An updated atlas of antibody evasion by SARS-CoV-2 Omicron sub-variants including BQ.1.1 and XBB

Emerging Omicron sub-variants are causing global concerns, and their immune evasion should be monitored continuously. We previously evaluated the escape of Omicron BA.1, BA.1.1, BA.2 and BA.3 from an atlas of 50 monoclonal antibodies (mAbs), covering seven epitope classes of the SARS-CoV-2 receptor-binding domain (RBD). Here, we update the atlas of totally 77 mAbs against emerging sub-variants including BQ.1.1 and XBB and find that BA.4/5, BQ.1.1 and XBB display further evasion. Besides, investigation into the correlation of binding and neutralization of mAbs reveals the important role of antigenic conformation in mAb functioning. Moreover, the complex structures of BA.2 RBD/BD-604/S304 and BA.4/5 RBD/BD-604/S304/S309 further elucidate the molecular mechanism of antibody evasion by these sub-variants. By focusing on the identified broadly potent mAbs, we find a general hotspot epitope on the RBD, which could guide the design of vaccines and calls for new broad-spectrum countermeasures against COVID-19. Graphical Immune evasion of SARS-CoV-2 variants needs to be monitored continuously. He et al. assess the efficacy of 77 neutralizing mAbs against recently emerging Omicron sub-variants including BQ.1.1 and XBB. They reveal the binding-neutralization correlation of mAbs and point out a hotspot epitope targeting by broadly neutralizing antibodies.

One-quarter of COVID-19 patients developed PTSD symptoms: a one-year longitudinal study

This study investigated the longitudinal development of PTSD symptoms and respiratory sequelae among COVID-19 patients one year after hospital discharge. The cumulative occurrence of probable PTSD in COVID-19 survivors (n=329) was 26.7%, which significantly decreased over the 12-month period (23.1% to 4.3%). Non-severe patients showed marked improvement in all four clusters of PTSD symptoms at 12 months compared to 3 months, while severe patients only showed improvements in re-experiencing and numbing symptoms. Moreover, being female and having respiratory sequelae increased the risk for chronic PTSD. Psychological interventions are required for COVID-19 patients during long-term convalescence.

An updated atlas of antibody evasion by SARS-CoV-2 Omicron sub-variants including BQ.1.1 and XBB.

Emerging Omicron sub-variants are causing global concerns, and their immune evasion should be monitored continuously. We previously evaluated the escape of Omicron BA.1, BA.1.1, BA.2, and BA.3 from an atlas of 50 monoclonal antibodies (mAbs), covering seven epitope classes of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor-binding domain (RBD). Here, we update the atlas of totally 77 mAbs against emerging sub-variants including BQ.1.1 and XBB and find that BA.4/5, BQ.1.1, and XBB display further evasion. Besides, investigation into the correlation of binding and neutralization of mAbs reveals the important role of antigenic conformation in mAb functioning. Moreover, the complex structures of BA.2 RBD/BD-604/S304 and BA.4/5 RBD/BD-604/S304/S309 further elucidate the molecular mechanism of antibody evasion by these sub-variants. By focusing on the identified broadly potent mAbs, we find a general hotspot epitope on the RBD, which could guide the design of vaccines and calls for new broad-spectrum countermeasures against COVID-19.

One-quarter of COVID-19 patients developed PTSD symptoms: A one-year longitudinal study.

This study investigated the longitudinal development of PTSD symptoms and respiratory sequelae among COVID-19 patients one year after hospital discharge. The cumulative occurrence of probable PTSD in COVID-19 survivors (n = 329) was 26.7%, which significantly decreased over the 12-month period (23.1% to 4.3%). Non-severe patients showed marked improvement in all four clusters of PTSD symptoms at 12 months compared to 3 months, while severe patients only showed improvements in re-experiencing and numbing symptoms. Moreover, being female and having respiratory sequelae increased the risk for chronic PTSD. Psychological interventions are required for COVID-19 patients during long-term convalescence.

Host range and structural analysis of bat-origin RshSTT182/200 coronavirus binding to human ACE2 and its animal orthologs.

