First-In-Human Trial of A Recombinant Stabilized Prefusion Sars-Cov-2 Spike Protein Vaccine With Adjuvant of Aluminum Hydroxide and CPG 1018

medRxiv preprint doi: https://doi.org/10.1101/2021.03.31.21254668; this version posted April 6, 2021.
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1 First-in-Human Trial of a Recombinant Stabilized Prefusion SARS-CoV-2 Spike Protein
2 Vaccine with Adjuvant of Aluminum Hydroxide and CpG 1018
4 Szu-Min Hsieh, M.D.1, Wang-Da Liu, M.D.1, Yu-Shan Huang, M.D.1, Yi-Jiun Lin, Ph.D.2,
5 Erh-Fang Hsieh, Ph.D.2, Wei-Cheng Lian, Ph. D.2, Charles Chen, Ad. Prof.2,3, I-Chen Tai,
6 M.D.2*, Shan-Chwen Chang, M.D., Ph.D.1*
7 1.
Section of Infectious Diseases, Division of Infectious Diseases, Department of Internal Medicine,
8 National Taiwan University Hospital and College of Medicine, National Taiwan University, Taiwan
9 2.
Medigen Vaccine Biologics Corp., Taiwan
10 3.
College of Science and Technology, Temple University, Philadelphia, PA 19122, U.S.A.
11 *Corresponding authors
12 I-Chen Tai, Corresponding Author
13 Email: [email protected]
14 Postal address: Medigen Vaccine Biologics Corp.
15 7F., No. 16, Ln. 120, Sec. 1, Neihu Rd., Taipei 114, Taiwan
16 TEL: +886-2-77450830 #604
17
18 Shan-Chwen Chang, Corresponding Author
19 Email: [email protected]
20 Postal address: National Taiwan University Hospital
21 No.7, Zhongshan S. Rd., Zhongzheng Dist., Taipei City 100, Taiwan
22 TEL: +886-2-23123456#887999
23 Keywords: COVID-19 vaccine; CpG 1018; S-2P protein;
24
25
NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.
medRxiv preprint doi: https://doi.org/10.1101/2021.03.31.21254668; this version posted April 6, 2021. The copyright holder for this preprint
26 Abstract
27 Design
28 This is a phase 1, dose-escalation open-label trial to evaluate the safety and
29 immunogenicity of MVC-COV1901, a recombinant stabilized prefusion SARS-CoV-2 spike
30 (S-2P) protein vaccine with adjuvant of aluminum hydroxide and CpG 1018.
31 Methods
32 We enrolled 45 healthy adults from 20 to 49 years of age to be administered with two
33 vaccinations of MVC-COV1901 in a low dose (LD), middle dose (MD), and high dose (HD)
34 of spike protein at 28 days apart. There were 15 participants in each dose group, and all of
35 them were followed up for 28 days after the second vaccination at the time of interim analysis.
36 Adverse events (AEs) and laboratory data were recorded for safety evaluation. Blood samples
37 were collected for wild-type SARS-CoV-2 and pseudovirus neutralization assays as well as
38 SARS-CoV-2 spike-specific immunoglobulin G (IgG) at various times. Overall, the study
39 duration will be 7 months.
40 Results
41 Solicited events were mostly mild and similar in the participants of all three dose groups.
42 No subject experienced fever. There were no serious nor adverse events of special interest at
43 the time point of this interim report. After the second vaccination, the SARS-CoV-2 spike
44 specific IgG titers increased with peak geometric mean titers at 7178.245 (LD), 7746.086
2
45 (MD), and 11220.58 (HD), respectively. Serum neutralizing activity was detected by two
46 methods in all participants of MD and HD groups, with geometric mean values generally
47 comparable to those of a panel of control convalescent serum specimens. All of the
48 participants in the MD and HD groups were seroconverted after the second vaccination.
49 Conclusions
50 The MVC-COV1901 vaccine is safe and elicits remarkable immune responses especially
51 in the MD and HD groups.
52 Trial Registration: ClinicalTrials.gov NCT 04487210
53
54
3
55 Introduction
56 Human infections due to SARS-CoV-2 began to spread globally following the outbreak
57 in Wuhan, China. WHO panel declared the COVID-19 outbreak as a public health emergency
58 of international concerns, and this outbreak was also subsequently characterized as a
59 pandemic declared by the WHO on March 11th, 2020.1
60 Approximately 15% of COVID-19 cases are severe that requires oxygen support, and
61 5% are critical disease with complications such as respiratory failure, acute respiratory
62 distress syndrome (ARDS), sepsis, septic shock, etc.2 A meta-analysis assessed the risk of
63 underlying diseases in severe patients compared to those in non-severe conditions and
64 showed the pooled odds ratios were 2.36 for hypertension, 2.46 for respiratory system disease,
