|Year : 2020 | Volume
| Issue : 4 | Page : 175-179
The race to find COVID-19 Vaccine: So near, yet so far!
Sonali Sachdeva, Udita Gupta, Anupam Prakash, Shubha Laxmi Margekar, Ritika Sud
Department of Medicine, Lady Hardinge Medical College and Associated Hospitals, New Delhi, India
|Date of Submission||04-Oct-2020|
|Date of Acceptance||05-Oct-2020|
|Date of Web Publication||26-Nov-2020|
Dr. Sonali Sachdeva
Department of Medicine, Lady Hardinge Medical College and Associated Hospitals, New Delhi
Source of Support: None, Conflict of Interest: None
In a brief span of time, coronavirus has become a major cause of concern worldwide ever since the first case was reported in Wuhan, China in December 2019. The pace at which the virus is being transmitted across the globe and the sudden increase in numbers of cases is much faster than severe acute respiratory syndrome and Middle East respiratory syndrome. With the rising number of cases, coronavirus disease 2019 (COVID-19) not only has an adverse effect on health, it has a deep seated impact on the economic and social front. Hence, the development of an effective vaccination strategy seems to be the only light at the end of the tunnel. The ongoing pandemic mandates the speedy evaluation of multiple approaches in order to elicit protective immunity and to curtail unwanted immune-potentiation which plays an important role in the pathogenesis of this virus. Being developed by more than 90 institutions in the world, a vaccine which is both effective and safe becomes all the more essential in the current time. Various types of vaccine strategies are being tested under different phases of clinical trials. The present paper hopes to provide an overview of the current work going on in this direction, with an aim to further fuel effects for an early and effective COVID-19 vaccine platform.
Keywords: Coronavirus disease 2019, coronavirus, pandemic, severe acute respiratory syndrome-coronavirus-2, vaccine
|How to cite this article:|
Sachdeva S, Gupta U, Prakash A, Margekar SL, Sud R. The race to find COVID-19 Vaccine: So near, yet so far!. Indian J Med Spec 2020;11:175-9
|How to cite this URL:|
Sachdeva S, Gupta U, Prakash A, Margekar SL, Sud R. The race to find COVID-19 Vaccine: So near, yet so far!. Indian J Med Spec [serial online] 2020 [cited 2021 Oct 24];11:175-9. Available from: http://www.ijms.in/text.asp?2020/11/4/175/301545
| Introduction|| |
Novel coronavirus disease 2019 (COVID-19) was declared a pandemic by the WHO on March 11, 2020. Since its outbreak in Wuhan, China, COVID-19 has claimed more than 18 million deaths across the globe and has emerged as a major cause of concern due to its widespread effect on the health and economic sectors worldwide. Since the disease is new to mankind and knowledge about the body's immune response against the virus is relatively unknown, no vaccine strategy has yet been able to surface that could guarantee protection. In such a scenario, it becomes imperative to establish platforms for vaccine-related research and development. An effective vaccination strategy seems to be the most promising way to contain the pandemic. Although this is a challenging situation and requires international collaboration, several institutions around the world have begun trials and are midway through the process of vaccine development against the virus. In this review, we have summarized the immunological basis and considerations for COVID-19 vaccine development, as well as ongoing strategies pertaining to the same.
| About the Virus|| |
The etiological pathogen has been identified as “severe acute respiratory syndrome coronavirus-2” (SARS-CoV-2). CoVs belong to the order “Nidovirales,” family “Coronaviridae,” and subfamily “Coronavirinae.” All viruses belonging to this order are non-segmented, positive-sense RNA viruses. The subfamily Coronavirinae is subdivided into four genera, the alpha, beta, gamma, and delta CoVs. SARS-CoV-2, a beta CoV is a spherical shaped virus, having club-shaped spikes on its surface. Surrounded by the envelope is the helically symmetrical nucleocapsid. The 4 main structural proteins include – spike (S), membrane (M), envelope (E), and nucleocapsid (N). The CoV makes use of the S-glycoprotein to attach to human ACE-2 receptors. All of these are encoded within the 3' end of the viral genome. Akin to the origin of SARS-CoV and Middle East respiratory syndrome CoV (MERS-CoV, SARS-CoV-2 also originated in bats and may have transmitted to humans via unknown intermediate hosts. The SARS-CoV-2 genomic sequence is 96.2% identical to that of a bat CoV RaTG13. The mortality rate of COVID-19 is believed to be less than that of SARS (9.6%) and MERS (35%).
