Safety and immunogenicity of nanocovax a sarscovid 2 recombinant spike protein vaccine

pe er re vie we Spike Protein Vaccine d Safety and Immunogenicity of Nanocovax, a SARS-CoV-2 Recombinant Thuy P Nguyen MD1#,Quyet Do MD PhD2#, Lan T Phan MD PhD3#, Duc V Dinh MD2#, Hiep Khong PhD1#, Luong V Hoang MD PhD2, Thuong V Nguyen MD PhD3, Hung N Pham MD PhD2, Men V Chu PharmD PhD2, Toan T Nguyen MD MSc3, Quang D Pham MD PhD3, Tri M Le MSc1, Tuyen N.T Trang PharmD1, Thanh T Dinh M.Sc1, Thuong V Vo B.PH1, Thao T Vu B.PH1, Quynh B.P Nguyen PharmD1, Vuong T Phan PharmD1, Luong V Nguyen MD PhD2, Giang T Nguyen MD PhD2, Phong M Tran MD PhD 2, Thuan D Nghiem MD PhD2, Tien V Tran MD PhD2, Tien G Nguyen MD PhD2, Tuynh Q Tran MD PhD2, Linh T Nguyen MD PhD2, Anh T Do MD PhD2, Dung D Nguyen MD PhD2, Son A Ho MD PhD2, Viet T Nguyen MD PhD2, Dung T Pham MD PhD2, Hieu B Tran MD Ph.D2, Son T Vu MD PhD2, Su X Hoang MD PhD2, Trung M Do MD PhD2, Xuan T Nguyen MD PhD2, Giang Q Le PhD2, Ton Tran MD PhD3, Thang M Cao MSc3, Huy M Dao PhD3, Thao T.T Nguyen MD3, Uyen Y Doan M.Sc3, Vy T.T Le PhD3, Linh P Tran M.Sc3, Ngoc M Nguyen MD3, Ngoc T Nguyen MSc3, Hang T.T Pham MSc3, Quan H Nguyen MSc3, Hieu T Nguyen BSc3, Hang L.K Nguyen PhD5, Vinh T Tran PhD1,Mai T.N Tran PhD1, Truc T.T Nguyen MSc1, Phat T Ha MSc1, Hieu T Huynh BSc1, Khanh D Nguyen BSc1, Ung T Thuan1, Chung C Doan PhD1, Si M Do Ph.D1* Affiliations: Nanogen Pharmaceutical Biotechnology JSC, Lot I-5C Saigon Hitech Park, Ho Chi Minh ot city, Vietnam Vietnam Military Medical University, 160 Phung Hung, Ha Dong, Ha Noi, Vietnam Pasteur Institute, 167 Pasteur, District 3, Ho Chi Minh City, Vietnam National Institute of Hygiene and Epidemiology (NIHE), Ha Noi, Vietnam # These authors contributed equally to this article rin tn * Corresponding author: Do Minh Si, PhD Nanogen Pharmaceutical Biotechnology JSC; Lot I-5C Saigon Hitech Park, Ho Chi Minh ep City, Vietnam; Phone: (+84)-93-846-3579, FAX: 84-283-730-9963; Email: Pr minhsi@nanogenpharma.com This preprint research paper has not been peer reviewed Electronic copy available at: https://ssrn.com/abstract=3931736 Summary d Background pe er re vie we Nanocovax is a recombinant severe acute respiratory syndrome coronavirus 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 doseescalation procedure The primary outcomes were reactogenicity and laboratory tests to evaluate the vaccine safety In phase 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 study, no serious adverse events (SAE) were observed for all 60 participants Most adverse events (AE) were grade and disappeared shortly after injection For phase study, ot 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 tn 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 rin 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 ep 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 trial to evaluate the vaccine efficacy Pr Funding Research funded by Nanogen Pharmaceutical Biotechnology JSC., and the Ministry of Science and Technology of Vietnam; ClinicalTrials.gov number, NCT04683484 This preprint research paper has not been peer reviewed Electronic copy available at: https://ssrn.com/abstract=3931736 Introduction d Global pandemic coronavirus disease 2019 (Covid-19) is caused by the severe acute pe er re vie we respiratory syndrome coronavirus (SARS-CoV-2) As of July 2021, more than 177 million cases and over million deaths due to Covid-19 have been reported worldwide1 SARS-CoV-2 is a member betacoronavirus, named for its corona of spike (S) proteins protruding from the viral envelope2,3 SARS-CoV-2 S, a heavily glycosylated protein, is responsible for the attachment to angiotensin-converting enzyme (ACE2) which helps the virus entry to host cells in human and animals4 SARS-CoV-2 S glycoprotein is the antigen of choice for Covid-19 vaccine development due to its highly antigenic property5 Nanocovax is a subunit vaccine, developed and manufactured at Nanogen Pharmaceutical Biotechnology JSC., containing full-length prefusion stabilized recombinant SARS-CoV-2 S glycoproteins and aluminum hydroxide adjuvant In rodent and monkey models, Nanocovax induced high levels of anti-S antibody (Ab) Neutralizing antibody titers were evaluated by microneutralization on Wuhan strain and surrogate virus neutralization test Importantly, Nanocovax conferred a remarkable protection against SARS-CoV-2 infection in hamster challenge model6 Here we report the findings of the phase and trials started in December 2020 and February 2021 respectively, to evaluate the safety and immunogenicity of 25 mcg, 50 mcg and ot 75 mcg dose strengths of recombinant SARS-CoV-2 S glycoprotein with aluminum adjuvant Method tn (0.5 mg/dose) in healthy adults of at least 18 years of age 2.1 Trial design and oversight Phase trial was conducted at the Military Medical University, Ha Noi, Vietnam This rin was an open-labeled, dose-escalation study with the emphasis on the vaccine safety (figure S1) Eligible participants were healthy men and nonpregnant women, 18 to 50 years of age with body-mass index (BMI) of 18 to 27 kg/m2 (table S1) In this phase, 60 participants were ep allocated into 2:2:2 ratio of 25 mcg, 50 mcg and 75 mcg dose groups, respectively For safety measure, the first participants of 25 mcg dose group were vaccinated and monitored for 72 hours After no SAE were observed, all remaining participants in this group plus participants Pr in 50 mcg dose group