65 and 3.42 for cardiovascular disease and 2.07 for diabetes.3
66 There is currently no cure medication for the potentially lethal COVID-19. Development
67 of a range of vaccines will provide flexibility with prevention strategies. For vaccines
68 intended to generate protective immune response, using an antigen with proper conformation
69 is critical. The neutralizing antibodies induced by spike (S) protein block viruses from
70 binding to their target receptor ACE2 and hence inhibit viral infection. S protein has two
71 major conformational stats, prefusion and postfusion.4 S-2P protein is a recombinant version
72 of the S protein developed by the laboratory of Dr. Barney S. Graham (Vaccine Research
73 Center, National Institute of Allergy and Infectious Diseases[NIAID], U.S.A.), and is a
4
74 stabilized prefusion S ectodomain, encoding residues 1−1208 of SARS-CoV-2 spike protein
75 with two proline substitutions at residues 986 and 987, a “GSAS” substitution at residues
76 682–685 to abolish the furin cleavage site, and a T4 fibritin trimerization motif at the
77 C-terminus.5 The cryo–electron microscopy structure showed the protein produced by this
78 construct is in the prefusion conformation and can bind to ACE2.5(p1261) Similar strategy had
79 been used to retain MERS-COV S protein in the prefusion conformation and demonstrated
80 that stabilized MERS-COV S protein was able to elicit high neutralizing antibody.6
81 Medigen’s MVC-COV1901 vaccine is formulated as S-2P adjuvanted with Dynavax’s CpG
82 1018 and aluminum hydroxide. CpG 1018 is an oligodeoxynucleotide which acts as a
83 toll-like receptor 9 agonist and has been shown in our preclinical studies to enhance
84 immunogenicity and induce a Th1-skewed immune response7.
85 Methods
86 Trial Design
87 This study was a phase 1, prospective, open-label, dose-escalation study to evaluate the
88 safety and immunogenicity of a SARS-CoV-2 vaccine in adults aged 20 to 49 years. The
89 study was commenced at the National Taiwan University Hospital in northern Taiwan from
90 September 2020. The trial protocol and informed consent form were approved by the Taiwan
91 Food and Drug Administration and the ethics committee at the site. The trial was conducted
92 in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice.
5
93 An independent data and safety monitoring board (DSMB) was established to monitor safety
94 data. (ClinicalTrials.gov NCT 04487210)
95 The Investigational Vaccine
96 We applied technology previously used for MERS-CoV to produce a
97 prefusion-stabilized SARS-CoV-2 spike protein, S-2P, designed by Dr. Barney S. Graham
98 (Vaccine Research Center, NIAID, U.S.A.). The MVC-COV1901 contained S-2P protein
99 adjuvanted with CpG 1018 and aluminum hydroxide as previous reported.7(p7). The vaccine
100 administered at a volume of 0.5 mL as a single dose via intramuscular injection. The
101 production of the vaccine was conducted in Medigen Vaccine Biologics Corp. facility which
102 is compliant with the current good manufacturing practices (cGMP).
103 Participants
104 Eligible participants were healthy adults from 20 to 49 years of age. Eligibility was
105 determined based on medical history, physical examination, laboratory tests, and
106 investigators’ clinical judgment. Exclusion criteria included a history of known potential
107 exposure to SARS CoV-1 or 2 viruses, having received any other COVID-19 vaccine,
108 impaired immune function, history of autoimmune disease, abnormal autoantibody tests,
109 febrile or acute illness within 2 days of first dose, and acute respiratory illness within 14 days
110 of first dose.
6
111 Interventions
112 This study was a dose escalation study with three separate sub-phases for participants
113 from 20 to 49 years of age. Each sub-phase consisted of 15 participants. The three different
114 dose levels employed in this clinical trial are LD, MD, and HD of S-2P protein adjuvanted
115 with CpG 1018 and aluminum hydroxide for phase 1a, 1b, and 1c, respectively. The
116 vaccination schedule consisted of two doses, administered by intramuscular (IM) injection of
117 0.5 mL in the deltoid region of non-dominant arm 28 days apart, on Day 1 and Day 29. The
118 protocol permitted an interim analysis to make decisions regarding vaccine strategy.
119 Phase 1a
120 Four sentinel participants would be recruited to receive LD of S-2P protein with
