A randomized, controlled study to evaluate the safety and immunogenicity of a heterologous booster dose of an adjuvanted SARS CoV-2 recombinant spike protein vaccine in adults

doi:10.21203/rs.3.rs-2549560/v1

Background

Due to waning immunity following primary immunization with Covid-19 vaccines, booster doses may be required. The present study assessed a heterologous booster of SII-NVX-CoV2373 (spike protein vaccine) in adults primed with viral vector and inactivated vaccines.

Methods

In this Phase 3, observer-blind, randomized, active controlled study, a total of 372 adults primed with ChAdOx1 nCoV-19 (n = 186) or BBV152 (n = 186) at least six months ago, were randomized to receive a booster of SII-NVX-CoV2373 or control vaccine. The control group received homologous booster of ChAdOx1 nCoV-19 or BBV152 depending upon the prime cohort. Anti-S IgG and neutralizing antibodies were assessed at baseline (day 1), day 29, day 91 and day 181 for immunogenicity assessments. Solicited reactions were collected for one week after vaccination. Unsolicited adverse events (AEs) were collected for 28 days while serious adverse events (SAE) and adverse events of special interest (AESI) were reported throughout the six-month study duration. (Identifier: CTRI/2022/04/042017)

Results

In both the ChAdOx1 nCoV-19 primed group and BBV152 primed group, 186 participants each received the study vaccines. In the ChAdOx1 nCoV-19 Prime cohort, at 28 days after the booster dose, there was a 3.9- to 5.1-fold-rise and 1.9- to 2.8-fold-rise in anti-S IgG and neutralizing antibody titres from the baseline in the SII-NVX-CoV2373 group and the ChAdOx1 nCoV-19 group, respectively. The same responses for the BBV152 prime cohort was 7.4- to 10.4-fold-rise and 1.5- to 2.5-fold-rise in the SII-NVX-CoV2373 group and the BBV152 group, respectively. There was 86.96% (95% CI 78.32, 93.07) to 94.57% (95% CI 87.77, 98.21) and 37.63% (95% CI 27.79, 48.28) to 79.57% (95% CI 69.95, 87.23) anti-S IgG and neutralizing antibody seroresponse (2-fold-rise from baseline) in the SII-NVX-CoV2373 group and ChAdOx1 nCoV-19 group, respectively. The same was 94.51% (95% CI 87.64, 98.19) to 98.90% (95% CI 94.03, 99.97) and 20.43% (95% CI 12.77, 30.05) to 74.19% (95% CI 64.08, 82.71) in the SII-NVX-CoV2373 group and BBV152 group, respectively. No SAE or AESI was caused by the study vaccines.

Conclusion

SII-NVX-CoV2373 showed a numerically higher boosting effect than homologous boosters in adults primed with ChAdOx1 nCoV-19 and BBV152. The vaccine was also safe and well tolerated.

Health sciences/Diseases/Infectious diseases/Viral infection

Health sciences/Medical research/Clinical trial design/Randomized controlled trials

SII-NVX-CoV2373

COVID-19

vaccine

booster

immunogenicity

safety

Evidence before this study

NVX-CoV2373 was developed in USA and there are two publications on its booster response: one as a heterologous booster and another as a homologous booster. Both the studies reported that immune responses against the prototype strain and all variants evaluated, were similar to or higher than those associated with high levels of efficacy in phase 3 studies of the vaccine. SII-NVX-CoV2373 was made in India after technology transfer from USA. We searched PubMed on Jan 27, 2023, for clinical trial reports with no language restrictions, using the terms “SII-NVX-CoV2373”, “vaccine”, “SARS-CoV-2 recombinant spike protein nanoparticle vaccine”, “clinical trial”, “heterologous booster”, and “adult” no publications were found on SII-NVX-CoV2373 in adults as a booster dose.

Added value of this study

This was, to our knowledge, the first data on NVX-CoV2373 wherein heterologous booster responses against omicron variants were evaluated. The vaccine had an acceptable safety profile and a high booster response against prototype strain as well as omicron variants (BA.1 and BA.5) was seen in adults that was numerically higher than that achieved with homologous viral vector vaccine (ChAdOx1 nCoV-19) and inactivated vaccine (BBV152) booster vaccination. These data indicate that heterologous boosting with the SII-NVX-CoV2373 vaccine resulted in enhanced cross-reactive immunity to SARS-CoV-2 variants.

Implications of all the available evidence

The available data shows NVX-CoV2373 as a heterologous booster is highly immunogenic with acceptable safety profile in adults. Though the pandemic has receded, but new variants of concerns are emerging and therefore, there could be a need for giving booster doses, possibly at periodic intervals. The excellent results from the present study could be important to the policy makers and the scientific community for deciding on booster dose strategy going forward as new variants emerges, particularly omicron sub-lineages.

In December 2019, a cluster of a novel coronavirus, known as 2019-nCoV, cases were identified in Wuhan, China.¹ As of 7 December 2022, there have been more than 642 million reported cases and more than 6.62 million deaths worldwide.² By the same time, India reported a total of more than 44.67 million cases with more than 0.53 million fatalities.³

The immunity achieved through natural infection by SARS-CoV-2 has been shown to last for many months⁴. The durability of immune response is affected by the waning of antibody titres over time, and the emergence of novel variants of the SARS-CoV-2 virus which may need higher titres to neutralize.⁵ This is likely to necessitate booster doses of COVID-19 vaccines, and potentially periodic boosters. Boosters will generate higher antibody levels against the original strain and may also generate immunity specifically against novel variants.⁶

A SARS-CoV-2 recombinant spike (rS) protein nanoparticle vaccine adjuvanted with Matrix-M™ (NVX-CoV2373) was developed in USA. NVX-CoV2373 was assessed in a Phase 1/2^7, Phase 2a/b⁸ and two Phase 3 studies^9,10 which showed that it was safe, immunogenic with high efficacy. The overall vaccine efficacy for PCR-confirmed symptomatic SARS-CoV-2 infection was around 90%.^9,10 After technology transfer, the vaccine is also manufactured in India (SII-NVX-CoV2373). SII-NVX-CoV2373 was tested for primary immunization in India when it was successfully immuno-bridged with NVX-CoV2373.¹¹

It has become evident that the protection offered against COVID-19 wanes after a two-dose schedule of COVID-19 vaccines¹². Therefore, the potential role of third or booster dose against COVID-19 was evaluated. In a Phase 2 study conducted in the USA and Australia, a single booster dose of NVX-CoV2373 was administered to adults approximately 6 months following their NVX-CoV2373 primary series which showed a high immune response for both the prototype strain and all variants evaluated.⁶ The vaccine also showed excellent boosting after two doses of ChAdOx1 nCov-19 or BNT162b2 vaccines¹³.

