. Coalition for Epidemic Preparedness Innovations. CEPI survey assesses potential COVID-19 vaccine manufacturing capacity. Oslo: Coalition for Epidemic Preparedness Innovations; 2020. Available at: https://cepi.net/news_cepi/cepi-survey-assesses-potential-covid-19-vaccine-manufacturing-capacity/.

15. Kim JH, Marks F, Clemens JD. Looking beyond COVID-19 vaccine phase 3 trials. Nat Med 2021; 27(2): 205-11. doi:https://10.1038/s41591-021-01230-y.

16. Baker S, Koons C. Inside Operation Warp Speed’s $18 Billion sprint for a vaccine. Bloomberg Businessweek. 2020. Available at: https://www.bloomberg.com/news/features/2020-10-29/inside-operation-warp-speed-s-18-billion-sprint-for-a-vaccine.

17. Wang N, Shang J, Jiang S, Du L. Subunit vaccines against emerging pathogenic human coronaviruses. Front Microbiol.2020;11:298. doi: https://10.3389/fmicb.2020.00298.

18. Wang M, Jiang S, Wang Y. Recent advances in the production of recombinant subunit vaccines in Pichia pastoris. Bioengineered.2016; 7(3): 155-65. doi: https://10.1080/21655979.2016.1191707.

19. World Health Organization. DRAFT Landscape of COVID-19 Candidate Vaccines-14 July 2020. 19. Geneva: World Health Organization; 2020. Available at: https://www.who.int/docs/default-source/blue-print/novel-coronavirus-landscape-covid-19-(7).pdf.

20. Mahase, E. Covid-19: Novavax vaccine efficacy is 86% against UK variant and 60% against South African variant. BMJ. 2021;372:296. doi: https://10.1136/bmj.n296.

21. Minor PD. Live attenuated vaccines: Historical successes and current challenges. Virology. 2015; 479-480: 379-92. doi: https://10.1016/j.virol.2015.03.032.

22. Muthumani K, Falzarano D, Reuschel EL, Tingey C, Flingai S, Villarreal DO, et al. A synthetic consensus anti–spike protein DNA vaccine induces protective immunity against Middle East respiratory syndrome coronavirus in nonhuman primates. Sci Transl Med 2015; 7(301): 301ra132. doi: https://10.1126/scitranslmed.aac7462.

23. Ura T, Okuda K, Shimada M. Developments in viral vector-based vaccines. Vaccines (Basel). 2014; 2(3): 624-41. doi: https://10.3390/vaccines2030624.

24. Bezbaruah R, Borah P, Kakoti BB, Al- Shar'I NA, Chandrasekaran B, Jaradat DMM. Developmental landscape of potential vaccine candidates based on viral vector for prophylaxis of COVID-19. Front Mol Biosci.2021;8:635337. doi: https://10.3389/fmolb.2021.635337.

25. Zhu FC, Li YH, Guan XH, Hou LH, Wang WJ, Li JX, et al. Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-randomised, first-in-human trial. Lancet. 2020; 395: 1845-54. doi: https://10.1016/ S0140-6736(20)31208-3.

26. Zhu FC, Guan XH, Li YH, Huang JY, Jiang T, Hou LH, et al. Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 2020; 396: 479-88. doi: https://10.1016/S0140-6736(20)31605-6.

27. Garcia-Arriaza J, Garaigorta U, Perez P, Lazaro-Frias A, Zamora C, Gastaminza P, et al. COVID-19 vaccine candidates based on modified vaccinia Ankara expressing the SARS-CoV-2 spike induce robust T- and B-cell immune responses and fully efficacy in mice. J Virol.2021;95(7): e02260-20. doi: https://10.1128/JVI.02260-20.

28. Clinicaltrials.gov [database on internet]. Bethesda (MD): National Library of Medicine (US);2020. Safety, Tolerability and Immunogenicity of the Candidate Vaccine MVA-SARS-2-S against COVID-19; unique ID: NCT04569383. Available at: https://clinicaltrials.gov/ct2/show/NCT04569383.

29. Logunov DY, Dolzhikova IV, Shcheblyakov DV, Tukhvatulin AI, Zubkova OV, Dzharullaeva AS, et al. Safety and efficacy of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine: an interim analysis of a randomised controlled phase 3 trial in Russia. Lancet.2021; 397: 671-81. doi: https://10.1016/S0140-6736(21)00234-8.