121 adjuvant to evaluate preliminary safety data of the vaccine. If no ≥ Grade 3 AE or SAE
122 occurred within 7 days after the first vaccination in the 4 sentinel participants, dosing of the
123 remaining participants in Phase 1a and Phase 1b would proceed.
124 Phase 1b
125 Another 4 sentinel participants would be enrolled to receive MD of S-2P protein with
126 adjuvant in Phase 1b. If no ≥ Grade 3 AE or SAE occurred within 7 days after the first
127 vaccination in the 4 sentinel participants, dosing of the remaining participants in Phase 1b
128 and Phase 1c would proceed.
7
129 Phase 1c
130 Another 4 sentinel participants would be enrolled to receive HD of S-2P protein with
131 adjuvant in phase 1c. If no ≥ Grade 3 AE or SAE occurred within 7 days after the first
132 vaccination in the 4 sentinel participants, dosing of the remaining participants in Phase 1c
133 would proceed.
134 An interim analysis of immunogenicity data and safety data from baseline to 28 days
135 after the second vaccination for all participants were carried out when all of the participants
136 have completed the visit (at 28 days after the second vaccination).
137 Safety Assessment
138 The primary endpoint was to evaluate the safety of MVC-COV1901 in three different
139 strengths (LD, MD, and HD of S-2P protein adjuvanted with CpG 1018 and aluminum
140 hydroxide) from Day 1 to 28 days after the second vaccination. Vital signs and
141 electrocardiogram (ECG) were performed before and after vaccination. Participants were
142 observed for at least 30 min after each vaccination to identify any immediate adverse events
143 (AEs), and were asked to record solicited local and systemic AEs in the participant’s diary
144 card for up to 7 days after each vaccination. Unsolicited AEs were recorded for 28 days
145 following each vaccination; all other AEs, serious adverse events (SAEs) and adverse events
146 of special interests (AESIs) were recorded throughout the study period.
147 Serum samples were collected for safety evaluations. Hematology, biochemistry and
8
148 immunology tests were measured as well.
149 Immunogenicity Analysis
150 The immunogenicity endpoints were to evaluate the immunogenicity in terms of
151 neutralizing antibody titers and binding antibody titers at 14 days (Day 15) and 28 days (Day
152 29) after first and at 14 days (Day 43) and 28 days (Day 57) after second vaccination, as well
153 as 90 days and 180 days after the second vaccination.
154 SARS-CoV-2 spike-specific immunoglobulin G (IgG)
155 Total serum anti-Spike IgG titers were detected with direct enzyme-linked
156 immunosorbent assay (ELISA) using customized 96-well plates coated with S-2P antigen.
157 SARS-CoV-2 pseudovirus neutralization assay
158 Pseudovirus production and titration followed the previous report.7(p7) Serial dilutions of
159 the samples to be tested were performed (initial dilution of 1:20; diluted two-fold to a final
160 dilution of 1:2560). The diluted serum was mixed with equal volume of pseudovirus (1000
161 TU) and incubated before adding to the plates with HEK293-hAce2 cells (1 × 104 cells/well).
162 The amount of pseudovirus entering the cells was calculated by lysing and measuring the
163 relative luciferase units (RLU). Fifty percent inhibition dilution (concentration) titers (ID50)
164 were calculated considering uninfected cells as 100% neutralization and cells transduced with
165 virus as 0% neutralization and reciprocal ID50 geometric mean titers (GMT) were both
166 determined.
9
167 Wildtype SARSCoV2 neutralization assay
168 SARS-CoV-2 virus (hCoV-19/Taiwan/CGMH-CGU-01/2020, GenBank accession
169 MT192759) was obtained and titrated to obtain TCID50, and Vero E6 cells (2.5 × 104
170 cells/well) were seeded in 96-well plates and incubated. The sera underwent a total of 11
171 two-fold dilutions with the final dilution being 1:8192, and the diluted sera were mixed with
172 equal volume of viral solution containing 100 TCID50. The serum-virus mixture was
173 incubated and then added to the cell plates containing the Vero E6 cells, followed by further
174 incubation. The neutralizing titer was defined as the reciprocal of the highest dilution capable
175 of inhibiting 50% of the CPE (NT50), which was calculated in accordance with the formula of
176 the Reed-Muench method.
177 Statistical Analysis
178 Safety analysis was performed on the total vaccinated group (TVG) population who
