key: cord-0255543-kff7ho04 authors: Ella, R.; Reddy, S.; Blackwelder, W.; Potdar, V.; Yadav, P.; Sarangi, V.; Aileni, V. K.; Kanungo, S.; Rai, S.; Reddy, P.; Verma, S.; Singh, C.; Redkar, S.; Mohapatra, S.; Pandey, A.; Ranganadin, P.; Gumashta, R.; Multani, M.; Mohammad, S.; Bhatt, P.; Kumari, L.; Sapkal, G.; Gupta, N.; Abraham, P.; Panda, S.; Prasad, S.; Bhargava, B.; Ella, K.; Vadrevu, K. M.; Group, COVAXIN Study title: Efficacy, safety, and lot to lot immunogenicity of an inactivated SARS-CoV-2 vaccine (BBV152): a double-blind, randomised, controlled phase 3 trial date: 2021-07-02 journal: nan DOI: 10.1101/2021.06.30.21259439 sha: 8829c4be7b3a895db5bc47846aeb15e1a47db65e doc_id: 255543 cord_uid: kff7ho04 Background: We report the clinical efficacy against COVID 19 infection of BBV152, a whole virion inactivated SARS CoV 2 vaccine formulated with a Toll like receptor 7/8 agonist molecule adsorbed to alum (Algel IMDG). Methods: We did a double-blind, randomised, multicentre, phase 3 clinical trial in 25 Indian hospitals to evaluate the efficacy, safety, and immunological lot consistency of BBV152. Healthy adults (age 18 to 98 years) randomised 1:1 using a sponsor-supplied randomisation scheme received two intramuscular doses of vaccine or placebo administered four weeks apart. The primary outcome was laboratory confirmed symptomatic COVID 19, occurring at least 14 days after the second dose. Secondary outcomes were efficacy in subgroups for age (18 to < 60 years and >=60 years) and in participants with pre-existing stable medical conditions. We also evaluated safety, reactogenicity, and consistency of immune responses for three consecutive manufacturing lots. Findings: Between November 16, 2020 and January 7, 2021 we recruited 25,798 participants who were randomised to BBV152 or placebo groups; 24,419 received two doses of BBV152 (n = 12,221) or placebo (n = 12,198). In a case-driven analysis, 130 cases of symptomatic COVID-19 were reported in 16,973 (0.77%) participants with follow-up at least two weeks after the second vaccination; 24 occurred in the vaccine group and 106 in placebo recipients giving an overall vaccine efficacy of 77.8% (95% CI: 65.2,86.4). Sixteen cases, one vaccinee and 15 placebo recipients, met the severe symptomatic COVID-19 case definition giving a vaccine efficacy of 93.4% (57.1,99.8). Efficacy against asymptomatic COVID 19 was 63.6% (29.0, 82.4). BBV152 conferred 65.2% (95% CI: 33.1, 83.0) protection against the SARS CoV 2 Variant of Concern, B.1.617.2 (Delta). BBV152 was well tolerated with no clinically or statistically significant differences in the distributions of solicited, unsolicited, or serious adverse events between vaccine and placebo groups. No cases of anaphylaxis or vaccine-related deaths were reported. Interpretation: BBV152 was immunogenic and highly efficacious against symptomatic and asymptomatic COVID 19 variant associated disease, particularly against severe disease in adults. Vaccination was well tolerated with an overall incidence of adverse events observed over a median of 146 days that was lower than that observed with other COVID-19 vaccines. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel human 71 coronavirus, has spread globally causing the COVID-19 pandemic [1] . Vaccines from 72 multiple manufacturers are needed to address the global demand for SARS-CoV-2 vaccines 73 as there is currently insufficient supply. Furthermore, the widely publicised mRNA-based and 74 viral vector vaccines that have been shown to be effective themselves introduce cold chain 75 hurdles and vaccine wastage making them difficult to adopt for many countries. adsorbed to alum (Algel-IMDG) for further clinical development [5, 6] . In use, BBV152 is 84 stored between 2°C and 8°C, which will ease immunisation cold chain requirements. Here, 85 we report findings from a phase 3 case-driven efficacy study including a sub-set analysis of 86 efficacy against newly identified variants of SARS-CoV-2. We also present a nested 87 controlled, randomised, double-blind trial on the safety and immunogenicity of the selected 88 BBV152 formulation, including comparisons of immune responses to three consecutive 89 manufacturing lots measured at day 56, one month after the second dose. 90 91 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 2, 2021. ; https://doi.org/10.1101/2021.06.30.21259439 doi: medRxiv preprint We assessed the efficacy, safety and immunogenicity of two intramuscular 6 µg Algel-IMDG 94 doses of BBV152 in a randomised, blinded, placebo-controlled, multi-centre study done in 25 95 centres in India. The trial was approved by the National Regulatory Authority (India) and the 96 respective Ethics Committees of each study centre and was conducted in compliance with all 97 International Conference for Harmonization (ICH) Good Clinical Practice guidelines. The 98 trial was registered on clinicaltrials.gov: NCT04641481. 