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Comparable neutralization of SARS-CoV-2 Delta AY.1 and Delta with individuals sera vaccinated with BBV152

Authors:
  • ICMR-National Institute of Virology, Pune

Abstract

Sera of COVID-19 naive vaccinees, COVID-19 recovered cases with vaccination and breakthrough cases demonstrated 1.3, 2.5 and 1.9-fold reduction in neutralization titers against Delta and 1.5, 3.5, 2.8-fold against Delta AY.1 compared to B.1 respectively. However, high neutralization titers would still effectively protect against Delta, Delta AY.1 and B.1.617.3 variants.
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Research letter
Comparable neutralization of SARS-CoV-2 Delta AY.1 and Delta with individuals sera
vaccinated with BBV152
Authors:
1*Pragya D. Yadav, Ph.D, 1Rima R Sahay, MD, 1Gajanan Sapkal, Ph.D, 1Dimpal Nyayanit, Ph.D,
1Anita M. Shete, Ph.D, 1Gururaj Deshpande, Ph.D, 1Deepak Y. Patil, Ph.D, 2Nivedita Gupta,
Ph.D, 3Sanjay Kumar, M.Ch, 1Priya Abraham, Ph.D, 2Samiran Panda, Ph.D, 2Balram Bhargava,
DM
Affiliations:
1Indian Council of Medical Research-National Institute of Virology, Pune, Maharashtra,
India, Pin-411021
2Indian Council of Medical Research, V. Ramalingaswami Bhawan, P.O. Box No. 4911,
Ansari Nagar, New Delhi, India Pin-110029
3Department of Neurosurgery, Command Hospital (Southern Command), Armed Forces
Medical College, Pune, Maharashtra, India - 411040.
© International Society of Travel Medicine 2021. Published by Oxford University Press. All
rights reserved. For Permissions, please e-mail: journals.permissions@oup.com
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*Corresponding author
Dr. Pragya D. Yadav,
Scientist ‘E’ and Group Leader,
Maximum Containment Facility,
Indian Council of Medical Research-National Institute of Virology,
Sus Road, Pashan, Pune, Maharashtra, India Pin-411021.
Phone: +9120-26006111, Fax No. 91-20-26122669
Email: hellopragya22@gmail.com
Keywords: SARS-CoV-2; Variant of concern; Delta; Delta AY.1; Neutralization; BBV152
Highlights
Sera of COVID-19 naive vaccinees, COVID-19 recovered cases with vaccination and
breakthrough cases demonstrated 1.3, 2.5 and 1.9-fold reduction in neutralization titers
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against Delta and 1.5, 3.5, 2.8-fold against Delta AY.1 compared to B.1 respectively.
However, high neutralization titers would still effectively protect against Delta, Delta AY.1
and B.1.617.3 variants.
Text
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) Delta variant
(B.1.617.2), a variant of concern (VOC), was associated with the second wave of pandemic
in India during March-May 2021. Delta variant has outpaced the other two sub-lineages
Kappa (B.1.617.1) and B.1.617.3 and was responsible for 90% of the cases reported in
India.1 It has spread across 112 countries and found to be more infectious than the Alpha,
Beta and Gamma variants. Reduced neutralization has been reported with the sera of
individuals vaccinated with BNT162b2, BBV152/Covaxin and chAdOx1-s against Delta
variant in recent reports.2,3 Delta variant has also been identified as the leading cause of
breakthrough infections globally among vaccinated individuals.4
Delta variant with its characteristic spike protein mutations (L452R, T478K, D614G
and P681R) has mutated further into four sub-lineages with additional mutations which
are associated with higher transmission and probable immune escape.1 Recently, Delta
variant has mutated to Delta AY.1, AY.2 and AY.3. Of these, apparently highly infectious
Delta AY.1 variant was first detected in India in April 2021 and subsequently from twenty
seven other countries as well.1 Cases of Delta AY.1 have also been reported from Europe,
Asia and America with the highest prevalence observed in United States of America,
Portugal, Japan, United Kingdom and Switzerland.5 The variant has characteristic
mutations in the genome at ORF1a (A1306S, P2046L, P2287S, V2930L, T3255I, T3646A),
ORF1b (P314L, G662S, P1000L, A1918V), S (T19R, L452R, T478K, D614G, P681R), ORF3a
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(S26L), M (I82T), ORF7a (V82A, T120I), ORF7b (T40I), ORF8 (del119/120) and N (D63G,
R203M, G215C, D377Y) which probably enhances the ability to escape immune response
and becomes a major concern for the ongoing vaccination programs.5 Moreover, this
variant contains an additional K417N mutation in the spike protein and emerging evidence
suggests that this mutation could lead to resistance against monoclonal antibodies i.e.,
Casirivimab and Imdevimab.6 However, it is uncertain whether Delta AY.1 is capable of
causing higher transmissibility, severe disease and evasion of immune response compared
to Delta variant. The prevalence of Delta AY.1 is found to be low in India and the rest of the
world. As of now no information is available on the efficacy of currently available vaccines
against Delta AY.1 variant.
