A Possible Path towards Rapid Development of Live-Attenuated SARS-CoV-2 Vaccines: Plunging into the Natural Pool
Abstract
:1. Introduction: Towards the Live-Attenuated SARS-CoV-2 Vaccines
2. The Key Steps of the Proposed Approach
- Identify populations at the highest risk for severe course of SARS-CoV-2 (e.g., elderly with severe co-morbidities/multiple major risk factors) and find locations of infection clusters in those populations.
- At or near the location of the infection cluster or simply in very high risk populations (e.g., nursing homes, retirement communities, etc.), screen and test all the highest risk individuals for active SARS-CoV-2 (PCR test).
- Among those screened, find a subset of individuals with active SARS-CoV-2 injection (positive PCR test), who show no or minimal symptoms and get the samples of the virus from each such person. Then wait till their infection is fully cleared (negative PCR test) and narrow down the selection to those who have not developed any serious symptoms or diagnostic indicators of any long-term health damage associated with COVID-19.
- In the above group (i.e., high risk individuals who have recovered from SARS-CoV-2 with little or no symptoms/consequences), performs immunological tests and find individuals who have a relatively weak immune system (which would be common in the high risk population you are working with) but still developed a robust immunity against SARS-CoV-2 (preferably both high level of antibodies as well as cellular immunity).
- Analyze the SARS-CoV-2 variants from the above subgroup of individuals identified in the previous step. Potentially, some of those SARS-CoV-2 variants would be capable of invoking a robust immune response but are sufficiently attenuated as not to cause major symptoms even in the most vulnerable/highest risk individuals. The analysis should include viral genome sequencing and, ideally, tissue cultures tests of infectivity (to verify attenuation and possibly ascertain its mechanism), etc. As an example, one could test for rates of virus binding to ACE2 receptors, for rates of infecting cultured lung cell, etc. Subsequent analyses could also include tests in animal models.
- The above steps should allow to select SARS-CoV-2 variants with weak infectivity and/or causing low intensity/mild infection. This alone might produce a sufficiently attenuated variant of the virus. Otherwise, one should consider additional steps to further attenuate the virus, such as passaging via human tissue culture while applying selection pressure towards survival of the more attenuated forms of the virus, targeted deletions, etc. The result would be the candidates for the live-attenuated SARS-CoV-2 vaccines.
- Among the candidate variants of the naturally live-attenuated SARS-CoV-2, identify the ones found in the greatest number of people fitting the above screening criteria. Perform additional screening of all the contacts of the individuals found to have carried naturally SARS-CoV-2 variants. If possible, also screen additional population around the infection cluster under study. Check that the additional individuals found to carry the identified attenuated SARS-CoV-2 variants do not develop a symptomatic infection (or have only mild symptoms) or suffer from any complications. Exclude the live-attenuated SARS-CoV-2 candidates that were found to cause any major issues during this broader screening. The remaining live-attenuated SARS-CoV-2 candidates could be (potentially) suitable for clinical testing.
- For the most promising live-attenuated SARS-CoV-2 candidate(s) identified in Step 7, keep recursively tracing the contacts of all individuals infected with the candidate strain, thereby (potentially) collecting data on a significant number of individuals infected with it. The goal of this step is to find as many individuals as possible who were infected with, carried, and recovered from the candidate live-attenuated SARS-CoV-2 strain and then to accumulate/analyze enough data to (at least tentatively) determine that the candidate strain: (a) does not cause severe or even moderate infection; (b) is robustly immunogenic; (c) does not revert to a more pathogenic form, etc.
- Evaluate whether the thus identified naturally live-attenuated SARS-COV-2 candidate(s) is/are suitable for clinical testing as a live-attenuated vaccine. If not, consider additional attenuation steps (e.g., via genetic engineering, such as directed deletion of some specific gene cluster open reading frame(s) [26] or passaging in tissue culture under selection pressure or etc).
- If the above steps are successful, one would have found a promising live-attenuated SARS-COV-2 vaccine candidate and have accumulated a considerable amount of human clinical data on it. The clinical trials still required to ensure the suitability for vaccination may be less extensive than otherwise, potentially providing a faster path to a safe and effective vaccine.