99 Participants were adult volunteers 18 years of age or older who were healthy or had stable 100 chronic medical conditions. Volunteers were screened for eligibility based on their health 101 status, including their medical history, vital signs, and physical examination results. Eligible 102 participants provided signed and dated informed consent forms at enrolment. Key exclusion 103 criteria included any diagnosis with an immunocompromising condition, or treatment with 104 immunosuppressive therapy. Detailed inclusion and exclusion criteria can be found in the 105 Protocol (Supplementary appendix 2) . A minimum of 20% of the entire sample size was to be 106 comprised of "at-risk participants" defined as being either over 60 years of age, having a 107 coexisting comorbidity (cardio-vascular, diabetes, or any other chronic stable condition), or 108 having a BMI ≥ 35 kg/m 2 . A maximum of 5% of the total enrolled participants were selected 109 from members of the healthcare community. 110 The primary study objective was to assess the efficacy of the study vaccine in preventing 111 Unblinded statisticians (Cytespace Research and Octalsoft) were involved in designing the 117 randomisation plan and the interactive web response system (IWRS) system for the study. 118 The randomisation plan, stratified for the presence or absence of chronic conditions, was used 119 to generate treatment allocation. The master randomisation list, containing the randomisation 120 number and intended treatment allocation, as well as the kit code, was sent to the IWRS and 121 kits were despatched to the sites according to the IWRS by an unblinded statistician from the 122 CRO tasked with labelling of vaccine vials and the generation of the master randomisation 123 code. Participants were assigned a computer-generated randomisation code and each vial was 124 labelled with a unique code that ensured appropriate masking. The IWRS system assigned the 125 same treatment group for the second visit. Participants, investigators, study coordinators, 126 study-related personnel, and the sponsor were masked to the treatment group allocation, and 127 masked study nurses at each site were responsible for vaccine preparation and administration. 128 Procedures 129 BBV152 (Bharat Biotech, Hyderabad, India) is a whole-virion ß-propiolactone-inactivated 130 SARS-CoV-2 vaccine. The vaccine strain NIV-2020-770 contains the D614G mutation, 131 which is characterised by an aspartic acid to glycine shift at amino acid position 614 of the 132 spike protein [7]. Each 0.5 mL dose contains 6 µg of virus antigen formulated with Algel-133 IMDG, an imidazoquinoline class molecule that is a Toll-like receptor (TLR) 7/8 agonist 134 (IMDG) adsorbed to Algel. Placebo vials contained the Algel formulation alone without 135 IMDG or inactivated virus antigen. Vaccine and placebo were supplied and stored in a single-136 use glass vials at 2°C to 8°C, with no on-site dose preparation necessary. The appearance, 137 colour, and viscosity were identical for vaccine and placebo. 138 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 2, 2021. Study sites were classified into three categories: Category 1: in addition to administering the 161 vaccine or placebo, a series of post-dose follow-up telephone calls (every two weeks) were 162 scheduled to detect suspected symptomatic COVID-19 (n = 16,477) and those who met 163 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 2, 2021. ; https://doi.org/10.1101/2021.06.30.21259439 doi: medRxiv preprint symptomatic criteria had a clinical assessment (Protocol, Supplementary appendix 2), and a 164 nasopharyngeal swab (NP) was taken for PCR confirmation. Category 2: in addition to 165 symptomatic follow-up, a series of post-dose 2 NP swabs were collected on-site for detection 166 of asymptomatic COVID-19 infection at monthly intervals (n = 8,721); Category 3: in 167 addition to follow-up for symptomatic and asymptomatic COVID-19 infection, blood 168 samples were collected for immunological assessments (n = 600). Unscheduled illness visits 169 were encouraged for participants till day 360 (± 14 days). All participants were instructed to 170 contact the team on an as-needed basis. 