In India, the nation-wide primary COVID-19 immunization programme started on 16 January 2021 with two vaccines: Covishield (ChAdOx1 nCoV-19, a viral vector vaccine) and Covaxin (BBV152, a whole virion inactivated vaccine)¹⁴ and these two vaccines were used for primary immunization of more than 90% of the target population¹⁵. On 10 January 2022, the country started homologous booster immunization with these vaccines¹⁶. Considering that heterologous boosters are known to give better immune response as compared to homologous boosters¹⁷, the present study assessed the heterologous booster response to SII-NVX-CoV2373 in Indian adults who had received 2 doses of ChAdOx1 nCoV-19 or BBV152 at least 6 months ago.

This was a Phase 3, multicentric, observer-blinded, randomized, active controlled study in adults who had completed primary immunization with either ChAdOx1 nCoV-19 or BBV152 against COVID-19 at least 6 months ago (6 months from the second dose). A total of 372 eligible participants were enrolled in 2 primed cohorts of 186 participants each with 1:1 allocation to SII-NVX-CoV2373 or control vaccine. The study was conducted from May 2022 to December 2022 at 8 centres in India.

The primary objective was to compare immunogenicity of the SII-NVX-CoV2373 heterologous booster dose with the homologous booster dose of Control vaccine using anti-S IgG and neutralizing antibodies (nAbs) for ChAdOx1 nCoV-19 Prime, and BBV152 Prime cohorts, separately. The secondary objective was to assess the tolerability and reactogenicity profile of SII-NVX-CoV2373 booster in comparison with the Control vaccine. As an exploratory objective, the study also assessed immune responses by neutralizing antibodies, anti-S IgG and human ACE2 (hACE2) receptor binding inhibition assay against variants of concern.

Study Participants

The study participants were healthy adults aged ≥ 18 years who gave written informed consent and who had completed primary COVID-19 immunization schedule with either ChAdOx1 nCoV-19 or BBV152 (2 doses) at least 6 months ago. Participants with a history of laboratory confirmed COVID-19, history of allergic reactions after previous vaccinations, hypersensitivity to any component of study vaccines, any condition with impaired/altered function of immune system, any clinically significant systemic disorder were excluded. Clinically well-controlled comorbidities were allowed.

Study Vaccines

SII-NVX-CoV2373 (SARS-CoV-2 recombinant spike protein nanoparticle vaccine [SARS-CoV-2 rS] with Matrix-M™ adjuvant manufactured by Serum Institute of India Pvt. Ltd.), was available as a ready to use liquid formulation. Each single dose of 0.5 mL contained 5 µg antigen and 50 µg Matrix-M adjuvant. Batch Number used was 4301MF017, Expiry date: August 2022.

The comparator in the ChAdOx1 nCoV-19 prime cohort was Covishield^™ [ChAdOx1 nCoV-19 Corona Virus Vaccine (Recombinant), SIIPL]. One dose (0.5 ml) contains ChAdOx1 nCoV-19 Corona Virus Vaccine (Recombinant) 5 × 10¹⁰ virus particles (vp) which is a recombinant, replication-deficient chimpanzee adenovirus vector encoding the SARS-CoV-2 Spike (S) glycoprotein. Batch Number was 4121MC169, Expiry date: August 2022.

The comparator used in the BBV152 prime cohort was Covaxin® [Whole Virion Inactivated Coronavirus (SARS-CoV-2) Vaccine, Bharat Biotech International Ltd]. Each dose of 0.5mL contains 6 µg of Whole Virion, Inactivated (SARS-CoV-2) Antigen (strain NIV-2020-770) along with Aluminum Hydroxide Gel, TLR7/8 Agonist and 2-Phenoxyethanol. Batch Number was C10/21004, Expiry date: November 2022.

All study vaccines (SII-NVX-CoV2373, ChAdOx1 nCoV-19 and BBV152) were administered as a single dose of 0.5 mL intramuscularly in the deltoid.

Randomization And Blinding

The randomization scheme was generated using SAS software version 9.4 (SAS Institute Inc, USA) for Interactive Response Technology (IRT) with 1:1 allocation to SII-NVX-CoV2373 or control vaccine within each of the two prime cohorts. The study participants, the study personnel responsible for the evaluation of any study endpoints and the laboratories involved in the immunogenicity testing were blinded to the treatment allocation. Personnel involved in getting randomization code by accessing interactive web response system (IWRS) and administration were unblinded and they did not conduct any study evaluations.

The unblinded monitors and statisticians from the contract research organization (CRO) could access the participants level unblinded data as per the need.

Study Procedures

Two cohorts of 186 participants each were: ChAdOx1 nCoV-19 Prime cohort (Primary immunization with two doses of ChAdOx1 nCoV-19) and BBV152 Prime cohort (Primary immunization with two doses of BBV152). The control vaccine in the two cohorts were ChAdOx1 nCoV-19 and BBV152, respectively. All participants received a single dose of 0.5 mL of either SII-NVX-CoV2373 or Control vaccine on day 1 as per randomization. Blood samples were collected at baseline (day 1), day 29, day 91 and day 181 for immunogenicity assessments including anti-S IgG and neutralizing antibodies. Additionally, a blood sample was collected in a subset of 36 participants (18 from each of the two prime cohorts) for assessment of cell mediated immune (CMI) responses at baseline, day 29 and day 181.

A nasopharyngeal / nasal and/or throat swab was collected for RT-PCR test for detection of SARS-CoV-2 infection at baseline before vaccination on day 1.

Physical examination (PE) and vital sign evaluations were performed and medical history and prior/concomitant medications were recorded on day 1, day 29 (+ 7 days), day 91 (+ 7 days) and day 181 (+ 14 days). Vital signs were measured at 30 minutes post-vaccination.

