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Inactivated COVID-19 vaccine BBV152/COVAXIN effectively neutralizes recently emerged B 1.1.7 variant of SARS-CoV-2

March 2021
Journal of Travel Medicine 28(4)

DOI:10.1093/jtm/taab051

Authors:

Gajanan Sapkal

Pragya D Yadav

Indian Council of Medical Research

Gururaj Rao Deahpande

Indian Council of Medical Research

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Neutralization of variant under investigation B.1.617 with sera of BBV152

vaccinees

*#1Pragya D. Yadav, Ph.D, 1#Gajanan N. Sapkal, Ph.D, 1Priya Abraham, M.D, Ph.D,

2Raches Ella, M.S., 1Gururaj Deshpande, Ph.D,1 Deepak Y. Patil, Ph.D, 1Dimpal A Nyayanit,

Ph.D, 3Nivedita Gupta, Ph.D., 1Rima R. Sahay, M.D., 1Anita M Shete, Ph.D, 3Samiran Panda,

M.D., Ph.D, 3Balram Bhargava, D.M.,2V. Krishna Mohan,Ph.D.

#Equal first author

1Indian Council of Medical Research-National Institute of Virology, Pune, Maharashtra,

India, Pin-411021

2Bharat Biotech International Limited, Genome Valley, Hyderabad, Telangana, India Pin-

500 078

3Indian Council of Medical Research, V. Ramalingaswami Bhawan, P.O. Box No. 4911,

Ansari Nagar, New Delhi, India Pin-110029

*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

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Dear Editor,

The emergence of SARS-CoV-2 variants in places where the virus is uncontained poses a

global threat from the perspective of public health and vaccine efficacy. Peng et al.

recently reported the increased transmissibility with the newly emerged VOC

(20C/S:452R and 20C/S:452R) with the L452R mutation in San Francisco [1]. We report

the immunological characteristics of a VUI B.1.617, playing a critical role in the current

surge of COVID-19 in the western state of Maharashtra, India.

Several SARS-CoV-2 variants B.1.1.7, B.1.351 and B.1.1.28.1 have been reported in India

during year 2021[2,3]. We had sequenced 146 nasopharyngeal/oropharyngeal swabs of

COVID-19 cases [4]. Among these, 15 sequences had a combination of L452R and E484Q

mutations which raised concern as both are found in the receptor-binding domain

(RBD) of the spike protein. However, the combined effect of these mutations is still

unknown.

A total of 23 non-synonymous changes were observed in the sequences. Out of which,

seven conserved non-synonymous changes were found at spike protein (G142D, E154K,

L452R, E484Q, D614G, P681R, Q1071H) along with other conserved mutations (Figure

1A). These sequences were classified as VUI B.1.617. Phylogenetic analysis revealed

three distinct sub-clusters of B.1.617 lineages with mutations in spike first T95I; second

H1101D and third V382L, V1175Y (Figure 1 B). So far 21 countries have reported the

presence of B.1.617 variants [5]. Virus isolation was attempted from fifteen specimens

using Vero-CCL-81 cells [6]. Twelve specimens displayed cytopathic effects on the 4th

post-infection day which further passaged and tittered for performing plaque reduction

neutralization test (PRNT) [7]. These isolates were obtained, from clinical specimens of

asymptomatic individuals (age range: 14-55 years) and cases with a low-grade fever,

cough, and sore throat (age range: 26-77 years).

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The neutralization efficacy of the VUI B.1.617 variant was compared with B1 (D614G)

and B.1.1.7 variant using sera of 28 BBV152 vaccinated individuals, collected during the

phase II clinical trial [8]. D614G vs. B.1.617 GMT ratio was 1.95, (95% CI:1.60-2.38 and

p-value <0.0001). Similarly, the GMT ratio comparison of B.1.1.7 was significantly

higher than the GMT for B.1.617 (GMT ratio 1.84, 95% CI: 1.50-2.27, p value< 0.0001)

(Figure 1C and 1D). The comparison of D614G and B.1.1.7 showed equivalent responses

with a GMT ratio of 1.06 and 95% CI (1.02-1.10).