171 The primary outcome was the efficacy of the BBV152 vaccine in preventing a first 173 occurrence of symptomatic COVID-19 (any severity) with onset at least 14 days after the 174 second dose in the per-protocol population composed of participants who were SARS-CoV-2 175 negative by PCR and serology at baseline, had no major protocol deviations, and followed-up 176 for at least two weeks after the second dose. End points were judged by an independent 177 adjudication committee masked to treatment allocation. COVID-19 cases were defined as 178 participants with at least two of the following symptoms: fever (temperature ≥ 38°C), chills, 179 myalgia, headache, sore throat, or new olfactory or taste disorder, or had at least one 180 respiratory sign or symptom (including cough, shortness of breath, or clinical or radiographic 181 evidence of pneumonia) and at least one SARS-CoV-2 PCR-positive nasopharyngeal swab. 182 COVID-19 cases were followed daily to assess symptom severity until symptoms resolved. 183 In PCR-positive participants who consented, an additional NP swab for genotyping and a 184 blood sample for evaluating correlates of protection were collected. Secondary efficacy 185 outcomes included efficacy in subgroups defined by age (18-59 years and ≥ 60 years), 186 gender, and health risk for severe disease (presence or absence of a coexisting chronic 187 medical condition), efficacy against variants of concern, and efficacy against asymptomatic 188 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 2, 2021. The study was designed to obtain a two-sided 95% CI for vaccine efficacy with lower bound 204 ≥ 30%. Based on a true efficacy of 60% and power of 85%, the case-driven trial was planned 205 to accrue 130 cases. Assuming 1% incidence of PCR-confirmed symptomatic COVID-19 206 disease among placebo recipients during follow-up beginning 14 days after the second dose, 207 the number of participants required to accrue 130 cases was approximately 18,572. To allow 208 for a 20% baseline seropositivity rate or PCR-confirmed COVID-19 and 10% loss to follow-209 up, we planned to enrol 25,800 participants. Sample size estimation was performed using 210 PASS 13 software (NCSS, Kaysville, Utah, USA). 211 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 2, 2021. used to test differences in proportions. A result with two-sided P ≤ 0.05 or one-sided P ≤ 231 0.025, as appropriate, was considered statistically significant. This report contains results 232 regarding immunogenicity and safety outcomes (captured on days 0 to 56) and efficacy 233 results with a median of 99 days (two weeks after a second dose). Certain prespecified 234 subgroup analyses are not included in this report but will be presented in future analyses 235 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 2, 2021. when a larger dataset is available. Descriptive and inferential statistics were performed using 236 SAS 9·4. 237 Bharat Biotech and the Indian Council of Medical Research (ICMR) were responsible for the 239 funding the study, designing the protocol, and writing this manuscript. The funder of the 240 study had no role in data collection or data analysis. However, the funder provided technical 241 guidance on deriving methodologies for data analysis. A CRO (IQVIA) was responsible for 242 overall conduct and data analysis. Masked laboratory assessments were done at Bharat 243 Biotech, and masked datasheets were sent to the CRO for decoding and analysis. The 244 unmasked randomisation list was not shared with the study sponsor. An independent data and 245 safety monitoring board (DSMB) periodically reviewed unblinded efficacy and unblinded 246 safety data. 247 Between November 16, 2020 and Jan 7, 2021, we screened 26,028 volunteers and recruited 249 and vaccinated 25,798 participants across 25 sites (Figure 1) . At the data cut-off date of May 250 17, 2021, a total of 23,803 (92·3%) participants had a median of 146 days of safety data 251 available after the first dose. Among these participants, 7058 (27·5%) had at least one 252 coexisting condition. The mean age was 40·1 years, and 10·7% of participants were older 253 than 60 years of age. A large proportion of participants were seropositive at baseline (30%) 254 and were thus excluded from the per-protocol analysis but contributed to the safety dataset. 255 All baseline characteristics were similar between vaccine and placebo groups ( Table 1) . 