Sample Collection:
1. Pregnancy test will be conducted by using rapid test kit.
2. Immunogenicity analysis: A total of 5 ml of blood is collected on Day 0, Day 28+2, Day 42±7, Day 90±7 and Day 180±7 (Subset of 640, 160 from each lot and control group). Sera will collect from the blood sample and stored as 3 aliquots at -20°C.
3. A saliva sample (5 mL) and an additional blood sample (10mL) will be collected on Day 0, Day 28+2, Day 42±7, Day 90±7 and Day 180±7 (Subset of 80, 60 from Group 1(20 from each lot) and 20 from Group 2).
4. Saliva will be collected by Passive droll method using Falcon tube.
Sample Size:
A total sample size of 3160 healthy volunteer's age's ≥18 years will be recruited in this study.
Randomization:
A total of 3000 participants will be randomized in to BBV154 two-dose study arm and 160 participants in the COVAXIN® two-dose arm. The first 640 participants are randomized with block size 4, in 1:1:1:1 ratio \[(3 (BBV154): 1 (COVAXIN®)\].
Remaining 2520 participants in the study are randomized with the block size 6 in 1:1:1 ratio (BBV154).
STUDY RATIONALE:
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is accelerating globally, leading to an increase in morbidity and mortality. The high-risk group includes the health care workers (HCW) (physicians and paramedical staff), working amid SARS-CoV-2 infected patients, all other people including household contacts of COVID-19 confirmed patients, people currently residing or working in COVID-19 hot-spots/outbreak areas where there is a high risk of transmission of SARS-CoV-2 infection and especially the elderly people (age \>60 Years). Though SARS-CoV-2 infection may cause mild symptoms in many, nearly 14% develop severe disease that requires hospitalization and oxygen support, and 5% require admission to an intensive care unit (ICU). In severe cases, COVID-19 can be complicated by acute respiratory distress syndrome, sepsis, septic shock, and multi organ failure (2,3).
Though the antiviral drugs such as Remdesivir has been approved for COVID-19 treatment by USFDA, but it fails to prevent COVID-19 deaths (3). Hence, there is a necessity to develop a vaccine to prevent SARS-CoV-2 infection. Various types of COVID-19 vaccines, such as DNA, RNA based formulations, recombinant subunit vaccines containing the viral protein (Spike) epitopes, vector-based mutations (eg: Adenovirus and traditional inactivated vaccines are under development(6-9). A chimpanzee adenoviral vaccine (Adenoviral vectored-SARS-CoV-2-S), encoding prefusion stabilized spike protein of SARS-CoV-2 virus was developed by Washington University School of Medicine, and evaluated the protective activity of the vaccine in challenge studies with SARS-CoV-2 virus and mice expressing human angiotensin-converting enzyme 2 (ACE2) receptor(10). Challenge study results were revealed that intramuscular dosing of Adenoviral vectored-SARS-CoV-2-S vaccine induces systemic humoral and cell mediated immunity and protects against lung infection whereas intranasal dosing of the same vaccine induces both systemic and mucosal immunoglobulins (IgG and IgA) ad protects from lower and upper respiratory tract infections (10). Bharat Biotech has collaborated with Washington University to manufacture the vaccine and conduct clinical trials.
BBV154 intranasal vaccine was evaluated for its safety and immunogenicity in a Phase 1 clinical study in 175 healthy participants and found to be safe and immunogenic with two dose regimen administered with 4 weeks interval. In a Phase 2/3 clinical study, BBV154 vaccine with two dose regimen is further evaluating in 152 participants for its safety and immunogenicity. Bharat Biotech has designed this pivotal Phase 3 study to immunogenicity, safety and lot- to-lot consistency of the BBV154 vaccine compared to COVAXIN® vaccine.
STUDY DESIGN:
The Phase-III study is designed to evaluate the immunogenicity, safety and lot-to-lot consistency of two groups of healthy volunteers who receive either BBV154 vaccine via intranasal route or COVAXIN® vaccine via intramuscular route. A total of 3160 participants will be enrolled and assess for the safety, immunogenicity and lot consistency.
Group 1 (BBV154): In this group, 3000 participants will be recruited, randomized in 1:1:1 ratio receive 3 consecutive lots (Lot 1: 1000, Lot 2: 1000, Lot 3: 1000) of the BBV154 vaccine (0.5 mL each dose) on day 0 and day 28 via intranasal route.
Group 2 (COVAXIN®): In this group, 160 participants will be recruited and administered with COVAXIN® vaccine on day 0 and on day 28 via intramuscular route.