| Immunopathological Considerations|| |
A significant portion of our understanding of the body's immune responses to SARS-CoV-2 can be attributed to our knowledge about the SARS and MERS viruses, given the limited information about the SARS-CoV-2 genome we currently have.
The innate immune response against SARS-CoV-2 is characterized by activated macrophages and dendritic cells (DCs) leading to the production of a plethora of cytokines and chemokines, resulting in the so-called SARS-CoV-2 associated “cytokine storm.” Multiorgan damage, including acute respiratory distress syndrome, can be ascribed to this phenomenon. As opposed to the prevailing belief, the body's innate immune response has a role to play in vaccine development. Innate immune memory (also known as trained immunity) has been recently acknowledged as a component of immunological memory, which has implications for vaccine strategies. BCG vaccination induces this kind of trained immunity and is being increasingly considered as a potential vaccine candidate and several clinical trials assessing its role in COVID-19 are already under way.
Neutralizing antibodies (nAbs) for SARS-CoV-2 limit the infection at a later phase and prevent reinfection on a future encounter with the virus. nAbs to RBD and non-RBD epitopes of the SARS-CoV-2 spike protein have been identified and have shown protection in small animal models. The titers of nAbs varied significantly in a cohort study of 175 recovered patients, the implications of which for prevention of future SARS-CoV-2 infection are unknown. The key target of nAbs noticed in COVID-19 is the S protein, which is composed of S1 and S2 domains.
Apart from just S protein, N and M protein addition to the vaccine could help in eliciting a T-cell response (CD4+ and CD8+) and resulting in a more adequate, specific response with a long-term immunological memory. Hence, not just S protein, but N and M proteins as well should be given due consideration while designing COVID-19 vaccines.
Both T-cell and antibody-mediated responses are important for adequate immunity against SARS-CoV-2. There is a similarity between the spike protein sequence of SARS-CoV-2 and SARS and between T-cell epitopes of SARS and MERS-CoV. This could give rise to the possibility of a potential universal vaccine for the CoVs due to existing cross-reactivity.
The risk of immune backfiring could turn out to be a major hurdle in the success of any eligible COVID-19 vaccine candidate, as antibody-dependent enhancement or Th2-mediated immunopathologic mechanisms may play a role. Keeping this in mind, trials should incorporate risk assessment for such adverse immune events.
| Vaccine Strategies|| |
According to the WHO: “vaccine must provide a highly favorable benefit-risk contour; with high efficacy, only mild or transient adverse effects and no serious ailments.” The vaccine must be suitable for all ages, pregnant and lactating women and should provide a rapid onset of protection, preferably with a single dose, and confer safety for at least up to a year of administration. The preferred and minimally accepted profiles for human COVID-19 vaccine for the purpose of both long-term protection of high-risk persons and for rapid onset of immunity in outbreak settings has been released by the WHO.
Genomic sequencing of SARS-CoV-2 has shown similarity in the genome with that of SARS-CoV (79%) and MERS-CoV (50%). This has helped vaccine developers worldwide to shape potential vaccine strategies that are now being worked upon to devise an effective vaccination against COVID-19. Most of the COVID-19 vaccine candidates developing around the world tend to produce either nAbs that prevent SARS-CoV-2 from entering and infecting host cells or induce antibody/immune cell responses that kill already infected cells, thereby limiting replication. The S protein plays a major role in eliciting protective nAbs and T-cell responses against SARS-CoV-2 and can be delivered to the host cells through a variety of mechanisms, giving rise to a number of potential vaccine platforms, which are shown in [Table 1].