Immunogenicity Assessments

Anti-spike protein (anti-S) IgG antibodies were assessed using validated enzyme-linked immunosorbent assay (ELISA) and neutralizing antibodies (nAbs) against prototype strain were assessed using by validated microneutralization (MN) assay using wild type virus (Ancestral strain). Seroresponse was defined as 2-fold increase in antibody titers from baseline. Immunogenicity against variants of concerns (; was assessed in a randomly selected subset of 46 participants for anti-S IgG against Omicron BA.1 and Omicron BA.5, and 50 participants for nAbs against Omicron B.1.1.529 (BA.1) from each of the two prime cohorts (maintaining 1:1 allocation). In addition, in the same subset of 46 participants, immune responses against ancestral strain (Wuhan), Omicron BA.1 and Omicron BA.5 variants were determined by validated hACE2 receptor binding inhibition assay, as an exploratory objective though not part of the study protocol. Immunogenicity testing was performed in compliance with Good Clinical Laboratory Practice (GCLP) requirements at Novavax, Gaithersburg, USA (Anti-S IgG antibodies and hACE2 receptor binding inhibition assay), at 360biolabs, Melbourne, Australia (Neutralizing antibodies) and at NARI-ICMR, Pune, India (CMI testing).

The lower limit of quantification (LLOQ) for ELISA assay was 200 ELISA units per mL (EU/mL), with titers below this level documented as 100 EU/mL. The LLOQ for MN assay was a titer of 20, with titers below this level documented as 10. The LLOQ for hACE2 receptor binding inhibition assay was a titer of 10, with titers below this level documented as 5. Cell-mediated immune responses were measured by enzyme-linked immune absorbent spot (ELISpot).

Safety Assessments

Solicited local and systemic AEs were actively collected for 7 days after vaccination using participant diary cards. The solicited local AEs to be collected included pain, tenderness, erythema, swelling and induration. The solicited systemic AEs to be collected included fever, headache, fatigue, malaise, arthralgia, myalgia, nausea and vomiting. Unsolicited adverse events were collected for 28 days after vaccination. Unsolicited AEs were any AEs reported by the participant, observed by the study staff during study visits or those identified during review of medical records or source documents. Serious adverse events (SAEs), and adverse events of special interest (AESIs) including potentially immune-mediated medical condition (PIMMCs) and AESIs relevant to COVID-19 were collected throughout the study participation.

Participants were tested for COVID-19 if they presented with symptoms of suspected COVID-19 or history of contact with a confirmed COVID-19 case.

The severity of all AEs, listed specifically as an event in the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, corrected Version 2.1, July 2017, of the US National Institute of Health, were assessed based on this table, which was available at: https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf. A subjective grading scale was used to grade the severity of all unsolicited AEs that were not listed as a specific event in the DAIDS Table.

Each SAE was reported by the investigator to the sponsor, DCGI, and respective IEC within 24 hours of learning of its occurrence, even if it was not felt to be treatment-related. Reporting procedures were as per the New Drugs and Clinical Trials Rules, 2019.

Safety was monitored during the study by on-site clinical staff. Periodic reviews of safety data was done by the protocol safety review team (PSRT), which included the SIIPL Medical Officers, a biostatistician, and medical officer from the CRO. In addition, there was an independent data safety monitoring board (DSMB) to review the safety data and provide oversight on the study.

Statistical Considerations

Total 372 participants were randomized in the study with 186 in each of 2 prime cohorts. Assuming non-evaluable participants ≤ 15% (which leads to a sample size of 158 evaluable participants for each cohort), group sample sizes of 93 each in each vaccine group would achieve 80% power to detect non-inferiority using a one-sided, two-sample t-test, with a true ratio of the means of 1.00, one-sided significance level (alpha) of 0.025 and coefficients of variation of 1.1. Non-inferiority of SII-NVX-CoV2373 booster over the control vaccine for each cohort was to be concluded separately if the lower limit of the two-sided 95% CI for the geometric mean ELISA units (GMEU) ratio for anti-S IgG antibodies and geometric mean titers (GMT) ratio for neutralizing antibodies between SII-NVX-CoV2373 and the control vaccine at day 29 was > 0.67 (non-inferiority margin). The same sample size served the statistical test for a non-inferiority difference in proportion of participants achieving ≥ 2-fold increase in anti-S and nAbs between SII-NVX-CoV2373 and the active control vaccine at day 29 would achieve 82% power, using a one-sided, two-sample z-test at alpha level of 0.025. Proportion of participants achieving ≥ 2-fold increase in both anti-S and nAbs for control arm was assumed 95% and the margin of non-inferiority was − 10%. The true difference of the proportion at which the power is evaluated is 0. Sample size calculations were performed using a non-inferiority test for the ratio of two means in PASS 15.0.7 Version software.

Enrolled Population was all participants who provided written informed consent, regardless of screening, randomization and treatment status in the study. Full Analysis Population comprised of all participants who received the study vaccine and provided an evaluable serum sample post vaccination for at least one assessment. Safety Population included all participants who received the study vaccines. Per Protocol population consisted of all participants who received the study vaccine, provided an evaluable serum sample post vaccination for at least one assessment, had baseline (day 1) data available, excluding any data from time points following a SARS-CoV-2 infection or major protocol deviation before day 29. All immunogenicity analyses were performed using this population.

Continuous data was described using descriptive statistics (n, mean, standard deviation, median, minimum, and maximum). Categorical data was described using the participant count and percentage for each category.

All statistical analyses were performed using SAS^® software version 9.4 or later.

Ethical Considerations

The study was approved by the Indian regulatory authorities and the Institutional Ethics Committees (IECs) of respective study sites. The study was to be conducted in compliance with Declaration of Helsinki (Revised Fortaleza, 2013) and the International Council for Harmonization (ICH) GCP Guideline, E6 R2 (2016). Prior to including any participant in the clinical study, the participant’s free and expressed informed consent was obtained in writing.

This report includes the safety data collected until day 180 and immunogenicity data until day 29 Visit for all participants.

Disposition of Participants

ChAdOx1 nCoV-19 Prime cohort: A total of 190 participants were enrolled and 187 were randomized (1 screen failed participant was wrongly randomized, but not vaccinated). Among these 187 participants, 186 received the study vaccine (92 SII-NVX-CoV2373 and 94 ChAdOx1 nCoV-19). Only a single participant withdrew the consent before day 29 visit. The safety population comprised all 186 participants who received the study vaccine, both full analysis and per protocol populations comprised 185 participants [Figure 1].

The demographic and baseline characteristics between the two groups were comparable. Mean age was about 36 years and 45% were males. About 15% of the participants had a comorbid condition. None of the participants was positive for SARS CoV-2 RT-PCR. Median duration between two doses of prime series of ChAdOx1 nCoV-19 was 90 days and that between second dose of prime series and the booster dose was 270 days (~9 months) [Table 1].