3. Additional Considerations and Concerns
3.1. Transmission Rates of the Live-Attenuated Virus
3.2. Rates of Natural Evolution of Live-Attenuated Virus
3.3. Virus Testing
3.4. Continuous Vaccine Upgrades
3.5. Potential Risks to Look Into
3.5.1. Missed Virulence in the Young
3.5.2. Reversal of Attenuation
3.5.3. Risk of Autoimmune Reactions
Author Contributions
Funding
Conflicts of Interest
References
- Nabel, G.J. Designing tomorrow’s vaccines. N. Engl. J. Med. 2013, 368, 551–560. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Vadala, M.; Poddighe, D.; Laurino, C.; Palmieri, B. Vaccination and autoimmune diseases: Is prevention of adverse health effects on the horizon? EPMA J. 2017, 8, 295–311. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Karch, C.P.; Burkhard, P. Vaccine technologies: From whole organisms to rationally designed protein assemblies. Biochem. Pharmacol. 2016, 120, 1–14. [Google Scholar] [CrossRef] [PubMed]
- Grubaugh, N.D.; Petrone, M.E.; Holmes, E.C. We shouldn’t worry when a virus mutates during disease outbreaks. Nat. Microbiol. 2020, 5, 529–530. [Google Scholar] [CrossRef] [Green Version]
- Holmes, E.C. The Evolution and Emergence of RNA Viruses; Oxford University Press: New York, NY, USA, 2009. [Google Scholar]
- Armengaud, J.; Delaunay-Moisan, A.; Thuret, J.Y.; van Anken, E.; Acosta-Alvear, D.; Aragon, T.; Arias, C.; Blondel, M.; Braakman, I.; Collet, J.F.; et al. The importance of naturally attenuated SARS-CoV-2in the fight against COVID-19. Environ. Microbiol. 2020, 22, 1997–2000. [Google Scholar] [CrossRef]
- Riedel, S. Edward Jenner and the history of smallpox and vaccination. Proc. Bayl Univ Med. Cent. 2005, 18, 21–25. [Google Scholar] [CrossRef]
- Lakhani, S. Early clinical pathologists: Edward Jenner (1749–1823). J. Clin. Pathol. 1992, 45, 756–758. [Google Scholar] [CrossRef] [Green Version]
- Smith, D.R.; Leggat, P.A. Pioneering figures in medicine: Albert Bruce Sabin—inventor of the oral polio vaccine. Kurume Med. J. 2005, 52, 111–116. [Google Scholar] [CrossRef] [Green Version]
- Hampton, L. Albert Sabin and the Coalition to Eliminate Polio from the Americas. Am. J. Public Health 2009, 99, 34–44. [Google Scholar] [CrossRef]
- Gudbjartsson, D.F.; Norddahl, G.L.; Melsted, P.; Gunnarsdottir, K.; Holm, H.; Eythorsson, E.; Arnthorsson, A.O.; Helgason, D.; Bjarnadottir, K.; Ingvarsson, R.F.; et al. Humoral Immune Response to SARS-CoV-2 in Iceland. N. Engl. J. Med. 2020. [Google Scholar] [CrossRef] [PubMed]
- Peng, Y.; Mentzer, A.J.; Liu, G.; Yao, X.; Yin, Z.; Dong, D.; Dejnirattisai, W.; Rostron, T.; Supasa, P.; Liu, C.; et al. Broad and strong memory CD4(+) and CD8(+) T cells induced by SARS-CoV-2 in UK convalescent individuals following COVID-19. Nat. Immunol. 2020. [Google Scholar] [CrossRef] [PubMed]
- Enjuanes, L.; Zuniga, S.; Castano-Rodriguez, C.; Gutierrez-Alvarez, J.; Canton, J.; Sola, I. Molecular Basis of Coronavirus Virulence and Vaccine Development. Adv. Virus Res. 2016, 96, 245–286. [Google Scholar] [CrossRef] [PubMed]
- Lan, J.; Yao, Y.; Deng, Y.; Chen, H.; Lu, G.; Wang, W.; Bao, L.; Deng, W.; Wei, Q.; Gao, G.F.; et al. Recombinant Receptor Binding Domain Protein Induces Partial Protective Immunity in Rhesus Macaques Against Middle East Respiratory Syndrome Coronavirus Challenge. EBioMedicine 2015, 2, 1438–1446. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bull, J.J.; Nuismer, S.L.; Antia, R. Recombinant vector vaccine evolution. PLoS Comput. Biol. 2019, 15, e1006857. [Google Scholar] [CrossRef] [Green Version]