179 received at least 1 dose of vaccine. The endpoints related to immunogenicity consisted of the
180 following: antigen specific immunoglobulins, neutralizing antibody titers of wild type virus
181 and pseudovirus, in terms of geometric mean titer (GMT) and seroconversion rate (SCR).
182 SCR is defined as the percentage of participants with ≥ 4-fold increase in titers from the
183 baseline or from half of the lower limit of detection (LoD) if undetectable at baseline.
184
185
10
186 Results
187 Study Population
188 In total, 77 participants were screened. Of these, 45 eligible participants had completed
189 two doses of MVC-COV1901. Participants’ baseline demographic characteristics are
190 summarized in Table 1.
191 Vaccine Safety
192 Neither SAEs nor AESI occurred at this time point of interim analysis. No participants
193 missed the second dose. All of the local and systemic AEs were mild, except for one
194 malaise/fatigue in the HD group. None of the participants had fever after either dose 1 or
195 dose 2. Solicited adverse events after the first and the second vaccination were similar.
196 Evaluation of safety laboratory values, ECG interpretation, and unsolicited adverse events
197 revealed no specific concern.
198 Immunogenicity
199 The humoral immunogenicity results are summarized in Figure 1.
200 SARS-CoV-2 spike specific immunoglobulin G (IgG)
201 Binding IgG titers to S protein increased rapidly after the second vaccination, with
202 seroconversion in all participants by Day 43 and 57. The GMTs peaked at Day 43 with value
203 of 7178.245 (95% CI: 4240.336 ~12151.68), 7746.086 (95% CI: 5530.230 ~10849.79),
204 11220.58 (95% CI: 8592.293 ~14652.84) in LD, MD, HD groups, respectively. The
11
205 responses in LD, MD, and HD groups were also similar to the values of convalescent serum
206 specimens.(2179.598, [95%CI: 1240.897~3828.396]). (Fig 1A)
207 Neutralization responses for SARS-CoV-2 pseudovirus
208 Before vaccination, no subject had detectable pseudovirus neutralizing titers (ID50) at the
209 lower limit of serum concentration tested (1:20 dilution) in the assay. At Day 43, the
210 pseudovirus neutralizing titers (ID50) showed peaked GMTs of 538.496 (95% CI: 261.9403
211 ~1107.036), 993.075 (95% CI: 654.9991 ~1505.648), and 1905.840 (95% CI: 1601.667
212 ~2267.779) in LD, MD, and HD groups, respectively. All of the participants in three doses
213 were seroconverted after the second vaccination (Fig 1B).
214 Neutralization responses for wild type SARS-CoV-2 virus
215 Before vaccination, no subject had detectable wild-type virus neutralizing titers (NT50)
216 at the lower limit of serum concentration tested (1:8 dilution) in the assay. However, after the
217 second vaccination, neutralizing responses were identified in serum samples from all
218 participants in MD and HD groups. At Day 43, the GMTs were 33.317 (95% CI: 18.5239
219 ~59.9256), 76.307 (95% CI: 53.7497 ~108.3309), and 167.402 (95% CI: 122.0492
220 ~229.6090) in LD, MD, and HD groups, respectively. The MD and HD groups were similar
221 in terms of GMT (52.205 [95% CI: 37.9448 ~71.8246] and 81.909 [95% CI: 55.8131
222 ~120.2070], respectively, at Day 57). These responses were also similar to the value of
223 convalescent serum specimens. (42.674, [95%CI: 26.37666~69.0403]) All participants in MD
12
224 and HD groups were seroconverted at Day 43 and Day 57. The results of wild-type
225 SARS-CoV-2 neutralizing antibody titer are summarized in Fig 1C.
226 Discussion
227 This is the first clinical trial report to address the protein-based vaccine using the S-2P
228 protein developed by NIAID, U.S.A. as the antigen, and adjuvanted with CpG 1018 and
229 aluminum hydroxide.
230 This interim analysis demonstrated that the MVC-COV1901 vaccine was well tolerated
231 and immunogenic in healthy adults aged 20 to 49 years. Across the three dose groups, local
232 injection-site reactions were all mild. This safety profile is similar to that described in the
233 previous report for subunit protein vaccines adjuvanted with CpG 1018 or aluminum
234 hydroxide.8, 9 With regards to the occurrence rate and severity of solicited AEs, no differences
235 were noticed among the LD, MD, and HD groups, or between the first and second
236 vaccination.
237 The rates of detectable neutralizing response in all three dose groups at baseline were
238 0%, aligning with the fact that there was no circulating SARS-CoV-2 in Taiwan. The
