Safety and immunogenicity of a hybrid-type vaccine booster in BBIBP-CorV recipients in a randomized phase 2 trial

Nawal Al Kaabi, Yun Kai Yang, Li Fang Du, Ke Xu, Shuai Shao, Yu Liang, Yun Kang, Ji Guo Su, Jing Zhang, Tian Yang, Salah Hussein, Mohamed Saif ElDein, Sen Sen Yang, Wenwen Lei, Xue Jun Gao, Zhiwei Jiang, Xiangfeng Cong, Yao Tan, Hui Wang, Meng Li, Hanadi Mekki Mekki, Walid Zaher, Sally Mahmoud, Xue Zhang, Chang Qu, Dan Ying Liu, Jing Zhang, Mengjie Yang, Islam Eltantawy, Jun Wei Hou, Ze Hua Lei, Peng Xiao, Zhao Nian Wang, Jin Liang Yin, Xiao Yan Mao, Jin Zhang, Liang Qu, Yun Tao Zhang, Xiao Ming Yang, Guizhen Wu, Qi Ming Li, Nawal Al Kaabi, Yun Kai Yang, Li Fang Du, Ke Xu, Shuai Shao, Yu Liang, Yun Kang, Ji Guo Su, Jing Zhang, Tian Yang, Salah Hussein, Mohamed Saif ElDein, Sen Sen Yang, Wenwen Lei, Xue Jun Gao, Zhiwei Jiang, Xiangfeng Cong, Yao Tan, Hui Wang, Meng Li, Hanadi Mekki Mekki, Walid Zaher, Sally Mahmoud, Xue Zhang, Chang Qu, Dan Ying Liu, Jing Zhang, Mengjie Yang, Islam Eltantawy, Jun Wei Hou, Ze Hua Lei, Peng Xiao, Zhao Nian Wang, Jin Liang Yin, Xiao Yan Mao, Jin Zhang, Liang Qu, Yun Tao Zhang, Xiao Ming Yang, Guizhen Wu, Qi Ming Li

Abstract

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 evaluate the safety and immunogenicity of NVSI-06-08 as a heterologous booster dose in BBIBP-CorV recipients 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 have administered two doses of BBIBP-CorV 4-6-month, 7-9-month and >9-month earlier, respectively, are randomized 1:1 to receive either a homologous booster of BBIBP-CorV or a heterologous booster of NVSI-06-08. The incidence of adverse reactions is low, and the overall safety profile is quite similar between two booster regimens. Both Neutralizing and IgG antibodies elicited by NVSI-06-08 booster are significantly higher than those by BBIBP-CorV booster against not only SARS-CoV-2 prototype strain but also multiple variants of concerns (VOCs). Especially, the neutralizing antibody GMT against Omicron variant induced by heterologous NVSI-06-08 booster reaches 367.67, which is substantially greater than that boosted by BBIBP-CorV (GMT: 45.03). In summary, NVSI-06-08 is safe and immunogenic as a booster dose following two doses of BBIBP-CorV, which is immunogenically superior to the homologous boost with another dose of BBIBP-CorV.

Conflict of interest statement

Y.K.Y., T.Y., M.L., X.Z., C.Q., D.Y.L., Z.N.W., J.L.Y., L.Q., Y.T.Z., and X.M.Y. are employees of the China National Biotec Group Company Limited. L.F.D., S.S., Y.L., Y.K., J.G.S., Jing Zhang (NVSI), S.S.Y., X.C., Y.T., J.W.H., Z.H.L., and Q.M.L. are employees of the National Vaccine and Serum Institute (NVSI). X.J.G. and X.Y.M. are employees of Lanzhou Institute of Biological Products Company Limited (LIBP). H.W. and Jin Zhang are employees of Beijing Institute of Biological Products Company Limited (BIBP). L.F.D., S.S., Y.L., J.G.S., Jing Zhang (NVSI), J.W.H., Z.H.L., and Q.M.L. are listed as inventors of the patent applications for the recombinant trimeric RBD-based vaccines (Application numbers: 202110348881.6, 202110464788.1 and 202110676901.2). The other authors declare no competing interests.

