Development and Applications of Viral Vectored Vaccines to Combat Zoonotic and Emerging Public Health Threats

Vaccination is arguably the most cost-effective preventative measure against infectious diseases. While vaccines have been successfully developed against certain viruses (e.g., yellow fever virus, polio virus, and human papilloma virus HPV), those against a number of other important public health threats, such as HIV-1, hepatitis C, and respiratory syncytial virus (RSV), have so far had very limited success. The global pandemic of COVID-19, caused by the SARS-CoV-2 virus, highlights the urgency of vaccine development against this and other constant threats of zoonotic infection. While some traditional methods of producing vaccines have proven to be successful, new concepts have emerged in recent years to produce more cost-effective and less time-consuming vaccines that rely on viral vectors to deliver the desired immunogens. This review discusses the advantages and disadvantages of different viral vaccine vectors and their general strategies and applications in both human and veterinary medicines. A careful review of these issues is necessary as they can provide important insights into how some of these viral vaccine vectors can induce robust and long-lasting immune responses in order to provide protective efficacy against a variety of infectious disease threats to humans and animals, including those with zoonotic potential to cause global pandemics.

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Influence of Respiratory Syncytial Virus F Glycoprotein Conformation on Induction of Protective Immune Responses

Journal of Virology ◽

10.1128/jvi.00338-16 ◽

2016 ◽

Vol 90 (11) ◽

pp. 5485-5498 ◽

Cited By ~ 22

Author(s):

Concepción Palomo ◽

Vicente Mas ◽

Michelle Thom ◽

Mónica Vázquez ◽

Olga Cano ◽

...

Keyword(s):

Respiratory Syncytial Virus ◽

Membrane Fusion ◽

Neutralizing Antibodies ◽

Vaccine Development ◽

Protective Antigen ◽

Protective Efficacy ◽

Viral Fusion ◽

Virus Challenge ◽

Advantages And Disadvantages ◽

Syncytial Virus

ABSTRACTHuman respiratory syncytial virus (hRSV) vaccine development has received new impetus from structure-based studies of its main protective antigen, the fusion (F) glycoprotein. Three soluble forms of F have been described: monomeric, trimeric prefusion, and trimeric postfusion. Most human neutralizing antibodies recognize epitopes found exclusively in prefusion F. Although prefusion F induces higher levels of neutralizing antibodies than does postfusion F, postfusion F can also induce protection against virus challenge in animals. However, the immunogenicity and protective efficacy of the three forms of F have not hitherto been directly compared. Hence, BALB/c mice were immunized with a single dose of the three proteins adjuvanted with CpG and challenged 4 weeks later with virus. Serum antibodies, lung virus titers, weight loss, and pulmonary pathology were evaluated after challenge. Whereas small amounts of postfusion F were sufficient to protect mice, larger amounts of monomeric and prefusion F proteins were required for protection. However, postfusion and monomeric F proteins were associated with more pathology after challenge than was prefusion F. Antibodies induced by all doses of prefusion F, in contrast to other F protein forms, reacted predominantly with the prefusion F conformation. At high doses, prefusion F also induced the highest titers of neutralizing antibodies, and all mice were protected, yet at low doses of the immunogen, these antibodies neutralized virus poorly, and mice were not protected. These findings should be considered when developing new hRSV vaccine candidates.IMPORTANCEProtection against hRSV infection is afforded mainly by neutralizing antibodies, which recognize mostly epitopes found exclusively in the viral fusion (F) glycoprotein trimer, folded in its prefusion conformation, i.e., before activation for membrane fusion. Although prefusion F is able to induce high levels of neutralizing antibodies, highly stable postfusion F (found after membrane fusion) is also able to induce neutralizing antibodies and protect against infection. In addition, a monomeric form of hRSV F that shares epitopes with prefusion F was recently reported. Since each of the indicated forms of hRSV F may have advantages and disadvantages for the development of safe and efficacious subunit vaccines, a direct comparison of the immunogenic properties and protective efficacies of the different forms of hRSV F was made in a mouse model. The results obtained show important differences between the noted immunogens that should be borne in mind when considering the development of hRSV vaccines.