Currently, more than 150 vaccine candidates for SARS-CoV-2 are being evaluated the world over, of which around 135 are in the preclinical stages of development. We have summarized the major vaccines that presently show some promise.
| Whole Virus Vaccines|| |
The development of inactivated vaccines poses a threat, for it requires the cultivation of high titers of infectious viruses. Another potential risk is incomplete inactivation of the virus, which may cause disease outbreaks in vaccinated populations and induce harmful immune or inflammatory responses. Despite these shortcomings, 2 promising vaccines can be seen being developed and are in their phase 1/2 (BBV152) and phase 3 (PiCoVacc) of trial.
- CoronaVac (formerly PiCoVacc) Company (Country): Sinovac Biotech
It is a chemically inactivated whole SARS-CoV-2 virus particle (PiCoVacc) developed in VERO monkey cells and the adjuvant alum. The seroconversion rate in Phase 1/2 of PiCoVacc was 90% in a 0, 14-day schedule indicating that 90% of subjects developed nAbs, and no systemic or local adverse events were reported. Results of phase 2 clinical trials are expected by end of 2020. Phase 3 clinical trials have been permitted in Brazil in collaboration with Instituto Butantan and possibly in Bangladesh.
- BBV152 - (Phase 1/2 clinical trials) - ICMR isolated the viral strain for vaccine development and transferred to Bharat Biotech which carried out the inactivation process at a BSL-3 facility
- COVID-19 vaccine Company (Country): Sinopharm (China) - Inactivated Novel CoV Pneumonia vaccine (Vero cells) - Phase1/2.
| Live Attenuated Vaccines|| |
Live attenuated vaccines are produced by modifying the disease producing (wild type) virus or bacterium in the laboratory. The problem with live attenuated vaccines for SARS-CoV-2 is that it can be excreted in the feces of infected individuals, thus putting unvaccinated individuals at risk. The risk of recombination of live attenuated virus with wild-type CoV is another concern which could potentially limit the development of live attenuated vaccines for use in COVID-19. Some institutes that are pursuing this alternative are:
- Codagenix (Farmingdale, NY, USA) and the Serum Institute of India (Pune, India)
- The German Center for Infection Research (DZIF, Braunschweig, Germany) and Zydus Cadila (Etna Biotech, Ahmedabad, India)
- Indian Immunologicals (Hyderabad, India) in collaboration with Griffith University (Brisbane, Australia)
- DelNS1-SARS-CoV2-RBD (University of Hong Kong) - influenza-based vaccine strain with deleted NS1 gene - It is attenuated by the deletion of a key virulent element and the immune antagonist, NS1, which is potentially more immunogenic than the wild-type influenza virus.” - A weakened version of the flu virus adapted to express the surface protein of the COVID-19 virus (preclinical).
| Subunit|| |
Subunit vaccines are based on synthetic peptide (s) or recombinant protein (s) of the target pathogen. Subunit vaccines contain specific antigenic fragments and no other components of the pathogenic viruses. This is in contrast to other vaccines such as inactivated viruses, live attenuated viruses, and virus-vectored vaccines. Hence, complications such as incomplete viral inactivation, virulence recovery, and pre-existing anti-vector immunity are not matters of concern in subunit vaccines. The drawbacks of subunit vaccine include low immunogenicity and requirement of an adjuvant to enhance the immune response induced by the virus. The most effective antigen of the SARS-CoV-2 to induce nAbs is the S protein.