The clinical efficacy against COVID-19 infection of BBV152, a whole-virion
inactivated SARS-CoV-2 vaccine was assessed in a double-blind, randomized, multicentre,
phase 3 clinical trial on 25,798 participants to evaluate the efficacy, safety, and
immunological lot consistency of BBV152. Overall efficacy against symptomatic COVID-19
disease was 77.8% and 65.2% protection against Delta variant has been reported with
BBV152.7
The second wave of the SARS-CoV-2 pandemic was devastating for public health
system of India and breakthrough cases were reported during this period. Besides this, the
association of Delta variant in the breakthrough cases created serious concerns among the
public health experts regarding the effectiveness of the available COVID-19 vaccines.
Considering this, we conducted this study to determine the neutralization potential in sera
of the BBV152 vaccinated individuals against Delta and Delta AY.1 variant.
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Here, we present the data from a cross-sectional study, where the sera of the fully
vaccinated study participants with two doses of BBV152 vaccine were evaluated for
neutralizing antibodies. The participants were divided in three separate groups viz. COVID-
19 naïve vaccinees (CNV), COVID-19 recovered cases (real time RT-PCR positive) and
vaccinated (CRV) and breakthrough infections post vaccination (BTI). The data of the
variants responsible for SARS-CoV-2 infection in CRV and BTI groups was not available.
However, the participants of CRV group were infected before the emergence of Delta
variant in India when the predominant circulating SARS-CoV-2 strain was B.1. The BTI
occurred mainly during the second wave of pandemic in India when the commonly
circulating variant in the country was Delta in March-May 2021.8-9
The sera of individuals of CNV group [n=42; Female (n=24; median age: 43.5yrs);
Male (n=18; median age: 46 yrs)] was collected between 2.5 to 22 weeks [median: 16
weeks] after second dose, CRV group [n=14; female (n=8; median age: 44.5yrs); male (n=6;
median age: 42 yrs)] 14-70 weeks [median: 38 weeks] after second dose and BTI group
[n=30; female (n=17; median age: 45 yrs); male (n=13; median age: 39 yrs)] collected
between 2-18 weeks (median: 9 weeks). The neutralizing potential of the individuals was
determined against Delta, Delta AY.1, B.1.617.3 compared to B.1 variant. Neutralizing
antibody titers of the serum samples against all the variants were determined using 50%
plaque reduction neutralization test. IgG response was also assessed using whole
inactivated SARS-CoV-2 antigen, nucleocapsid and S1-RBD protein IgG ELISA.