© 2022. The Author(s).

Figures

Fig. 1. Randomization and analysis populations.
Fig. 1. Randomization and analysis populations.
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.
Fig. 2. Incidence and severity of solicited…
Fig. 2. Incidence and severity of solicited adverse reactions after booster vaccinations with NVSI-06-08 and BBIBP-CorV, respectively.
a, b Incidence and severity of local (a) and systemic (b) adverse reactions after boosted with NVSI-06-08 were compared to those boosted with BBIBP-CorV. Adverse reactions are graded according to the relevant guidance of the China National Medical Products Administration (NMPA).
Fig. 3. Neutralizing antibody levels against prototype…
Fig. 3. Neutralizing antibody levels against prototype SARS-CoV-2 before and 15 and 30 days after the booster vaccinations.
a GMTs of neutralizing antibodies increased from baseline (day 0) to day 15 and 30 post-boosting elicited by heterologous NVSI-06-08 booster, compared with those induced by homologous BBIBP-CorV booster. b Correspondingly, the four-fold rise rates of neutralizing antibodies on day 15 and 30 after boosting elicited by NVSI-06-08 booster, compared with those induced by BBIBP-CorV booster. Both in a and b, for NVSI-06-08 booster vaccination, n = 285 in 4–6-month group, n = 270 in 7–9-month group, and n = 286 in >9-month group. For BBIBP-CorV booster vaccination, n = 289 in 4–6-month group, n = 270 in 7–9-month group, and n = 278 in >9-month group. Data are presented as GMTs and 95% CIs. Differences in neutralizing antibody titers between heterologous and homologous booster groups were tested with two-sided grouped t-test after log transformation. The four-fold rise rates between heterologous and homologous booster groups were compared by two-sided Fisher’s exact test. A two-sided p value < 0.05 was considered significant. *p < 0.05, ****p < 0.0001. The exact p values are presented in the figure.
Fig. 4. RBD-binding IgG antibody levels against…
Fig. 4. RBD-binding IgG antibody levels against prototype SARS-CoV-2 before and 15 and 30 days after the booster vaccinations.
a GMCs of RBD-binding IgG antibodies increased from baseline (day 0) to day 15 and 30 post-boosting elicited by heterologous NVSI-06-08 booster, compared with those induced by homologous BBIBP-CorV booster. b Correspondingly, the fourfold rise rates of IgG antibodies on days 15 and 30 after boosting elicited by NVSI-06-08 booster, compared with those induced by BBIBP-CorV booster. Both in a and b, for NVSI-06-08 booster vaccination, n = 285 in 4–6-month group, n = 270 in 7–9-month group, and n = 286 in >9-month group. For BBIBP-CorV booster vaccination, n = 289 in 4–6-month group, n = 270 in 7–9-month group, and n = 278 in >9-month group. Data are presented as GMCs and 95% CIs. Differences in RBD-binding IgG antibody concentrations between heterologous and homologous booster groups were tested with two-sided grouped t test after log transformation. The fourfold rise rates between heterologous and homologous booster groups were compared by two-sided Fisher’s exact test. A two-sided p value < 0.05 was considered significant. *p < 0.05, ****p < 0.0001. The exact p values are presented in the figure.
Fig. 5. Cross-neutralizing antibody titers against SARS-CoV-2…
Fig. 5. Cross-neutralizing antibody titers against SARS-CoV-2 prototype stain and several VOCs, including Alpha, Beta, Delta, and Omicron, elicited by heterologous NVSI-06-08 booster, compared with those elicited by homologous BBIBP-CorV booster.
A subset 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 a booster dose of NVSI-06-08 and 101 receiving a third dose of BBIBP-CorV) were tested using live-virus neutralization assay. Data are presented as GMTs and 95% CIs. The GMT values are given on the graph. Differences between NVSI-06-08 and BBIBP-CorV booster groups were tested with two-sided grouped t test after log transformation. A two-sided p value < 0.05 was considered significant. ****p < 0.0001. The exact p values are presented in the figure.

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