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Background: Nanocovax is a recombinant severe acute respiratory syndrome coronavirus 2 subunit vaccine composed of full-length prefusion stabilized recombinant SARS-CoV-2 spike glycoproteins (S-2P) and aluminum hydroxide adjuvant. Methods: We conducted a dose-escalation, open label trial (phase 1) and a randomized, double-blind, placebo-controlled trial (phase 2) to evaluate the safety and immunogenicity of the Nanocovax vaccine (in 25 microgram (mcg), 50 mcg, and 75 mcg doses, aluminum hydroxide adjuvanted). In phase 1, 60 participants received two intramuscular injection of the vaccine following dose-escalation procedure. The primary outcomes were reactogenicity and laboratory tests to evaluate the vaccine safety. In phase 2 which involved in 560 healthy adults, the primary outcomes are vaccine safety, and anti-S IgG antibody response. Secondary outcomes were surrogate virus neutralization, wild-type SARS-CoV-2 neutralization, and T-cell responses by intracellular staining (ICS) for interferon gamma (IFNg). Anti-S IgG and neutralizing antibody levels were compared with convalescent serum samples from symptomatic Covid-19 patients. Findings: For phase 1 study, no serious adverse events (SAE) were observed for all 60 participants. Most adverse events (AE) were grade 1 and disappeared shortly after injection. For phase 2 study, after randomization, 480 participants were assigned to receive the vaccine with adjuvant, and 80 participants were assigned to receive placebo. Reactogenicity was absent or mild in the majority of participants and of short duration (mean ≤3 days). Unsolicited adverse events were mild in most participants. There were no serious adverse events related to Nanocovax. Regarding the immunogenicity, Nanocovax induced robust anti-S antibody responses. In general, there humoral responses were similar among vaccine groups up to day 90. Anti S-IgG levels and neutralizing antibody titers at the peak response on day 42 were all higher than those of convalescent sera. Interpretation: Up to day 90, Nanocovax was found to be safe, well tolerated, and induced robust immune responses. 25 mcg was selected for a phase 3 trial to evaluate the vaccine efficacy. Trial Registration: ClinicalTrials.gov number, NCT04683484. NCT04683484, registration date in clinicaltrial.gov is Dec24, 2020, We has started our Phase 1 clinical trial in Vietnam on Dec 17, 2020, Funding: Research funded by Nanogen Pharmaceutical Biotechnology JSC., and the Ministry of Science and Technology of Vietnam Declaration of Interest: The following authors Thuy Phuong Nguyen, Hiep Khong, Tri Minh Le, Tuyen Thi Ngoc Trang, Thanh Thi Dinh, Thuong Van Vo, Thao Thi Thu Vu, Quynh Bao Phuong Nguyen, Vuong Tan Phan, Vinh The Tran, Mai Thi Nhu Tran, Truc Thi Thanh Nguyen, Phat Tan Ha, Hieu Trong Huynh, Khanh Duy Nguyen, Chung Chinh Doan, Thuan Trong Ung, Si Minh Do are employees of Nanogen Pharmaceutical Biotechnology JSC. All other authors declare no competing interests. Ethical Approval: The trials were designed and funded by Nanogen Pharmaceutical Biotechnology JSC and the Ministry of Science and Technology (MOST) of Vietnam. The trial protocol was approved by the Ethics Committee/Protocol Review Board of the Ministry of Health (Vietnam)