Genetics and Molecular Biology, 44, 1(suppl 1), e20200320 (2021) Copyright © Sociedade Brasileira de Genética. DOI: https://doi.org/10.1590/1678-4685-GMB-2020-0320 Review Article COVID-19 – Special Issue SARS-CoV-2 vaccine development and how Brazil is contributing Alex I. Kanno1*, Mayra M.F. Barbosa1,2*, Luana Moraes1,2 and Luciana C.C. Leite1 1Instituto Butantan, Laboratório de Desenvolvimento de Vacinas, São Paulo, SP, Brazil. 2Universidade de São Paulo, Programa de Pós-Graduação Interunidades em Biotecnologia, São Paulo, Brazil. Abstract The SARS-CoV-2 coronavirus pandemic calls for coordinated efforts by the scientific community for the development of vaccines. The most advanced strategies have focused on modifications of technologies that were already under development for other viruses, such as SARS, MERS, and even Influenza. Classic and new technologies, such as inactivated and attenuated viruses (non-replicative and replicative), DNA and mRNA vaccines, and nanoparticles containing SARS-CoV-2 antigens, are some of the strategies currently investigated. Although there is a very high expectation for the effectiveness of the most advanced vaccine candidates, there are still no established correlates of protection. Previous experience in vaccine development for other pathogens shows that differences in vaccine formulation can result in diverse immune responses and consequently, different protective properties. Therefore the importance of continuing investigations on a broad range of strategies. Expertise in vaccine development in Brazil was refocused to the new coronavirus. Impressive collaboration between institutions will support further developments until we have available a safe, effective, and economically viable vaccine. Established competence and collaborations will allow preparedness for future challenges and can also be used to address local issues as neglected infectious diseases. Keywords: SARS-CoV-2, vaccine, immunization strategies. Received: September 03, 2020; Accepted: February 19, 2021. Importance of vacines in disease control effective vaccine against SARS-CoV-2 and protect against Vaccination is one of the most important human the COVID-19 disease, have driven many collaborations, achievements in biomedical sciences. It has successfully along with unprecedented governmental support, leading to reduced the burden of infectious diseases worldwide. hundreds of strategies in pre-clinical and clinical evaluations According to the World Health Organization (WHO), the and so far, eight vaccine candidates are in phase III clinical benefits of vaccination go beyond the individual protection trials, the last before registration (WHO, 2020a). provided by the vaccine against the targeted pathogen. The race for vaccine development Ideally, it targets the complete eradication of the pathogen so it cannot re-emerge. The eradication of smallpox allowed The outbreak of COVID-19 has led to a global race the discontinuation of routine immunization. Furthermore, for the development of vaccines and treatments in record vaccination can be used to control mortality, morbidity, and time. The initiatives involve hundreds of countries, public- mitigate disease severity (Greenwood, 2014). Other advantages private partnerships, multinational pharmaceuticals, and include the protection of the non-vaccinated population (herd biotech companies. The Landscape of COVID-19 candidate immunity), against related and unrelated diseases, healthcare vaccines as of 12 November 2020 reports 48 candidates savings, prevention of antibiotic resistance, and extension of in clinical trials (Table 1) and 164 others in the preclinical life expectancy (Andre et al., 2008). stage. Different websites, (WHO, 2020a), (Milken Institute, The first cases of an “unknown cause” of pneumonia 2020) and others, provide updated information on the were reported in December 2019, to the WHO office in vaccines in development as they progress into clinical trials. China. By January, it had been identified as a new coronavirus In general, vaccine development undergoes several (SARS-CoV-2, leading to COVID-19 disease) and crossed steps: discovery, pre-clinical tests, and clinical trials, the Chinese borders. It was declared a pandemic in March. subdivided into phases I, II, and III, registration and phase The rate at which the SARS-CoV-2 virus spread through the IV (Figure 1). The discovery phase comprises the choice world and shutdown country borders, industries and local of the platform, design of targets, preparation of small businesses, only reinforces the importance of vaccines in batches, and in vitro testing. The pre-clinical stage involves disease control. The cost-effectiveness of a vaccine in this target validation in vivo from mice to