Bat-origin RshSTT182 and RshSTT200 coronaviruses (CoV) from Rhinolophus shameli in Southeast Asia (Cambodia) share 92.6% whole-genome identity with SARS-CoV-2 and show identical receptor-binding domains (RBDs). In this study, we determined the structure of the RshSTT182/200 receptor binding domain (RBD) in complex with human angiotensin-converting enzyme 2 (hACE2) and identified the key residues that influence receptor binding. The binding of the RshSTT182/200 RBD to ACE2 orthologs from 39 animal species, including 18 bat species, was used to evaluate its host range. The RshSTT182/200 RBD broadly recognized 21 of 39 ACE2 orthologs, although its binding affinities for the orthologs were weaker than those of the RBD of SARS-CoV-2. Furthermore, RshSTT182 pseudovirus could utilize human, fox, and Rhinolophus affinis ACE2 receptors for cell entry. Moreover, we found that SARS-CoV-2 induces cross-neutralizing antibodies against RshSTT182 pseudovirus. Taken together, these findings indicate that RshSTT182/200 can potentially infect susceptible animals, but requires further evolution to obtain strong interspecies transmission abilities like SARS-CoV-2.

Two pan-SARS-CoV-2 nanobodies and their multivalent derivatives effectively prevent Omicron infections in mice.

With the widespread vaccinations against coronavirus disease 2019 (COVID-19), we are witnessing gradually waning neutralizing antibodies and increasing cases of breakthrough infections, necessitating the development of drugs aside from vaccines, particularly ones that can be administered outside of hospitals. Here, we present two cross-reactive nanobodies (R14 and S43) and their multivalent derivatives, including decameric ones (fused to the immunoglobulin M [IgM] Fc) that maintain potent neutralizing activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) after aerosolization and display not only pan-SARS-CoV-2 but also varied pan-sarbecovirus activities. Through respiratory administration to mice, monovalent and decameric R14 significantly reduce the lung viral RNAs at low dose and display potent pre- and post-exposure protection. Furthermore, structural studies reveal the neutralizing mechanisms of R14 and S43 and the multiple inhibition effects that the multivalent derivatives exert. Our work demonstrates promising convenient drug candidates via respiratory administration against SARS-CoV-2 infection, which can contribute to containing the COVID-19 pandemic.

Cross-reaction of current available SARS-CoV-2 MAbs against the pangolin-origin coronavirus GX/P2V/2017.

Since the identification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of COVID-19, multiple SARS-CoV-2-related viruses have been characterized, including pangolin-origin GD/1/2019 and GX/P2V/2017. Our previous study indicated that both viruses have the potential to infect humans. Here, we find that CB6 (commercial name etesevimab), a COVID-19 therapeutic monoclonal antibody (MAb) developed by our group, efficiently inhibits GD/1/2019 but not GX/P2V/2017. A total of 50 SARS-CoV-2 MAbs divided into seven groups based on their receptor-binding domain (RBD) epitopes, together with the COVID-19 convalescent sera, are systematically screened for their cross-binding and cross-neutralizing properties against GX/P2V/2017. We find that GX/P2V/2017 displays substantial immune difference from SARS-CoV-2. Furthermore, we solve two complex structures of the GX/P2V/2017 RBD with MAbs belonging to RBD-1 and RBD-5, providing a structural basis for their different antigenicity. These results highlight the necessity for broad anti-coronavirus countermeasures and shed light on potential therapeutic targets.

Stigmatization related COVID-19 and PTSD among Chinese graduates.

BACKGROUND: Since COVID-19 broke out worldwide, it had caused extensive public health concerns and psychological distress, including PTSD and stigmatization towards recovered patients and people from high-risk areas. However, the association between PTSD, stigmatization and certain related factors have not been confirmed. METHODS: Through cluster random sampling, 946 Chinese graduates were investigated from 5 universities in Shanghai at three months after China lifted its coronavirus lockdown. PTSD symptoms were evaluated with PCL-5. Demographic and disease-related characteristics including stigmatization, educational attainment and working position were collected to assess their association with PTSD. RESULTS: 12.4% graduates were reported significant PTSD symptoms in PCL-5 screening with a cut-off of 33. Graduates with a Master's degree (P = 0.02) or working position like "looking for a job" and "planning to go abroad" (P = 0.038) showed severer stigmatization related to COVID-19. Stigmatization towards both patients recovering from COVID-19 and people from high-risk areas had significant association with PTSD symptoms. Multivariate linear regression analysis showed that stigmatization can explain 5% of variation of PCL-5 scores after controlling gender, age, educational attainments and working position. CONCLUSION: Graduates who were looking for jobs or preparing to go abroad showed more stigmatization related to COVID-19. There was a positive correlation between stigma against COVID-19 and PTSD symptoms. More attention should be paid to the mental health status of graduates who are preparing to go abroad or looking for jobs.