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Vaccine-enhanced disease: case studies and ethical implications for research and public health

Wellcome Open Research ◽

10.12688/wellcomeopenres.16849.1 ◽

2021 ◽

Vol 6 ◽

pp. 154

Author(s):

Euzebiusz Jamrozik ◽

George Heriot ◽

Susan Bull ◽

Michael Parker ◽

Keyword(s):

Public Health ◽

Measles Virus ◽

Animal Studies ◽

Vaccine Development ◽

Global Public Health ◽

Serious Adverse Events ◽

Ethical Implications ◽

Immunological Mechanisms ◽

Disease Case ◽

Syncytial Virus

Vaccination is a cornerstone of global public health. Although licensed vaccines are generally extremely safe, both experimental and licensed vaccines are sometimes associated with rare serious adverse events. Vaccine-enhanced disease (VED) is a type of adverse event in which disease severity is increased when a person who has received the vaccine is later infected with the relevant pathogen. VED can occur during research with experimental vaccines and/or after vaccine licensure, sometimes months or years after a person receives a vaccine. Both research ethics and public health policy should therefore address the potential for disease enhancement. Significant VED has occurred in humans with vaccines for four pathogens: measles virus, respiratory syncytial virus, Staphylococcus aureus, and dengue virus; it has also occurred in veterinary research and in animal studies of human coronavirus vaccines. Some of the immunological mechanisms involved are now well-described, but VED overall remains difficult to predict with certainty, including during public health implementation of novel vaccines. This paper summarises the four known cases in humans and explores key ethical implications. Although rare, VED has important ethical implications because it can cause serious harm, including death, and such harms can undermine vaccine confidence more generally – leading to larger public health problems. The possibility of VED remains an important challenge for current and future vaccine development and deployment. We conclude this paper by summarising approaches to the reduction of risks and uncertainties related to VED, and the promotion of public trust in vaccines.

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Gamma-irradiated SARS-CoV-2 vaccine candidate, OZG-38.61.3, confers protection from SARS-CoV-2 challenge in human ACEII-transgenic mice

Scientific Reports ◽

10.1038/s41598-021-95086-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Raife Dilek Turan ◽

Cihan Tastan ◽

Derya Dilek Kancagi ◽

Bulut Yurtsever ◽

Gozde Sir Karakus ◽

...

Keyword(s):

Transgenic Mice ◽

Neutralizing Antibodies ◽

Vaccine Development ◽

Vaccine Candidate ◽

Protective Efficacy ◽

Phase 1 ◽

Challenge Test ◽

Viral Rna ◽

Viral Vaccine ◽

Gamma Irradiated

AbstractThe SARS-CoV-2 virus caused the most severe pandemic around the world, and vaccine development for urgent use became a crucial issue. Inactivated virus formulated vaccines such as Hepatitis A and smallpox proved to be reliable approaches for immunization for prolonged periods. In this study, a gamma-irradiated inactivated virus vaccine does not require an extra purification process, unlike the chemically inactivated vaccines. Hence, the novelty of our vaccine candidate (OZG-38.61.3) is that it is a non-adjuvant added, gamma-irradiated, and intradermally applied inactive viral vaccine. Efficiency and safety dose (either 1013 or 1014 viral RNA copy per dose) of OZG-38.61.3 was initially determined in BALB/c mice. This was followed by testing the immunogenicity and protective efficacy of the vaccine. Human ACE2-encoding transgenic mice were immunized and then infected with the SARS-CoV-2 virus for the challenge test. This study shows that vaccinated mice have lowered SARS-CoV-2 viral RNA copy numbers both in oropharyngeal specimens and in the histological analysis of the lung tissues along with humoral and cellular immune responses, including the neutralizing antibodies similar to those shown in BALB/c mice without substantial toxicity. Subsequently, plans are being made for the commencement of Phase 1 clinical trial of the OZG-38.61.3 vaccine for the COVID-19 pandemic.

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A yeast expressed RBD-based SARS-CoV-2 vaccine formulated with 3M-052-alum adjuvant promotes protective efficacy in non-human primates

Science Immunology ◽

10.1126/sciimmunol.abh3634 ◽

2021 ◽

Vol 6 (61) ◽

pp. eabh3634

Author(s):

Maria Pino ◽

Talha Abid ◽

Susan Pereira Ribeiro ◽

Venkata Viswanadh Edara ◽

Katharine Floyd ◽

...