Sera samples collected from COVID-19 recovered individuals (n=17) infected with

lineage B.1.1.7, B.1.351, B.1.1.28.2, and B1 were used to perform PRNT50 against

B.1.617 variants and the results were compared with the vaccine recipients’ sera

samples. The GMT values for vaccine recipients were 88.48 (95% CI: 62.02-126.2) and

for recovered cases 86.85 (95% CI 52.04-144.9). The sera of BNT162b2 vaccinees which

effectively neutralized B.1.1.7 and P.1 variants; was reduced with B.1.351 variant [9].

The B.1.617 variant performance with vaccine sera was better than recovered cases.

The result of B.1.1.7 variant neutralization with BBV152 vaccine sera and findings of

B.1.617 emphasize that this vaccine is robust against emerging mutation and maintains

the efficacy of the vaccine (Figure 1 E) [10]. Assessing the clinical efficacy of BBV152

against such variants is underway.

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Author Contributions

PDY, GNS and PA contributed to study design, data collection, data analysis,

interpretation and writing and critical review. RE, RRS, AMS, DYP, DAN and GRD

contributed to data collection, interpretation, writing and critical review. NG, SP, VKM,

and BB contributed to the critical review and finalization of the paper.

Acknowledgement

Authors gratefully acknowledge the staff of ICMR-NIV, Pune including Mr. Prasad

Sarkale, Mr. Shrikant Baradkar, Dr. Abhinendra Kumar, Mrs. Triparna Majumdar, Mrs.

Savita Patil, Mr. Rajen Lakra, Mr. Vishwajeet Dhanure, Ms. Pranita Gawande, Mrs.

Kaumudi Kalele, Mrs. Ashwini Waghmare, Ms. Jyoti Yemul, Ms. Manisha Dudhmal, Ms.

Aasha Salunkhe and Mr. Chetan Patil for extending excellent technical support. The

study was approved by the Institutional Biosafety Committee and Institutional Human

Ethics Committee of ICMR-NIV, Pune, India. under project ‘Molecular epidemiological

analysis of SARS-COV-2 circulating in different regions of India’ (20-3-18N).

Financial support & sponsorship

Financial support was provided by the Indian Council of Medical Research (ICMR), New

Delhi at ICMR-National Institute of Virology, Pune under intramural funding ‘COVID-19’.

Conflicts of Interest

Authors do not have a conflict of interest.

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References

1. Peng J, Sabrina A, Mitchell AM, et al. Estimation of secondary household attack

rates for emergent SARS-CoV-2 variants detected by genomic surveillance at a

community-based testing site in San Francisco. medRxiv. 2021.

2. Yadav PD, Nyayanit DA, Sahay RR, et al. Isolation and characterization of the new

SARS-CoV-2 variant in travellers from the United Kingdom to India: VUI-

202012/01 of the B.1.1.7 lineage. J Travel Med 2021; 28.

3. Menon GI. The Novel Coronavirus Variants and India’s Uncertain Future. The

Wire Science. 2021; Available at: https://science.thewire.in/health/sars-cov-2-

variants-b117-b1617-india-second-wave-uncertain-future/. Accessed 22 April

2021.

4. Yadav PD, Nyayanit DA, Shete AM, et al. Complete genome sequencing of Kaisodi

virus isolated from ticks in India belonging to Phlebovirus genus, family

Phenuiviridae. Ticks Tick Borne Dis 2019; 10:23–33.

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lineages.org/lineages/lineage_B.1.617.html. Accessed 22 April 2021.

6. Sarkale P, Patil S, Yadav PD, et al. First isolation of SARS-CoV-2 from clinical

samples in India. Indian J Med Res 2020; 151:244–250.

7. Deshpande GR, Sapkal GN, Tilekar BN, et al. Neutralizing antibody responses to

SARS-CoV-2 in COVID-19 patients. Indian J Med Res. 2020; 152:82-7. Ella R,

Reddy S, Jogdand H, et al. Safety and immunogenicity of an inactivated SARS-

CoV-2 vaccine, BBV152: interim results from a double-blind, randomised,

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multicentre, phase 2 trial, and 3-month follow-up of a double-blind, randomised

phase 1 trial. Lancet Infect Dis. 2021; 21(5): P637-646.