Atlas of currently available human neutralizing antibodies against SARS-CoV-2 and escape by Omicron sub-variants BA.1/BA.1.1/BA.2/BA.3.

SARS-CoV-2 Omicron variant has presented significant challenges to current antibodies and vaccines. Herein, we systematically compared the efficacy of 50 human monoclonal antibodies (mAbs), covering the seven identified epitope classes of the SARS-CoV-2 RBD, against Omicron sub-variants BA.1, BA.1.1, BA.2, and BA.3. Binding and pseudovirus-based neutralizing assays revealed that 37 of the 50 mAbs lost neutralizing activities, whereas the others displayed variably decreased activities against the four Omicron sub-variants. BA.2 was found to be more sensitive to RBD-5 antibodies than the other sub-variants. Furthermore, a quaternary complex structure of BA.1 RBD with three mAbs showing different neutralizing potencies against Omicron provided a basis for understanding the immune evasion of Omicron sub-variants and revealed the lack of G446S mutation accounting for the sensitivity of BA.2 to RBD-5 mAbs. Our results may guide the application of the available mAbs and facilitate the development of universal therapeutic antibodies and vaccines against COVID-19.

Persistence of Symptoms After Discharge of Patients Hospitalized Due to COVID-19.

Many patients who had coronavirus disease 2019 (COVID-19) had at least one symptom that persisted after recovery from the acute phase. Our purpose was to review the empirical evidence on symptom prevalence, complications, and management of patients with long COVID. We systematically reviewed the literature on the clinical manifestations of long COVID-19, defined by the persistence of symptoms beyond the acute phase of infection. Bibliographic searches in PubMed and Google Scholar were conducted to retrieve relevant studies on confirmed patients with long COVID that were published prior to August 30, 2021. The most common persistent symptoms were fatigue, cough, dyspnea, chest pains, chest tightness, joint pain, muscle pain, loss of taste or smell, hair loss, sleep difficulties, anxiety, and depression. Some of the less common persistent symptoms were skin rash, decreased appetite, sweating, inability to concentrate, and memory lapses. In addition to these general symptoms, some patients experienced dysfunctions of specific organs, mainly the lungs, heart, kidneys, and nervous system. A comprehensive understanding of the persistent clinical manifestations of COVID-19 can improve and facilitate patient management and referrals. Prompt rehabilitative care and targeted interventions of these patients may improve their recovery from physical, immune, and mental health symptoms.

Machine Learning Approach Effectively Predicts Binding Between SARS-CoV-2 Spike and ACE2 Across Mammalian Species - Worldwide, 2021.

INTRODUCTION: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a recently emergent coronavirus of natural origin and caused the coronavirus disease (COVID-19) pandemic. The study of its natural origin and host range is of particular importance for source tracing, monitoring of this virus, and prevention of recurrent infections. One major approach is to test the binding ability of the viral receptor gene ACE2 from various hosts to SARS-CoV-2 spike protein, but it is time-consuming and labor-intensive to cover a large collection of species. METHODS: In this paper, we applied state-of-the-art machine learning approaches and created a pipeline reaching >87% accuracy in predicting binding between different ACE2 and SARS-CoV-2 spike. RESULTS: We further validated our prediction pipeline using 2 independent test sets involving >50 bat species and achieved >78% accuracy. A large-scale screening of 204 mammal species revealed 144 species (or 61%) were susceptible to SARS-CoV-2 infections, highlighting the importance of intensive monitoring and studies in mammalian species. DISCUSSION: In short, our study employed machine learning models to create an important tool for predicting potential hosts of SARS-CoV-2 and achieved the highest precision to our knowledge in experimental validation. This study also predicted that a wide range of mammals were capable of being infected by SARS-CoV-2.

PTSD Symptoms and Sleep Quality of COVID-19 Patients During Hospitalization: An Observational Study from Two Centers.