Keyword(s):

T Cell ◽

Neutralizing Antibodies ◽

Plasma Cells ◽

Vaccine Development ◽

Protective Efficacy ◽

Rhesus Macaques ◽

Cost Effective ◽

Blood Monocytes ◽

Middle Income ◽

Adjuvanted Vaccine

Ongoing SARS-CoV-2 vaccine development is focused on identifying stable, cost-effective, and accessible candidates for global use, specifically in low and middle-income countries. Here, we report the efficacy of a rapidly scalable, novel yeast expressed SARS-CoV-2 specific receptor-binding domain (RBD) based vaccine in rhesus macaques. We formulated the RBD immunogen in alum, a licensed and an emerging alum adsorbed TLR-7/8 targeted, 3M-052-alum adjuvants. The RBD+3M-052-alum adjuvanted vaccine promoted better RBD binding and effector antibodies, higher CoV-2 neutralizing antibodies, improved Th1 biased CD4+T cell reactions, and increased CD8+ T cell responses when compared to the alum-alone adjuvanted vaccine. RBD+3M-052-alum induced a significant reduction of SARS-CoV-2 virus in respiratory tract upon challenge, accompanied by reduced lung inflammation when compared with unvaccinated controls. Anti-RBD antibody responses in vaccinated animals inversely correlated with viral load in nasal secretions and BAL. RBD+3M-052-alum blocked a post SARS-CoV-2 challenge increase in CD14+CD16++ intermediate blood monocytes, and Fractalkine, MCP-1, and TRAIL in the plasma. Decreased plasma analytes and intermediate monocyte frequencies correlated with reduced nasal and BAL viral loads. Lastly, RBD-specific plasma cells accumulated in the draining lymph nodes and not in the bone marrow, contrary to previous findings. Together, these data show that a yeast expressed, RBD-based vaccine+3M-052-alum provides robust immune responses and protection against SARS-CoV-2, making it a strong and scalable vaccine candidate.

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Gamma-irradiated SARS-CoV-2 vaccine candidate, OZG-38.61.3, confers protection from SARS-CoV-2 challenge in human ACEII-transgenic mice

10.1101/2020.10.28.356667 ◽

2020 ◽

Cited By ~ 1

Author(s):

Raife Dilek Turan ◽

Cihan Tastan ◽

Derya Dilek Kancagi ◽

Bulut Yurtsever ◽

Gozde Sir Karakus ◽

...

Keyword(s):

Transgenic Mice ◽

Neutralizing Antibodies ◽

Vaccine Development ◽

Vaccine Candidate ◽

Protective Efficacy ◽

Challenge Test ◽

Viral Copy Number ◽

Viral Vaccine ◽

Viral Copy ◽

Gamma Irradiated

AbstractThe SARS-CoV-2 virus caused the most severe pandemic around the world, and vaccine development for urgent use became a crucial issue. Inactivated virus formulated vaccines such as Hepatitis A, oral polio vaccine, and smallpox proved to be reliable approaches for immunization for prolonged periods. During the pandemic, we produced an inactivated SARS-CoV-2 vaccine candidate, having the advantages of being manufactured rapidly and tested easily in comparison with recombinant vaccines. In this study, an inactivated virus vaccine that includes a gamma irradiation process for the inactivation as an alternative to classical chemical inactivation methods so that there is no extra purification required has been optimized. The vaccine candidate (OZG-38.61.3) was then applied in mice by employing the intradermal route, which decreased the requirement of a higher concentration of inactivated virus for proper immunization, unlike most of the classical inactivated vaccine treatments. Hence, the novelty of our vaccine candidate (OZG-38.61.3) is that it is a non-adjuvant added, gamma-irradiated, and intradermally applied inactive viral vaccine. Efficiency and safety dose (either 1013 or 1014 viral copy per dose) of OZG-38.61.3 was initially determined in Balb/c mice. This was followed by testing the immunogenicity and protective efficacy of OZG-38.61.3. Human ACE2-encoding transgenic mice were immunized and then infected with a dose of infective SARS-CoV-2 virus for the challenge test. Findings of this study show that vaccinated mice have lower SARS-CoV-2 viral copy number in oropharyngeal specimens along with humoral and cellular immune responses against the SARS-CoV-2, including the neutralizing antibodies similar to those shown in Balb/c mice without substantial toxicity. Subsequently, plans are being made for the commencement of Phase 1 clinical trial of the OZG-38.61.3 vaccine for the COVID-19 pandemic.

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Protective Efficacy and Immunogenicity of an Adenoviral Vector Vaccine Encoding the Codon-Optimized F Protein of Respiratory Syncytial Virus

Journal of Virology ◽

10.1128/jvi.01036-09 ◽

2009 ◽

Vol 83 (23) ◽

pp. 12601-12610 ◽

Cited By ~ 36

Author(s):

Rebekka Kohlmann ◽

Sarah Schwannecke ◽

Bettina Tippler ◽

Nicola Ternette ◽

Vladimir V. Temchura ◽

...

