key: cord-0965904-ter7j32f
authors: Kaabi, N. A.; Yang, Y. K.; Du, L. F.; Xu, K.; Shao, S.; Liang, Y.; Kang, Y.; Su, J. G.; Zhang, J.; Yang, T.; Hussein, S.; ElDein, M. S.; Yang, S. S.; Lei, W.; Gao, X. J.; Jiang, Z.; Cong, X.; Tan, Y.; Wang, H.; Li, M.; Mekki, H. M.; Zaher, W.; Mahmoud, S.; Zhang, X.; Qu, C.; Liu, D. Y.; Yang, M.; Eltantawy, I.; Hou, J. W.; Lei, Z. H.; Xiao, P.; Wang, Z. N.; Yin, J. L.; Mao, X. Y.; Qu, L.; Zhang, Y. T.; Yang, X. M.; Wu, G.; Li, Q. M.
title: Safety and immunogenicity of a hybrid-type vaccine booster in BBIBP-CorV recipients: a randomized controlled phase 2 trial
date: 2022-03-10
journal: nan
DOI: 10.1101/2022.03.08.22272062
sha: a58d33ce0d1835814b40f4034f2f2dea1701f755
doc_id: 965904
cord_uid: ter7j32f

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with immune escape ability raises the urgent need for developing cross-neutralizing vaccines against the virus. NVSI-06-08 is a potential broad-spectrum recombinant COVID-19 vaccine that integrates the antigens from multiple SARS-CoV-2 strains into a single immunogen. Here, we evaluated the safety and immunogenicity of NVSI-06-08 as a heterologous booster dose in adults previously vaccinated with the inactivated vaccine BBIBP-CorV in a randomized, double-blind, controlled, phase 2 trial conducted in the United Arab Emirates (NCT05069129). Three groups of healthy adults over 18 years of age (600 participants per group) who had administered two doses of BBIBP-CorV 4-6-month, 7-9-month and >9-month earlier, respectively, were vaccinated with either a homologous booster of BBIBP-CorV or a heterologous booster of NVSI-06-08. The primary outcome was immunogenicity and safety of booster vaccinations. The exploratory outcome was cross-reactive immunogenicity against multiple SARS-CoV-2 variants of concerns (VOCs). The incidence of adverse reactions was low in both booster vaccinations, and the overall safety profile of heterologous boost was quite similar to that of homologous boost. Heterologous NVSI-06-08 booster was immunogenically superior to homologous booster of BBIBP-CorV. Both Neutralizing and IgG antibodies elicited by NVSI-06-08 booster were significantly higher than by the booster of BBIBP-CorV against not only SARS-CoV-2 prototype strain but also multiple VOCs. Especially, the neutralizing activity induced by NVSI-06-08 booster against the immune-evasive Beta variant was no less than that against the prototype strain, and a considerable level of neutralizing antibodies against Omicron (GMT: 367.67; 95%CI, 295.50-457.47) was induced by heterologous booster, which was substantially higher than that boosted by BBIBP-CorV (GMT: 45.03; 95%CI, 36.37-55.74). Our findings showed that NVSI-06-08 was safe and immunogenic as a booster dose following two doses of BBIBP-CorV, which was immunogenically superior to homologous boost with another dose of BBIBP-CorV. Our study also indicated that the design of hybrid antigen may provide an effective strategy for broad-spectrum vaccine developments.

A total of 1833 healthy adults (≥18 years old) were enrolled, and these participants were classified into three groups with different prime-boosting intervals, i.e., 4-6 months, 7-9 months and >9 months. For each group, participants were randomly assigned to receive either a heterologous boost of NVSI-06-08 or a homologous boost of BBIBP-CorV. Among the enrolled participants, 1800 individuals completed booster vaccination, with 600 participants in each group (Fig. 1) . The majority of the participants were Bangladeshis, Indian or Pakistanis, and more men than women participated in the trial. The demographic characteristics were broadly similar between heterologous and homologous boosting groups (Table 1 and Extended Data Table 1 ). The participants in two groups had similar age, sex, race, height and weight distributions. All the 1800 participants who had received the booster dose of vaccination were included in Safety Set (SS) for safety analysis. A total of 1678 participants who had no protocol deviations from the follow-up visits were included in Perprotocol set (PPS) for baseline analysis immunogenicity evaluation (Fig. 1) .