non-human primates scenario is indisputable. The worldwide efforts to develop an (toxicity, immune response, safety, and protection). Finally, the vaccine candidate is tested in human subjects in clinical Send correspondence to Luciana C. C. Leite. Instituto Butantan, trials. In phase I, safety is evaluated in a small group of Laboratório de Desenvolvimento de Vacinas, São Paulo, SP, Brazil. E-mail: [email protected]. healthy volunteers; in phase II, safety and immunogenicity are evaluated in a few hundreds of healthy volunteers; and in *These authors have contributed equally. phase III, safety and efficacy are evaluated in thousands of 2 Table 1 – Vaccine candidates currently in Clinical trials. General safety Vaccine platform Name Institution Country Route Details of platform Clinical Stage Trial number and Advantages NCT04456595 CoronaVac Sinovac Biotech China i.m. Ph III NCT04582344 Sinopharm/ BBIBP-CorV China i.m. Ph III ChiCTR2000034780 Beijing Institute Inactivated vaccines Sinopharm/ Unnamed China i.m. used throughout the world Ph III ChiCTR2000034780 Wuhan Institute with a generally excellent The SARS-CoV-2 BBV152 Bharat Biotech India i.m. safety profile. Ph III CTRI/2020/11/028976 Inactivated virus virus inactivation Chinese Acad. Of Unnamed (Yunnan) China i.m. + adjuvant. Ph I/II NCT04470609 Medical Sciences Straightforward process; favorable safety and Research Institute tolerability profile QazCovid-in for Biological Kazakhstan i.m. Ph I/II NCT04530357 Safety Problems Beijing Minhai Unnamed China i.m. Ph I/II ChiCTR2000039462 Biotech Co Ltd AZD1222 Oxford/Astra Zeneca UK i.m. Ph III ISRCTN89951424 i.m./ Ph III NCT04526990 Ad5-nCov CanSino Biological China mucosal In general, safe and well Ph I NCT04552366 tolerated; concerns for Gamaleya Research Gam-COVID-Vac Russia i.m. Different Adenovirus immunocompromised Ph III NCT04530396 Institute expr. S glycoprotein individuals. Janssen ChAdOx1 (Chimp Ad26.COV2-S USA i.m. Ph III NCT04505722 Pharmaceutical – Oxford), Ad5 Vector used in gene therapy Non-replicating viral vector Pasteur/Thera/ i.m. (CanSino), Ad26 (J&J), & vaccination. Ad5 and Ad26 GRAd-COV2 Italy Ph I NCT04528641 (Adenovirus and MVA) LEUKOCARE 1-dose RD-Ad5 (Altimune) – high titer stable stocks. Ad26 – low preexisting ImmunityBio hAd5-S-Fusion+N-ETSD USA s.c. antibodies to the vector. Ph I NCT04591717 & NantKwest VXA-CoV2-1 Vaxart USA oral Ph I NCT04563702 Safety attested by its Ludwig-Maximilians/ Attenuated poxvirus use as against smallpox. MVA-SARS-2-S Germany i.m. Ph I NCT04569383 Univ. of Munich expressing Spike High immunogenicity including in the lungs. Kanno et al . COVID-19 vaccineinBrazil Table 1 – Cont. General safety Vaccine platform Name Institution Country Route Details of platform Clinical Stage Trial number and Advantages Beijing Wantai Flu-based vaccine In general, safe DelNS1-2019-nCoV-RBD-OPT1 Biological Pharmacy/ China i.n. Ph II ChiCTR2000039715 expressing RBD and well tolerated Xiamen Univ. Israel Institute for rVSV-SARS-CoV-2-S Israel i.m. Severely attenuated. Ph I/II NCT04608305 Biological Research Vesicular Stomatitis Virus Replicating viral vector No prior immunity. Merck Sharp (VSV) expressing Spike V590 USA i.m. High protein expression Ph I NCT04569786 & Dohme/IAVI In general, safe and well Institut Pasteur/ Live-attenuated measles TMV-083 France i.m. tolerated. Vector tested Ph I NCT04497298 Themis Bioscience vaccine expr. Spike in chikungunya vaccine Inovio i.d. Plasmid/ Spike NCT04336410 INO-4800 USA Ph I/II Pharmaceuticals electro electroporation NCT04447781 Favorable safety Osaka Univ./ NCT04463472 AG0301-COVID19 Japan i.m. Plasmid/ Spike and tolerability profile. Ph I/II AnGes/Takara Bio No DNA vaccines currently NCT04527081 Cadila Healthcare in use in humans. DNA ZyCoV-D India i.d. Plasmid/ M protein Ph I/II CTRI/2020/07/026352 Limited South Fast design/manufacturing; GX-19 Genexine Consortium i.m. Plasmid/Spike Ph I/II NCT04445389 Korea no cold chain for storage/distribution. Plasmid/ Trim. Spike bacTRL-Spike Symvivo Canada oral Ph I NCT04334980 in Bifidobacterium RNA vaccine for Zika, CMV, Chikungunya well-tolerated. No RNA vaccines currently mRNA-1273 Moderna USA i.m.d mRNA mixed w/ LNP Ph III NCT04470427 in use in humans. Fast design and manufacturing i.m. BioNTech/Fosun Germany/ mRNA mixed BNT162 (prime/ Ph III NCT04368728 Pharma/Pfizer USA with lipoplex. RNA boost) CVnCoV Curevac Germany i.m. mRNA mixed w/ LNPs. Ph II NCT04515147 self-replicating mRNA ARCT-021 Arcturus/Duke-NUS USA i.m Ph I/II NCT04480957 expr. Spike in a LNP Imperial College Self-amplifying LNP-nCoVsaRNA UK i.m. Ph I ISRCTN17072692 London Spike mRNA PLA Acad of Mil Sci Unnamed China i.m. mRNA Ph I ChiCTR2000034112 / Walvax Biotech 3 4 Table 1 – Cont. General safety Vaccine platform