would be vaccinated and monitored for 72 hours If no SAE were observed among participants of 50 mcg dose group, the remaining participant in this group plus participants in 75 mcg dose group would be vaccinated If no SAE were observed among This preprint research paper has not been peer reviewed Electronic copy available at: https://ssrn.com/abstract=3931736 participants in 75 mcg dose group, the remaining participants in this group will be vaccinated d All participants received doses of vaccine by intramuscular injections into the deltoid on day pe er re vie we and day 28 Sample size of phase was not based on formal statistical power calculation but on the range of 30 – 150 recommended in Article 10 of Appendix 10/2020/TT-BYT by the Vietnam Ministry of Health Phase trial was conducted at two sites: Military Medical Academy, Ha Noi and the Pasteur Institute at Ho Chi Minh city, Vietnam This was a randomized, double-blind, placebocontrolled study (figure 1) Eligible participants were healthy men and nonpregnant women, at least 18 years of age with BMI of 17 to 35 They were stratified into age groups: from full 18 to full 60 years old and over 60 years old (table 1) A total of 560 participants will be randomly assigned to groups, into 2:2:2:1 ratio for 25 mcg, 50 mcg, 75 mcg, and placebo, respectively In details, 480 volunteers would receive the vaccine (160 volunteers receiving 25 µg dose; 160 volunteers receiving 50 µg dose and 160 volunteers receiving dose of 75 µg dose) and 80 volunteers would receive the placebo (aluminum adjuvant only) All participants received either doses of vaccine or the placebo on day and day 28 Trial staffs responsible for the vaccine preparation and administration, as well as participants were unaware of vaccine assignment Randomization lists, using block randomization stratified by the study group and study site, were generated by the study statistician Computer randomization was done with full allocation concealment within the secure web platform used for the study electronic case ot report form (service provided by Medprove company) All participants were screened by their medical history, clinical and biological tn examinations, sampling and laboratory tests (complete blood count, biochemistry, urine analysis, testing pregnancy and diagnostic imaging) Participants with a history of Covid-19 or positive results for SARS-CoV-2 at screening period confirmed by real-time reverse rin transcriptase polymerase-chain-reaction (RT-PCR) were excluded from the trials All participants provided written consent before being enrolled into the trial ep 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) and was Pr performed in accordance with the ICH-GCP good clinical practice guidelines, with an ethical policy consistent with the “Declaration of Helsinki” and applicable Vietnamese laws and regulations The authors take responsibility for the data integrity and the fidelity of the trial to the protocol This preprint research paper has not been peer reviewed Electronic copy available at: https://ssrn.com/abstract=3931736 d Trial vaccine, adjuvant, and placebo The recombinant SARS-CoV-2 spike (S) glycoprotein in Nanocovax were constructed pe er re vie we with two proline substitutions (K986P and V987P) for stabilized prefusion conformation (S- 2) The production of the full-length (including the transmembrane domain) recombinant S protein was optimized in the established Chinese Hamster Ovary (CHO) cell-expression system Clinical grade aluminum hydroxide was manufactured by Croda (Denmark) Recombinant SARS-CoV-2 S protein were absorbed to aluminum adjuvant in mild shaking condition for 18 hours at 2°C to 8°C Placebo was sterile 0·5 mg aluminum 2.3 Safety assessments In phase 1, the onsite safety follow-up time after was 72 hours after 1st injection and 24 hours after the 2nd injection Participants would return to the study site for follow-up visits at scheduled timepoints (table S2) In phase 2, the onsite safety follow-up time was 60 minutes after each vaccination Follow-up visits to evaluate safety were scheduled on days 28, 35, 42, 90, 180 after vaccination (table 2) Participants were observed for 60 minutes after each vaccination for assessment of reactogenicity In both phases, participants received instruction for self-monitoring and reporting adverse events during days after each vaccination, as facilitated by the use of a diary with predefined reactogenicity Predefined local (injection site) reactogenicity included pain, tenderness, erythema, and swelling Predefined systemic ot reactogenicity included fever, nausea or vomiting, headache, fatigue, malaise, myalgia, and appendix) tn arthralgia Vaccination pause rules were in place to monitor participants’ safety (supplementary The primary safety outcomes were the number and percentage of participants with solicited local and systemic adverse events occurred within days after vaccination and rin laboratory results (serum biochemistry and hematology) at days 0, 7, 28, 35 according to FDA toxicity scoring7 Secondary safety outcomes were occurrence rate and severity rating of unsolicited AE/SAE until the end of the studies and laboratory results at up to 42 (phase 2) and ep 56 (phase 1) AE/SAE were recorded and evaluated basing on the Common Terminology Criteria for Adverse Events 5·0 (CTCAE v5·0) and Guidelines for assessing toxicity in healthy volunteers Pr in FDA's Preventive Vaccine