|Ahead of print publication
Novel coronavirus vaccine: An international holy grail
Prafull Mohan1, Anuj Singhal2, Vishal Mangal2
1 Department of Pharmacology, Armed Forces Medical College, Pune, Maharashtra, India
2 Department of Internal Medicine, Armed Forces Medical College, Pune, Maharashtra, India
|Date of Submission||14-Jul-2020|
|Date of Decision||15-Jul-2020|
|Date of Acceptance||31-Jul-2020|
|Date of Web Publication||25-Aug-2020|
Department of Internal Medicine, Armed Forces Medical College, Pune - 411 040, Maharashtra
Source of Support: None, Conflict of Interest: None
Coronavirus disease 2019 (COVID-19) pandemic is raging in the world with no definitive cure or vaccine at hand. As of July 17, 2020, there have been 13,937,253 cases and 591,957 deaths globally. Hence the rush to find a cure, or a vaccine, or both. We proceed to outline some of the scientific challenges that lie in the path of the successful development of the COVID-19 vaccine. Coronaviruses do not induce long-lasting immunity; enhancing the vaccine candidate's immunogenicity is an essential imperative for the COVID-19 vaccine. On the one hand developing a COVID-19 vaccine should be relatively easy as compared to the vaccine development for HIV and hepatitis C, primarily because of the slower mutation rate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). On the other hand, there are different types of challenges, such as identifying optimum immunogenic antigen, safety issues encountered with vaccine development programs for SARS and MERS, identification of suitable adjuvants, and getting the vaccine as soon as possible. Globally, more than 150 projects are working toward the development of the SARS-CoV-2 vaccine; however, only 25 are approved for clinical trials. While existing knowledge of conventional vaccine technologies and next-generation technologies for innovative vaccine platforms has hastened vaccine development, however, the time and finances have both been constrained. Fast-tracking of research, human challenge studies, and inclusion of specific animal models such as ACE2A are some suggested strategies to hasten the process. In addition, there is a need for generous funding, collaborative effort, and comprehensive data sharing to get the world the COVID vaccine sooner.
Keywords: Clinical trials, coronavirus disease 2019, mRNA-1273 vaccine, pandemics, severe acute respiratory syndrome virus, vaccine
| Introduction|| |
Toward the end of 2019, China testified many pneumonia cases caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).,, In view of the widespread transmission of coronavirus disease 2019 (COVID-19) worldwide, the World Health Organization (WHO) declared COVID-19 “a pandemic” on March 11, 2020. Currently, our understanding of the illness is limited, and the COVID pandemic is raging in the world with no definitive cure or vaccine at hand, as of now. The world has faced similar minor or localized outbreaks such as SARS (2003), H1N1 (2009–2010), and Ebola (2014–2016) earlier also. However, the pathogen this time is a lethal mix of infectivity and virulence. As of July 17, 2020, there have been 13,937,253 cases and 591,957 deaths globally. The case fatality rate on July 16, 2020, is 2.57% in India and 4.32% for the rest of the world. Hence the rush to find a cure, or a vaccine, or both.
Vaccine development is a tricky financial decision with no guarantee of success, and the worst part is that there is no guarantee of financial windfall post development. While H1N1 vaccine could be developed well when the outbreak was still around, vaccines for SARS and Zika came after the epidemics, leading to financial loss for the developers. Ebola vaccine also got around well after the 2014–2016 epidemic; however, it finds use in sporadic outbreaks.
We proceed to outline some of the scientific challenges that lie in the path of the successful development of the COVID vaccine.
| Understanding the Novel Coronavirus|| |
Coronaviruses (CoVs) are the most significant known single-stranded RNA viruses. They are divided into three groups, based on phylogenetic studies and antigenic criteria;, specifically: (a) alpha-CoVs, causing gastrointestinal symptoms in dogs, cats, pigs, and humans; (b) beta-CoVs, including the Bat CoV, the human SARS virus, and the Middle Eastern respiratory syndrome (MERS) virus; and (c) gamma-CoVs, which infect avian species. The full RNA sequence of the SARS CoV-2 virus was revealed on January 13, 2020. The SARS CoV-2 virus is an enveloped RNA virus with a genome size of 29,903 base pairs. The sequence was closely related to two bat-derived SARS-like CoV strains, bat-SL-CoVZC45 and bat-SL-CoVZXC21 that are known to infect humans, including the virus, which led to the 2003 SARS-CoV-1 outbreak. The 2019-nCoV is now named SARS-CoV-2 and the disease caused by it as COVID-19.
This virus bears a class 1 viral fusion protein (S) that helps in attachment of virus particle to the host cell membrane during entry. As a result, S protein regulates the choice of host and cell tropism. S protein is also the leading site of action for the antibodies produced during infection, and hence, it is one of the crucial targets of vaccine designs. These S proteins act as spikes and bind to human cells, leading to a conformational change that allows the viral membrane to fuse with the cell membrane. SARS-CoV-2 spikes bind to angiotensin-converting enzyme 2 (ACE2) receptors on the surface of the human cell.