For the participants, baseline IgG concentrations and neutralizing antibody titers were quantified using a chemiluminescence enzyme immunoassay kit and the live-virus neutralization assay, respectively, before booster vaccination. The baseline antibody levels were statistically similar between the participants in heterologous and homologous boosting groups. Before boosting vaccination, the baseline IgG GMCs were similar in the participants among groups with different prime-boosting intervals. However, neutralizing GMTs in the participants from >9-month group were lower than from 7-9-month group, and those from 7-9-month group were also lower than from 4-6-month group, which demonstrated wanning of neutralizing immunity over time (Table 1 ). The decay of neutralizing immunity highlighted the need for booster vaccination to top-up the immune response.

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In the trial, 146 (16.29%) participants receiving NVSI-06-08 boost and 115 (12.72%) receiving BBIBP-CorV boost reported at least one solicited adverse reaction within 7 days after vaccination, and most of them were of grade 1 or 2. The overall incidence of solicited adverse reactions was low in both booster vaccinations (Fig. 2a,b and Extended Data Table 2 ). The occurrence of solicited local adverse reactions was quite similar between heterologous and homologous booster groups. All the reported local reactions were of grade 1 or 2, and most of them were injection-site pain (Fig. 2a and Extended Data Table 2 ). Solicited systemic adverse reactions reported by participants in heterologous boosting groups were also similar to those reported by homologous boosting groups.

The reported systemic reactions were mostly of grade 1 or 2, and the most frequent reactions were headache, muscle pain, fatigue and fever. Grade 3 systemic reactions, including fever and muscle pain, were only observed in 0.45% participants of heterologous groups and 0.22% participants of homologous group, respectively. No grade 4 or above systemic reaction was found ( Fig. 2b and Extended Data Table 2 ). The proportion of participants reporting unsolicited adverse reactions was also comparable between heterologous and homologous booster groups (5.36% vs 5.31%). The observed unsolicited reactions primarily included myalgia (0.56% vs 0.66%), fever (0.45% vs 0.55%) and cough (0.33% vs 0.88%), most of which were graded as level 1 or 2 (Extended Data Table 2 ). In both groups, no AESI and vaccination-related SAE was reported as of the time of this report. Overall, these data suggest that the heterologous boosting with a dose of NVSI-06-08 following two doses of BBIBP-CorV has a good safety profile, which were quite similar to homologous boosting with BBIBP-CorV.

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Significantly increase in neutralizing antibody titers against the prototype SARS-CoV-2 virus, detected by live-virus neutralization assays, were observed after both homologous and heterologous boosting vaccinations compared to the pre-boosting baseline values. However, the post-vaccination neutralizing antibody GMTs of heterologous boosting group were dramatically higher than those of homologous boosting groups. On day 15 post-vaccination, GMTs of neutralizing antibodies elicited by homologous BBIBP-CorV boost were increased by 2.93-fold (95%CI, 2.54-3.37) in 4-6-month group, 10. 34-fold (8.78-12.19 ) in 7-9-month group and 21. 44-fold (18.56-24.77 ) in >9-month group, respectively, compared to the pre-boosting baseline levels. Whereas, those elicited by heterologous NVSI-06-08 boost were improved by 40.10-fold (95%CI, and 246. 81-fold (207.02-294.26 ) in the three groups, respectively ( Fig. 3a and Extended Data Table   3 ). Correspondingly, the 4-fold rise rates of neutralizing antibodies boosted by BBIBP-CorV were 22.84% (95%CI, 18.13%-28.12%), 75.19% (69.59%-80.22%), and 94.24% (90.82%-96.67%) in 4-6-month, 7-9-month and >9-month groups, while those boosted by NVSI-06-08 reached 93.68% (95%CI, 90.20%-96.21%), 98.15% (95.73%-99.40%) and 99.65% (98.07%-99.99%) in the three groups, respectively ( Fig. 3b and Extended Data Table 3 ). Neutralizing antibody GMTs and 4-fold rise rates further increased on day 30 after booster vaccination, and the neutralizing responses induced by heterologous boost was also remarkably superior to those by homologous boost (P<0.0001). On day 30 post-vaccination, homologous boost of BBIBP-CorV led to 4.38-fold (95%CI, ) increases from baselines in neutralizing antibody GMTs for participants from 4-6-month, 7-9-month and >9-month . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity.