BBV152 Prime cohort: A total of 190 participants were enrolled and 186 were randomized and received the study vaccine (92 SII-NVX-CoV2373 and 94 BBV152). Two participants withdrew consent before day 29 visit. The safety population comprised all 186 participants who received the study vaccine, both full analysis and per protocol populations comprised 184 participants [Figure 2].

The demographic and baseline characteristics between the two groups were comparable. Mean age was about 37 years and about 64% were males. About 15% of the participants had a comorbid condition. None of the participants was positive for SARS CoV-2 RT PCR. Median duration between two doses of prime series of BBV152 was 35 days and that between second dose of prime series and the booster dose was 298 days (~10 months) [Table 1].

In total, one participant from ChAdOx1 nCoV-19 prime cohort and two participants from BBV152 prime cohort withdrew consent. None of these withdrawals were for safety reasons.

Immunogenicity Results:

ChAdOx1 nCoV-19 Prime cohort:

Anti-S IgG data: Baseline GMEUs of anti-S IgG against ancestral strain were comparable between the SII-NVX-CoV2373 and the ChAdOx1 nCoV-19 groups. At 28 days after the booster dose (day 29 visit), there was a 3.9-fold-rise (95% CI 3.4, 4.5) from the baseline in the SII-NVX-CoV2373 group [GMEU 66085.8 (95% CI 57028.0, 76582.4)] and 1.9-fold-rise (95% CI 1.7, 2.3) from the baseline in the ChAdOx1 nCoV-19 group [GMEU 31673.6 (95% CI 27149.5, 36951.6)] [Table 2]. The primary endpoint of non-inferiority was met with 1.73 as the lower bound of 95% CI (GMEU ratio 2.05 [95% CI: 1.73, 2.43]) [Table 3].

There was 86.96% (95% CI 78.32, 93.07) and 37.63% (95% CI 27.79, 48.28) seroresponse (2-fold-rise from baseline) at 28 days after the booster dose in the SII-NVX-CoV2373 group and ChAdOx1 nCoV-19 group, respectively. The difference in seroresponse between the SII-NVX-CoV2373 and the ChAdOx1 nCoV-19 group was highly significant. The primary endpoint of non-inferiority was met with 36.49% as the lower bound of 95% CI (Difference in proportion of seroresponse 49.32 [95% CI: 36.49, 60.45]) [Table 3].

Neutralizing antibodies (nAbs) data: Baseline GMTs of nAbs against ancestral strain were comparable between the SII-NVX-CoV2373 and the ChAdOx1 nCoV-19 groups. At 28 days after the booster dose, there was a 5.1-fold-rise (95% CI 4.2, 6.2) from the baseline in the SII-NVX-CoV2373 group [GMT 3963.0 (95% CI 3343.8, 4696.7)] and 2.8-fold-rise (95% CI 2.3, 3.4) in the ChAdOx1 nCoV-19 group [GMT 2031.9 (95% CI 1690.6, 2442.1)] [Table 2]. The primary endpoint of non-inferiority was met with 1.55 as the lower bound of 95% CI (GMT ratio 1.89 [95% CI: 1.55, 2.32]) [Table 3].

There was 94.57% (95% CI 87.77, 98.21) and 79.57% (95% CI 69.95, 87.23) seroresponse at 28 days after the booster dose in the SII-NVX-CoV2373 group and ChAdOx1 nCoV-19 group, respectively. The difference in seroresponse between the SII-NVX-CoV2373 and the ChAdOx1 nCoV-19 group was significant. Primary endpoint of non-inferiority was met with 5.65% as the lower bound of 95% CI (Difference in proportion of seroresponse 15.00 [95% CI: 5.65, 25.05]) [Table 3].

BBV152 Prime cohort:

Anti-S IgG data: Baseline GMEUs of anti-S IgG against ancestral strain were comparable between the SII-NVX-CoV2373. At 28 days after the booster dose, there was a 7.4-fold-rise (95% CI 5.9, 9.1) from the baseline in the SII-NVX-CoV2373 group [GMEU 64868.7 (95% CI 56178.7, 74903.1)] and 1.5-fold-rise (95% CI 1.3, 1.8) from the baseline in the BBV152 group [GMEU 12344.1 (95% CI 10137.5, 15031.1)] [Table 2]. The primary endpoint of non-inferiority was met with 4.20 as the lower bound of 95% CI (GMEU ratio 5.12 [95% CI: 4.20, 6.24]) [Table 3].

There was 94.51% (95% CI 87.64, 98.19) and 20.43% (95% CI 12.77, 30.05) seroresponse at 28 days after the booster dose in the SII-NVX-CoV2373 group and BBV152 group, respectively. The difference in seroresponse between the SII-NVX-CoV2373 and the BBV152 group was highly significant. The primary endpoint of non-inferiority was met with 63.24% as the lower bound of 95% CI (Difference in proportion of seroresponse 74.08 [95% CI: 63.24, 82.17]) [Table 3].

Neutralizing antibodies (nAbs) data: Baseline GMTs of nAbs against ancestral strain were comparable between the SII-NVX-CoV2373 and the BBV152 groups. At 28 days after the booster dose, there was a 10.4-fold-rise (95% CI 7.9, 13.5) from the baseline in the SII-NVX-CoV2373 group [GMT 2848.1 (95% CI 2370.0, 3422.6)] and 2.5-fold-rise (95% CI 2.1, 3.1) in the BBV152 group [GMT 515.6 (95% CI 395.4, 672.3)] [Table 2]. The primary endpoint of non-inferiority was met with 3.76 as the lower bound of 95% CI of the GMT ratio (GMT ratio 4.80 [95% CI: 3.76, 6.12]) Table 3].

There was 98.90% (95% CI 94.03, 99.97) and 74.19% (95% CI 64.08, 82.71) seroresponse at 28 days after the booster dose in the SII-NVX-CoV2373 group and BBV152 group, respectively. The difference in seroresponse between the SII-NVX-CoV2373 and the BBV152 group was significant. The primary endpoint of non-inferiority was met with 16.26% as the lower bound of 95% CI of the difference in proportion of seroresponse (Difference in proportion of seroresponse 24.71 [95% CI: 16.26, 34.62]) [Table 3].