239 neutralizing antibody titers were measurable at Day 43 and Day 57 for all dose levels. All
240 participants in MD and HD groups were seroconverted in terms of wild-type SARS-CoV-2
241 neutralizing response. Besides, the wild type neutralizing antibody response profile also
242 demonstrated a good correlation with IgG and pseudovirus neutralizing antibody titers.
13
243 Although the correlation of protection is not available at present, serum neutralizing activity
244 has been shown to be correlate of protection for other viruses while developing vaccines,
245 such as yellow fever vaccine, polio vaccine, and Japanese encephalitis vaccine,10 and is
246 generally accepted as a useful biomarker of the in vivo humoral response. Besides, the
247 preclinical study of MVC-COV190111 had shown that hamsters were protected from
248 SARS-CoV-2 virus challenge after two vaccinations of S-2P protein adjuvanted with CpG
249 and aluminum hydroxide. The geometric mean titers in the MD and HD groups were
250 comparable with those of a panel of control convalescent serum specimens with all
251 participants in both groups seroconverted after two vaccinations. Therefore, a MD of S-2P
252 combined with CpG 1018 and aluminum hydroxide was deemed adequate to elicit a profound
253 humoral immune response.
254 This interim report has some limitations: small size of the trial, the short period of
255 follow-up at this time point, and the participants’ young age and good health status. We were
256 not able to assess the durability of the immune responses after Day 57 in this interim report.
257 However, participants will be followed up for 6 months after the second vaccination with
258 scheduled blood collections throughout that period to evaluate the humoral immunologic
259 responses. Although the level of immunity needed to protect from COVID-19 remains
260 unknown, NIBSC 20/130 standard serum was tested in terms of wild-type SARS-CoV-2
261 neutralizing antibody titer for the development and evaluation of serological assays for the
14
262 detection of antibodies against SARS-CoV-2, as a positive control.
263 These safety and immunogenicity findings support further advancement of the
264 MVC-COV1901 vaccine to subsequent clinical trials. Of the three doses evaluated, both the
265 MD and HD elicited high neutralizing antibody responses with all participants seroconverted
266 after second vaccination. Further phase 2 trial with 3700 participants (including the
267 populations at greatest risk for serious Covid-19 such as those with chronic medical diseases
268 and older adults) is on-going (ClinicalTrials.gov number, NCT04695652)
269
15
270 Acknowledgements
271 Author contributions
272 SM Hsieh, SC Chang and IC Tai had full access to all of the data in the study and take
273 responsibility for the integrity of the data and the accuracy of the data analysis. SC Chang
274 and IC Tai contributed equally and are joint corresponding authors.
275 Concept and design: SM Hsieh and IC Tai
276 Acquisition, or interpretation of data: SM Hsieh, SC Chang, WD Liu, and YS Huang
277 Drafting and preparing the manuscript: SM Hsieh, SC Chang, WD Liu, YS Huang, YJ Lin,
278 EF Hsieh, and IC Tai
279 Critical revision of the manuscript for important intellectual content: SM Hsieh, SC Chang
280 Laboratory assays set up and analysis of data: YJ Lin, and EF Hsieh
281 Administrative, technical, or material support: Charles Chen and WC Lian
282 All authors reviewed and approved of the final version of the manuscript.
283 Conflict of interests Disclosure
284 Szu-Min Hsieh, Shan-Chwen Chang, Wang-Da Liu, Yu-Shan Huang declared that they have
285 no known competing financial interests or personal relationships that could have appeared to
286 influence the work reported in this paper; Yi-Jiun Lin, Erh-Fang Hsieh, Wei-Cheng Lian,
287 Charles Chen, I-Chen Tai reported grants from Taiwan Centers for Disease Control, Ministry
288 of Health and Welfare, during the conduct of the study. In addition, Yi-Jiun Lin and Charles
16
289 Chen have a patent US63/040,696 pending.
290 Funding/Support
291 Taiwan Centers for Disease Control, Ministry of Health and Welfare provided grant funding
292 for this study, but does not necessarily stand by any commentary made in this paper.
293 Medigen Vaccine Biologics Corp. was the study sponsor and manufacturer of the
294 investigational vaccine, and co-designed the trial, provided the study product, and