9. Liu Y, Liu J, Xia H, Zhang X, et al. Neutralizing activity of BNT162b2-elicited

serum. N Engl J Med. 2021.

10. Sapkal GN, Yadav PD, Ella R, et al. Inactivated COVID-19 vaccine

BBV152/COVAXIN effectively neutralizes recently emerged B 1.1.7 variant of

SARS-CoV-2. J Travel Med. 2021. taab051, https://doi.org/10.1093/jtm/taab051

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Figure 1: Characteristics and neutralization of VUI B.1.617 variant: A) The

common nucleotide changes observed in the majority of the isolates and clinical

sequences. B) A neighbor-joining tree was generated using a Tamura 3-parameter

model with gamma distribution and a bootstrap replication of 1000 cycles. Isolates

are marked in red color and sequences from foreign travelers marked in pink color.

The representative sequences from other clades are represented as B.1.1.7 (red),

B.1.617 (blue), B.1.351 (black), B.1.525 (purple) Brazil P2 (light green), and B1

(light blue). Individual spike mutations specific to the clusters are marked using the

arrows. One of sequences (MCL-21-H-741) had E484K mutation, that lead to its

distinct clustering, in B.1.617 lineage (blue) belonged to a traveler who had returned

from UAE to India.

C) Scatter plot depicting the neutralizing response of the individual sera (n=28)

vaccinated with BBV152 (Covaxin) collected during phase II clinical trial for the

prototype B1 (D614G) (pink), B.1.1.7 (red), B.1.617 (blue). The red solid line

indicates the geometric mean titer and the error bar depicts a 95% confidence

interval. D) Neutralization of the matched-pair samples compared to prototype

D614G (pink), B.1.1.7 (red) and B.1.617 (blue). Neutralization reduction by a factor

of 1.95 and 1.8 was observed against the B.1.617 variant for B1 (D614G) and B.1.1.7

variant respectively. A reduction factor of 1.06 was observed between the B1

(D614G) and B.1.1.7 variant. A two-tailed pair-wise comparison was performed

using the Wilcoxon matched-pairs signed-rank test with a p-value of 0.05. ****

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represent p-value <0.001 and **p value=0.0038,ns= non-significant p-

value. E) Neutralization of the COVID-19 recovered cases sera (n=17) of B.1.1.7

(n=2), B.1.351 (n=2), B.1.1.28.2 (n=2) and B1 lineage (n=11) infected individuals

PRNT50 values against B.1.167 variant were compared with vaccine recipient serum

samples. A two-tailed pair-wise comparison was performed using the Mann-

Whitney test with a p-value of 0.05.

