Nature Medicine: Sequential Vaccination Shows Greater Immunogenicity Than Homologous Vaccination

At present, more than 2 billion doses of the COVID-19 vaccine have been administered in mainland China, of which the vaccination rate of CoronaVac is more than 50%¹. With the continuous emergence of SARS-CoV-2 variants and the weakening of neutralizing antibodies from inactivated vaccines, the protective effect of vaccination gradually decreases². The schedules of Sequential vaccination that integrate COVID-19 vaccines across different platforms may promote antibody affinity maturation and affect the breadth of vaccine-elicited neutralizing antibodies³.

On January 27, 2022, Professor Zhu Fengcai and Academician Chen Wei’s team published an important article in the journal Nature Medicine. The article confirmed that the level of humoral immunity induced by sequential booster vaccination with recombinant adenovirus type 5 (AD5) vaccine (hereinafter referred to as ‘intramuscular injection of Convidecia®’) was higher than CoronaVac homologous vaccination, and the safety was good. The intramuscular injection of Convidecia^® used is produced by the team of Academician Chen Wei and CanSino Bio Co., Ltd. (hereinafter referred to as ‘CanSino Bio’, CanSino-U 688185. SH, CanSino-B 06185. HK) jointly developed.

The team of Professor Zhu Fengcai has successively presided over several clinical studies of COVID-19 vaccines covering all technical routes in China and has a deep understanding of the immune response of various COVID-19 vaccines. Nanjing Vazyme Biotech Co., Ltd. (hereinafter referred to as ‘Vazyme’, stock code: 688105) provided relevant support work in this clinical study.

01/Research design and purpose

This study followed the principles of a randomized, observer-blind, parallel-controlled design to evaluate the immunogenicity and safety of COVID-19 inactivated vaccine (CoronaVac, Beijing Kexing Zhongwei) homologous immunization vaccination and intramuscular injection of Convidecia^® sequential immunization vaccination in healthy adults aged 18-59 years.

The grouping was as follows, group A (sequential booster immunization): 2 doses of CoronaVac + 1 dose of Convidecia^®; Group B (homologous booster immunization): 2 doses of CoronaVac + 1 dose of CoronaVac; Group C (sequential basal immunization): 1 dose of CoronaVac + 1 dose of Convidecia^®; Group D (homologous basal immunity): 1 dose of CoronaVac + 1 dose of CoronaVac.

The primary endpoint of immunogenicity was the geometric mean titer (GMT) of neutralizing antibodies against the SARS-CoV-2 virus within 14 days after vaccination; the secondary endpoint was IgG antibody levels against SARS-CoV-2 virus spike protein receptor-binding domain (S-RBD) and nucleocapsid (N) proteins on the 14th and 28th day after vaccination, and levels of cytokines secreted by T cells on the 14th day after vaccination; the exploratory endpoint was neutralizing antibody titers of against SARS-CoV-2 B.1.617.2 (Delta) and antibody levels of anti-RBD IgG subtypes (IgG1, 2, 3, 4) after vaccination.

02/Major Findings

The results of the study showed that the neutralizing antibody GMTs against the SARS-CoV-2 wild-type virus in the sequential booster immunization group was 197.4 (95% confidence interval (CI) = 167.7, 232.4) after 14 days, which was about 78.3 times higher than that before the booster. If the 3rd dose is homologously boosted with CoronaVac, the level of neutralizing antibody is 33.6 (95% CI = 28.3, 39.8), which is about 15.2 times higher than that before the booster. For the sequential basal immunization program, the level of neutralizing antibody GMT in the sequential basal immunization group after 14 days was 4.3 times that of the homologous basal immunization group.

Although the level of neutralizing antibodies against the Delta variant virus decreased after 14 days of immunization compared with the wild-type virus, sequential vaccination still induced higher neutralizing antibody levels compared with homologous vaccination. On the 14th day after immunization, the level of neutralizing antibody (GMT) induced by sequential boost immunization was 6.7 times that of homologous boost, and the level of neutralizing antibody (GMT) induced by sequential basal immunization was 3 times that of homologous basal immunization.