- Shim, B.S.; Stadler, K.; Nguyen, H.H.; Yun, C.H.; Kim, D.W.; Chang, J.; Czerkinsky, C.; Song, M.K. Sublingual immunization with recombinant adenovirus encoding SARS-CoV spike protein induces systemic and mucosal immunity without redirection of the virus to the brain. Virol. J. 2012, 9, 215. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kim, E.; Okada, K.; Kenniston, T.; Raj, V.S.; AlHajri, M.M.; Farag, E.A.; AlHajri, F.; Osterhaus, A.D.; Haagmans, B.L.; Gambotto, A. Immunogenicity of an adenoviral-based Middle East Respiratory Syndrome coronavirus vaccine in BALB/c mice. Vaccine 2014, 32, 5975–5982. [Google Scholar] [CrossRef]
- Guo, X.; Deng, Y.; Chen, H.; Lan, J.; Wang, W.; Zou, X.; Hung, T.; Lu, Z.; Tan, W. Systemic and mucosal immunity in mice elicited by a single immunization with human adenovirus type 5 or 41 vector-based vaccines carrying the spike protein of Middle East respiratory syndrome coronavirus. Immunology 2015, 145, 476–484. [Google Scholar] [CrossRef] [Green Version]
- Roberts, A.; Lamirande, E.W.; Vogel, L.; Baras, B.; Goossens, G.; Knott, I.; Chen, J.; Ward, J.M.; Vassilev, V.; Subbarao, K. Immunogenicity and protective efficacy in mice and hamsters of a beta-propiolactone inactivated whole virus SARS-CoV vaccine. Viral. Immunol. 2010, 23, 509–519. [Google Scholar] [CrossRef] [Green Version]
- Bolles, M.; Deming, D.; Long, K.; Agnihothram, S.; Whitmore, A.; Ferris, M.; Funkhouser, W.; Gralinski, L.; Totura, A.; Heise, M.; et al. A double-inactivated severe acute respiratory syndrome coronavirus vaccine provides incomplete protection in mice and induces increased eosinophilic proinflammatory pulmonary response upon challenge. J. Virol. 2011, 85, 12201–12215. [Google Scholar] [CrossRef] [Green Version]
- Tseng, C.T.; Sbrana, E.; Iwata-Yoshikawa, N.; Newman, P.C.; Garron, T.; Atmar, R.L.; Peters, C.J.; Couch, R.B. Immunization with SARS coronavirus vaccines leads to pulmonary immunopathology on challenge with the SARS virus. PLoS ONE 2012, 7, e35421. [Google Scholar] [CrossRef]
- Iwata-Yoshikawa, N.; Uda, A.; Suzuki, T.; Tsunetsugu-Yokota, Y.; Sato, Y.; Morikawa, S.; Tashiro, M.; Sata, T.; Hasegawa, H.; Nagata, N. Effects of Toll-like receptor stimulation on eosinophilic infiltration in lungs of BALB/c mice immunized with UV-inactivated severe acute respiratory syndrome-related coronavirus vaccine. J. Virol. 2014, 88, 8597–8614. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tang, L.; Zhu, Q.; Qin, E.; Yu, M.; Ding, Z.; Shi, H.; Cheng, X.; Wang, C.; Chang, G.; Zhu, Q.; et al. Inactivated SARS-CoV vaccine prepared from whole virus induces a high level of neutralizing antibodies in BALB/c mice. DNA Cell Biol. 2004, 23, 391–394. [Google Scholar] [CrossRef] [PubMed]
- Gao, Q.; Bao, L.; Mao, H.; Wang, L.; Xu, K.; Yang, M.; Li, Y.; Zhu, L.; Wang, N.; Lv, Z.; et al. Development of an inactivated vaccine candidate for SARS-CoV-2. Science 2020, 369, 77–81. [Google Scholar] [CrossRef] [PubMed]
- Wang, H.; Zhang, Y.; Huang, B.; Deng, W.; Quan, Y.; Wang, W.; Xu, W.; Zhao, Y.; Li, N.; Zhang, J.; et al. Development of an Inactivated Vaccine Candidate, BBIBP-CorV, with Potent Protection against SARS-CoV-2. Cell 2020, 182, 713–721.e719. [Google Scholar] [CrossRef] [PubMed]
- Haijema, B.J.; Volders, H.; Rottier, P.J. Live, attenuated coronavirus vaccines through the directed deletion of group-specific genes provide protection against feline infectious peritonitis. J. Virol. 2004, 78, 3863–3871. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Callaway, E. The coronavirus is mutating-does it matter? Nature 2020, 585, 174–177. [Google Scholar] [CrossRef] [PubMed]