STUDY PROCEDURES
Visit 1: Baseline (Day 0):
1. The participant will be screened for eligibility based on medical history, vitals, and physical examination and urine pregnancy test for female participants.
2. If the participant is eligible (in good general health or stable pre-existing disease as per the discretion of the Principal investigator), a blood sample will be withdrawn prior to vaccination (Subset).
3. Blood sample (5 mL) will be collected from subset (n=640, 160 from each lot of Group 1 \& Group 2) of participants.
4. Saliva sample (5 mL) will be collected from subset (n=80, 60 from Group 1 (20 from each lot) and 20 from Group 2) of participants.
5. An additional 10 mL of blood sample will be collected from subset (n=80, 60 from Group 1 (20 from each lot) and 20 from Group 2) of participants.
6. An intranasal vaccine or COVAXIN® will be administered. Following vaccination, participants will remain at the study site for at least 30 minutes of observation to record any immediate adverse event.
7. Diary card will be distributed to the participants.
8. Telephonic follow-up (7-days post-vaccination) for adverse event recording.
Visit 2 (Day 28+2):
9. Study participants will return to the OPD for vitals and physical examination (general and systemic examination and urine pregnancy test for female participants), and specific symptoms for COVID-19.
10. Blood sample (5 mL) will be collected from subset (n=640, 160 from each lot of Group 1 \& Group 2) of participants.
11. Saliva sample (5 mL) will be collected from subset (n=80, 60 from Group 1(20 from each lot) and 20 from Group 2) of participants.
12. An additional 10 mL of blood sample will be collected from subset (n=80, 60 from Group 1(20 from each lot) and 20 from Group 2) of participants.
13. An intranasal vaccine or COVAXIN® will be administered. Following vaccination, participants will remain at the study site for at least 30 minutes of observation to record any adverse event.
14. Diary card will be collected and a new diary card distributed to the participants.
15. Telephonic follow-up (7-days post-vaccination) for adverse event recording.
Visit 3 (Day 42 ± 7 days):
1. Study participants will return to the OPD for physical examination (general and systemic examination and urine pregnancy test for female participants), and specific symptoms for COVID-19.
2. Blood sample (5 mL) will be collected from subset (n=640, 160 from each lot of Group 1 \& Group 2) of participants.
3. Saliva sample (5 mL) will be collected from subset (n=80, 60 from Group 1(20 from each lot) and 20 from Group 2) of participants.
4. An additional 10 mL of blood sample will be collected from subset (n=80, 60 from Group 1(20 from each lot) and 20 from Group 2) of participants.
5. Diary card will be collected from the participants.
Visit 4 (Day 90 ± 7 days):
1. Study participants (Subset) will return to the OPD for physical examination (general and systemic examination), and specific symptoms for COVID-19.
2. Urine pregnancy test for female participants (Immunogenicity subset)
3. Blood sample (5 mL) will be collected from subset (n=640, 160 from each lot of Group 1 \& Group 2) of participants.
4. Saliva sample (5 mL) will be collected from subset (n=80, 60 from Group 1(20 from each lot) and 20 from Group 2) of participants.
4\. An additional 10 mL of blood sample will be collected from subset (n=80, 60 from Group 1(20 from each lot) and 20 from Group 2) of participants.
5\. Safety data will be collected from all the participants through telephonically other than immunogenicity subset (Day 90 ± 7 days).
Visit 5 (Day 180± 7 days):
1. Study participants (Subset) will return to the OPD for physical examination (general and systemic examination), and specific symptoms for COVID-19.
2. Urine pregnancy test for female participants (Immunogenicity subset)
3. Blood sample (5 mL) will be collected from subset (n=640, 160 from each lot of Group 1 \& Group 2) of participants.
4. Saliva sample (5 mL) will be collected from subset (n=80, 60 from Group 1(20 from each lot) and 20 from Group 2) of participants.
5. An additional 10 mL of blood sample will be collected from subset (n=80, 60 from Group 1 (20 from each lot) and 20 from Group 2) of participants.
6. Safety data will be collected from all the participants through telephonically other than immunogenicity subset (Day 180 ± 7 days).
Safety Monitoring:
Subjects will be observed for 30 minutes after vaccination for immediate adverse events. Active surveillance will be conducted for all participants for seven days after each dose of vaccine to ascertain information on solicited adverse events ("Reactogenicity"). Safety data will be collected from all the participants through telephonically on Day 90± 7 and 180± 7.