Fig. 1 Neutralizing antibody GMT to the wild-type virus (left) and Delta variant (right) before and after immunization

Anti-RBD IgG binding antibody levels were consistent with neutralizing antibody titers (correlation coefficients ranged from 0.61 to 0.8). On the 14th day after vaccination, both sequential boosting and homologous boosting induced a significant increase in IgG levels, and sequential immunization was higher than homologous immunization, and the anti-RBD IgG level was in group A (3,090.1; 95% CI=2,636.1, 3,622.3), Group C (941.8; 95% CI=663.9, 1,336.1), Group B (369.0; 95% CI=304.2, 447.5), Group D (154.1; 95% CI=116.3, 204.3). The results of detecting the levels of IgG subtypes (IgG1/2/3/4) showed that the level of anti-RBD IgG antibodies was mainly related to the level of IgG1 after boosting. The Vazyme vaccine clinical testing team undertook and completed the work, and established the SARS-CoV-2 RBD IgG total antibodies (SARS-CoV-2 RBD Antibody (IgG) Detection Kit, Cat. No.: DD3103) / IgG1 (SARS-CoV-2 RBD Antibody (IgG1) Detection Kit, Cat. No.: DD3104) detection method.

From 2020 till now, the detection reagents and methodology used by Vazyme in the humoral immunity evaluation service of the COVIS-19 vaccine have been developed under the requirements of diagnostic reagents. Especially for the COVID-19 combined antibody detection products, WHO/20-136 international reference materials were introduced to carry out quantitative value traceability, providing customers with more objective and effective immunogenicity test results, which won high recognition from customers in terms of service quality and response speed.

Fig. 2 GMT of anti-RBD IgG(a) and GMT of anti-RBD IgG1(b) before and after immunization

In terms of cellular immunity, this study used ELISpot technology to detect the secretion levels of IFN-γ, TNF-α, IL-4, IL-5, and IL-13 to quantify virus-specific T cell responses. The results showed that on the 14th day after booster vaccination, sequential booster immunizations induced high levels of Th1 cellular immune responses compared with homologous booster immunizations. This work was undertaken and completed by the Vazyme vaccine clinical testing team.

Fig. 3 SARS-CoV-2 spike-specific T cell cytokine responses before and after boosting.

(T_H1/T_H2 ratios were calculated by summing IFN-γ.)

In conclusion, for healthy adults aged 18-59 years, a sequential booster regimen of intramuscular Convidecia^® administered 3-6 months after two doses of inactivated vaccine is safe and highly immunogenic⁴. Globally, at least four studies on heterologous prime-boost regimens have been reported, and multiple countries and regions have approved booster vaccination strategies using heterologous sequential immunization.

The Vazyme team has actively participated in the clinical research of various COVID-19 vaccine technology routes in China, and has established methodologies and solutions for humoral immunity, cellular immunity, and immune persistence analysis. Vazyme is master of enzymology-related products and has a complete antigen and antibody development and production platform, which can ensure the development quality and speed of vaccine evaluation methodologies. In the future, Vazyme will continue to work hard and contribute to the victory over the SARS-CoV-2 pandemic.

Reference

1. Xinhua. Over 1.8 bln doses of COVID-19 vaccines administered in China. Xinhua. http://www.xinhuanet.com/english/202108/11/c_1310121275.htm (4 August 2021).

2. Lim, W. W., Mak, L., Leung, G. M., Cowling, B. J. & Peiris, M. Comparative immunogenicity of mRNA and inactivated vaccines against COVID-19. Lancet Microbe 2, e423 (2021).

3. Excler, J. L. & Kim, J. H. Novel prime-boost vaccine strategies against HIV-1. Expert Rev. Vaccines 18, 765–779 (2019).

4. Jingxin Li, Lihua Hou, Xiling Guo, Pengfei Jin, et al.Heterologous AD5-nCOV plus CoronaVac versus homologous CoronaVac vaccination: a randomized phase 4 trial.Nature Medicine https://doi.org/10.1038/s41591-021-01677-z(2022).