295 coordinated interactions with regulatory authorities. The sponsors used contract clinical
296 research organization to oversee clinical site operations. Data were collected by the clinical
297 site research staff, managed by a contract research organization data management team,
298 monitored by a contract research organization, and overseen by the sponsor and an
299 independent data and safety monitoring board. The interim analysis was performed by the
300 contract research organization. Data interpretation, manuscript preparation were performed
301 by the authors and the decision to submit the manuscript for publication was made by the
302 authors.
303 Additional Contributions
304 All the participants for their dedication to this trial; Dr. Barney S. Graham at Vaccine
305 Research Center, National Institute of Allergy and Infectious Diseases, U.S.A., team
306 members at Dynavax Technologies, Emeryville, CA 94608, USA. and TsunYung Kuo at
307 Department of Biotechnology and Animal Science, National Ilan University, Ilan, Taiwan for
17
308 providing technical guidance and helpful advice; The investigational staff at National Taiwan
309 University Hospital, Taiwan and A2 Healthcare Taiwan Corp. for the conduction of the trial;
310 Leo Lee, Tzay Huar Hong, Hui-Yi Wang, Chian-En Lien, Hao-Yuan Cheng and at Medigen
311 Vaccine Biologics Corp. for collaboration on protocol development, significant contribution
312 to the Investigational New Drug (IND) application, and participation in weekly meeting with
313 the regulatory authority; The members of the safety monitoring committee; Dr. Yu-Chi Chou
314 and his team members at the RNAi Core Facility, Academia Sinica for the pseudovirus
315 neutralization assay; Dr. Shin-Ru Shih at Chang Gung University, Taoyuan, Taiwan and Dr.
316 ChungGuei Huang as well as her team members at Chang Gung Memorial Hospital,
317 Taoyuan, Taiwan for the wild type SARS-CoV-2 neutralization assay; Team members at
318 Protech Pharmaservices Corporation for spike specific IgG ELISA assay. Dr. Chia En Lien,
319 Dr. Meei-Yun Lin, Luke Tzu-Chi Liu, and Meng-Ju Tsai at Medigen Vaccine Biologics Corp.,
320 Taiwan for manuscript editing and revision.
321
18
322 References
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327 arks-at-the-media-briefing-on-covid-19---11-march-2020
328 2. World Health Organization. COVID-19 Clinical management: living guidance, 25
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336 5. Wrapp D, Wang N, Corbett KS, et al. Cryo-EM structure of the 2019-nCoV spike in the
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339 6. Pallesen J, Wang N, Corbett KS, et al. Immunogenicity and structures of a rationally
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359 January 7, 2021. doi: https://doi.org/10.1101/2021.01.07.425674
21
360 Figure
361
362 Fig 1. Summary of Humoral Immune Response
363 Sera of participants vaccinated with LD, MD, or HD of MVC-COV1901 were measured for
364 anti-spike IgG by (A) ELISA, and neutralization titers were measured by (B) pseudovirus
22
365 neutralization assay or (C) live virus neutralization assay. Human convalescent sera (HCS)
366 from 35 recovered COVID-19 patients were analysed by the same assays for comparison and
367 NIBSC 20/130 standard was used in the live virus neutralization assay as a standard (asterisk
368 in panel C). Bars indicate geometric mean titers and error bars indicate 95% confidence
369 intervals. A: The GMTs at Day 43 in terms of SARS-CoV-2 spike specific IgG were
370 7178.245 (LD), 7746.086 (MD), 11220.58 (HD), and 2179.598 (HCS); B: The GMTs at Day
371 43 in terms of SARS-CoV-2 pseudovirus ID50 were 538.496 (LD), 993.075 (MD), 1905.840
372 (HD), and 430.468 (HCS); C: The GMTs at Day 43 in terms of wild type SARS-CoV-2 NT50
373 were 33.317 (LD), 76.307 (MD), 167.402 (HD), and 42.674 (HCS). The value of NIBSC
374 20/130 standard was 281.84. (as shown in asterisk)
375
376
23
377 Tables
378 Table 1. Demographic Characteristics of Eligible Participants
Demographic
LD MD HD Total
characteristics
No. of Participants 15 15 15 45
Age
Mean (SD), years 36.7 (8.97) 33.3 (8.03) 31.5 (5.78) 33.8 (7.84)
Gender
Male, No. (%) 7 (46.7%) 9 (60.0%) 12 (80.0%) 28 (62.2%)
Female, No. (%) 8 (53.3%) 6 (40.0%) 3 (20.0%) 17 (37.8%)
2
BMI (kg/m )
Mean (SD) 23.18 (3.394) 23.30 (3.084) 23.17 (2.429) 23.22 (2.928)
379
24