Neutralizing Antibodies and anti-S IgG Antibodies against Variants of Concern:

In the ChAdOx1 nCoV-19 prime cohort, SII-NVX-CoV2373 booster induced 3.5-fold-rise in GMTs and 84% seroresponse rate for nAbs against Omicron B.1.1.529 (BA.1) while a 1.3-fold-rise in GMTs and 40% seroresponse rate was seen with ChAdOx1 nCoV-19 booster [Tables 2 and 4]. In the BBV152 prime cohort, SII-NVX-CoV2373 booster induced 3.8-fold-rise in GMTs and 72% seroresponse rate for nAbs against Omicron B.1.1.529 while there was no rise in GMTs and only 24% seroresponse rate was seen with BBV152 booster [Table 2 and 4].

In the ChAdOx1 nCoV-19 prime cohort, SII-NVX-CoV2373 booster induced more than 3.9-fold-rise in GMEUs and more than 73% seroresponse rate for anti-S IgG antibodies against Omicron BA.1 and BA.5 while more than 2-fold-rise in GMEUs and more than 43% seroresponse rate was seen with ChAdOx1 nCoV-19 booster [Table 2 and 4]. In the BBV152 prime cohort, SII-NVX-CoV2373 booster induced more than 8-fold-rise in GMEUs and more than 91% seroresponse rate for anti-S IgG antibodies against Omicron BA.1 and BA.5 while there was no rise in GMTs or no seroresponse rate seen with BBV152 booster [Tables 2 and 4].

hACE2 receptor binding inhibition antibodies:

In the ChAdOx1 nCoV-19 prime cohort, SII-NVX-CoV2373 booster induced more than 3-fold-rise in hACE2 receptor binding inhibition antibodies GMTs and more than 69% seroresponse rate against Wuhan, Omicron BA.1 and Omicron BA.5 variants while more than 1.8-fold-rise in GMTs and more than 39% seroresponse rate was seen with ChAdOx1 nCoV-19 booster [Suppl. Tables 1 and 2]. In BBV152 prime cohort, SII-NVX-CoV2373 booster induced more than 7-fold-rise in hACE2 receptor binding inhibition antibodies GMTs and more than 86% seroresponse rate against Wuhan, Omicron BA.1 and Omicron BA.5 variants while there was no rise in GMTs and only 13.04% seroresponse rate was seen against Wuhan with BBV152 booster [Suppl. Tables 1 and 2].

CMI Response:

IFN-γ secreting T-Cell response to SARS-CoV-2 spike protein: There was increase in T cells responses to SARS-CoV-2 Spike protein at 28 days after booster dose in each group in both ChAdOx1 nCoV-19 and BBV152 prime cohorts [Suppl. Table 3].

Safety Results

SAEs and AESIs:

Two SAEs in 2 participants were reported in the study – lower respiratory tract infection and gastroenteritis with dehydration. Both were causally unrelated to the study vaccines. No AESI was reported.

Unsolicited AEs:

ChAdOx1 nCoV-19 prime cohort: Only a single unsolicited AE (1.1%) was reported in the SII-NVX-CoV2373 group and 6 unsolicited AEs in 4 participants (4.3%) in the ChAdOx1 nCoV-19 group and none was treatment-related. All AEs were of mild severity (except for 1 event of joint injury in the SII-NVX-CoV2373 group of moderate severity) and resolved without any sequelae.

BBV152 prime cohort:

A total of 5 unsolicited AEs (5.4%) were reported in the SII-NVX-CoV2373 group and 6 unsolicited AEs in 5 participants (5.3%) in the BBV152 group. None was treatment related in the SII-NVX-CoV2373 group and 2 events in the BBV152 group were treatment related (diarrhoea and injection site pain). All AEs were of mild to moderate severity (except for 1 severe event of hypertension in the BBV152 group) and resolved without any sequelae.

There were no AEs which led to study discontinuation in both the prime cohorts. There was only one case of COVID-19 reported in the study. This event occurred 3 months after the booster dose and was mild in severity, resolved without any sequalae.

Solicited AEs:

ChAdOx1 nCoV-19 prime cohort

There were 69 solicited AEs in 33 participants (35.9%) in the SII-NVX-CoV2373 group compared to 61 solicited AEs in 29 participants (30.9%) in the ChAdOx1 nCoV-19 group. The most common local solicited AEs were injection site pain, tenderness, swelling and erythema in the SII-NVX-CoV2373 group and injection site pain, tenderness and induration in the ChAdOx1 nCoV-19 group [Table 5].

The common systemic solicited AEs were headache, arthralgia, fatigue, malaise, myalgia, fever, vomiting and nausea in the SII-NVX-CoV2373 group and headache, arthralgia, fatigue, malaise, myalgia, vomiting and nausea in the ChAdOx1 nCoV-19 group [Table 5].

Almost all AEs were of mild severity and all resolved without any sequelae.

BBV152 prime cohort:

There were 84 solicited AEs in 34 participants (37%) in the SII-NVX-CoV2373 group compared to 87 solicited AEs in 43 participants (45.7%) in the BBV152 group. The most common local solicited AEs were injection site pain, tenderness, swelling, induration and erythema in the SII-NVX-CoV2373 group and injection site pain, tenderness, swelling, and induration in the BBV152 group [Table 5].

The common systemic solicited AEs were fatigue, headache, malaise, myalgia, arthralgia, fever, nausea and vomiting in the SII-NVX-CoV2373 group while fatigue, headache, malaise, myalgia, arthralgia, fever, nausea and vomiting in the BBV152 group [Table 5].

Almost all AEs (98%) were of mild severity and all resolved without any sequelae.

This Phase 3 study was conducted to assess heterologous booster effect of SII-NVX-CoV2373 in 372 adults who were primed with ChAdOx1 nCoV-19 or BBV152. The heterologous booster dose of SII-NVX-CoV2373 was non-inferior to both homologous booster dose of ChAdOx1 nCoV-19 and BBV152 in terms of anti-S IgG and neutralizing antibodies. Also, the SII-NVX-CoV2373 booster showed numerically better immune responses than BBV152 homologous booster in terms of anti-S IgG, neutralizing antibodies and hACE2 receptor binding inhibition antibodies against variant of concern (omicron). All three vaccines were found safe and well tolerated.

The homologous booster dose of COVID-19 vaccine in India started in January 2022 when the at-risk population (elderly, healthcare workers, etc.) were offered a free dose six months after the last dose. The programme opened for 18-59-year age group in April 2022 but it was a paid vaccination¹⁸. In July 2022, free booster vaccination was started for this group¹⁹. Our study started in May 2022 and this age group was ineligible to receive free booster dose through government program at the study initiation. this population could not earlier receive the booster from the government programme due to ineligibility. As a result, most of the participants in the study were between 18–59 years with only 20 participants above 60 years of age. Also, the mean duration from the last dose and booster dose was around nine months in both the cohorts.