- Pfefferle, S.; Huang, J.; Norz, D.; Indenbirken, D.; Lutgehetmann, M.; Oestereich, L.; Gunther, T.; Grundhoff, A.; Aepfelbacher, M.; Fischer, N. Complete Genome Sequence of a SARS-CoV-2 Strain Isolated in Northern Germany. Microbiol. Resour. Announc. 2020, 9. [Google Scholar] [CrossRef]
- Wang, H.; Li, X.; Li, T.; Zhang, S.; Wang, L.; Wu, X.; Liu, J. The genetic sequence, origin, and diagnosis of SARS-CoV-2. Eur. J. Clin. Microbiol. Infect. Dis. 2020, 39, 1629–1635. [Google Scholar] [CrossRef]
- Smith, E.C.; Blanc, H.; Surdel, M.C.; Vignuzzi, M.; Denison, M.R. Coronaviruses lacking exoribonuclease activity are susceptible to lethal mutagenesis: Evidence for proofreading and potential therapeutics. PLoS Pathog. 2013, 9, e1003565. [Google Scholar] [CrossRef] [Green Version]
- Graham, R.L.; Becker, M.M.; Eckerle, L.D.; Bolles, M.; Denison, M.R.; Baric, R.S. A live, impaired-fidelity coronavirus vaccine protects in an aged, immunocompromised mouse model of lethal disease. Nat. Med. 2012, 18, 1820–1826. [Google Scholar] [CrossRef] [Green Version]
- Eckerle, L.D.; Becker, M.M.; Halpin, R.A.; Li, K.; Venter, E.; Lu, X.; Scherbakova, S.; Graham, R.L.; Baric, R.S.; Stockwell, T.B.; et al. Infidelity of SARS-CoV Nsp14-exonuclease mutant virus replication is revealed by complete genome sequencing. PLoS Pathog. 2010, 6, e1000896. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Minskaia, E.; Hertzig, T.; Gorbalenya, A.E.; Campanacci, V.; Cambillau, C.; Canard, B.; Ziebuhr, J. Discovery of an RNA virus 3′-′5′ exoribonuclease that is critically involved in coronavirus RNA synthesis. Proc. Natl. Acad. Sci. USA 2006, 103, 5108–5113. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Regla-Nava, J.A.; Nieto-Torres, J.L.; Jimenez-Guardeno, J.M.; Fernandez-Delgado, R.; Fett, C.; Castano-Rodriguez, C.; Perlman, S.; Enjuanes, L.; DeDiego, M.L. Severe acute respiratory syndrome coronaviruses with mutations in the E protein are attenuated and promising vaccine candidates. J. Virol. 2015, 89, 3870–3887. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- DeDiego, M.L.; Alvarez, E.; Almazan, F.; Rejas, M.T.; Lamirande, E.; Roberts, A.; Shieh, W.J.; Zaki, S.R.; Subbarao, K.; Enjuanes, L. A severe acute respiratory syndrome coronavirus that lacks the E gene is attenuated in vitro and in vivo. J. Virol. 2007, 81, 1701–1713. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Jimenez-Guardeno, J.M.; Regla-Nava, J.A.; Nieto-Torres, J.L.; DeDiego, M.L.; Castano-Rodriguez, C.; Fernandez-Delgado, R.; Perlman, S.; Enjuanes, L. Identification of the Mechanisms Causing Reversion to Virulence in an Attenuated SARS-CoV for the Design of a Genetically Stable Vaccine. PLoS Pathog. 2015, 11, e1005215. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Shoenfeld, Y.; Aharon-Maor, A.; Sherer, Y. Vaccination as an additional player in the mosaic of autoimmunity. Clin. Exp. Rheumatol. 2000, 18, 181–184. [Google Scholar] [PubMed]
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Todorov, G.; Uversky, V.N. A Possible Path towards Rapid Development of Live-Attenuated SARS-CoV-2 Vaccines: Plunging into the Natural Pool. Biomolecules 2020, 10, 1438. https://doi.org/10.3390/biom10101438
Todorov G, Uversky VN. A Possible Path towards Rapid Development of Live-Attenuated SARS-CoV-2 Vaccines: Plunging into the Natural Pool. Biomolecules. 2020; 10(10):1438. https://doi.org/10.3390/biom10101438
Chicago/Turabian StyleTodorov, German, and Vladimir N. Uversky. 2020. "A Possible Path towards Rapid Development of Live-Attenuated SARS-CoV-2 Vaccines: Plunging into the Natural Pool" Biomolecules 10, no. 10: 1438. https://doi.org/10.3390/biom10101438