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The copyright holder for this this version posted March 10, 2022. ; https://doi.org/10.1101 https://doi.org/10. /2022 groups, respectively, whereas much greater increases of 47. were obtained by heterologous boost of NVSI-06-08 ( Fig. 3a and Extended Data Table 3) . A similar increase trend was also observed in 4fold rise rates. For 4-6-month, 7-9-month and >9-month groups, the 4-fold rise rates induced by homologous boost were 38.75% (95%CI, 33.11%-44.64%), 92.96% (95%CI, 89.23%-95.71%) and 98.20% (95.85%-99.41%), respectively, which were increased to 96.84% (95%CI, 94.09%-98.55%), 99.26% (97.35%-99.91%) and 100.00% (98.72%-100.00%) induced by heterologous boost (Fig. 3b and Extended Data Table 3 ). Our data indicate that heterologous boosting with NVSI-06-08 is dramatically more immunogenic than homologous boosting with BBIBP-CorV. Among three groups with different prime-boosting intervals, the post-vaccination neutralizing antibody levels in the participants of 7-9-month group were comparable to those of >9-month group, both of which were significantly higher than those of 4-6-month group. Especially, the neutralizing GMTs elicited by NVSI-06-08 in 7-9-month group reached as high as 7719.35 against wild-type SARS-CoV-2 virus. The results suggest that a booster dose with a prime-boosting interval over 6 months is immunogenically optimal.

The immunogenic superiority of heterologous NVSI-06-08 booster to homologous BBIBP-CorV booster was also confirmed by anti-RBD IgG response. In line with the neutralizing antibody titers, both homologous and heterologous boosting vaccinations significantly improved the RBDspecific IgG antibody levels. However, heterologous booster induced dramatically higher IgG GMCs than homologous booster in all groups with different boosting intervals. Compared to preboosting baselines, anti-RBD IgG GMCs were increased by 2.56-3.58 folds at 15 days after vaccination in the groups boosted with BBIBP-CorV, whereas, much higher 49.15 to 62.62-fold . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity.

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The copyright holder for this this version posted March 10, 2022. ; https://doi.org/10.1101/2022.03.08.22272062 doi: medRxiv preprint increases were observed in the groups boosted with heterologous NVSI-06-08 ( Fig. 4a and Extended Data Table 4 ).

NVSI-06-08 was designed as a hybrid-type vaccine with broader neutralizing profiles, the crossreactive immunogenicity of heterologous NVSI-06-08 booster against multiple SARS-CoV-2 VOCs, including Omicron, was evaluated as an exploratory study. A total of 200 serum samples, collected on day 15 post-boosting, from the participants with sequential enrollment numbers in 7-9-month group (99 participants receiving heterologous boost and 101 receiving homologous boost) were used in the cross-neutralizing activity tests.

In participants receiving the homologous boost of BBIBP-CorV, compared to the neutralizing . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity.

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The copyright holder for this this version posted March 10, 2022. ; https://doi.org/10.1101/2022.03.08.22272062 doi: medRxiv preprint antibody level against prototype SARS-CoV-2 strain [GMT: 460.39 (95%CI, 369.08-574.29)], the anti-Omicron neutralizing GMT significantly reduced to 45.03 (95%CI, 36.37-55.74), indicating distinct escape of Omicron variant from the immunity given by BBIBP-CorV. Our results are consistent with other studies 11-14 . By comparison, in participants receiving the heterologous boost of NVSI-06-08, the neutralizing antibody GMT against Omicron still maintained at a high level of 367.67 (95%CI, 295.50-457.47), which was much higher than that induced by homologous boost ( Fig. 5 and Extended Data Table 5 ). Given that Omicron-specific vaccine is not yet available, a booster dose of NVSI-06-08 may serve as a possible choice against Omicron for BBIBP-CorV recipients.

We also evaluated the neutralizing antibody response against other several SARS-CoV-2 VOCs, including Alpha, Beta and Delta. All the tested VOCs were significantly less sensitive to the neutralization induced by BBIBP-CorV booster. However, the neutralizing antibody response against Alpha and Beta variants offered by NVSI-06-08 booster was comparable to that against prototype strain. For all the tested variants, heterologous booster induced substantially greater neutralizing antibody levels than homologous booster. The GMTs of neutralizing antibodies boosted by NVSI-06-08 were 11.04-fold, 14.98-fold and 9.48-fold higher than those boosted by BBIBP-CorV against Alpha, Beta and Delta variants, respectively ( Fig. 5 and Extended Data Table 5 ).

NVSI-06-08 boosting vaccination is immunogenically superior to homologous BBIBP-CorV boosting against not only prototype SARS-CoV-2 strain but also other immune-evasive VOCs, including Omicron.