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Figure 1

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LANCET INFECT DIS

Background To mitigate the effects of COVID-19, a vaccine is urgently needed. BBV152 is a whole-virion inactivated SARS-CoV-2 vaccine formulated with a toll-like receptor 7/8 agonist molecule adsorbed to alum (Algel-IMDG) or alum (Algel). Methods We did a double-blind, multicentre, randomised, controlled phase 1 trial to assess the safety and immunogenicity of BBV152 at 11 hospitals across India. Healthy adults aged 18–55 years who were deemed healthy by the investigator were eligible. Individuals with positive SARS-CoV-2 nucleic acid and/or serology tests were excluded. Participants were randomly assigned to receive either one of three vaccine formulations (3 μg with Algel-IMDG, 6 μg with Algel-IMDG, or 6 μg with Algel) or an Algel only control vaccine group. Block randomisation was done with a web response platform. Participants and investigators were masked to treatment group allocation. Two intramuscular doses of vaccines were administered on day 0 (the day of randomisation) and day 14. Primary outcomes were solicited local and systemic reactogenicity events at 2 h and 7 days after vaccination and throughout the full study duration, including serious adverse events. Secondary outcome was seroconversion (at least four-fold increase from baseline) based on wild-type virus neutralisation. Cell-mediated responses were evaluated by intracellular staining and ELISpot. The trial is registered at ClinicalTrials.gov (NCT04471519). Findings Between July 13 and 30, 2020, 827 participants were screened, of whom 375 were enrolled. Among the enrolled participants, 100 each were randomly assigned to the three vaccine groups, and 75 were randomly assigned to the control group (Algel only). After both doses, solicited local and systemic adverse reactions were reported by 17 (17%; 95% CI 10·5–26·1) participants in the 3 μg with Algel-IMDG group, 21 (21%; 13·8–30·5) in the 6 μg with Algel-IMDG group, 14 (14%; 8·1–22·7) in the 6 μg with Algel group, and ten (10%; 6·9–23·6) in the Algel-only group. The most common solicited adverse events were injection site pain (17 [5%] of 375 participants), headache (13 [3%]), fatigue (11 [3%]), fever (nine [2%]), and nausea or vomiting (seven [2%]). All solicited adverse events were mild (43 [69%] of 62) or moderate (19 [31%]) and were more frequent after the first dose. One serious adverse event of viral pneumonitis was reported in the 6 μg with Algel group, unrelated to the vaccine. Seroconversion rates (%) were 87·9, 91·9, and 82·8 in the 3 μg with Algel-IMDG, 6 μg with Algel-IMDG, and 6 μg with Algel groups, respectively. CD4⁺ and CD8⁺ T-cell responses were detected in a subset of 16 participants from both Algel-IMDG groups. Interpretation BBV152 led to tolerable safety outcomes and enhanced immune responses. Both Algel-IMDG formulations were selected for phase 2 immunogenicity trials. Further efficacy trials are warranted. Funding Bharat Biotech International.

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To investigate the evolution of SARS-CoV-2 in the immune population, we co-incubated authentic virus with a highly neutralizing plasma from a COVID-19 convalescent patient. The plasma fully neutralized the virus for 7 passages, but after 45 days, the deletion of F140 in the spike N-terminal domain (NTD) N3 loop led to partial breakthrough. At day 73, an E484K substitution in the receptor-binding domain (RBD) occurred, followed at day 80 by an insertion in the NTD N5 loop containing a new glycan sequon, which generated a variant completely resistant to plasma neutralization. Computational modeling predicts that the deletion and insertion in loops N3 and N5 prevent binding of neutralizing antibodies. The recent emergence in the United Kingdom and South Africa of natural variants with similar changes suggests that SARS-CoV-2 has the potential to escape an effective immune response and that vaccines and antibodies able to control emerging variants should be developed. One Sentence Summary Three mutations allowed SARS-CoV-2 to evade the polyclonal antibody response of a highly neutralizing COVID-19 convalescent plasma.

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Full-text available

Dec 2020

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 adsorbed to alum (Algel-IMDG). Earlier, we reported findings from a phase 1 (vaccination regimen on days 0 and 14) randomised, double-blind trial on the safety and immunogenicity of three different formulations of BBV152 and one control arm containing Algel (without antigen). Two formulations were selected for the phase 2 (days 0 and 28) study. Here, we report interim findings of a controlled, randomised, double-blind trial on the immunogenicity and safety of BBV152: 3 µg and 6 µg with Algel-IMDG. Methods We conducted a double-blind, randomised, multicentre, phase 2 clinical trial to evaluate the immunogenicity and safety of BBV152. A total of 380 healthy children and adults were randomised to receive two vaccine formulations (n=190 each) with 3 µg with Algel-IMDG and 6 µg with Algel-IMDG. Two intramuscular doses of vaccines were administered (four weeks apart). Participants, investigators, and laboratory staff were blinded to the treatment allocation. The primary outcome was seroconversion (≥4-fold above baseline) based on wild-type virus neutralisation (PRNT 50 ). Secondary outcomes were reactogenicity and safety. Cell-mediated responses were evaluated. A follow-up blood draw was collected from phase 1 participants at day 104 (three months after the second dose). Findings Among 921 participants screened between Sep 7-13, 2020, 380 participants were randomised to the safety and immunogenicity population. The PRNT 50 seroconversion rates of neutralising antibodies on day 56 were 92·9% (88·2, 96·2) and 98·3% (95·1, 99·6) in the 3 µg and 6 µg with Algel-IMDG groups, respectively. Higher neutralising titres (2-fold) were observed in the phase 2 study than in the phase 1 study (p<0.05). Both vaccine groups elicited more Th1 cytokines than Th2 cytokines. After two doses, the proportion (95% CI) of solicited local and systemic adverse reactions were 9.7% (6·9, 13·2) and 10.3% (7·4, 13·8) in the 3 µg and 6 µg with Algel-IMDG groups, respectively. No significant difference was observed between the groups. No serious adverse events were reported in this study. Phase 1 follow-up immunological samples at day 104 showed seroconversion in 73·5% (63·6, 81·9), 81·1% (71·4, 88·1), and 73·1% (62·9, 81·8) of individuals in the 3 µg with Algel-IMDG, 6 µg with Algel-IMDG, and 6 µg with Algel groups, respectively. Interpretation In the phase 1 trial, BBV152 produced high levels of neutralising antibodies that remained elevated in all participants three months after the second vaccination. In the phase 2 trial, BBV152 led to tolerable safety outcomes and enhanced humoral and cell-mediated immune responses. The safety profile of BBV152 is noticeably lower than the rates for other SARS-CoV-2 vaccine platform candidates. The 6 µg Algel-IMDG formulation was selected for the phase 3 efficacy trial. Funding This work was supported and funded by Bharat Biotech International Limited. Clinicaltrials.gov : NCT04471519