GMTs/GMEUs of both the antibodies with SII-NVX-CoV2373 booster were at around 2 times higher than the ChAdOx1 nCoV-19 booster and more than 5 times higher than the BBV152 booster. Even the seroresponse rates with SII-NVX-CoV2373 were numerically higher than those in the ChAdOx1 nCoV-19 and BBV152 arms. In the COV-BOOST study conducted on various vaccine boosters, NVX-CoV2373 was found to show higher immune response as compared to viral vector vaccines and inactivated vaccines.¹⁷ The results in our study are in line with these findings.

There are no head to head efficacy studies but in general, primary immunization with NVX-CoV2373 has been found more protective against symptomatic Covid-19 than viral vector vaccines and inactivated vaccines. The vaccine gave around 90% efficacy^9,10 while the same estimate for ChAdOx1 nCoV-19 was around 70%²⁰ and for BBV152, it was around 77%²¹. Our study shows that the vaccine is more immunogenic than these two vaccines when given as a booster vaccination. One reason for this difference could be the Matrix M adjuvant in the vaccine. Matrix M enhances immune response through a combination of activities including recruitment and activation of innate immune cells to the site of vaccine injection, rapid antigen delivery to antigen-presenting cells, and enhanced antigen presentation via both major histocompatibility complex (MHC) I and MHC II molecules in the draining lymph nodes.²² In general heterologous booster is speculated to give better immune response than homologous booster but it is not always the case.²³ Therefore, the higher immune response seen with SII-NVX-CoV2373 in our study may not be only because it was used as a heterologous booster.

Solante R et al²⁴ reported that the real-world evidence from different COVID-19 vaccines (parent strain) supports the completion of primary series and booster vaccinations where appropriate, especially to restore waning vaccine effectiveness against the more infectious Omicron variant and protect populations from severe outcomes, hospital admissions, and longer lasting post-COVID-19 complications, as well as mortality. Though our study was not powered to assess effectiveness, only one case of mild COVID-19 was reported even during the strong omicron wave in India, thus implying good protection from the booster doses.

Neutralizing antibody titers are an accepted measure of immunity against COVID-19 while there is a strong correlation for neutralizing antibody titers with anti-Spike antibodies and ACE-2 Inhibition among vaccinated individuals.²⁵ We also found the similar trend in our study.

It is interesting to note that the baseline titres of both anti-S IgG and neutralizing antibodies in the ChAdOx1 nCoV-19 prime group were almost two times as compared to the BBV152 prime group even though the intervals since the last vaccination were quite similar. This has been reported before that ChAdOx1 nCoV-19 gave higher, more durable antibody response than BBV152.^26–29 Moreover, the post-booster titres in the ChAdOx1 nCoV-19 prime-ChAdOx1 nCoV-19 boost participants were much higher than in the BBV152 prime-BBV152 boost participants. This has also been reported previously.³⁰

Effectiveness of ChAdOx1 nCoV-19 has also been higher than BBV152.^31–34 The same effectiveness data for NVX-COV2373 booster are not available because the vaccine was approved much later than these two vaccines. As a result, it was not used in the programme in India to a great extent. However, the higher immune response seen in this study shows that NVX-COV2373 booster may give similar or higher effectiveness than ChAdOx1 nCoV-19 and BBV152.

In our study we did not assess the homologous booster dose of SII-NVX-CoV2373 as in India most of the population had already received primary immunization with either ChAdOx1 nCoV-19 or BBV152 when the study was initiated. However, NVX-CoV2373 was evaluated as homologous booster dose in a study in the USA and Australia.⁶ This study showed that for both the prototype strain and all variants evaluated, immune responses following the booster were similar to or higher than those associated with high levels of efficacy in phase 3 studies of the vaccine.

A UK-based study which assessed booster doses found that the heterologous booster induced greater systemic reactogenicity than their homologous counterparts.¹³ However, in our study heterologous booster induced numerically more systemic reactions than homologous booster in ChAdOx1 nCoV-19 prime cohort while homologous booster induced numerically more local reactions than heterologous booster in BBV152 prime cohort, though our study was not powered to detect these differences.

To conclude, heterologous booster vaccination with SII-NVX-CoV2373 in ChAdOx1 nCoV-19 and BBV152 primed adults demonstrated a booster response that was numerically higher than that achieved with homologous ChAdOx1 nCoV-19 and BBV152 booster vaccination. The vaccine had an acceptable safety profile. Further studies on the vaccine for pediatric boosters are being planned.

Contributors

PSK, BG, DK, and CSP contributed to the study design and protocol development. PSK, BG and DK accessed and verified the data. PSK, BG, DK, and AD contributed to the manuscript preparation. Manuscript was finalized with considerable inputs from all the authors. SK, SL, ST, SK, SR, PK, AA, AB, and HLB contributed to the data collection. US contributed to immunogenicity experiments oversight and supervision. JSP, MZ, SCC, MP, SH and MT contributed to the immunogenicity experiments.

Declaration of interests

PSK, BG, DK, AD and US are employees of SIIPL. JSP, MZ and SCC are employees of Novavax Inc. CSP is Chairman and Managing Director of SIIPL. All other authors declare no competing interests.

Acknowledgments

We gratefully acknowledge the contributions of our study participants. We acknowledge the DSMB members Dr Jayaprakash Muliyil, Dr Oommen John and Mr Charudatta Vaman Joglekar, and PPD for clinical monitoring and data management services.

Funding

The study was funded by Serum Institute of India Pvt Ltd.

Data sharing statement

Individual level participant data will not be made available to others due to privacy concerns. Anonymized study protocol will be appended to this paper.