256 Among the 16,973 participants in the per protocol analysis population (Supplementary table 258 2, page 10), the planned efficacy analysis occurred after the accrual of 130 symptomatic 259 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 2, 2021. ; https://doi.org/10.1101/2021.06.30.21259439 doi: medRxiv preprint COVID-19 cases which started to present soon after the beginning of the observation period 260 (Figure 2 ). There were 24 (0·28%) cases among 8471 participants in the vaccine arm and 261 106 (1·25%) cases among 8502 participants in the placebo group, resulting in estimated 262 vaccine efficacy of 77·8% (95% CI: 65·2-86·4). There were sixteen cases who met the 263 severe symptomatic COVID-19 cases definition, all but one of whom were in the placebo 264 group, resulting in a vaccine efficacy of 93·4% (95% CI: 57·1-99·8). Efficacy against 265 asymptomatic COVID-19 infections was 63·6% (29·0-82·4). In the 1858 elderly participants 266 in the analysis, the split of cases between vaccine and placebo groups was 5 (0·56%) of 893 267 participants and 16 (1·66%) of 965, respectively, giving an efficacy of 67·8% (8·0-90·0). 268 Efficacy in the 15,115 participants who were younger than 60 years was 79·4% (66·0-88·2) 269 (Table 2) . 270 At day 56 in the groups who received lots 1, 2, 3 or placebo GMTs (MNT50) of SARS-CoV-2 272 neutralising antibodies were 130·3 (95% CI: 105·8-160·4), 121·2 (97·6-150·5), 125·4 273 (101·3-155·1), and 13·7 (10·7-17·4), respectively ( Table 4) . GMT ratios between all three 274 pairs of lots were consistently similar: lots 1:2 GMT ratio 1·08 (95% CI: 0·80-1·45), lots 1:3 275 GMT ratio 1·04 (0·77-1·40), and lots 2:3 GMT ratio 0·97 (0·71-1·31). All the 95% CIs for 276 the GMT ratios were contained within the interval [0·50, 2·0] (Supplementary figure 1, page 277 11), meeting the predefined criterion for a consistent immune response across lots. 278 There were no marked differences in GMTs for neutralizing antibodies at Day 56 when 279 assessed based on age or gender (Supplementary table 3, page 12) . The GMT was higher 280 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 2, 2021. 5, page 14) . Overall, incidence rates were lower after the second dose 304 than the first, and tended to be slightly higher in the BBV152 group than the placebo group. 305 However, all incidence rates were low, with only 12·4% reporting any solicited AE after 306 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 2, 2021. We report findings from the phase 3 efficacy, safety and immunogenicity clinical trial of 321 BBV152, a whole-virion inactivated SARS-CoV-2 vaccine. In the final per-protocol analysis, 322 measured 14 days after the second of two doses of BBV152, there was a vaccine efficacy of 323 77·8% (95% CI: 65·2-86·4) against symptomatic COVID-19 disease, and perhaps more 324 importantly a higher efficacy against severe COVID-19 of 93·4% (57·1-99·8). Thus, cases of 325 severe disease which require hospitalisation and have threatened to overwhelm healthcare 326 facilities will be markedly decreased in fully vaccinated populations Although the study was 327 not powered to definitively assess efficacy in subgroups with different ages, gender, or the 328 presence of pre-existing comorbid conditions, efficacy rates for symptomatic COVID-19 329 were all high in these sub-groups (>66%) with the lower limits of the respective 95% CIs 330 being above 30% in all cases except for the > 60 years group. 331 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 2, 2021. ; https://doi.org/10.1101/2021.06.30.21259439 doi: medRxiv preprint profiles of BBV152 in phase 1 and 2 trials [5,6]. There were no safety concerns raised, no 333 reports of anaphylactic events after BBV152 administration, and all adverse events (solicited, 334 unsolicited, and serious adverse events) were well balanced between BBV152 and placebo 335 groups. One possibly related serious adverse event in the BBV152 group was a case of 336 immune thrombocytic purpura that occurred 39 days after the second dose in a participant 337 who was SARS-CoV-2 seropositive at baseline, which resolved in four days. After any dose, 338 the combined incidence rate of local and systemic adverse events in this study is noticeably 339 better than the rates for other SARS-CoV-2 vaccine platform candidates [10,11], and 340 comparable to the rates for other inactivated SARS-CoV-2 vaccine candidates [12] . 341 When measured as neutralising antibodies, the three consecutive manufacturing lots of 342 vaccine induced consistent humoral immune responses, and when measured as ELISA IgG 343 responses against three SARS-CoV-2 epitopes (S1 and RBD of the spike protein, and the 344 nucleocapsid antigen) antibody titres were similar across all lots ( . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 2, 2021. BNT162b2, has been associated with decreased asymptomatic SARS-CoV-2 infections in 379 healthcare workers [22] . Several other vaccine studies employed surrogate markers to assess 380 asymptomatic efficacy by periodically collecting serum from trial participants and assessing 381 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 2, 2021. This study has several limitations. Due to the low number of cases reported between doses 1 393 and 2, we cannot calculate vaccine efficacy after a single dose. This report contains a median 394 safety follow-up of 146 days for all participants, so long-term safety follow-up of BBV152 is 395 required and is currently underway. The data presented on efficacy against variants other than 396 Delta must be considered preliminary as the numbers reported are small. Additional efforts to 397 assess the clinical efficacy of BBV152 against VoC are being planned. The potential 398 establishment of a correlate of protection is not feasible at the time of this report. Finally, this 399 study population lacked ethnic and racial diversity, underscoring the importance of 400 evaluating the efficacy of BBV152 in other populations. 401 Although the study was designed to vaccinate and follow participants for one year after the 402 second dose, given the nature of the pandemic in India and the emergency use authorization 403 for BBV152, after meeting the pre-defined efficacy success criteria, the DSMB and sponsor 404 decided to unblind those placebo participants who were eligible to receive an approved 405 COVID-19 vaccine. Unblinding in such cohorts was planned only after the accrual of the 406 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 2, 2021. ; https://doi.org/10.1101/2021.06.30.21259439 doi: medRxiv preprint protocol pre-specified 130 cases, in a phased manner: health care professionals, individuals 407 ≥45 years, followed by those <45 years. Our sample estimations accounted for 20% 408 seropositivity. As we observed baseline seropositivity rates of 30% and due to the unblinding 409 of the health care professionals and elderly individuals (who are eligible for COVID-19 410 vaccination), the protocol was amended to expand the sample size to 30,800, with 5,000 411 additional participants now being enrolled in Brazil. This will ensure the study evaluates the 412 efficacy of BBV152 against VoC and provides an opportunity to accrue additional severe 413 COVID-19 cases as well as more racial diversity. This manuscript contains data from the 414 Indian cohort only. 415 However, this study does have several strengths. The study enrolled participants with ages 416 ranging from 18 to 98 years and found no major differences in immune responses across the 417 broad age groups of under-and over-60 year-olds. Participants considered to be at-risk of 418 acquiring COVID-19 were prioritised, so a total of 2,750 participants were above 60 years of 419 age and 7,065 reported at least one pre-existing medical condition across ages. To ensure 420 generalisability, this study was conducted with participants from diverse geographic 421 locations, enrolling 25,798 participants across 25 hospitals. This is the first trial to report 422 preliminary promising findings on the efficacy against asymptomatic infections and clinical 423 lot-to-lot immunological comparability. 424 The most common solicited adverse event was pain at the injection site, followed by 425 headache, fatigue, and fever. No severe or life-threatening (Grade 4 and 5) solicited adverse 426 events were reported. Although the study was not powered to find such differences, no 427 meaningful safety differences were observed between the groups. After any dose, the 428 combined incidence rate of local and systemic adverse events in this study is noticeably 429 better than the rates for other SARS-CoV-2 vaccine platform candidates [23-27] and 430 comparable to the rates for other inactivated SARS-CoV-2 vaccine candidates [28, 29] . 431 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 2, 2021. The study protocol is provided as Supplementary Appendix 2. Individual participant (de-475 identified) data will be made available when the trial is complete upon direct request to the 476 corresponding author with an appropriate research proposal. Once such a proposal is 477 approved data will be shared through a secure online platform. 478 479 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 2, 2021. ; https://doi.org/10.1101/2021.06.30.21259439 doi: medRxiv preprint . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 2, 2021. ; https://doi.org/10.1101/2021.06.30.21259439 doi: medRxiv preprint . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted July 2, 2021. * 95.006% CI used for primary analysis of symptomatic COVID-19 to adjust for interim analyses, 95% CI otherwise. Primary efficacy was based on the 573 per protocol population, including randomly assigned participants who were seronegative at baseline and received two doses of either vaccine or placebo, 574 and remained on study at least 14 days after their second dose with no previous virologically-confirmed SARS-CoV-2 infection. COVID-19 cases were 575 defined as occurring in participants who had at least two of the following symptoms: fever (temperature ≥ 38°C), chills, myalgia, headache, sore throat, or 576 a new olfactory or taste disorder, or as occurring in those who had at least one respiratory sign or symptom (including cough, shortness of breath, or 577 clinical or radiographic evidence of pneumonia) and at least one nasopharyngeal swab that was PCR positive for SARS-CoV-2. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 2, 2021. ; https://doi.org/10.1101/2021.06.30.21259439 doi: medRxiv preprint . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 2, 2021. ; https://doi.org/10.1101/2021.06.30.21259439 doi: medRxiv preprint WHO Coronavirus Disease (COVID-19) Dashboard. Available at 481 Th1 skewed immune response of whole virion 483 inactivated SARS CoV 2 vaccine and its safety evaluation Immunogenicity and protective efficacy of inactivated SARS-CoV-2 vaccine candidate, BBV152 in rhesus macaques Immunogenicity and protective efficacy of BBV152, whole virion inactivated SARS-CoV-2 vaccine candidates in the Syrian 489 hamster model Safety and immunogenicity of an inactivated BBV152: a double-blind, randomised, phase 1 trial Safety and immunogenicity of an inactivated SARS CoV-2 vaccine, BBV152: interim results from a double-blind, randomised, multicentre, 495 phase 2 trial, and 3-month follow-up of a double-blind, randomised phase 1 trial First isolation of SARS-CoV-2 from clinical samples 499 in India Interim analysis: the alpha spending function approach Comparing vaccines: a 503 systematic review of the use of the non-inferiority margin in vaccine trials Efficacy of the ChAdOx1 nCoV vaccine against the B.1.351 variant Immunogenicity and safety of a SARS-CoV-2 511 inactivated vaccine in healthy adults aged 18-59 years: report of the randomized, double-512 blind, and placebo-controlled phase 2 clinical trial Levels of SARS-CoV-2 lineage P.1 515 neutralization by antibodies elicited after natural infection and vaccination Efficacy of ChAdOx1 nCoV-19 (AZD1222) 518 vaccine against SARS-CoV-2 variant of concern 202012/01 (B.1.1.7): an exploratory 519 analysis of a randomised controlled trial Effectiveness of COVID-19 vaccines against the 1.617.2 variant. Prepublication on medRxiv Development of in vitro transcribed RNA as 524 positive control for laboratory diagnosis of SARS-CoV-2 in India Full-genome sequences of the first two SARS-CoV-2 viruses from India BBV152/COVAXIN effectively neutralizes recently emerged B 1.1.7 variant of SARS 617 with sera of BBV152 vaccinees SARS-CoV-2 infections after BNT162b2 vaccination in a routinely screened workforce Phase 1/2 study of COVID-19 RNA vaccine 545 BNT162b1 in adults An mRNA vaccine against SARS-CoV-2 547 -preliminary report Safety and immunogenicity of the ChAdOx1 549 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, 550 randomised controlled trial Immunogenicity and safety of a recombinant 552 adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: 553 a randomised, double-blind, placebo-controlled, phase 2 trial Based Covid-19 Vaccine Candidates Immunogenicity and safety of a SARS-CoV-2 557 inactivated vaccine in healthy adults aged 18-59 years: report of the randomized, double-558 blind, and placebo-controlled phase 2 clinical tTrial Effect of an inactivated vaccine against SARS-CoV-2 on 561 safety and immunogenicity outcomes: interim analysis of 2 randomized clinical tTrials neutralising response expressed as MNT50 at Days 0 (baseline) and Day 56, four weeks after the second vaccination. Day 56 IgG antibody titres are 588 expressed as arbitrary ELISA units, all baseline titres being at the cut-off for the assay Geometric mean titres (95% CI) at Day 56 in sub-sets of the different study groups We would like to sincerely thank the volunteers, investigators, study coordinators and 442 healthcare workers involved in this study. We express our gratitude to the teams at IQVIA, 443