Clinical Trial Study7,8 The procedures for recording and evaluating take place continuously from the time of using the first dose to the end of the last visit in each research volunteer Adverse events were assessed in terms of severity score (mild, This preprint research paper has not been peer reviewed Electronic copy available at: https://ssrn.com/abstract=3931736 moderate, severe, potentially life-threatening, or fatal), and relatedness to the vaccine Vital d sign measurements were assessed according to FDA toxicity scoring after vaccination In pe er re vie we addition, participants had nasopharyngeal swab tests for SARS-CoV-2 on screening day (before 1st vaccination), day 28 (before 2nd vaccination) and any time that they developed symptoms of possible SARS-CoV-2 infection 2.4 Immunogenicity assessments The primary outcome was anti-S IgG responses to Nanocovax evaluated by chemiluminescence immunoassay (CLIA) Secondary outcomes were neutralizing antibody titer evaluated by 50 percent plaque reduction neutralization test (PRNT50) on Wuhan strain and UK variant (B.1.1.7), competitive enzyme-linked immunosorbent assay (ELISA) based surrogate virus neutralization test (sVNT), and the T cell response by intracellular cytokinestaining (ICS) The immunogenicity (IgG and neutralizing antibody titers) of vaccine groups were compared with convalescent serum specimens’ from symptomatic Covid-19 patients at the Pasteur Institute at Ho Chi Minh City, Vietnam (table S3) Detail of immunological assays were provided in the supplementary appendix 2.5 Statistical analysis Descriptive analyses of safety and reactogenicity analysis were shown For an adverse event occurred more than once, the analysis was based on only the most severe occurrence and ot the cause of the event Reactogenicity analyses were presented as counts and percentages In addition, all serious adverse events were summarized separately Geometric means (of anti-S tn IgG concentration and neutralizing antibody titer) and associated 95% confidence intervals (CI) were calculated basing on log-transformed data The estimated vaccine efficacy was calculated basing the predictive model by Khoury and Cromer et al.9 rin Result 3.1 Trial population The phase trial was started on December 17, 2020 60 participants were allocated into ep groups of doses: 20 received 25 mcg (group 1.1), 20 received 50 mcg (group 1.2), and 20 received 75 mcg (group 1.3) There was no placebo group in phase Pr For phase 2, the study was started on February 26, 2021 560 participants were recruited and randomly assigned into groups of different doses: 161 received 25 mcg doses of Nanocovax (group 2.1), 160 received 50 mcg doses of Nanocovax (group 2.2), 159 received 75 mcg doses of Nanocovax (group 2.3), and 80 received placebo (group 2.4) Participants were stratified This preprint research paper has not been peer reviewed Electronic copy available at: https://ssrn.com/abstract=3931736 characteristics of participants in phase and were shown in table and table S1 pe er re vie we 3.2 Safety outcomes d into age groups: from over 18 to below 60 years old and over 60 years old Demographic In phase 1, no serious adverse events were observed, and vaccination pause rules were not implemented Overall reactogenicity was largely absent or mild, and second vaccinations were neither withheld nor delayed due to reactogenicity The incidences of solicited adverse events in each vaccine group with FDA toxicity grade (grade 1: mild, grade 2: moderate, grade 3: severe, grade 4: potentially life-threatening) were presented in figure S2 In phase 2, 554 out of 560 enrolled participants received doses of vaccine or placebo withdrew from the study after the 2nd visit, before getting the boosting dose The incidences of solicited local and systemic AE of each group after the 1st and 2nd injection were shown (figure 2) After the 1st injection, local and systemic AE of grade or were not observed in group 2.1, case in group 2.2 (0·6%), case in group 2.3 (0·6%) and case in group 2.4 (1·3%) After the 2nd injection, one local or systemic AE of grade or occurred in each group (0·6%) and placebo (1.3%) Incidences of any solicited local AE were 37·7% (211/560) after 1st vaccination and 35·7% (198/554) after 2nd vaccination The most common AE was local pain with incidence of 32·8% (184/560) after 1st injection and 32·1% (178/554) after 2nd injection Incidences of mild pain were 32·3% (181/560) after 1st injection and 30·7% ot (170/554) after 2nd injection Moderate pain of was uncommon, reported by 0·5% participants (3/560) after the 1st injection and 1·4% (8/554) after the 2nd injection participant (out of tn 554) experienced severe pain after 2nd injection (0.2%) Grade local sensitivity incidences were 19·1 % (107/560) after 1st injection and 14·6% (81/554) after 2nd injection Grade local sensitivity incidences were 5·9% (33/560) after 1st injection and 4·8% (27/554) after 2nd rin injection Grade local redness was observed in participant (0·2%) after 2nd injection Incidences of any systemic AE were 27·8% (156/560) after 1st injection and 21·8% (121/554) after 2nd injection Most common systemic AE were fatigue (17·1%/12·9%), headache ep (13·3%/8·3%) and fever (4·4%/2·5%) after 1st/2nd injections Fatigue decreased gradually and disappeared within days after injection Mild fever incidences were 4·4% (25/560) after 1st injection and 2·5% (14/554) after 2nd injection One