30. Higgins TS, Wu AW, Illing EA, Sokoloski KJ, Weaver BA, Anthony BP, et al. Intranasal antiviral drug delivery and coronavirus disease 2019 (COVID-19): a state of the art review. Otolaryngol Head Neck Surg.2020; 163(4): 682-94. doi: https://10.1177/0194599820933170.

31. Chinese Clinical Trial Registry [database on internet]. Chengdu: Chinese Clinical Trial Registry;2020. A Phase I Clinical Trial of Influenza Virus Vector COVID-19 Vaccine for intranasal Spray (DelNS1-2019-nCoV-RBD-OPT1); unique ID: ChiCTR2000037782. Available at: www.chictr.org.cn/showprojen.aspx?proj=55421.

32. Jiang HD, Li JX, Zhang P, Huo X, Zhu FC. The COVID-19 Vaccine in Clinical Trials: Where Are We Now? Infect Dis Immun. 2021; 1(1): 43-51. doi: https://10.1097/ID9.0000000000000003.

33. Yi C, Yi Y, Li J. mRNA vaccines: possible tools to combat SARS-CoV-2. Virol Sin. 2020; 35(3): 259-62. doi: https://10.1007/s12250-020-00243-0.

34. Pardi N, Hogan MJ, Porter FW, Weissman D. mRNA vaccines-a new era in vaccinology. Nat Rev Drug Discov. 2018; 17(4): 261-79. doi: https://10.1038/nrd.2017.243.

35. Baden LR, El Sahly HM, Essink B, Kotloff K, Frey S, Novak R, et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. New Engl J Med. 2021; 384(5): 403-16. doi: https://10.1056/NEJMoa2035389.

36. Food and Drug Administration US. Development and licensure of vaccines to prevent COVID-19. Guidance for Industry. Silver Spring (MD): US Department of Health and Human Services Food and Drug Administration; 2020. Available at: https://www.fda.gov/media/139638/download.

37. Corbett KS, Flynn B, Foulds KE, Francica JR, Boyoglu-Barnum S, Werner AP, et al. Evaluation of the mRNA-1273 vaccine against SARS-CoV-2 in nonhuman primates. New Engl J Med. 2020; 383(16): 1544-55. doi: https://10.1056/NEJMoa2024671.

38. Zhang C, Maruggi G, Shan H, Li, J. Advances in mRNA vaccines for infectious diseases. Front Immunol. 2019; 10: 594. doi: https://10.3389/fimmu.2019.00594.

39. Zhang KC, Fang Y, Cao H, Chen H, Hu T, Chen YQ, et al. Parental acceptability of COVID-19 vaccination for children under the age of 18 years: cross-sectional online survey. JMIR Pediatr Parent.2020; 3(2): e24827. doi: https://10.2196/24827.

40. World Health Organization. mRNA vaccines against COVID-19: Pfizer-BioNTech COVID-19 vaccine BNT162b2: prepared by the Strategic Advisory Group of Experts (SAGE) on immunization working group on COVID-19 vaccines, 22 December 2020. Geneva: World Health Organization; 2020. Available at: https://apps.who.int/iris/handle/10665/338096.

41. Food and Drug Administration. Fact sheet for healthcare providers administering vaccine (vaccination providers): emergency use authorization (EUA) of the Pfizer-BioNTech COVID-19 vaccine to prevent coronavirus disease 2019 (COVID-19). Silver Spring, MD: US Department of Health and Human Services Food and Drug Administration; 2021. Available at: https://www.fda.gov/media/144413/download.

42. Hobernik D, Bros M. DNA vaccines-how far from clinical use? Int J Mol Sci.2018; 19(11): 3605. doi: https://10.3390/ijms19113605.

43. Smith TR, Patel A, Ramos S, Elwood D, Zhu X, Yan J, et al. Immunogenicity of a DNA vaccine candidate for COVID-19. Nat Commun 2020; 11(1): 2601. doi: https://10.1038/s41467-020-16505-0.

44. MacDonald NE, SAGE Working Group on Vaccine Hesitancy. Vaccine hesitancy: definition, scope and determinants. Vaccine.2015; 33(34): 4161-4. doi: https://10.1016/j.vaccine.2015.04.036.

45. Sallam M, Dababseh D, Eid H, Al-Mahzoum K, Al-Haidar A, Taim D, et al. High Rates of COVID-19 Vaccine Hesitancy and Its Association with Conspiracy Beliefs: A Study in Jordan and Kuwait among Other Arab Countries. Vaccines (Basel).2021; 9(1):42. doi: https://10.3390/vaccines9010042.