Keyword(s):

Respiratory Syncytial Virus ◽

Vaccine Development ◽

Protective Efficacy ◽

Neutralizing Antibody ◽

Soluble Form ◽

Booster Immunization ◽

Vector Vaccine ◽

F Gene ◽

Viral Loads ◽

Syncytial Virus

ABSTRACT Adenoviral vectors (AdV) have received considerable attention for vaccine development because of their high immunogenicity and efficacy. In previous studies, it was shown that DNA immunization of mice with codon-optimized expression plasmids encoding the fusion protein of respiratory syncytial virus (RSV F) resulted in enhanced protection against RSV challenge compared to immunization with plasmids carrying the wild-type cDNA sequence of RSV F. In this study, we constructed AdV carrying the codon-optimized full-length RSV F gene (AdV-F) or the soluble form of the RSV F gene (AdV-Fsol). BALB/c mice were immunized twice with AdV-F or AdV-Fsol and challenged with RSV intranasally. Substantial levels of antibody to RSV F were induced by both AdV vaccines, with peak neutralizing-antibody titers of 1:900. Consistently, the viral loads in lung homogenates and bronchoalveolar lavage fluids were significantly reduced by a factor of more than 60,000. The protection against viral challenge could be measured even 8 months after the booster immunization. AdV-F and AdV-Fsol induced similar levels of immunogenicity and protective efficacy. Therefore, these results encourage further development of AdV vaccines against RSV infection in humans.

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Efforts at COVID-19 Vaccine Development: Challenges and Successes

Vaccines ◽

10.3390/vaccines8040739 ◽

2020 ◽

Vol 8 (4) ◽

pp. 739 ◽

Cited By ~ 1

Author(s):

Azizul Haque ◽

Anudeep B. Pant

Keyword(s):

Public Health ◽

Clinical Trials ◽

Vaccine Development ◽

Public Health Emergency ◽

Safety And Efficacy ◽

Vast Array ◽

Advantages And Disadvantages ◽

Rapid Spread ◽

The World ◽

The U.S

The rapid spread of SARS-CoV-2, the new coronavirus (CoV), throughout the globe poses a daunting public health emergency. Different preventive efforts have been undertaken in response to this global health predicament; amongst them, vaccine development is at the forefront. Several sophisticated designs have been applied to create a vaccine against SARS-CoV-2, and 44 candidates have already entered clinical trials. At present, it is unclear which ones will meet the objectives of efficiency and safety, though several vaccines are gearing up to obtain emergency approval in the U.S. and Europe. This manuscript discusses the advantages and disadvantages of various vaccine platforms and evaluates the safety and efficacy of vaccines in advance stages. Once a vaccine is developed, the next challenge will be acquisition, deployment, and uptake. The present manuscript describes these challenges in detail and proposes solutions to the vast array of translational challenges. It is evident from the epidemiology of SARS-CoV-2 that the virus will remain a threat to everybody as long as the virus is still circulating in a few. We need affordable vaccines that are produced in sufficient quantity for use in every corner of the world.

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Evaluation of a New Field Epidemiology Training Program Intermediate Course to Strengthen Public Health Workforce Capacity in Tanzania

Public Health Reports ◽

10.1177/0033354920974663 ◽

2021 ◽

pp. 003335492097466

Author(s):

Kate Wilson ◽

Amir Juya ◽

Ahmed Abade ◽

Senga Sembuche ◽

Devotha Leonard ◽

...

Keyword(s):