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medRxiv preprint doi: https://doi.org/10.1101/2021.03.31.21254668; this version posted April 6, 2021.

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1 First-in-Human Trial of a Recombinant Stabilized Prefusion SARS-CoV-2 Spike Protein

2 Vaccine with Adjuvant of Aluminum Hydroxide and CpG 1018

6 M.D.2*, Shan-Chwen Chang, M.D., Ph.D.1*

12 I-Chen Tai, Corresponding Author

14 Postal address: Medigen Vaccine Biologics Corp.

16 TEL: +886-2-77450830 #604

18 Shan-Chwen Chang, Corresponding Author

20 Postal address: National Taiwan University Hospital

21 No.7, Zhongshan S. Rd., Zhongzheng Dist., Taipei City 100, Taiwan

23 Keywords: COVID-19 vaccine; CpG 1018; S-2P protein;

28 This is a phase 1, dose-escalation open-label trial to evaluate the safety and

29 immunogenicity of MVC-COV1901, a recombinant stabilized prefusion SARS-CoV-2 spike

32 We enrolled 45 healthy adults from 20 to 49 years of age to be administered with two

38 SARS-CoV-2 spike-specific immunoglobulin G (IgG) at various times. Overall, the study

39 duration will be 7 months.

47 comparable to those of a panel of control convalescent serum specimens. All of the

51 in the MD and HD groups.

52 Trial Registration: ClinicalTrials.gov NCT 04487210

58 of international concerns, and this outbreak was also subsequently characterized as a

59 pandemic declared by the WHO on March 11th, 2020.1

63 underlying diseases in severe patients compared to those in non-severe conditions and

65 and 3.42 for cardiovascular disease and 2.07 for diabetes.3

73 Center, National Institute of Allergy and Infectious Diseases[NIAID], U.S.A.), and is a

74 stabilized prefusion S ectodomain, encoding residues 1−1208 of SARS-CoV-2 spike protein

81 Medigen’s MVC-COV1901 vaccine is formulated as S-2P adjuvanted with Dynavax’s CpG

82 1018 and aluminum hydroxide. CpG 1018 is an oligodeoxynucleotide which acts as a

84 immunogenicity and induce a Th1-skewed immune response7.

88 safety and immunogenicity of a SARS-CoV-2 vaccine in adults aged 20 to 49 years. The

94 data. (ClinicalTrials.gov NCT 04487210)

95 The Investigational Vaccine

96 We applied technology previously used for MERS-CoV to produce a

97 prefusion-stabilized SARS-CoV-2 spike protein, S-2P, designed by Dr. Barney S. Graham

102 is compliant with the current good manufacturing practices (cGMP).

110 of first dose.

123 remaining participants in Phase 1a and Phase 1b would proceed.

128 and Phase 1c would proceed.

133 would proceed.

137 Safety Assessment

148 immunology tests were measured as well.

149 Immunogenicity Analysis

150 The immunogenicity endpoints were to evaluate the immunogenicity in terms of

153 as 90 days and 180 days after the second vaccination.

154 SARS-CoV-2 spike-specific immunoglobulin G (IgG)

157 SARS-CoV-2 pseudovirus neutralization assay

167 Wildtype SARSCoV2 neutralization assay

168 SARS-CoV-2 virus (hCoV-19/Taiwan/CGMH-CGU-01/2020, GenBank accession

176 the Reed-Muench method.

177 Statistical Analysis

187 Study Population

189 two doses of MVC-COV1901. Participants’ baseline demographic characteristics are

190 summarized in Table 1.

191 Vaccine Safety

197 revealed no specific concern.

199 The humoral immunogenicity results are summarized in Figure 1.

200 SARS-CoV-2 spike specific immunoglobulin G (IgG)

206 specimens.(2179.598, [95%CI: 1240.897~3828.396]). (Fig 1A)

207 Neutralization responses for SARS-CoV-2 pseudovirus

6 M.D.2, Shan-Chwen Chang, M.D., Ph.D.1