The sera of individuals of CNV group showed a geometric mean titer (GMT) of NAb
to be 310.6 (95% confidence interval (CI): 222-434.6); 241.6 (95% CI: 167.8-347.7); 209.1
(95% CI: 146.5-298.3); 165.3 (95% CI: 115.6-236.5) against B.1, Delta, Delta AY.1 and
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B.1.617.3 respectively. The sera of the individuals of CRV showed uniformly increased NAb
titer with GMT of 820.1 (95% CI: 469-1434)’ 328.6 (95% CI: 186.9-577.9)’ 234.5 (95% CI:
138.7-396.4) and 217.8 (95% CI: 136.7-347.1) against B.1, Delta, Delta AY.1 and B.1.617.3
respectively. Sera of individuals of BTI group had higher NAb titer compared to the CNV
and CRV groups. The GMT titers were 896.6 (95% CI: 550.3-1461), 465.6 (95% CI: 213.2-
1016), 317.2 (95% CI: 125.5-801.4), 259.7 (95% CI: 157.1-429.4) against B.1, Delta, Delta
AY.1 and B.1.617.3 respectively (Figure 1a-d).
The sera of individuals of CNV group showed moderate fold-reduction in the NAb
titer against Delta, Delta AY.1 and B.1.617.3 [1.29 (p-value: < 0.0001); 1.49 (p-value :
<0.0001); 1.88 (p-value: <0.0001)] compared to B.1 (Figure 1e). However, the sera of
individuals of CRV and BTI groups had higher fold-reductions in the NAb titer [2.5 (p-value:
0.0011); 3.5 (p-value: 0.0007); 3.77 (p-value: 0.0007)] and [1.93 (p-value: <0.0001); 2.83
(p-value: <0.0001); 3.45 (p-value: <0.0001)] against Delta, Delta AY.1 and B.1.617.3
variants respectively compared to the B.1 strain (Figure 1f-g). However, NAb titer of sera of
CRV and BTI groups were significantly higher compared to CNV group.
Sera of individuals of CNV and BTI groups had 3.04 fold (p-value: 0.0019), 3.56 fold
(p-value: <0.0001) and 4.42 fold (p-value: <0.0001) higher antibodies than sera of CRV
group for inactivated SARS-CoV-2, S1-RBD protein and N protein based anti-SARS-CoV-2
ELISA respectively (Figure 1h-j).
A significant increase in the NAb titer against B.1, Delta, Delta AY.1 and B.1.617.3
variants in CRV and BTI groups was observed compared to the CNV group individuals. This
demonstrates the possible role of memory cells in immune boosting with post-infection or
infection after immunization. The NAb titre in sera of the individuals from CRV and BTI
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groups were higher due to boosting effect of vaccination and natural infection or vice versa
than individuals from CNV group. In a recent studies by Gupta et al., has shown that two
dose vaccinated individuals though got infected with COVID-19 with Delta variant; but
severity, admission to ICU and mortality was negligible during second wave of Pandemic in
India.9 The comparative analysis of three different cohorts revealed that B.1.617.3 variant
showed reduced neutralization followed by Delta AY.1 and Delta variants when compared
to B.1 (Figure 1a-g). A recent study demonstrated a reduction in neutralization by 4 fold
and 11 fold against Delta variant with the sera of healthy individuals vaccinated with two
doses of ChAdOx1 and BNT162b2 vaccine respectively.2 Our earlier studies with
BBV152/Covaxin™ and Covishield™ have shown 2.7- and 3.2-fold reduction in NAb titer
against Delta variant compared to B.1.3,10 The present study revealed 1.5, 3.5, 2.8-fold
reduction in NAb titer for Delta AY.1, 1.3, 2.5 and 1.9-fold reduction against Delta variant
compared to B.1 variant in sera of CNV, CRV and BTI respectively.
The primary objective of this study was to determine the neutralization efficacy of
BBV152 vaccine against Delta variants in real time scenario as oppose to the controlled
clinical trial scenario. The time interval for collection of the serum samples is a limitation of
this study. However, the results demonstrated reduction in the neutralization titer in the
individual cohorts against the Delta, Delta AY.1 and B.1.617.3 variants compared to B.1
strain. In conclusion, reduction in the NAb titer was observed in the sera of COVID-19 naïve
vaccinated individuals, COVID-19 recovered followed by vaccination and breakthrough
cases post two doses of BBV152. The sera of individuals belonging to three different
cohorts had high NAb titer. This suggests that BBV152 would still be able to protect
vaccinated individuals with severe disease from Delta, Delta AY.1 and B.1.617.3 variants.