46. World Health Organization/Europe. Vaccination and trust—How concerns arise and the role of communication in mitigating crises. Copenhagen: World Health Organization Regional Office for Europe; 2017. Available at:  https://www.euro.who.int/__data/assets/pdf_file/0004/329647/Vaccines-and-trust.PDF 

47. Vergara RJD, Sarmiento PJD, Lagman JDN. Building public trust: a response to COVID-19 vaccine hesitancy predicament. J Public Health (Oxf).2021;43(2): e291-e292. doi: https://10.1093/pubmed/fdaa282.

48. Ali M, Ahmad N, Khan H, Ali S, Akbar F, Hussain Z. Polio vaccination controversy in Pakistan. Lancet.2019; 394: 915-6. doi: https://10.1016/S0140-6736(19)32101-4.

49. Robertson E, Reeve KS, Niedzwiedz CL, Moore J, Blake M, Green M, et al. Predictors of COVID-19 vaccine hesitancy in the UK household longitudinal study. Brain Behav Immun 2021; 94: 41-50. doi: https://10.1016/j.bbi.2021.03.008.

50. Browne M, Thomson P, Rockloff MJ, Pennycook G. Going against the herd: psychological and cultural factors underlying the ‘vaccination confidence gap’. PLoS One. 2015; 10(9): e0132562. doi: https://10.1371/journal.pone.0132562.

51. Hornsey MJ, Harris EA, Fielding KS. The psychological roots of anti-vaccination attitudes: A 24-nation investigation. Health Psychol.2018; 37(4): 307-15. doi: https://1010.1037/hea0000586.

52. Lin C, Tu P, Beitsch LM. Confidence and receptivity for COVID-19 vaccines: A Rapid Systematic Review. Vaccines (Basel).2020; 9(1):16. doi: https://10.3390/vaccines9010016.

53. de Figueiredo A, Simas C, Karafillakis E, Paterson P, Larson HJ. Mapping global trends in vaccine confidence and investigating barriers to vaccine uptake: a large-scale retrospective temporal modelling study. Lancet. 2020; 396: 898-908. doi: https://10.1016/S0140-6736(20)31558-0.

54. Wong LP, Alias H, Wong PF, Lee HY, AbuBakar S. The use of the health belief model to assess predictors of intent to receive the COVID-19 vaccine and willingness to pay. Hum Vaccin Immunother. 2020; 16(9): 2204-14. doi: https://10.1080/21645515.2020.1790279.

55. Lazarus JV, Ratzan SC, Palayew A, Gostin LO, Larson HJ, Rabin K, et al. A global survey of potential acceptance of a COVID-19 vaccine. Nat Med. 2021; 27(2): 225-8. doi: https://10.1038/s41591-020-1124-9.

56. Zhang NN, Li XF, Deng YQ, Zhao H, Huang YJ, Yang G, et al. A thermostable mRNA vaccine against COVID-19. Cell. 2020; 182(5): 1271-83. doi: https://10.1016/j.cell.2020.07.024.

57. Harapan H, Wagner AL, Yufika A, Winardi W, Anwar S, Gan AK, et al. Acceptance of a COVID-19 vaccine in southeast Asia: a cross-sectional study in Indonesia. Front Public Health.2020; 8: 381. doi: https://10.3389/fpubh.2020.00381.

58. Neumann-Böhme S, Varghese NE, Sabat I, Barros PP, Brouwer W, van Exel J, et al. Once we have it, will we use it? A European survey on willingness to be vaccinated against COVID-19. Eur J Health Econ.2020; 21: 977-82. doi: https://10.1007/s10198-020-01208-6.

59. Chevallier C, Hacquin AS, Mercier H. COVID-19 vaccine hesitancy: Shortening the last mile. Trends Cogn Sci.2021; 25(5): 331-3. doi: https://10.1016/j.tics.2021.02.002.

60. Naeem SB, Bhatti R, Khan A. An exploration of how fake news is taking over social media and putting public health at risk. Health Info Libr J. 2020; 37. doi: https://10.1111/hir.12320.

Conflict of interest

The authors declare that there is no conflict of interest.

Author’s contributions

Ayisha Shaukat designed the title, did the literature survey, wrote the content of the manuscript and revised it during the peer-review process.

Khalid Hussain assisted in the literature survey, writing the manuscript content and revision during the peer-review process.

Naureen Shehzadi assisted in the literature survey and writing the manuscript content.

All authors reviewed and approved the final version of this manuscript for publication.

* Pharmaceutical Chemistry, Punjab University, Pakistan.