BACKGROUND: The outbreak of COVID-19 has developed into a pandemic. Data are required that specifically address the psychological consequences in COVID-19 confirmed patients. This study mainly aimed to examine posttraumatic stress disorder (PTSD) symptoms and sleep quality among COVID-19 confirmed patients during hospitalization. METHODS: An observational study was conducted in two designated hospitals in Wuhan, China. Data were collected from 190 patients hospitalized with laboratory-confirmed COVID-19 infection between February 10, 2020 and March 13, 2020. RESULTS: The mean age of the 190 confirmed patients was 55.7 years (SD = 13.7), of which 96 (50.5%) were female and 88 (46.3%) had family members or acquaintances infected with COVID-19. Lymphocytopenia was presented in 62 (32.6%) patients and 25 (13.2%) patients showed oxygen desaturation. The prevalence of high PTSD symptoms was 22.6% among the 190 patients. The median time from symptom onset to first medical visit and hospitalization was 2 days (IQR, 1-5) and 16 days (IQR, 10-27), respectively. Patients' PTSD symptoms were positively related to the time from symptom onset to first medical visit (r = 0.156, p < 0.05) and hospitalization (r = 0.181, p < 0.01). There were significant correlations between sleep quality and PTSD symptoms (r = 0.312-0.547, p < 0.01). CONCLUSION: The prevalence of high PTSD symptoms was 22.6% among hospitalized COVID-19 patients. Early diagnosis and treatment of COVID-19 symptoms are beneficial to infected patients both physically and psychologically. With the recovery of physical symptoms, psychological intervention is desired to promote the trauma recovery in COVID-19 patients.

Binding and molecular basis of the bat coronavirus RaTG13 virus to ACE2 in humans and other species.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been spreading worldwide, causing a global pandemic. Bat-origin RaTG13 is currently the most phylogenetically related virus. Here we obtained the complex structure of the RaTG13 receptor binding domain (RBD) with human ACE2 (hACE2) and evaluated binding of RaTG13 RBD to 24 additional ACE2 orthologs. By substituting residues in the RaTG13 RBD with their counterparts in the SARS-CoV-2 RBD, we found that residue 501, the major position found in variants of concern (VOCs) 501Y.V1/V2/V3, plays a key role in determining the potential host range of RaTG13. We also found that SARS-CoV-2 could induce strong cross-reactive antibodies to RaTG13 and identified a SARS-CoV-2 monoclonal antibody (mAb), CB6, that could cross-neutralize RaTG13 pseudovirus. These results elucidate the receptor binding and host adaption mechanisms of RaTG13 and emphasize the importance of continuous surveillance of coronaviruses (CoVs) carried by animal reservoirs to prevent another spillover of CoVs.

Is Higher Subjective Fear Predictive of Post-Traumatic Stress Symptoms in a Sample of the Chinese General Public?

Background: COVID-19 has taken a huge toll on medical resources and the economy and will inevitably have an impact on public mental health. Post-traumatic stress disorder (PTSD), as the most common mental illness after an epidemic, must be seriously addressed. This study aimed to investigate the subjective fear of the Chinese general public during COVID-19 and to explore how it affected the development of PTSD. Methods: An online questionnaire survey was conducted among 1,009 people from January 30 to February 14, 2020 (about 1 month after the COVID-19 outbreak). The subjective fear was measured by a self-reported single-choice question. Four items from the Pittsburgh Sleep Quality Index (PSQI) were selected to measure the subjects' sleep quality. Their post-traumatic stress symptoms (PTSS) were measured by the PTSD Checklist for DSM-5 (PCL-5). Pearson correlation, hierarchical multivariate regression analysis, multiple mediator model, and bootstrapping were used in statistical analyses. Results: Different people showed different levels of subjective fear in response to the outbreak. There was a significant positive correlation between subjective fear and the total score of PCL-5 (R = 0.513, P < 0.01), meaning that the higher the degree of subjective fear, the more severe the symptoms of post-traumatic stress are. Subjective fear was an important predictor of PTSS, accounting for 24.3% of the variance. The total effect of subjective fear on PCL-5 scores was significant (total effect = 7.426, SE = 0.405, 95% CI = 6.631-8.221). The total indirect effect of subjective fear on PCL-5 scores through sleep quality was also significant (total indirect effect = 1.945, SE = 0.258, 95% CI = 1.436-2.470). Conclusions: Subjective fear has an important predictive effect on PTSS. In addition to the direct effect, our findings firstly demonstrate the mediating role of sleep quality in the relationship between subjective fear and PTSS.

The impact of the COVID-19 pandemic on the mental health of young people: A comparison between China and the United Kingdom.