Studies have shown that the SARS-CoV-2 “S” protein binds ACE2 on the human cells more avidly than the spike from the SARS virus from 2002, resulting in increased infectivity. SARS-CoV-2 and SARS 2000 have many similarities between the structures of their “S” protein; still, antibodies against the 2002 SARS virus could not successfully neutralize SARS-CoV-2. This fact suggests that both active and passive immunization strategies have to be distinct to the new virus. A nonstructural protein (nsp) 12, also known as RNA-dependent RNA polymerase, is a crucial component of the virus genome, which catalyzes the production of viral RNA, and it plays a very crucial role in the replication of SARS CoV-2. Nsp7 and nsp8 assist this process as co-factors.
| Vaccine Development: an Overview|| |
In general, vaccine development is a long, drawn, and costly process. [Figure 1] depicts the various steps involved in the development of a successful vaccine.
Two critical deliverables of any vaccine development program are (a) developing a safe vaccine with minimum harm to research participants and (b) development of a vaccine that gives durable immunity, preferably in a single dose.
A vaccine that can be given by oral route and stored at room temperature makes its mass use easy. In the case of pandemics such as COVID-19, speed is another essential feature. For SARS CoV-2, a vaccine should also be suitable for adult healthcare workers and for adults aged more than 60 years of age with underlying chronic health conditions and should be amenable to stockpiling. Since CoVs do not induce long-lasting immunity, vaccine candidates should be sufficiently immunogenic as well.
| Coronavirus Disease 2019 Vaccine :current Landscape|| |
On the one hand, developing a COVID-19 vaccine should be relatively easy as compared to the vaccine development for HIV and hepatitis C, primarily because of the slower mutation rate of SARS-CoV-2. On the other hand, there are different types of challenges, such as identifying optimum immunogenic antigen, safety issues encountered with vaccine development programs for SARS and MERS, identification of suitable adjuvants, and getting the vaccine as soon as possible.
A large number of strategies are being pursued for developing the COVID-19 vaccine. Some are traditional platforms, while some are next-generation platforms powered by the rapid understanding of the SARS-CoV-2 structure and genome. The strategies currently being utilized are whole-virus vaccine (live-attenuated whole-virus vaccine, inactivated virus vaccines, and nonreplicating vector), protein subunit vaccines (trimerized S protein), receptor-binding domain (of S protein), and nucleic acid-based vaccine (mRNA-based and DNA-based vaccines). The details of different vaccines still in the preclinical phase are depicted in [Table 1]. Whole-virus vaccines are highly immunogenic but require extensive safety testing as there are chances of increased infectivity. Subunit vaccines elicit high levels of immunity with minimal host immunopotentiation. Nucleic acid-based vaccines are a novel strategy with no candidate entering Phase III clinical trials ever. Of the two, mRNA-based vaccines are being pursued aggressively as they are accessible to mass manufacture. Indeed, the first COVID-19 vaccine to undergo trial in humans uses the same mRNA platform to express the viral “S” protein to provoke an immune response. There has been much interest in repositioning other vaccines for COVID-19. Bacille-Calmette-Guerin (BCG) immunization for the prevention of COVID-19 is being studied with interest, and clinical trials are underway to evaluate its use among healthcare workers. Studies have suggested that, although its primary purpose is to prevent tuberculosis, BCG immunization induces a nonspecific immune response that may have protective effects against nonmycobacterial, including viral infections., Currently, the WHO does not recommends BCG vaccination for prevention, or lessening the severity of COVID-19, pending further data. Other vaccines that are candidates for repositioning are oral polio vaccine and the MMR vaccine. The most exciting prospect about repositioning of the existing vaccines is that, if existing evidence permits, then these vaccines can be taken up directly for Phase III trials. Globally, more than 150 projects are working toward the development of the SARS-CoV-2 vaccine; however, only two dozen has been approved for clinical trials. In March, the first human trial began in the United States of America. The mRNA-based vaccine, of Modena Inc., was administered 63 days after the complete genome of SARS CoV-2 was revealed. The preliminary report of the Phase 1 study with mRNA-1273 demonstrated that the mRNA-1273 vaccine-induced anti-SARS-CoV-2 immune responses in all participants, and no trial-limiting safety concerns were identified. These findings support further development of this vaccine. Oxford initiative also has begun trialing a potential vaccine in April. Academy of Military Medical Sciences and the Hong Kong-listed Biotech Firm Can Sino Bio had also started its first human trial for a potential vaccine in March, and preliminary data have shown “positive results.” This adenovirus-5 (Ad-5)-based vaccine program has had both success and failures in the past. The Ad-5-based HIV vaccine was found to be a failure while an Ebola vaccine on the same platform was strongly immunogenic., Johnson & Johnson is also using an adenovirus platform (Ad26) for its proposed vaccine. Despite the pandemic speed of human vaccine trials, most experts still feel that a successful vaccine is at least a year away. Out of the 25 vaccine candidates in clinical trials, the most promising ones are tabulated in [Table 2].,, India is also actively participating in this race for COVID-19 vaccine. Two indigenous vaccine candidates from Cadila Healthcare Limited and Bharat Biotech are in the early clinical phases. Bharat Biotech developed an “inactivated” vaccine “Covaxin” at its high-containment facility at Genome Valley in Hyderabad from a strain of the novel CoV isolated by the National Institute of Virology in Pune.