Neutralizing antibody responses to SARS-CoV-2 in COVID-19 patients

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Full-text available

Aug 2020
INDIAN J MED RES

Background & objectives: : The global pandemic caused by SARS-CoV-2 virus has challenged public health system worldwide due to the unavailability of approved preventive and therapeutic options. Identification of neutralizing antibodies (NAb) and understanding their role is important. However, the data on kinetics of NAb response among COVID-19 patients are unclear. To understand the NAb response in COVID-19 patients, we compared the findings of microneutralization test (MNT) and plaque reduction neutralization test (PRNT) for the SARS-CoV-2. Further, the kinetics of NAb response among COVID-19 patients was assessed. Methods: : A total of 343 blood samples (89 positive, 58 negative for SARS-CoV-2 and 17 cross-reactive and 179 serum from healthy individuals) were collected and tested by MNT and PRNT. SARS-CoV-2 virus was prepared by propagating the virus in Vero CCL-81 cells. The intra-class correlation was calculated to assess the correlation between MNT and PRNT. The neutralizing endpoint as the reduction in the number of plaque count by 90 per cent (PRNT 90) was also calculated. Results: : The analysis of MNT and PRNT quantitative results indicated that the intra-class correlation was 0.520. Of the 89 confirmed COVID-19 patients, 64 (71.9%) showed NAb response. Interpretation & conclusions: : The results of MNT and PRNT were specific with no cross-reactivity. In the early stages of infection, the NAb response was observed with variable antibody kinetics. The neutralization assays can be used for titration of NAb in recovered/vaccinated or infected COVID-19 patients.

Deep Mutational Scanning of SARS-CoV-2 Receptor Binding Domain Reveals Constraints on Folding and ACE2 Binding

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Aug 2020
CELL

The receptor binding domain (RBD) of the SARS-CoV-2 spike glycoprotein mediates viral attachment to ACE2 receptor, and is a major determinant of host range and a dominant target of neutralizing antibodies. Here we experimentally measure how all amino-acid mutations to the RBD affect expression of folded protein and its affinity for ACE2. Most mutations are deleterious for RBD expression and ACE2 binding, and we identify constrained regions on the RBD’s surface that may be desirable targets for vaccines and antibody-based therapeutics. But a substantial number of mutations are well tolerated or even enhance ACE2 binding, including at ACE2 interface residues that vary across SARS-related coronaviruses. However, we find no evidence that these ACE2-affinity enhancing mutations have been selected in current SARS-CoV-2 pandemic isolates. We present an interactive visualization and open analysis pipeline to facilitate use of our dataset for vaccine design and functional annotation of mutations observed during viral surveillance.

Genomic analysis of SARS-CoV-2 strains among Indians returning from Italy, Iran & China, & Italian tourists in India

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