participant (0.2%) experienced high fever Pr (grade 3) within days after 2nd injection Incidence of any unsolicited AE in phase was 28% (157/560) and most of which was mild to moderate Unsolicited AE rates were similar among vaccine groups and the placebo (appendix 7) In details, unsolicited AE incidence of groups 2.1 to 2.4 were 30·4%, 27·5%, This preprint research paper has not been peer reviewed Electronic copy available at: https://ssrn.com/abstract=3931736 23·3% and 33·8%, respectively Two cases of grade AE were back pain and dizziness There d were AE of grade 3: case of sepsis, case of back pain, case of spondylolisthesis, case pe er re vie we of sore throat, case of high blood pressure The most frequently reported adverse events were sore throat 27 (4·8%) and coughing 11 (2·0%) The most laboratory-related AE were hyperglycemia 13 cases (2·3%), leukocytosis: cases (1·4%), the most vital events related to hypothermia with 12 cases (2·1%) In similar to phase 1, vaccination pause rules were not implemented in phase Four SAE were determined unrelated to Nanocovax, including case of angina (history of stent graft), case of fever (determined to be sepsis), case of abscess at axillary lymph nodes occurred on the unvaccinated arm and case of personal injury One case of SAE grade anaphylaxis was undetermined to be related to vaccine or not because the symptoms were unclear (table S4) Overall incidences of unsolicited AE of vaccine groups and the placebo were similar: 27·1% (130/480) versus 33·8% (27/80), respectively Laboratory abnormalities in phase included increased white blood cell in participants, (0·6%), increased neutrophil in participants (0·4%), elevated ALT (grade 2) in participants (0·6%), and elevated AST (grade 2) in participants (0·4%) The other biochemistry and hematology parameters such as red blood cell (RBC), hemoglobin (HGB), creatinine, bilirubin, prothrombin time (PT) fluctuated within normal limits (appendix 7) 3.3 Immunogenicity outcomes ot Geometric mean concentration (GMC) of anti-S IgG (U/ml) was reported Before the 1st injection, anti-S IgG level of the groups were all below the lower limit of detection (0.5 U/ml) Anti-S IgG of the vaccine groups increased remarkably after the 2nd injection (day 28) tn At day 35, anti-S IgG levels of group 2.1, 2.2 and 2.3 were 6·78 (95% CI: [5·09-9·03]), 9·38 [6·99 – 12·58], and 13·04 [9·46 – 17·98] respectively At day 42, their respective anti-S IgG increased sharply: 60·48 [51·12 – 71·55], 49·11 [41·26 – 58·46] and 57·18 [48·4-67·5], rin respectively By day 90, their respective anti-S IgG levels dropped to 16·26 [13·76-19·21], 15·73 [13·44-18·41], 18·08 [15·19-21·51] but were still higher than IgG level of convalescent group’s (7·10 [6·32-13·92]) Anti-S IgG levels of the placebo group on days 35, 42 and 90 ep were 0.29 with respective 95% CI [0·25 – 0·33], [0·25 – 0·32], and [0·25-0·33] (figure 3) Geometric mean fold rise (GMFR) of anti-S IgG was defined as the fold increase in GMC Pr of a given timepoint compared to baseline GMC value of the same group at day GMFR of 2.1, 2.2 and 2.3 groups at day 35 were 25·7 [19·3 – 34·1], 34·7 [ 25·7 – 46·9], and 49·8 [36·0 – 68·9], respectively At day 42, the GMFR of 2.1, 2.2 and 2.3 groups were 229·0 [193·2271·4], 181·8 [152·0 – 217·4] and 218·3 [185·0 – 257·7] By day 90, GMFR of vaccinated This preprint research paper has not been peer reviewed Electronic copy available at: https://ssrn.com/abstract=3931736 groups were 61·54 [52·12-72·67], 58·21 [49·40-68·53] and 69·01 [58·04-82·05] Meanwhile, pe er re vie we 1·04 [0·95-1·13] respectively (figure S3) d GMFR of the group 2.4 on days 35, 42 and 90 were 1·05 [0·97-1·13], 1·04 [0·98-1·09], and The seroconversion rate was defined as GMFR > Based on the GMFR of anti-S IgG, the seroconversion rates of groups 2.1, 2.2 and 2.3 on day 35 were 84%, 84% and 85% At day 42, the seroconversion rates of groups 2.1, 2.2 and 2.3 were 100%, 99% and 100% By day 90, seroconversion rates were still very high in vaccine groups: 100%, 100% and 99·4% (Figure S4) sVNT results were reported as mean inhibition rate (%) Up to day 28 (before 2nd vaccination), inhibition rates of all groups were below cut-off value of 30% At day 35, mean inhibition of groups 2.1 to 2.4 were 58·5% [54·1 – 63·0], 63·8% [59·1 – 68·5], 70·2% [65·8 – 74·5], 11·1% [9·3 – 12·7), respectively At day 42, their respective mean inhibition rates were 87·5% [85·5 – 89·5], 86·4% [ 84·08 – 88·65], 87·1% [ 85·06 – 89·16], and 10·8% [8·9 – 12·67] By day 90, respective sVNT were 72·7% [69·4-76·0], 74·2% [71·1-77·3], 74·4 [10·977·8] and 19·1% [13·4-24·9] Meanwhile, mean inhibition rate of convalescent samples was 61·1% [50·1-72·5] (figure 4A) Individual samples with an inhibition higher than 30% were considered positive for sVNT10 Accordingly, at day 35, positive rates for sVNT of groups 2.1 to 2.4 were 80·4%, 82·4%, 86·7% and 1·3%, respectively At day 42, their respective sVNT ot positive rates were 100%, 100%, 99.4% and 1·3% By day 90, the respective sVNT positive rates were 94·9, 96·8, 94·9 and 15·2 (figure S5) tn Neutralizing antibody levels were evaluated by plaque reduction neutralization test with inhibitory dilution greater than 50% (PRNT50) and expressed as geometric mean titers (GMT) 112 serum samples of groups 2.1 to 2.4 were randomly selected for PRNT50 on the original rin (Wuhan) strain and the UK variant At day 35, GMT of groups 2.1 to 2.3 were 20·9 [12·8 – 