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Ethical approval
The study was approved by the Institutional Human Ethics Committee of ICMR-NIV, Pune,
India under the project ‘Assessment of immunological responses in breakthrough cases of
SARS-CoV-2 in post-COVID-19 vaccinated group’.
Author Contributions
PDY contributed to study design, data analysis, interpretation and writing. RRS, GS, GRD,
DAN, AMS, DYP and SK contributed to data collection, data analysis, interpretation and
writing. PA, NG, SP, and BB contributed to the critical review and finalization of the paper.
Conflicts of Interest
Authors do not have a conflict of interest among themselves.
Financial support & sponsorship
The grant was provided from Indian Council of Medical Research (ICMR), New Delhi under
intramural funding ‘COVID-19 to ICMR-National Institute of Virology, Pune for conducting
this study.
Acknowledgement
We sincerely acknowledge the excellent support of Mr. Prasad Sarkale, Mr. Shreekant
Baradkar, Dr. Rajlaxmi Jain, Ms. Aasha Salunkhe, Mr. Chetan Patil, Mrs. Triparna Majumdar
and Mrs. Savita Patil during the study.
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doi:10.1016/j.jinf.2021.08.006
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9. Gupta N, Kaur H, Yadav PD, et al. Clinical Characterization and Genomic Analysis of
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Legend of Figures:
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Figure 1: Neutralization of individual sera vaccinated with BBV152 vaccines from
different scenarios against B.1, Delta, Delta AY.1 and B.1.617.3 strains and ELISA titer
of individual sera vaccinated from different scenarios: Neutralization titer comparison
of individual cases sera immunized with two dose vaccine BBV152, recovered case sera
immunized with two dose vaccine BBV152 and breakthrough cases; B.1 (GISAID identifier:
EPL_ISL_825088). Dotted lines represents the cut-off value of the assay (20) (a), Delta
(GISAID accession number: EPI_ISL_2400521) (b), Delta AY1 (GISAID accession number
EPI_ISL_2671901) (c), and B.1.617.3 (GISAID accession number: EPL_ISL_2497905) (d).
The statistical significance was assessed using a two-tailed Kruskal Wallis test with Dunn’s
test of multiple comparisons was performed to analyze the statistical significance. NAb titer
of individual sera vaccinated with two doses of BBV152 (e), recovered cases administered
with two doses of BBV152 (f) and breakthrough cases (g). A matched pair two-tailed pair-
wise comparison was performed using the Wilcoxon signed-rank test to analyze the
statistical significance. Anti-SARS-CoV-2 IgG titers of vaccinated individual’s sera for
inactivated SARS-CoV-2, dotted lines represents the cut-off value of the assay (100) (h), S1-
RBD protein, dotted lines represents the cut-off value of the assay (50) (i) and N protein,
dotted lines represents the cut-off value of the assay (50) (j). The statistical significance
was assessed using a two-tailed Kruskal-Wallis test with Dunn’s test of multiple
comparisons. P-value less than 0.05 were considered to be statistically significant for the
tests applied. The dotted line on the figures indicates the limit of detection of the assay.
Data are presented as mean values +/− standard deviation (SD).
... However, as a vaccine target, this protein has a major flaw such as higher mutations frequency leading to the emergence of the new SARS-CoV-2 strains (Planas et al., 2021). Emerging SARS-CoV-2 variants have missense mutations in S protein: delta variant has aa changes L452R, D614G, P681R, T478K (Tao et al., 2021;Yadav et al., 2021) and delta plus variants (AY.1 and AY.2) has K417N (Tao et al., 2021;Yadav et al., 2021). These mutation could facilitate virus entry as was shown with N501Y mutation in alpha, beta and gamma strains which increased binding affinity of S protein with ACE2 receptor (Tao et al., 2021). ...