|Table 1: Vaccines for severe acute respiratory syndrome coronavirus 2 in preclinical stage|
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|Table 2: Most promising vaccine candidates for coronavirus disease-19 in clinical phase trials|
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| Challenges to Severe Acute Respiratory Syndrome Coronavirus 2 Vaccine Program (S)|| |
There are three formidable challenges that the COVID vaccine development faces: (a) availability of financial resources for vaccine development; (b) limited available time; and (c) creating mass manufacturing infrastructure.
There are ancillary challenges to make COVID-specific animal models such as ACE2 transgenic mice to fast-track animal testing. Problems of resources and speed are interlinked. If there is a reasonable surety of vaccine hitting the market soon enough, many investors will be forthcoming to finance the vaccine development.
Coalition for Epidemic Preparedness Innovation (CEPI), an international nongovernmental organization, addresses this issue. CEPI is already supporting vaccine development for five priority pathogens. It is also investing in developing “platform technologies” so that vaccine development time is reduced to as less as 16 weeks when a new pathogen erupts. For COVID also, CEPI is providing financial support to eight groups/companies, including Moderna, Inovio, University of Queensland, Clover Biopharmaceuticals, AstraZeneca, Novavax, University of Oxford, and Institut Pasteur. CEPI had planned to take at least three candidates to Phase III clinical trials, and already two candidate vaccines have reached Phase III trials. They are working with a new paradigm wherein multiple candidates are developed simultaneously instead of working in a linear, “one candidate at a time” manner. They are also simultaneously trying to bolster manufacturing facilities. The endeavor is to do multiple steps knowing that some candidates, technology platforms, and facilities will be wasted; however, this is a novel paradigm to develop a vaccine as fast as possible. Finances remain a problem as the estimated cost of vaccine development is around 2 billion USD.
Another critical “deviation” suggested to truncate vaccine development time is to undertake human challenge studies wherein uninfected volunteers are randomized to receive either candidate vaccine or placebo. Both the cohorts will be exposed to a controlled quantum of SARS CoV-2. These types of studies are ethically loaded but can truncate vaccine development substantially. Care has to be taken to enroll the least vulnerable groups (healthy young adults in case of COVID-19) and keep the number to a minimum. A suitable viral load to ensure effective infection also needs to be estimated a priori. A strong argument in favor of such studies is that the participants of this study are getting exposed at a defined time and in a controlled manner, thereby undergoing what they would have undergone otherwise also.
Other strategies to shorten the time of vaccine development consist of having abridged animal studies with statistical modeling in COVID-specific animal models. Phase I clinical trials can also be initiated, while animal studies are in the final stages, and relevant information has been obtained through interim analysis. These Phase I studies can be done in several groups with small participant numbers with different dose ranges, in an adaptive manner. This way, different dose levels can be evaluated simultaneously. After Phase II trial/human challenge studies' results are known, multiple Phase III studies can be done with a common control comparator group to minimize patients receiving placebo and also to reduce time.
Along with the preclinical and clinical development program, capacity building to mass manufacture successful candidates should also be done, so that once a vaccine secures licensure, it can be brought to market quickly. It is apparent that this type of developmental plan will increase the cost manifolds but will ensure that the vaccine is available during the pandemic itself [Figure 2].
|Figure 2: Coronavirus disease 2019-an accelerated vaccine development process|
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| Conclusion|| |
Getting a vaccine as fast as possible is the only predictable way out of this pandemic. While existing knowledge of traditional vaccine technologies and next-generation technologies for innovative vaccine platforms has hastened the vaccine development, there remain substantial challenges in the path of the COVID-19 vaccine. Time and finances both stand constrained. There is a need for generous funding, collaborative effort, and novel study designs so that the world gets the COVID-19 vaccine sooner. This large-scale vaccine development has happened for the first time in the history of humanity that 164 vaccine candidates for the single disease are under development simultaneously.
We must also realize that the world is facing an infectious disease outbreak every decade, SARS in the 2000s, MERS in the 2010s, and COVID-19 in 2020. Although it is unlikely that the current epidemic will end abruptly, pan-CoV vaccine development and stockpiling have to become a global priority, and the world needs to identify the international funding agencies and mechanisms to support the development, manufacturing, and storage of these vaccines even if the epidemic ends abruptly.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2]