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The copyright holder for this this version posted March 10, 2022. ; https://doi.org/10.1101/2022.03.08.22272062 doi: medRxiv preprint Findings from this trial show that the heterologous prime-boosting vaccination with one dose of NVSI-06-08 following two doses of BBIBP-CorV was safe, tolerant and immunogenic in healthy adults. The heterologous prime-boosting regimen with BBIBP-CorV/NVSI-06-08 was immunogenically superior to homologous BBIBP-CorV boost. The neutralizing antibody GMTs elicited by heterologous boost were 9.72-15.96-fold higher than those elicited by homologous boost (GMT, The overall safety profile of heterologous boost was quite similar to that of homologous boost, which was also comparable to the safety of the priming with two doses of BBIBP-CorV as reported previously 15 . A booster dose did not distinctly increase the risk of more serious side effects. The antigen of NVSI-06-08 was designed to realize trimerization of RBDs without introducing any . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity.

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The copyright holder for this this version posted March 10, 2022. ; https://doi.org/10.1101/2022.03.08.22272062 doi: medRxiv preprint exogenous sequence, which facilitated the cross-links of B cell receptors but without introducing additional safety risks. In the vaccine, aluminum adjuvant was used, whose safety has been verified for a long time. All these features contributed to the high safety profile of NVSI-06-08.

NVSI-06-08 was designed as a hybrid-type COVID-19 vaccine with broad protection potential, which integrated multiple antigens into a single molecule without introduction any exogenous linker.

Our studies show that booster vaccination of NVSI-06-08 elicited potent cross-neutralizing response against various SARS-CoV-2 VOCs. Especially, the neutralizing activity induced by NVSI-06-08 booster against the highly immune-evasive Beta variant was no less than that against the prototype strain, which demonstrated the immunological superiority of hybrid-type vaccine. Although the immunity offered by NVSI-06-08 booster was less effective against Omicron variant as compared to that against prototype virus, the anti-Omicron neutralizing GMT still maintained at a considerable level of 367.67 (95%CI, 295.50-457.47) on day 15 after booster vaccination, which was substantially higher than that boosted by BBIBP-CorV. According to the increasing trends in immune response, a greater anti-Omicron neutralizing GMT can be obtained on day 30 post-boost.

Given that Omicron-specific vaccine is not yet available, the prime-boost vaccination with inactivated COVID-19 vaccine plus NVSI-06-08 may be an optional strategy against the pandemic of Omicron. The RBD of Omicron harbors numerous mutations, most of which were not integrated into the antigen of NVSI-06-08. We think that update of the vaccine to incorporate the Omicron- is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted March 10, 2022. ; https://doi.org/10.1101/2022.03.08.22272062 doi: medRxiv preprint superior immunogenicity of heterologous immunogen may be attributed to the avidity advantage to cross-reactive B cells 9 . Our studies provide a promising method for broad-spectrum COVID-19 vaccine development.

Considering that inactivated COVID-19 vaccines have been inoculated in large-scale populations worldwide, and the immunity offered by the vaccine decays obviously over time 19 , it is of significance to choose a preferred vaccine as a booster dose to restore and even top-up the immunity against SARS-CoV-2. Our studies provided a quite effective booster strategy for the inactivated vaccine recipients. The high level of neutralizing antibodies induced by heterologous BBIBP-CorV/NVSI-06-08 vaccination could alleviate the waning of immunity and facilitate the formation of immune barrier, which then may suppress virus mutations.

Our findings show that the prime-boost vaccination with an interval over 6 months was immunogenically superior to the interval of 4-6 months. Many studies have revealed that primeboost interval has significant influence on the immune efficacy of COVID vaccines 20,21 . Our results are consistent with those previously reported studies. An over-6-month interval may facilitate better maturation of memory cells, and improve binding affinity and production level of antibodies. This trial has several limitations. Firstly, among participants, the proportion of elderly persons aged ≥60 years was low, and the immune response of the BBIBP-CorV/NVSI-06-08 booster strategy in older population should be further assessed in the future. Secondary, the number of male participants were much larger than female, and the data may not well reflect the effect in women.

In summary, heterologous prime-boosting vaccination with BBIBP-CorV plus NVSI-06-08 was well tolerated and immunogenic against not only SARS-CoV-2 prototype strain but also the VOCs including Omicron. It was immunogenically superior to the booster with a third dose of . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity.

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We conducted a randomized, double-blind, controlled phase 2 trial to evaluate the immunogenicity and safety of NVSI-06-08 (Sinopharm) as a booster dose following a primary series of BBIBP-CorV (Sinopharm). Trial participants included three groups of healthy adults aged ≥18 years who had received two doses of BBIBP-CorV 4-6 months, 7-9 months and >9 months before, respectively.