... However, as a vaccine target, this protein has a major flaw such as higher mutations frequency leading to the emergence of the new SARS-CoV-2 strains (Planas et al., 2021). Emerging SARS-CoV-2 variants have missense mutations in S protein: delta variant has aa changes L452R, D614G, P681R, T478K (Tao et al., 2021;Yadav et al., 2021) and delta plus variants (AY.1 and AY.2) has K417N (Tao et al., 2021;Yadav et al., 2021). These mutation could facilitate virus entry as was shown with N501Y mutation in alpha, beta and gamma strains which increased binding affinity of S protein with ACE2 receptor (Tao et al., 2021). ...
... The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) Delta variant (B.1.617.2) was the cause of coronavirus disease 2019 infection and the second wave of the pandemic in India from March to May 2021 [1]. These patients became vulnerable to fungal infection (mycosis) because of the compromised immune system, associated comorbidities such as diabetes mellitus, decompensated pulmonary functions, and the use of immunosuppressive therapy for the management of moderate to severe cases [2]. ...
... It was 50% more transmissible than the Alpha variant (or B.1.1.7), with more severe disease and deaths [1,7]. The second wave also exhibited features such as headache, localized pain, nasal discharge, sinusitis, orbital cellulitis, and diminution of vision due to fungal rhinosinusitis with orbital or cerebral involvement occurring mainly after recovery from COVID-19. ...
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... In this case, the phase III clinical trial did evaluate the efficacy of Covaxin in response to variants circulating in mid-2020 to late 2020 (107 (107). Another study reported that sera from individuals immunized with Covaxin produced effective nAbs against the Delta variant and the so-called Delta plus variant (AY.1) (109). Indeed, sera obtained from Covaxin-boosted individuals (n = 13) (112) and those who were vaccinated with Covaxin but recovered from a breakthrough infection (n = 31) also neutralized the Omicron variant (113). ...
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible and virulent human-infecting coronavirus that emerged in late December 2019 in Wuhan, China, causing a respiratory disease called coronavirus disease 2019 (COVID-19), which has massively impacted global public health and caused widespread disruption to daily life. The crisis caused by COVID-19 has mobilized scientists and public health authorities across the world to rapidly improve our knowledge about this devastating disease, shedding light on its management and control, and spawned the development of new countermeasures. Here we provide an overview of the state of the art of knowledge gained in the last 2 years about the virus and COVID-19, including its origin and natural reservoir hosts, viral etiology, epidemiology, modes of transmission, clinical manifestations, pathophysiology, diagnosis, treatment, prevention, emerging variants, and vaccines, highlighting important differences from previously known highly pathogenic coronaviruses. We also discuss selected key discoveries from each topic and underline the gaps of knowledge for future investigations.
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Emerging variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are of clinical concern. In a cohort of 417 persons who had received the second dose of BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) vaccine at least 2 weeks previously, we identified 2 women with vaccine breakthrough infection. Despite evidence of vaccine efficacy in both women, symptoms of coronavirus disease 2019 developed, and they tested positive for SARS-CoV-2 by polymerase-chain-reaction testing. Viral sequencing revealed variants of likely clinical importance, including E484K in 1 woman and three mutations (T95I, del142-144, and D614G) in both. These observations indicate a potential risk of illness after successful vaccination and subsequent infection with variant virus, and they provide support for continued efforts to prevent and diagnose infection and to characterize variants in vaccinated persons. (Funded by the National Institutes of Health and others.).