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Table 1: Demographics and Baseline Characteristics – Safety Population

Parameter		ChAdOx1 nCoV-19 Prime Cohort		BBV152 Prime Cohort
Parameter		SII-NVX-CoV2373 (N=92)	ChAdOx1 nCoV-19 (N=94)	SII-NVX-CoV2373 (N=92)	BBV152 (N=94)
Age (Years), Mean (SD)		36.0 (11.04)	35.7 (9.56)	38.0 (14.13)	35.8 (14.44)

Age Group (Years), n (%)
18 - 59		90 (97.8)	94 (100)	83 (90.2)	85 (90.4)
>= 60		2 (2.2)	0	9 (9.8)	9 (9.6)

Sex, n (%)
Male		41 (44.6)	43 (45.7)	64 (69.6)	56 (59.6)
Female		51 (55.4)	51 (54.3)	28 (30.4)	38 (40.4)

SARS-CoV-2 RT-PCR Result, n (%)	Positive	0	0	0	0
SARS-CoV-2 RT-PCR Result, n (%)	Negative	92 (100)	94 (100)	92 (100)	94 (100)

Co-morbidities, n (%)	Yes	12 (13.0)	16 (17.0)	17 (18.5)	12 (12.8)
	No	80 (87.0)	78 (83.0)	75 (81.5)	82 (87.2)

Duration between two doses of prime vaccine (Days) Median (Min, Max)		87.00 (29.0, 285.0)	93.00 (30.0, 248.0)	35.50 (29.0, 214.0)	35.50 (29.0, 184.0)

Duration between Last dose of primary vaccination and booster vaccine (Days) Median (Min, Max)		261.50 (182.0, 606.0)	273.00 (186.0, 548.0)	295.50 (182.0, 417.0)	299.50 (182.0, 416.0)

Table 2: Summary of Anti-S IgG antibodies and neutralizing antibodies - Per Protocol Population

		ChAdOx1 nCoV-19 Prime Cohort		BBV152 Prime Cohort
Timepoint	Statistic	SII-NVX-CoV2373 (N=92)	ChAdOx1 nCoV-19 (N=93)	SII-NVX-CoV2373 (N=91)	BBV152 (N=93)
Anti-S IgG - Wuhan
Baseline	n	92	93	91	93
Baseline	GMEU (95% CI)	16870.1 (14053.1, 20251.8)	16378.4 (13610.2, 19709.7)	8811.9 (6990.4, 11108.2)	8001.5 (6243.4, 10254.7)

Visit 2 – Day 29	n	92	93	91	93
Visit 2 – Day 29	GMEU (95% CI)	66085.8 (57028.0, 76582.4)	31673.6 (27149.5, 36951.6)	64868.7 (56178.7, 74903.1)	12344.1 (10137.5, 15031.1)
	GMFR (95% CI)	3.9 (3.4, 4.5)	1.9 (1.7, 2.3)	7.4 (5.9, 9.1)	1.5 (1.3, 1.8)
Anti-S IgG - Omicron BA.1
Baseline	n	23	23	23	23
	GMEU (95% CI)	10149.6 (6579.2, 15657.6)	8943.0 (6365.5, 12564.1)	3772.4 (2358.3, 6034.5)	5253.7 (3736.1, 7387.7)

Visit 2 – Day 29	n	23	23	23	23
	GMEU (95% CI)	39758.2 (28381.2, 55695.8)	18595.6 (13678.3, 25280.6)	31142.0 (22349.8, 43392.9)	5080.1 (3954.1, 6526.8)
	GMFR (95% CI)	3.9 (2.7, 5.6)	2.1 (1.4, 3.0)	8.3 (5.1, 13.3)	1.0 (0.8, 1.1)
Anti-S IgG - Omicron BA.5
Baseline	n	23	23	23	23
	GMEU (95% CI)	10529.0 (6925.9, 16006.5)	8962.5 (6453.1, 12447.7)	3311.7 (2071.0, 5295.9)	5620.3 (3987.3, 7922.2)

Visit 2 – Day 29	n	23	23	23	23
	GMEU (95% CI)	43119.9 (30406.8, 61148.2)	21098.4 (15562.1, 28604.2)	31910.3 (22922.3, 44422.6)	6271.8 (4719.4, 8334.8)
	GMFR (95% CI)	4.1 (2.9, 5.7)	2.4 (1.7, 3.3)	9.6 (5.9, 15.8)	1.1 (1.0, 1.3)
Neutralizing antibodies - Wuhan
Baseline	n	92	93	91	93
Baseline	GMT (95% CI)	772.6 (606.7, 984.0)	726.5 (582.0, 906.8)	274.8 (202.6, 372.8)	203.1 (145.6, 283.4)

Visit 2 – Day 29	n	92	93	91	93
Visit 2 – Day 29	GMT (95% CI)	3963.0 (3343.8, 4696.7)	2031.9 (1690.6, 2442.1)	2848.1 (2370.0, 3422.6)	515.6 (395.4, 672.3)
	GMFR (95% CI)	5.1 (4.2, 6.2)	2.8 (2.3, 3.4)	10.4 (7.9, 13.5)	2.5 (2.1, 3.1)
Neutralizing antibodies - Omicron B.1.1.529 (BA.1)
Baseline	n	25	25	25	25
Baseline	GMT (95% CI)	47.2 (29.5, 75.5)	67.7 (44.4, 103.4)	51.3 (32.9, 80.0)	49.9 (32.1, 77.7)

Visit 2 – Day 29	n	25	25	25	25
	GMT (95% CI)	164.5 (105.9, 255.6)	86.9 (57.9, 130.7)	194.3 (120.4, 313.4)	41.1 (27.8, 60.8)
	GMFR (95% CI)	3.5 (2.3, 5.3)	1.3 (1.0, 1.7)	3.8 (2.3, 6.3)	0.8 (0.6, 1.2)

n: number of participants with a non-missing value at respective visit, GMEU: Geometric Mean ELISA Units, GMT: Geometric Mean Titres, GMFR: Geometric Mean Fold Rise, CI: Confidence Interval

For each study vaccine, the GMT and GMFR of nAbs and 95% CI were calculated by transforming to the original scale of log 10-transformed mean and its two-sided 95% CI limits at each visit.

Table 3: Non-inferiority of SII-NVX-CoV2373 heterologous booster to homologous booster in terms for Anti-S IgG and neutralizing antibodies at Visit 2-Day 29 - Per Protocol Population

ChAdOx1 nCoV-19 Prime Cohort

BBV152 Prime Cohort

SII-NVX-CoV2373
(N=92)

ChAdOx1 nCoV-19
(N=93)

SII-NVX-CoV2373
(N=91)

BBV152

(N=93)

Anti-S IgG

GMEU [1] with 95% CI

65550.37

(58155.85, 73885.11)

31945.42

(28366.25, 35976.20)

65155.31

(56348.14, 75339.04)

12719.72

(11063.37, 14624.05)

GMEU Ratio (GMR) [1] with 95% CI

2.05 (1.73, 2.43)

5.12 (4.20, 6.24)

Seroresponse

n (%)

95% CI

80 (86.96)

(78.32, 93.07)

35 (37.63)

(27.79, 48.28)

86 (94.51)

(87.64, 98.19)

19 (20.43)

(12.77, 30.05)