Some potential candidates are:
- SCB-2019 - A recombinant 2019-nCoV S protein subunit-trimer vaccine (S-Trimer) - Phase 1
- COVID-19 XWG-03 - preclinical vaccine
- CEPI/University of Queensland- Protein-based vaccine using Molecular Clamp platform
- Novavax- Recombinant Nanotechnology-based vaccine.
| Viral Vector Vaccines|| |
Certain viruses, used as agents to deliver vaccine antigens to the target cell/tissue are called “viral vectors,” examples of which include adenovirus and poxvirus. For both of these, replicating and non-replicating forms are available. There are several disadvantages associated with the use of viral vectors to deliver genetic material to cells. First, the viral vector itself can induce an immune response in the body. Second, the same viral vector cannot be reused if a vaccine fails during clinical testing because it has the ability to induce an immune response. Third, the vaccine can be ineffective because of pre-existing immunity against the viral vector. There are other possible issues with viral vectors such as genetic toxicity, and low transgenic expression, which can be conquered by using hybrid viral vectors. Despite these shortcomings, vector vaccines are among the most promising candidates of a possible vaccine.
| Nonreplicating Viral Vector Vaccines|| |
ChAdOx1 (University of Oxford) - Nonreplicating viral vector vaccine
The ChAdOx1 nCoV-19 vaccine (AZD1222), now in its phase 3 of clinical trial, consists of the replication-deficient simian adenovirus vector ChAdOx1, containing the full-length structural surface glycoprotein (spike protein) of SARS-CoV-2, with a tissue plasminogen activator leader sequence. ChAdOx1 nCoV-19 expresses a codon-optimized coding sequence for the spike protein (GenBank accession number MN908947). The preliminary report of phase 1/2 trials indicated that ChAdOx1 nCoV-19 was safe, tolerated, and immunogenic, and that its reactogenicity reduced with paracetamol intake. Both humoral and cellular immune responses were elicited, and a booster immunization was noted to augment titers of nAbs.
LV-SMENP-DC (Shenzhen Geno-Immune Medical Institute)
This vaccine is in its Phase 1/2 of clinical trial. DCs have been engineered with the lentiviral vector expressing the conserved domains of the SARS-CoV-2 structural proteins and the protease using the SMENP minigenes, to make this vaccine. When the vaccine is inoculated subcutaneously, antigens on the antigen presenting cells activate the cytotoxic T cells and generate the immune response.
Adenovirus serotype 5 (Ad5)-nCoV (CanSino Biologics Inc | Beijing Institute of Biotechnology) - Phase 2. It is a recombinant adenovirus type-5 vector (Ad5), that encodes full length spike protein of SARS-CoV-2. Phase I clinical trials show a four-fold increase in the RBD and S protein-specific nAbs within 14 days of immunization peaking at day 28 post-vaccination while the T cell (both CD4 + and CD8 +) response peaked at day 14 post-vaccination.
According to results of phase 2 trial of this vaccine, seroconversion of the nAbs in 59% and 47% of participants, and seroconversion of binding antibody in 96% and 97% of participants, in the 1 × 1011 and 5 × 1010 viral particles dose groups, was produced respectively. Majority of participants also demonstrated positive T-cell specific responses, as measured by IFNγ-ELISpot.
| Replicating Viral Vector Vaccines|| |
University of Pittsburgh/CEPI- Name: “Lead candidate” Company (Country): Institut Pasteur (France)/Merck (USA).
It is a live attenuated replicating measles vector (MV) vaccine- The proprietary MV technology is chosen to develop the vaccine against SARS-CoV-2 which was used in the MV-SARS-CoV vaccine candidate (Pre-clinical testing phase).
| Nucleic Acid Vaccines|| |
This type of vaccine contains selected gene (s) of the virus in the form of DNA. Upon injection, the DNA is used as a template for in situ expression of potentially harmless viral protein (s), which induces a protective immune response. One of the greatest advantages of this type of vaccine is the safety and scalability for mass production. DNA-based viral vaccines have been shown to induce strong immune responses in animal models, especially in mice., However, there is limited positive clinical data on DNA-based viral vaccines in humans, and no commercial DNA vaccine against any disease has yet been approved. Nevertheless, several DNA vaccine candidates are tested preclinically and two candidates have progressed into Phase I clinical testing.