Participants were enrolled after undergoing a health screening by inquiry, medical history review and physical examination. Confirmed, suspected or asymptomatic COVID-19 cases, individuals with a history of SARS or MERS infections, and those vaccinated with any other COVID-19 vaccines were excluded. The detailed inclusion and exclusion criteria are available at ClinicalTrials.gov (NCT05069129). is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted March 10, 2022. (CNBG) of Sinopharm designed the trial, performed the analyses and interpreted the data. All authors had full access to study data and the corresponding authors were responsible for the decision to submit the manuscript.

NVSI-06-08 is a potential broad-spectrum recombinant COVID-19 vaccine, using a hybrid mutItri-RBD as the antigen, which was developed by the National Vaccine and Serum Institute (NVSI) of Sinopharm and manufactured by Beijing Institute of Biological Products Co., Ltd (BIBP) of Sinopharm and Lanzhou Institute of Biological Products Co., Ltd (LIBP) of Sinopharm in accordance with good manufacturing practice (GMP). One dose of NVSI-06-08 contains 20 μg antigen and 0·3 mg aluminum hydroxide adjuvant. BBIBP-CorV is an inactivated vaccine produced by Beijing Institute of Biological Products Co., Ltd (BIBP) of Sinopharm, which has been approved by WHO for emergency use and applied in many countries worldwide.

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In each of the three groups with different prime-boost intervals, the participants were randomly assigned to receive either a heterologous boost of NVSI-06-08 or a homologous boost of BBIBP-CorV. After booster vaccination, participants were observed at study site for 30 min to identify immediate adverse reactions. Solicited adverse events (AEs) were recorded for 7 days and unsolicited AEs for 30 days post-vaccination. Serious adverse events (SAEs) and adverse events of special interest (AESIs) were collected up to 6 months after full course of immunization. The grades of local and systemic adverse events were determined according to the relevant guidance of China National Medical Products Administration (NMPA).

The primary immunogenicity outcome was the neutralizing response on 15 days and 30 days after booster vaccination, by evaluation of the geometric mean titers (GMTs) of neutralizing antibodies and the corresponding 4-fold rise rate (i.e., post-/pre-boost ≥4). The secondary immunogenicity outcome was geometric mean concentrations (GMCs) of IgG antibodies and the corresponding 4fold rise rate. The safety outcome was occurrence and severity of any adverse reactions within 30 days post-boost. As an exploratory study, the immunogenicity of booster vaccination against SARS-CoV-2 variants of concerns (VOCs), including Omicron, was also evaluated in a subset of participants from 7-9-month group.

Spike receptor-binding domain (RBD)-specific IgG antibodies against the prototype SARS-CoV-2 strain was measured using a commercially available magnetic particle-based chemiluminescence . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity.

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A total of 1833 participants were enrolled, and 1800 received booster vaccinations. Participants were classified into three groups with different prime-boost intervals. The participants in each group were randomly assigned to receive a booster dose of eighter NVSI-06-08 or BBIBP-CorV. All the 1800 participants receiving booster vaccination were included in safety set (SS) for safety analysis.

A total of 1678 participants who had no protocol deviations on follow-up visits were included in Per-protocol set (PPS) for immunogenicity analysis. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted March 10, 2022. ; https://doi.org/10.1101/2022.03.08.22272062 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted March 10, 2022. ; https://doi.org/10.1101/2022.03.08.22272062 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted March 10, 2022. ; https://doi.org/10.1101/2022.03.08.22272062 doi: medRxiv preprint booster (b). Data are presented as GMTs and 95% CIs. *: P<0.05, ****: P<0.0001. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted March 10, 2022. ; https://doi.org/10.1101/2022.03.08.22272062 doi: medRxiv preprint GMCs of RBD-binding IgG antibodies increased from baseline (day 0) to day 15 and 30 postboosting elicited by heterologous NVSI-06-08 booster, compared with those induced by homologous BBIBP-CorV boosting (a). Correspondingly, the 4-fold rise rates of IgG antibodies on day 15 and 30 after boosting elicited by NVSI-06-08 booster, compared with those induced by BBIBP-CorV booster (b). Data are presented as GMCs and 95% CIs. *: P<0.05, ****: P<0.0001. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted March 10, 2022. ; https://doi.org/10.1101/2022.03.08.22272062 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint [2] The ratio of GMT between two groups was calculated by "NVSI-06-08/ BBIBP-CorV", and the non-inferiority threshold of ratio between groups on day 15 post-booster was set to 0·67.

[3] Rate of 4-fold rise was defined as percentage of participants with a ≥4-fold rise from baseline in neutralizing antibody titer.

[4] Rate difference=(NVSI-06-08)-(BBIBP-CorV). Rate difference and 95%CI were estimated by Miettnen-Nurminen method without considering stratification factors. (0) 289 (0) 

GMC between two groups (95%CI