Public Health ◽

Training Program ◽

Health Workforce ◽

Outcome Evaluation ◽

Exit Interviews ◽

Field Epidemiology ◽

Health Threats ◽

Before And After ◽

Workforce Capacity ◽

Field Epidemiology Training Program

Objectives Sub-Saharan Africa faces a shortage of skilled epidemiologists to prevent, detect, and respond to health threats. Tanzania has implemented one of the first Centers for Disease Control and Prevention Field Epidemiology Training Program (FETP) Intermediate courses in Africa. This course aims to strengthen health workforce capacity in surveillance system assessment, outbreak investigation, and evaluation, prioritizing HIV control. We conducted an outcome evaluation of this new course. Methods We used a pre/post evaluation design using data from 4 cohorts of trainees who took the FETP Intermediate course from 2017 to 2020. We conducted knowledge assessments before and after each cohort and combined those results. Outcomes included knowledge and self-rated competency and trends in integrated disease surveillance and response (IDSR) data. We collected data through tests, field assignments, exit interviews, and data audits. We compared the mean change in pre-/posttest scores using linear regression and 95% CIs. We used content analysis to summarize exit interviews. Results Fifty-three FETP trainees from 10 regions enrolled in the FETP Intermediate course, and 52 (99.0%) completed the course. We found substantial increases in mean knowledge (44.0 to 68.0 points) and self-rated competency (4.14 to 4.43) scores before and after the course. Trainees evaluated 52 surveillance systems and 52 district HIV care programs, and 39 (75.0%) trainees participated in outbreak investigations. From before to after cohort 1, timeliness and completeness of IDSR reports increased from 4.2% to 52.1% and from 27.4% to 76.5%, respectively. Course strengths were quality of instruction, individualized mentoring, and practical skills gained. Challenges were mentor availability, limited time for data analysis practice, and balancing work and field assignments. Conclusions The Tanzania FETP Intermediate course substantially improved trainee knowledge and helped to improve local data quality and reporting. This course is a promising model to strengthen subnational capacity to prevent, detect, and respond to public health threats in Africa.

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Platforms for Production of Protein-Based Vaccines: From Classical to Next-Generation Strategies

Biomolecules ◽

10.3390/biom11081072 ◽

2021 ◽

Vol 11 (8) ◽

pp. 1072

Author(s):

Raquel Cid ◽

Jorge Bolívar

Keyword(s):

Infectious Diseases ◽

Mammalian Cells ◽

Vaccine Development ◽

Low Cost ◽

Cost Effective ◽

Insect Larvae ◽

Subunit Vaccines ◽

Effective Strategies ◽

Alternative Systems ◽

Inactivated Vaccines

To date, vaccination has become one of the most effective strategies to control and reduce infectious diseases, preventing millions of deaths worldwide. The earliest vaccines were developed as live-attenuated or inactivated pathogens, and, although they still represent the most extended human vaccine types, they also face some issues, such as the potential to revert to a pathogenic form of live-attenuated formulations or the weaker immune response associated with inactivated vaccines. Advances in genetic engineering have enabled improvements in vaccine design and strategies, such as recombinant subunit vaccines, have emerged, expanding the number of diseases that can be prevented. Moreover, antigen display systems such as VLPs or those designed by nanotechnology have improved the efficacy of subunit vaccines. Platforms for the production of recombinant vaccines have also evolved from the first hosts, Escherichia coli and Saccharomyces cerevisiae, to insect or mammalian cells. Traditional bacterial and yeast systems have been improved by engineering and new systems based on plants or insect larvae have emerged as alternative, low-cost platforms. Vaccine development is still time-consuming and costly, and alternative systems that can offer cost-effective and faster processes are demanding to address infectious diseases that still do not have a treatment and to face possible future pandemics.

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Strategies for Vaccination: Conventional Vaccine Approaches Versus New-Generation Strategies in Combination with Adjuvants

Pharmaceutics ◽

10.3390/pharmaceutics13020140 ◽

2021 ◽

Vol 13 (2) ◽

pp. 140

Author(s):

Abdellatif Bouazzaoui ◽

Ahmed A. H. Abdellatif ◽

Faisal A. Al-Allaf ◽

Neda M. Bogari ◽

Saied Al-Dehlawi ◽

...

Keyword(s):

Viral Vectors ◽

Protein Production ◽

Vaccine Development ◽

Effective Vaccine ◽

The Novel ◽

Research Teams ◽

Advantages And Disadvantages ◽

Rapid Spread ◽

New Generation ◽

Conventional Vaccine

The current COVID-19 pandemic, caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), has raised significant economic, social, and psychological concerns. The rapid spread of the virus, coupled with the absence of vaccines and antiviral treatments for SARS-CoV-2, has galvanized a major global endeavor to develop effective vaccines. Within a matter of just a few months of the initial outbreak, research teams worldwide, adopting a range of different strategies, embarked on a quest to develop effective vaccine that could be effectively used to suppress this virulent pathogen. In this review, we describe conventional approaches to vaccine development, including strategies employing proteins, peptides, and attenuated or inactivated pathogens in combination with adjuvants (including genetic adjuvants). We also present details of the novel strategies that were adopted by different research groups to successfully transfer recombinantly expressed antigens while using viral vectors (adenoviral and retroviral) and non-viral delivery systems, and how recently developed methods have been applied in order to produce vaccines that are based on mRNA, self-amplifying RNA (saRNA), and trans-amplifying RNA (taRNA). Moreover, we discuss the methods that are being used to enhance mRNA stability and protein production, the advantages and disadvantages of different methods, and the challenges that are encountered during the development of effective vaccines.

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