- INO-4800 (Inovio Pharmaceuticals): It is a prophylactic DNA vaccine against SARS-CoV-2. It has codon optimized S protein sequence of SARS-CoV-2 with an IgE leader sequence attached. Preclinical trials raise the hope of an early effective immune response within 7 days post-vaccination. The vaccine has already entered the Phase I clinical trials (Phase I: NCT04336410), to establish immunological profile, safety and tolerability on intradermal injection and electroporation in healthy human beings
- ZyCoV-D: ZyCoV-D is a DNA plasmid-based vaccine (encoding for viral membrane proteins) in phase 1/2 of clinical trials. Three doses will be administered at an interval of 28 days in 1048 individuals, and immunogenicity and safety of the vaccine will be studied.
Similar to DNA vaccines, RNA vaccines contain specific genes of the virus in the form of mRNA, and following cytosolic delivery, these genes are translated into viral proteins.
- mRNA-1273 (Moderna TX, Inc.,) - It is a vaccine composed of synthetic mRNA encapsulated in Lipid nanoparticle (LNP) which codes for the full-length spike protein (S) of SARS-CoV-2 which elicits a S-protein specific antiviral response. It is relatively safe as neither the components of inactivated pathogen nor the subunits of live pathogen are contained in this vaccine. The vaccine got fast-track approval from the US Food and Drug Administration for Phase II trials. The vaccine was found to be more or less safe in the majority, though grade 3 systemic symptoms were reported by three participants after the administration of additional doses. Phase 3 trial of this vaccine began in late July this year
- BNT162b, the mRNA-based vaccine induced significant dose-dependent nAb titers along with the RBD-binding IgG concentrations. Few adverse effects such as fever, chills, fatigue, and muscle pains, were reported after vaccine administration, but no serious symptoms were seen.
| Others|| |
Virus like particles
A self-assembled nanostructure incorporating important viral structural proteins, resembling the molecular and morphological features of authentic viruses, but is non-replicating and non-infectious due to absence of genetic material. It induces humoral immune response. Its potential drawbacks include its uncertainty in terms of stability, quality control, heterogeneity, and possibility of contamination. Xu et al. in their study described construction of SARS-CoV-2 VLPs using a Mammalian expression system.
The biotinylated immunogenic fusion protein is sandwiched between heat shock protein and avidin. One such candidate in its preclinical stage is the HaloVax.
British American Tobacco Company (BAT) recently launched a potential vaccine candidate using their fast-growing tobacco plant technology.
Worthy of mention is the oral vaccine developed by the Tianjin University, employing food-grade safe Saccharomyces cerevisiae as the carrier of S-protein. The Generally Regarded as Safe status of the yeast provides high extensibility, robustness, and cost-effective production of greatly increased dosages required to fight off this pandemic.
| Conclusion|| |
Scientists world over are enthused as well as pressured to adopt unconventional approaches in order to expedite the process of vaccine development for CoV. Vaccine development has started in the right earnest and several candidate vaccine trials are underway. It is only a matter of time before a suitable vaccine candidate establishes its safety and efficacy to provide an effective option for combating the CoV pandemic. The upcoming vaccine strategies should ideally fulfill the target product profile for a human COVID-19 vaccine as laid down by the WHO. The need of the hour is to establish joint multidisciplinary international efforts to actively mobilize data and technology in pursuit of a safe and effective vaccine.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, et al
. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020;579:270-3.
de Wit E, van Doremalen N, Falzarano D, Munster VJ. SARS and MERS: Recent insights into emerging coronaviruses. Nat Rev Microbiol 2016;14:523-34.
O'Neill LAJ, Netea MG. BCG-induced trained immunity: Can it offer protection against COVID-19? Nat Rev Immunol 2020;20:335-7.
Jiang S, Hillyer C, Du L. Neutralizing Antibodies against SARS-CoV-2 and other human coronaviruses. Trends Immunol 2020;41:355-9.
Rogers TF, Zhao F, Huang D, Beutler N, Burns A, He WT, et al
. Isolation of potent SARS-CoV-2 neutralizing antibodies and protection from disease in a small animal model. Science 2020;369:956-63.