Difference in Proportions 95% CI

49.32 (36.49, 60.45)

74.08 (63.24, 82.17)

Neutralizing antibodies

GMT [1]

95 % Confidence Interval

3883.22

(3363.26, 4483.56)

2050.29

(1777.55, 2364.88)

2654.90

(2221.75, 3172.49)

553.59

(466.46, 657.00)

GMT Ratio (GMR) [1]

95 % Confidence Interval

1.89 (1.55, 2.32)

4.80 (3.76, 6.12)

Seroresponse

n (%)

95% CI

87 (94.57)

(87.77, 98.21)

74 (79.57)

(69.95, 87.23)

90 (98.90)

(94.03, 99.97)

69 (74.19)

(64.08, 82.71)

Difference in Proportions 95% CI

15.00 (5.65, 25.05)

24.71 (16.26, 34.62)

LS=Least Squares; GMT=Geometric Mean Titers; GMR=Geometric Mean Ratio

[1] ANCOVA results, LS Mean and it's 95% CI values by treatment were used to generate the GMEU/GMT and 95% CI and the differences in LS Means and corresponding 95% CI limits were used to obtain GMEU/GMT Ratio and 95% CI using back transforming to the original scale.

ANCOVA model includes vaccine group, log baseline titer, age, sex, duration between first and second vaccine dose of the prime vaccine, duration between second dose of the prime vaccine to booster dose of the study vaccine.

The 95% CIs for each vaccine group were calculated by using the Clopper-Pearson method.

Estimate of difference in proportion along with associated 95% CI was obtained using Miettinen and Nurminen method.

Table 4: Summary of Proportion of Participants with Seroresponse for anti-S IgG and nAbs against Variants of Concern at day 29 - Per Protocol Population

	ChAdOx1 nCoV-19 Prime Cohort		BBV152 Prime Cohort
Statistic	SII-NVX-CoV2373 (N=92)	ChAdOx1 nCoV-19 (N=93)	SII-NVX-CoV2373 (N=91)	BBV152 (N=93)
Anti-S IgG - Omicron BA.1
N Evaluated	23	23	23	23
n (%)	17 (73.91)	10 (43.48)	21 (91.30)	1 (4.35)
95% CI	(51.59, 89.77)	(23.19, 65.51)	(71.96, 98.93)	(0.11, 21.95)

Anti-S IgG - Omicron BA.5
N Evaluated	23	23	23	23
n (%)	20 (86.96)	11 (47.83)	22 (95.65)	1 (4.35)
95% CI	(66.41, 97.22)	(26.82, 69.41)	(78.05, 99.89)	(0.11, 21.95)

Neutralizing Antibodies - B.1.1.529 (BA.1)
N Evaluated	25	25	25	25
n (%)	21 (84.00)	10 (40.00)	18 (72.00)	6 (24.00)
95% CI	(63.92, 95.46)	(21.13, 61.33)	(50.61, 87.93)	(9.36, 45.13)

N Evaluated is the number of participants with a non-missing value at Baseline and Post-baseline visit-day 29.

n is the number of participants with Seroresponse (i.e. at least two-fold increase from baseline) at day 29 as compared to baseline titres.

The 95% CIs for each vaccine group were calculated by using the Clopper-Pearson method.

Table 5: Summary of Solicited Adverse Events – Safety Population

	ChAdOx1 nCoV-19 Prime Cohort		BBV152 Prime Cohort
	SII-NVX-CoV2373 (N=92) n (%) [E]	ChAdOx1 nCoV-19 (N=94) n (%) [E]	SII-NVX-CoV2373 (N=92) n (%) [E]	BBV152 (N=94) n (%) [E]

Participants with at Least One Solicited Adverse Event	33 (35.9) [69]	29 (30.9) [61]	34 (37.0) [84]	43 (45.7) [87]

Participants with at Least One Local Solicited AE	18 (19.6) [26]	24 (25.5) [28]	20 (21.7) [29]	36 (38.3) [43]
Injection Site Pain	17 (18.5) [17]	24 (25.5) [24]	20 (21.7) [20]	35 (37.2) [35]
Injection Site Tenderness	5 (5.4) [5]	3 (3.2) [3]	4 (4.3) [4]	6 (6.4) [6]
Injection Site Swelling	3 (3.3) [3]	0	3 (3.3) [3]	1 (1.1) [1]
Injection Site Erythema	1 (1.1) [1]	0	1 (1.1) [1]	0
Injection Site Induration	0	1 (1.1) [1]	1 (1.1) [1]	1 (1.1) [1]

Participants with at Least One Systematic Solicited AE	24 (26.1) [43]	17 (18.1) [33]	25 (27.2) [55]	25 (26.6) [44]
Headache	12 (13.0) [12]	11 (11.7) [11]	13 (14.1) [13]	9 (9.6) [9]
Arthralgia	7 (7.6) [7]	6 (6.4) [6]	5 (5.4) [5]	5 (5.3) [5]
Fatigue	7 (7.6) [7]	6 (6.4) [6]	11 (12.0) [11]	11 (11.7) [11]
Malaise	5 (5.4) [5]	4 (4.3) [4]	12 (13.0) [12]	7 (7.4) [7]
Myalgia	5 (5.4) [5]	3 (3.2) [3]	7 (7.6) [7]	5 (5.3) [5]
Fever	5 (5.4) [5]	0	4 (4.3) [4]	4 (4.3) [4]
Vomiting	1 (1.1) [1]	2 (2.1) [2]	1 (1.1) [1]	1 (1.1) [1]
Nausea	1 (1.1) [1]	1 (1.1) [1]	2 (2.2) [2]	2 (2.1) [2]

n: number of participants, E: number of events

There is a conflict of interest Authors PSK, BG, DK, AD, MG and US are employees of SIIPL. JSP, MZ and SCC are employees of Novavax Inc. CSP is Chairman and Managing Director of SIIPL. All other authors declare no competing interests.

A randomized, controlled study to evaluate the safety and immunogenicity of a heterologous booster dose of an adjuvanted SARS CoV-2 recombinant spike protein vaccine in adults

Status:

Version 1

Abstract

Background

Methods

Results

Conclusion

Figures

Research In Context

Introduction

Materials And Methods

Study Participants

Study Vaccines

Randomization And Blinding

Study Procedures

Immunogenicity Assessments

Safety Assessments

Statistical Considerations

Ethical Considerations

Results

Discussion

Declarations

References

Tables

Additional Declarations

Supplementary Files

Status:

Version 1