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Background BBV152 is a whole-virion inactivated SARS-CoV-2 vaccine (3 μg or 6 μg) formulated with a toll-like receptor 7/8 agonist molecule (IMDG) adsorbed to alum (Algel). We previously reported findings from a double-blind, multicentre, randomised, controlled phase 1 trial on the safety and immunogenicity of three different formulations of BBV152 (3 μg with Algel-IMDG, 6 μg with Algel-IMDG, or 6 μg with Algel) and one Algel-only control (no antigen), with the first dose administered on day 0 and the second dose on day 14. The 3 μg and 6 μg with Algel-IMDG formulations were selected for this phase 2 study. Herein, we report interim findings of the phase 2 trial on the immunogenicity and safety of BBV152, with the first dose administered on day 0 and the second dose on day 28. Methods We did a double-blind, randomised, multicentre, phase 2 clinical trial to evaluate the immunogenicity and safety of BBV152 in healthy adults and adolescents (aged 12–65 years) at nine hospitals in India. Participants with positive SARS-CoV-2 nucleic acid and serology tests were excluded. Participants were randomly assigned (1:1) to receive either 3 μg with Algel-IMDG or 6 μg with Algel-IMDG. Block randomisation was done by use of an interactive web response system. Participants, investigators, study coordinators, study-related personnel, and the sponsor were masked to treatment group allocation. Two intramuscular doses of vaccine were administered on day 0 and day 28. The primary outcome was SARS-CoV-2 wild-type neutralising antibody titres and seroconversion rates (defined as a post-vaccination titre that was at least four-fold higher than the baseline titre) at 4 weeks after the second dose (day 56), measured by use of the plaque-reduction neutralisation test (PRNT50) and the microneutralisation test (MNT50). The primary outcome was assessed in all participants who had received both doses of the vaccine. Cell-mediated responses were a secondary outcome and were assessed by T-helper-1 (Th1)/Th2 profiling at 2 weeks after the second dose (day 42). Safety was assessed in all participants who received at least one dose of the vaccine. In addition, we report immunogenicity results from a follow-up blood draw collected from phase 1 trial participants at 3 months after they received the second dose (day 104). This trial is registered at ClinicalTrials.gov, NCT04471519. Findings Between Sept 5 and 12, 2020, 921 participants were screened, of whom 380 were enrolled and randomly assigned to the 3 μg with Algel-IMDG group (n=190) or 6 μg with Algel-IMDG group (n=190). Geometric mean titres (GMTs; PRNT50) at day 56 were significantly higher in the 6 μg with Algel-IMDG group (197·0 [95% CI 155·6–249·4]) than the 3 μg with Algel-IMDG group (100·9 [74·1–137·4]; p=0·0041). Seroconversion based on PRNT50 at day 56 was reported in 171 (92·9% [95% CI 88·2–96·2] of 184 participants in the 3 μg with Algel-IMDG group and 174 (98·3% [95·1–99·6]) of 177 participants in the 6 μg with Algel-IMDG group. GMTs (MNT50) at day 56 were 92·5 (95% CI 77·7–110·2) in the 3 μg with Algel-IMDG group and 160·1 (135·8–188·8) in the 6 μg with Algel-IMDG group. Seroconversion based on MNT50 at day 56 was reported in 162 (88·0% [95% CI 82·4–92·3]) of 184 participants in the 3 μg with Algel-IMDG group and 171 (96·6% [92·8–98·8]) of 177 participants in the 6 μg with Algel-IMDG group. The 3 μg with Algel-IMDG and 6 μg with Algel-IMDG formulations elicited T-cell responses that were biased to a Th1 phenotype at day 42. No significant difference in the proportion of participants who had a solicited local or systemic adverse reaction in the 3 μg with Algel-IMDG group (38 [20·0%; 95% CI 14·7–26·5] of 190) and the 6 μg with Algel-IMDG group (40 [21·1%; 15·5–27·5] of 190) was observed on days 0–7 and days 28–35; no serious adverse events were reported in the study. From the phase 1 trial, 3-month post-second-dose GMTs (MNT50) were 39·9 (95% CI 32·0–49·9) in the 3μg with Algel-IMDG group, 69·5 (53·7–89·9) in the 6 μg with Algel-IMDG group, 53·3 (40·1–71·0) in the 6 μg with Algel group, and 20·7 (14·5–29·5) in the Algel alone group. Interpretation In the phase 1 trial, BBV152 induced high neutralising antibody responses that remained elevated in all participants at 3 months after the second vaccination. In the phase 2 trial, BBV152 showed better reactogenicity and safety outcomes, and enhanced humoral and cell-mediated immune responses compared with the phase 1 trial. The 6 μg with Algel-IMDG formulation has been selected for the phase 3 efficacy trial. Funding Bharat Biotech International. Translation For the Hindi translation of the abstract see Supplementary Materials section.