34·1], 22·5 [14·5 – 34·7] and 33·6 [20·9 – 54·1], respectively At day 42, their respective GMT were 89·2 [52·2 – 152·3], 80·0 [50·8 – 125.9] and 95·1 [63·1 – 143·6] These were ep approximately 1·5 times higher than the GMT of convalescent samples (55·1 [33·4-91·0]) Meanwhile, GMT of group 2.4 (placebo) at days 35 and 42 were [5-5] (half of limit of detection -LOD) (figure 4B) Among 112 serum samples (at day 42) tested on Wuhan strain, a Pr subset of 21 was randomly selected to evaluate neutralizing titer on UK variant (B.1.1.7, also known as the alpha variant) GMT in group 2.1 to 2.3 on UK variant were 35·6 [7·0-180·3], This preprint research paper has not been peer reviewed Electronic copy available at: https://ssrn.com/abstract=3931736 56·57 [14·51-220·6] and 40 [10·9-147·0], an approximately 1·9-fold decrease, compared to d the original strain (figure S6) pe er re vie we Type helper T cell (Th1) response of 84 randomly selected participants (28 for each vaccine group and 14 for placebo group) were undetectable (data not shown) This was likely due to the nature of aluminum adjuvant which has been well established for Th2 response induction11 Discussion The results of these phase and phase studies demonstrated an excellent safety profile of Nanocovax at all doses Most adverse events were grade which disappeared within 48 hours after injection In comparison to similar studies of approved vaccines, Nanocovax appeared to have lower reactogenicity12–18 IgG level and neutralizing antibody were found to be similar among vaccine groups We observed negative correlations between the immunogenicity and age The negative effect of age on IgG level and neutralizing titer was found to be highest at day 35 and lowest at day 42 (figure S7-S9) These observations suggests that age is more likely to influence on the kinetics rather than the peak of antibody response In other words, antibody responses of high age group may take more time to reach the peak and contract faster than younger groups The vaccine was found to elicit high level of anti-S IgG which closely correlated with neutralizing antibody ot titers (figure S10) Although the efficacy of Nanocovax remains to be seen in phase trial, accumulated evidences have correlated neutralizing antibody level with the immunity against tn Covid-19 Khoury and Cromer et al provided a model to predict the vaccine efficacy by comparing the neutralizing antibody titers of vaccines to convalescent samples’9 By using their predictive model, we estimated the efficacy of Nanocovax would be approximately 89·1% rin (figure 5) The cellular immune response, evaluated by ICS for IFNg, was not observable However, undetectable IFNg signal, a marker of Th1 response, does not guarantee the absence ep T cell response but rather the Th2 promoting nature of aluminum adjuvant11 In fact, Th2 cell responses will be reevaluated in a subset of participants in phase with the addition of Th2 cytokines The Th2 polarization may raise a theoretical concern of vaccine-associated Pr enhanced respiratory disease (ERD)19,20 This concern has been partially addressed with vaccine studies of hamster models challenged with SARS-CoV-2 as well as the approval of This preprint research paper has not been peer reviewed Electronic copy available at: https://ssrn.com/abstract=3931736 N A N O C O V A X P H A S E I I C L I N I C A L T R I A L P a g e o f Appendix 7: Unsolicited Adverse Events by System Organ Classes, Preferred Term and Relationship to Study Drug S a f e t y A n a l y s i s S e t - P l a c e b o V s N a n o c o v a x ( m c g / m c g / m c g Body System Preferred Term Relationship U n l i k e l y G e n e r a l R e l a t e d d i s o r d e r s L i k e y N o t Nanocovax N=480 a n d a d m i n i s t r a t i o n s i t e R e l a t e d R e l a t e d P r o b a b l y R e l a t e d R e l a t e d t o R e l a t e d n t D r o w s y L i k e y D y s p e p s i a R e l a t e d P r o b a b l y r P R e l a t e d p e F a t i g u e N o t ir n f l a t u l e n c e R e l a t e d P r o b a b l y R e l a t e d w ie Placebo N= 80 % ) ( % ) ( % ) ( % ) ( % ) ( ( OVERALL N=560 v e % ) r r e e p ( 1 A n o r e x i a P r o b a b l y 2 R e l a t e d U n l i k e l y c o n d i t i o n s ( d e ( % ) ( % ) ( ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) % ) ( % ) ( % ) % ) ( % ) % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) Created by D.D.G with SAS 9.4 on 11MAY2021 Program: SAS/folders/myfolders/NANOCOVAXP2/AE/UnSoliAE/AEREL2.SAS This preprint research paper has not been peer reviewed Electronic copy available at: https://ssrn.com/abstract=3931736 N A N O C O V A X P H A S E I I C L I N I C A L T R I A L P a g e o f Appendix 7: Unsolicited Adverse Events by System Organ Classes, Preferred Term and Relationship to Study Drug S a f e t y A n a l y s i s S e t - P l a c e b o V s N a n o c o v a x ( m c g / m c g / m c g Body System Preferred Term Relationship U n l i k e l y Nanocovax N=480 R e l a t e d F e v e r N o t R e l a t e d P r o b a b l y R e l a t e d R e l a t e d U n l i k e l y R e l a t e d H e a d a c h e N o t H y p o t h e r m i a N o t p e r P L o s s R e l a t e d R e l a t e d P r o b a b l y o f R e l a t e d ir n U n l i k e l y N o t n t R e l a t e d P r o b a b l y I n s o m n i a t o R e l a t e d t a s t e R e l a t e d ( % ) w ie Placebo N= 80 ( % ) v e r r e e p ( d e % ) OVERALL N=560 ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) Created