PURPOSE: As COVID-19 spreads globally and affects people's health, there are concerns that the pandemic and control policies may have psychological effects on young people (age from 17 to 35 years). This psychological impact might vary in different countries, and thus we compared the prevalence of self-reported psychological distress, loneliness and posttraumatic stress symptoms (PTSS) among young people in the United Kingdom (UK) and China at the beginning of the COVID-19 pandemic. METHODS: Data of this study came from two sources. One source was the first wave of COVID-19 study in Understanding Society, a special wave of the UK household longitudinal study, which provided the high-quality, national-wide representative panel data. The sample comprised 1054 young people. The other source was an online survey on the mental health of 1003 young people from Shanghai, a highly developed area in China. The questionnaire included questions on the prevalence of common mental disorders (cut-off score ≥ 4), loneliness and potential PTSS (cut-off ≥ 33). Univariable analyses were conducted to test the differences in the self-reported prevalence of psychological distress and loneliness between the two groups. Multivariable logistic regression analyses were run to explore the predictors of psychological distress and loneliness among all the young people from England and Shanghai. RESULTS: Among the samples with self-reported psychological distress, the UK sample accounted for 34.4% (n=1054) and the Chinese sample accounted for 14.1% (n=1003). The difference between the two groups was statistically significant (p < 0.001). Additionally, 57.1% of people in the UK and 46.7% in China reported that they sometimes or often felt lonely, of which the difference is statistically significant (p < 0.001). Regression analysis of the entire samples showed that nationality, gender, psychotherapy and loneliness were significant predictors of 12-item General Health Questionnaire scores, while the variables of age and living alone were not. Significant predictors of self-reported loneliness were the nationality, gender, age, living alone and psychotherapy. In China, 123 (12.3%) young people, 49 men (11.3%) and 74 women (13.0%), met the criteria of PTSS symptoms (cut-off scores ≥ 33). These scores were only collected in China. CONCLUSION: This evidence suggests that mental health and loneliness reported by young people were lower in China than that in the UK during the studied period. More research is needed to understand these differences. If the differential negative psychological impacts are confirmed, country-specific measures of prevention and intervention should be adopted to improve the mental health of young people under the ongoing impact of the pandemic.

Molecular basis of cross-species ACE2 interactions with SARS-CoV-2-like viruses of pangolin origin.

Pangolins have been suggested as potential reservoir of zoonotic viruses, including SARS-CoV-2 causing the global COVID-19 outbreak. Here, we study the binding of two SARS-CoV-2-like viruses isolated from pangolins, GX/P2V/2017 and GD/1/2019, to human angiotensin-converting enzyme 2 (hACE2), the receptor of SARS-CoV-2. We find that the spike protein receptor-binding domain (RBD) of pangolin CoVs binds to hACE2 as efficiently as the SARS-CoV-2 RBD in vitro. Furthermore, incorporation of pangolin CoV RBDs allows entry of pseudotyped VSV particles into hACE2-expressing cells. A screen for binding of pangolin CoV RBDs to ACE2 orthologs from various species suggests a broader host range than that of SARS-CoV-2. Additionally, cryo-EM structures of GX/P2V/2017 and GD/1/2019 RBDs in complex with hACE2 show their molecular binding in modes similar to SARS-CoV-2 RBD. Introducing the Q498H substitution found in pangolin CoVs into the SARS-CoV-2 RBD expands its binding capacity to ACE2 homologs of mouse, rat, and European hedgehog. These findings suggest that these two pangolin CoVs may infect humans, highlighting the necessity of further surveillance of pangolin CoVs.

Safety and immunogenicity of a recombinant tandem-repeat dimeric RBD-based protein subunit vaccine (ZF2001) against COVID-19 in adults: two randomised, double-blind, placebo-controlled, phase 1 and 2 trials.