He Y, Zhou Y, Liu S, Kou Z, Li W, Farzan M, et al
. Receptor-binding domain of SARS-CoV spike protein induces highly potent neutralizing antibodies: Implication for developing subunit vaccine. Biochem Biophys Res Commun 2004;324:773-81.
Al-Kassmy J, Pedersen J, Kobinger G. Vaccine candidates against coronavirus infections. Where does COVID-19 stand? Viruses 2020;12:861.
Sariol A, Perlman S. Lessons for COVID-19 immunity from other coronavirus infections. Immunity 2020;53:248-63.
Liu WJ, Zhao M, Liu K, Xu K, Wong G, Tan W, et al
. T-cell immunity of SARS-CoV: Implications for vaccine development against MERS-CoV. Antiviral Res 2017;137:82-92.
Hotez PJ, Corry DB, Bottazzi ME. COVID-19 vaccine design: The Janus face of immune enhancement. Nat Rev Immunol 2020;20:347-8.
Prompetchara E, Ketloy C, Palaga T. Immune responses in COVID-19 and potential vaccines: Lessons learned from SARS and MERS epidemic. Asian Pac J Allergy Immunol 2020;38:1-9.
Du L, He Y, Zhou Y, Liu S, Zheng BJ, Jiang S. The spike protein of SARS-CoV A target for vaccine and therapeutic development. Nat Rev Microbiol 2009;7:226-36.
Gao Q, Bao L, Mao H, Wang L, Xu K, Yang M, et al
. Development of an inactivated vaccine candidate for SARS-CoV-2. Science 2020;369:77-81.
Chinese Clinical Trial Register (Chictr)-The World Health Organization International Clinical Trials Registered Organization Registered Platform. Chictr.org.cn. 2020. Available from: http://www.chictr.org.cn/showprojen.aspx?proj=52227
. [Last accessed on 2020 Oct 02].
Nayak S, Herzog RW. Progress and prospects: Immune responses to viral vectors. Gene Ther 2010;17:295-304.
Huang S, Kamihira M. Development of hybrid viral vectors for gene therapy. Biotechnol Adv 2013;31:208-23.
Thanh Le T, Andreadakis Z, Kumar A, Gómez Román R, Tollefsen S, Saville M, et al
. The COVID-19 vaccine development landscape. Nat Rev Drug Discov 2020;19:305-6.
Wu S, Zhong G, Zhang J, Shuai L, Zhang Z, Wen Z, et al
. A single dose of an adenovirus-vectored vaccine provides protection against SARS-CoV-2 challenge. Nat Commun 2020;11:4081.
Wang L, Shi W, Joyce MG, Modjarrad K, Zhang Y, Leung K, et al
. Evaluation of candidate vaccine approaches for MERS-CoV. Nat Commun 2015;6:7712.
Larocca RA, Abbink P, Peron JP, Zanotto PM, Iampietro MJ, Badamchi-Zadeh A, et al
. Vaccine protection against Zika virus from Brazil. Nature 2016;536:474-8.
Smith TRF, Patel A, Ramos S, Elwood D, Zhu X, Yan J, et al
. Immunogenicity of a DNA vaccine candidate for COVID-19. Nat Commun 2020;11:2601.
Mulligan MJ, Lyke KE, Kitchin N, Absalon J, Gurtman A, Lockhart S, et al
. Phase 1/2 study of COVID-19 RNA vaccine BNT162b1 in adults. Nature 2020;586:589-93. Available from: https://www.nature.com/articles/s41586-020-2639-4
. [Last accessed on 2020 Oct 03].
Xu R, Shi M, Li J, Song P, Li N. Construction of SARS-CoV-2 virus-like particles by mammalian expression system. Front Bioeng Biotechnol 2020;8:862.
Zhai P, Ding Y, Wu X, Long J, Zhong Y, Li Y. The epidemiology, diagnosis and treatment of COVID-19. Int J Antimicrob Agents 2020;55:105955.