by D.D.G with SAS 9.4 on 11MAY2021 Program: SAS/folders/myfolders/NANOCOVAXP2/AE/UnSoliAE/AEREL2.SAS This preprint research paper has not been peer reviewed Electronic copy available at: https://ssrn.com/abstract=3931736 N A N O C O V A X P H A S E I I C L I N I C A L T R I A L P a g e o f Appendix 7: Unsolicited Adverse Events by System Organ Classes, Preferred Term and Relationship to Study Drug S a f e t y A n a l y s i s S e t - P l a c e b o V s N a n o c o v a x ( m c g / m c g / m c g Body System Preferred Term Relationship P r o b a b l y T e n d e r n e s s R e l a t e d I m m u n e s y s t e m N o t d i s o r d e r s R e l a t e d P r o b a b l y A l l e r g i c N o t R e l a t e d R e l a t e d R e l a t e d G r a d e N o t ir n r P R e l a t e d a n d p e N o t I n t A n a p h y l a x i s - I n f e c t i o n s t o r e a c t i o n P r o b a b l y i n f e s t a t i o n s R e l a t e d P r o b a b l y R e l a t e d A t r i o v e n t r i c u l a r w ie Nanocovax N=480 R e l a t e d n o d e a b s c e s s ( % ) ( % ) d e Placebo N= 80 v e r r e e p OVERALL N=560 ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) Created by D.D.G with SAS 9.4 on 11MAY2021 Program: SAS/folders/myfolders/NANOCOVAXP2/AE/UnSoliAE/AEREL2.SAS This preprint research paper has not been peer reviewed Electronic copy available at: https://ssrn.com/abstract=3931736 N A N O C O V A X P H A S E I I C L I N I C A L T R I A L P a g e o f Appendix 7: Unsolicited Adverse Events by System Organ Classes, Preferred Term and Relationship to Study Drug S a f e t y A n a l y s i s S e t - P l a c e b o V s N a n o c o v a x ( m c g / m c g / m c g Body System Preferred Term Relationship N o t Nanocovax N=480 R e l a t e d F l u N o t R e l a t e d P r o b a b l y I n j u r y , R e l a t e d N o t P r o b a b l y p e U n l i k e l y r P E l e v a t e d v e r r e e p ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) R e l a t e d ( % ) ( % ) ( % ) R e l a t e d ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) a n d R i g h t t o p r o c e d u r a l n t H e e l ir n W h i t e P r o b a b l y % ) % ) R e l a t e d I n v e s t i g a t i o n s ( ( % ) R e l a t e d B o n e , w ie ( p o i s o n i n g B r o k e n % ) OVERALL N=560 R e l a t e d N o t ( Placebo N= 80 S e p s i s N o t d e B l o o d R e l a t e d C e l l s c o m p l i c a t i o n s Created by D.D.G with SAS 9.4 on 11MAY2021 Program: SAS/folders/myfolders/NANOCOVAXP2/AE/UnSoliAE/AEREL2.SAS This preprint research paper has not been peer reviewed Electronic copy available at: https://ssrn.com/abstract=3931736 N A N O C O V A X P H A S E I I C L I N I C A L T R I A L P a g e o f Appendix 7: Unsolicited Adverse Events by System Organ Classes, Preferred Term and Relationship to Study Drug S a f e t y A n a l y s i s S e t - P l a c e b o V s N a n o c o v a x ( m c g / m c g / m c g Body System Preferred Term Relationship U n l i k e l y E l e v a t e d W B C Nanocovax N=480 R e l a t e d l i v e r f u n c t i o n P r o b a b l y R e l a t e d U n l i k e l y R e l a t e d f o r m u l a N o t a n d t o d i s o r d e r s R e l a t e d R e l a t e d n t ir n R e l a t e d P r o b a b l y U n l i k e l y p e R e l a t e d R e l a t e d v e r r e e p H y p e r g l y c e m i a N o t % ) n u t r i t i o n w ie Placebo N= 80 R e l a t e d U n l i k e l y ( t e s t s s h i f t e d P r o b a b l y M e t a b o l i s m d e OVERALL N=560 ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) 1 ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) 1 ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) U r i n a r y g l u c o s e ( % ) ( % ) ( % ) N o t R e l a t e d ( % ) ( % ) ( % ) ( % ) ( % ) r P U n l i k e l y R e l a t e d Created by D.D.G with SAS 9.4 on 11MAY2021 Program: SAS/folders/myfolders/NANOCOVAXP2/AE/UnSoliAE/AEREL2.SAS This preprint research paper has not been peer reviewed Electronic copy available at: https://ssrn.com/abstract=3931736 N A N O C O V A X P H A S E I I C L I N I C A L T R I A L P a g e o f Appendix 7: Unsolicited Adverse Events by System Organ Classes, Preferred Term and Relationship to Study Drug S a f e t y A n a l y s i s S e t - P l a c e b o V s N a n o c o v a x ( m c g / m c g / m c g Body System Preferred Term Relationship M u s c u l o s k e l e t a l L i k e y N o t Nanocovax N=480 a n d c o n n e c t i v e t i s s u e R e l a t e d - s i d e d R e l a t e d R e l a t e d b r e a s t P r o b a b l y p a i n U n l i k e l y A r t h r i t i s p e N o t r P B a c k n t R e l a t e d P r o b a b l y t o R e l a t e d A r t h r a l g i a N o t ( ( R e l a t e d ir n R e l a t e d % ) % ) ( % ) ( % ) ( % ) ( p a i n ( ( % ) % ) OVERALL N=560 ( ( % ) % ) ( % ) ( % ) ( % ) ( % ) % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) R e l a t e d U n l i k e l y v e 1 % ) ( w ie Placebo N= 80 r r e e p R e l a t e d U n l i k e l y 1 R e l a t e d P r o b a b l y d i s o r d e r s d e R e l a t e d ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) Created by D.D.G with SAS 9.4 on 11MAY2021 Program: SAS/folders/myfolders/NANOCOVAXP2/AE/UnSoliAE/AEREL2.SAS This preprint research paper has not been peer reviewed Electronic copy available at: https://ssrn.com/abstract=3931736 N A N O C O V A X P H A S E I I C L I N I C A L T R I A L P a g e 1 Body System Preferred Term Relationship d e o f Appendix 7: : Unsolicited Adverse Events by System Organ Classes, Preferred Term and Relationship to