BACKGROUND: Although several COVID-19 vaccines have been developed so far, they will not be sufficient to meet the global demand. Development of a wider range of vaccines, with different mechanisms of action, could help control the spread of SARS-CoV-2 globally. We developed a protein subunit vaccine against COVID-19 using a dimeric form of the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein as the antigen. We aimed to assess the safety and immunogenicity of this vaccine, ZF2001, and determine the appropriate dose and schedule for an efficacy study. METHODS: We did two randomised, double-blind, placebo-controlled, phase 1 and phase 2 trials. Phase 1 was done at two university hospitals in Chongqing and Beijing, China, and phase 2 was done at the Hunan Provincial Center for Disease Control and Prevention in Xiangtan, China. Healthy adults aged 18-59 years, without a history of SARS-CoV or SARS-CoV-2 infection, an RT-PCR-positive test result for SARS-CoV-2, a history of contact with confirmed or suspected COVID-19 cases, and severe allergies to any component of the vaccine were eligible for enrolment. In phase 1, participants were randomly assigned (2:2:1) to receive three doses of the vaccine (25 µg or 50 µg) or placebo intramuscularly, 30 days apart. In phase 2, participants were randomly assigned (1:1:1:1:1:1) to receive the vaccine (25 µg or 50 µg) or placebo intramuscularly, 30 days apart, in either a two-dose schedule or a three-dose schedule. Investigators, participants, and the laboratory team were masked to group allocation. For phase 1, the primary outcome was safety, measured by the occurrence of adverse events and serious adverse events. For phase 2, the primary outcome was safety and immunogenicity (the seroconversion rate and the magnitude, in geometric mean titres [GMTs], of SARS-CoV-2-neutralising antibodies). Analyses were done on an intention-to-treat and per-protocol basis. These trials are registered with ClinicalTrials.gov (NCT04445194 and NCT04466085) and participant follow-up is ongoing. FINDINGS: Between June 22 and July 3, 2020, 50 participants were enrolled into the phase 1 trial and randomly assigned to receive three doses of placebo (n=10), the 25 µg vaccine (n=20), or the 50 µg vaccine (n=20). The mean age of participants was 32·6 (SD 9·4) years. Between July 12 and July 17, 2020, 900 participants were enrolled into the phase 2 trial and randomly assigned to receive two doses of placebo (n=150), 25 µg vaccine (n=150), or 50 µg vaccine (n=150), or three doses of placebo (n=150), 25 µg vaccine (n=150), or 50 µg vaccine (n=150). The mean age of participants was 43·5 (SD 9·2) years. In both phase 1 and phase 2, adverse events reported within 30 days after vaccination were mild or moderate (grade 1 or 2) in most cases (phase 1: six [60%] of ten participants in the placebo group, 14 [70%] of 20 in the 25 µg group, and 18 [90%] of 20 in the 50 µg group; phase 2: 37 [25%] of 150 in the two-dose placebo group, 43 [29%] of 150 in the two-dose 25 µg group, 50 [33%] of 150 in the two-dose 50 µg group, 47 [31%] of 150 in the three-dose placebo group, 72 [48%] of 150 in the three-dose 25 µg group, and 65 [43%] of 150 in the three-dose 50 µg group). In phase 1, two (10%) grade 3 or worse adverse events were reported in the 50 µg group. In phase 2, grade 3 or worse adverse events were reported by 18 participants (four [3%] in the two-dose 25 µg vaccine group, two [1%] in the two-dose 50 µg vaccine group, two [1%] in the three-dose placebo group, four [3%] in the three-dose 25 µg vaccine group, and six [4%] in the three-dose 50 µg vaccine group), and 11 were considered vaccine related (two [1%] in the two-dose 25 µg vaccine group, one [1%] in the two-dose 50 µg vaccine group, one [1%] in the three-dose placebo group, two [1%] in the three-dose 25 µg vaccine group, and five [3%] in the three-dose 50 µg vaccine group); seven participants reported serious adverse events (one [1%] in the two-dose 25 µg vaccine group, one [1%] in the two-dose 50 µg vaccine group, two [1%] in the three-dose placebo group, one [1%] in the three-dose 25 µg vaccine group, and two [1%] in the three-dose 50 µg vaccine group), but none was considered vaccine related. In phase 2, on the two-dose schedule, seroconversion rates of neutralising antibodies 14 days after the second dose were 76% (114 of 150 participants) in the 25 µg group and 72% (108 of 150) in the 50 µg group; on the three-dose schedule, seroconversion rates of neutralising antibodies 14 days after the third dose were 97% (143 of 148 participants) in the 25 µg group and 93% (138 of 148) in the 50 µg group. In the two-dose groups in phase 2, the SARS-CoV-2-neutralising GMTs 14 days after the second dose were 17·7 (95% CI 13·6-23·1) in the 25 µg group and 14·1 (10·8-18·3) in the 50 µg group. In the three-dose groups in phase 2, the SARS-CoV-2-neutralising GMTs 14 days after the third dose were 102·5 (95% CI 81·8-128·5) in the 25 µg group and 69·1 (53·0-90·0) in the 50 µg group. INTERPRETATION: The protein subunit vaccine ZF2001 appears to be well tolerated and immunogenic. The safety and immunogenicity data from the phase 1 and 2 trials support the use of the 25 µg dose in a three-dose schedule in an ongoing phase 3 trial for large-scale evaluation of ZF2001's safety and efficacy. FUNDING: National Program on Key Research Project of China, National Science and Technology Major Projects of Drug Discovery, Strategic Priority Research Program of the Chinese Academy of Sciences, and Anhui Zhifei Longcom Biopharmaceutical. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.