Study Drug S a f e t y A n a l y s i s S e t - P l a c e b o V s N a n o c o v a x ( m c g / m c g / m c g N o t R e l a t e d C e r v i c a l s c a p u l o h u m e r a l P r o b a b l y D e g e n e r a t i v e N o t D i s c s y n d r o m e R e l a t e d S p i n e R e l a t e d h e r n i a t i o n L i k e y H a n d R e l a t e d ir n p a i n N o t p e n t R e l a t e d P r o b a b l y K n e e R e l a t e d M y a l g i a N o t t o R e l a t e d p a i n N o t r P Nanocovax N=480 R e l a t e d P r o b a b l y R e l a t e d ( % ) ( % ) Placebo N= 80 ( % ) w ie OVERALL N=560 ( v e r r e e p % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) Created by D.D.G with SAS 9.4 on 11MAY2021 Program: SAS/folders/myfolders/NANOCOVAXP2/AE/UnSoliAE/AEREL2.SAS This preprint research paper has not been peer reviewed Electronic copy available at: https://ssrn.com/abstract=3931736 N A N O C O V A X P H A S E I I C L I N I C A L T R I A L P a g e o f Appendix 7: Unsolicited Adverse Events by System Organ Classes, Preferred Term and Relationship to Study Drug S a f e t y A n a l y s i s S e t - P l a c e b o V s N a n o c o v a x ( m c g / m c g / m c g Body System Preferred Term Relationship Nanocovax N=480 R e l a t e d U n l i k e l y N e c k R e l a t e d s h o u l d e r N o t p a i n P r o b a b l y R e l a t e d U n l i k e l y R e l a t e d O s t e o a r t h r i t i s N o t R h e u m a t o i d N o t a r t h r i t i s r P R e l a t e d ir n f e e t N o t p e S p i n a l N o t n t R e l a t e d U n l i k e l y S o r e t o R e l a t e d ( % ) ( % ) v e p a i n R e l a t e d r r e e p ( % ) ( ( ( ( ( % ) ( % ) % ) ( % ) % ) ( % ) % ) ( % ) % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) R e l a t e d m u s c l e OVERALL N=560 R e l a t e d Placebo N= 80 w ie ( % ) d e ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) Created by D.D.G with SAS 9.4 on 11MAY2021 Program: SAS/folders/myfolders/NANOCOVAXP2/AE/UnSoliAE/AEREL2.SAS This preprint research paper has not been peer reviewed Electronic copy available at: https://ssrn.com/abstract=3931736 N A N O C O V A X P H A S E I I C L I N I C A L T R I A L P a g e o f Appendix 7: Unsolicited Adverse Events by System Organ Classes, Preferred Term and Relationship to Study Drug S a f e t y A n a l y s i s S e t - P l a c e b o V s N a n o c o v a x ( m c g / m c g / m c g Body System Preferred Term Relationship S p i n a l N e r v o u s P r o b a b l y R e l a t e d s y s t e m d i s o r d e r s N o t R e l a t e d P r o b a b l y R e l a t e d U n l i k e l y R e l a t e d D i z z i n e s s N o t R e l a t e d U n l i k e l y R e l a t e d n t H e a d a c h e N o t ir n R e l a t e d P r o b a b l y R e l a t e d U n l i k e l y R e l a t e d p e V e s t i b u l a r r P t o R e l a t e d P r o b a b l y d i s o r d e r s U n l i k e l y R e l a t e d w ie Nanocovax N=480 p a i n ( % ) ( % ) Placebo N= 80 v e r r e e p ( % ) ( % ) ( % ) ( d e ( % ) OVERALL N=560 ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) Created by D.D.G with SAS 9.4 on 11MAY2021 Program: SAS/folders/myfolders/NANOCOVAXP2/AE/UnSoliAE/AEREL2.SAS This preprint research paper has not been peer reviewed Electronic copy available at: https://ssrn.com/abstract=3931736 N A N O C O V A X P H A S E I I C L I N I C A L T R I A L P a g e o f Appendix 7: Unsolicited Adverse Events by System Organ Classes, Preferred Term and Relationship to Study Drug S a f e t y A n a l y s i s S e t - P l a c e b o V s N a n o c o v a x ( m c g / m c g / m c g Body System Preferred Term Relationship R e n a l a n d u r i n a r y N o t Nanocovax N=480 d i s o r d e r s R e l a t e d P r o b a b l y R e l a t e d U n l i k e l y R e l a t e d C y s t i t i s U n l i k e l y R e l a t e d H e m a t u r i a N o t P r o b a b l y R e l a t e d U n l i k e l y R e l a t e d P a i n f u l ir n r P t r a c t p e N o t R e l a t e d i n f e c t i o n R e l a t e d R e p r o d u c t i v e N o t n t u r i n a t i o n P r o b a b l y U r i n a r y t o R e l a t e d s y s t e m R e l a t e d a n d b r e a s t d i s o r d e r s ( ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) v e r r e e p w ie Placebo N= 80 % ) d e OVERALL N=560 ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) Created by D.D.G with SAS 9.4 on 11MAY2021 Program: SAS/folders/myfolders/NANOCOVAXP2/AE/UnSoliAE/AEREL2.SAS This preprint research paper has not been peer reviewed Electronic copy available at: https://ssrn.com/abstract=3931736 N A N O C O V A X P H A S E I I C L I N I C A L T R I A L P a g e o f Appendix 7: Unsolicited Adverse Events by System Organ Classes, Preferred Term and Relationship to Study Drug S a f e t y A n a l y s i s S e t - P l a c e b o V s N a n o c o v a x ( m c g / m c g / m c g Body System Preferred Term Relationship P r o b a b l y M e n s t r u a t i o n N o t R e s p i r a t o r y , L i k e y ( % ) i r r e g u l a r ( % ) R e l a t e d t h o r a c i c a n d U n l i k e l y R e l a t e d N o t ir n N a s o p h a r y n g i t i s p e A l l e r g i c R e l a t e d R e l a t e d r h i n i t i s P r o b a b l y R e l a t e d t o n t s i n u s i t i s U n l i k e l y d i s o r d e r s ( % ) ( % ) ( ( % ) w ie Placebo N= 80 ( % ) v e r r e e p 1 R e l a t e d R e l a t e d A l l e r g i c m e d i a s t i n a l R e l a t e d P r o b a b l y A c u t e r P R e l a t e d R e l a t e d P r o b a b l y N o t Nanocovax N=480 d e ( % ) OVERALL N=560 ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) % ) ( ( % ) % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) Created by D.D.G with SAS 9.4 on 11MAY2021 Program: SAS/folders/myfolders/NANOCOVAXP2/AE/UnSoliAE/AEREL2.SAS This preprint research paper has not been peer reviewed Electronic copy available at: https://ssrn.com/abstract=3931736 N A N O C O V A X P H A S E I I C L I N I C A L T R I A L P a g e o f Appendix 7: Unsolicited Adverse Events by System Organ Classes, Preferred Term and Relationship to Study Drug S a f e t y A n a l y s i s S e t - P l a c e b o V s N a n o c o v a x ( m c g / m c g / m c g Body System Preferred Term Relationship A m i d a n N o t Nanocovax N=480 s w e l l i n g ( % ) R e l a t e d ( % ) C o u g h N o t R e l a t e d P r o b a b l y R e l a t e d U n l i k e l y R e l a t e d D y s p n e a N o t U n l i k e l y R e l a t e d n t H o a r s e n e s s P r o b a b l y N a s a l r P R e l a t e d ir n D i s c h a r g e N o t p e t o R e l a t e d R e l a t e d v e r r e e p ( % ) ( % ) ( ( % ) ( ( % ) ( ( % ) ( % ) ( % ) 1 ( % ) ( % ) % ) ( % ) % ) ( % ) % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) R e l a t e d ( % ) U n l i k e l y R e l a t e d ( % ) p a i n OVERALL N=560 P r o b a b l y N a s a l Placebo N= 80 w ie d e ( % ) ( % ) ( % ) ( % ) Created by D.D.G with SAS 9.4 on 11MAY2021 Program: SAS/folders/myfolders/NANOCOVAXP2/AE/UnSoliAE/AEREL2.SAS This preprint research paper has not been peer reviewed Electronic copy available at: https://ssrn.com/abstract=3931736 N A N O C O V A X P H A S E I I C L I N I C A L T R I A L P a g e o f Appendix 7: : Unsolicited Adverse Events by System Organ Classes, Preferred Term and Relationship to Study Drug S a f e t y A n a l y s i s S e t - P l a c e b o V s N a n o c o v a x ( m c g / m c g / m c g Body System Preferred Term Relationship N o t Nanocovax N=480 R e l a t e d S i n u s i t i s U n l i k e l y S o r e N o t R e l a t e d P r o b a b l y R e l a t e d U n l i k e l y R e l a t e d T h r o a t s e n s a t i o n U n l i k e l y U p p e r p e r P a n d d i s o r d e r s n t R e l a t e d ir n r e s p i r a t o r y N o t R e l a t e d s u b c u t a n e o u s L i k e y N o t t o t r a c t i n f e c t i o n t i s s u e d i s o r d e r s ( % ) P r o b a b l y R e l a t e d OVERALL N=560 v e % ) ( ( % ) ( % ) ( ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) % ) ( % ) ( % ) 1 ( % ) ( % ) % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) R e l a t e d R e l a t e d % ) % ) ( R e l a t e d ( r r e e p T h r o a t L i k e y S k i n R e l a t e d ( w ie Placebo N= 80 1 ( % ) ( % ) d e ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) Created by D.D.G with SAS 9.4 on 11MAY2021 Program: SAS/folders/myfolders/NANOCOVAXP2/AE/UnSoliAE/AEREL2.SAS This preprint research paper has not been peer reviewed Electronic copy available at: https://ssrn.com/abstract=3931736 N A N O C O V A X P H A S E I I C L I N I C A L T R I A L P a g e o f Appendix 7: : Unsolicited Adverse Events by System Organ Classes, Preferred Term and Relationship to Study Drug S a f e t y A n a l y s i s S e t - P l a c e b o V s N a n o c o v a x ( m c g / m c g / m c g Body System Preferred Term Relationship Nanocovax N=480 B u r n N o t R e l a t e d I t c h i n g N o t I t c h y h e a d R e l a t e d r a s h L i k e y a t R e l a t e d t h e P r o b a b l y S k i n r P i n j e c t i o n p e R e l a t e d d i s o r d e r s N o t R e l a t e d P r o b a b l y s i t e n t R e l a t e d ir n P r o b a b l y t o R e l a t e d i n f e c t i o n V a s c u l a r ( % ) ( % ) R e l a t e d ( % ) OVERALL N=560 v e 1 r r e e p P r o b a b l y L u m p s s k i n Placebo N= 80 w ie ( ( 1 d e ( % ) ( % ) % ) ( % ) % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) ( % ) Created by D.D.G with SAS 9.4 on 11MAY2021 Program: SAS/folders/myfolders/NANOCOVAXP2/AE/UnSoliAE/AEREL2.SAS This preprint research paper has not been peer reviewed Electronic copy available at: https://ssrn.com/abstract=3931736 N A N O C O V A X P H A S E I I C L I N I C A L T R I A L P a g e o f Appendix 7: : Unsolicited Adverse Events by System Organ Classes, Preferred Term and Relationship to Study Drug S a f e t y A n a l y s i s S e t - P l a c e b o V s N a n o c o v a x ( m c g / m c g / m c g Body System Preferred Term Relationship Nanocovax N=480 ( % ) ( N o t ( % ) ( ( % ) R e l a t e d P r o b a b l y R e l a t e d H y p o t e n s i o n N o t R e l a t e d t o w ie Placebo N= 80 H y p e r t e n s i o n % ) OVERALL N=560 v e % ) r r e e p ( ( ( % ) ( % ) ( % ) % ) ( % ) % ) ( % ) n t r P p e d e ir n Created by D.D.G with SAS 9.4 on 11MAY2021 Program: SAS/folders/myfolders/NANOCOVAXP2/AE/UnSoliAE/AEREL2.SAS This preprint research paper has not been peer reviewed Electronic copy available at: https://ssrn.com/abstract=3931736 ... doses of vaccine or the placebo on day and day 28 Trial staffs responsible for the vaccine preparation and administration, as well as participants were unaware of vaccine assignment Randomization... 383: 23 20– 32 Pr 13 Chu L, McPhee R, Huang W, et al A preliminary report of a randomized controlled phase trial of the safety and immunogenicity of mRNA- 127 3 SARS-CoV -2 vaccine Vaccine 20 21; 39: 27 91–9... intervention (n=0) Analysis Safety analysis (n =20 ) -Excluded from safety analysis (n=0) Safety analysis (n =20 ) -Excluded from safety analysis (n=0) Safety analysis (n =20 ) -Excluded from safety analysis (n=0)