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BackgroundRising concerns over waning immunity and reduction in neutralizing activity against variants of concern (VOCs) have contributed to deploying booster doses by different strategies to tackle the COVID-19 pandemic. Preliminary findings from Phase I and II have shown that V-01, a recombinant fusion protein vaccine against COVID-19, exhibited favorable safety and immunogenicity profiles in 1060 adult participants of both younger and senior age. Herein, we aimed to assess the immunogenicity and safety for a booster dose in participants previously primed with a two-dose 10g V-01 regimen (day 0, 21) from phase I trial, providing reassuring data for necessity and feasibility of a homogenous booster dose. MethodsWe conducted a single-arm, open-label trial at the Guangdong Provincial Center for Disease Control and Prevention (Gaozhou, China). Forty-three eligible participants who were previously primed 4-5 months earlier with two-dose 10g V-01 regimen from phase I trial received booster vaccination. We primarily assessed the immunogenicity post-booster vaccination, measured by RBD-binding antibodies using ELISA and neutralizing activity against wild-type SARS-CoV-2 and emerging variants of concern (VOCs) using neutralization assays. We secondarily assessed the safety and reactogenicity of the booster vaccination. ResultsThe third dose of V-01 exhibited significant boosting effects of humoral immune response in participants primed with two-dose 10g V-01 regimen regarding both wild-type SARS-CoV-2 and VOCs. We observed a 60.4-folds increase in neutralizing titres against SARS-CoV-2 of younger adults, with GMTs of 17 (95%CI: 12-23) prior to booster vaccination in comparison to 1017 (95%CI: 732-1413) at day 14 post booster vaccination; and a 53.6-folds increase in that of older adults, with GMTs of 14 (95%CI: 9-20) before booster vaccination in comparison to 729(95%CI: 397-1339) at day 14 post-booster vaccination. The neutralizing titres against SARS-CoV-2 Delta strain also demonstrated a sharp increase from the day of pre booster vaccination to day 14 post booster vaccination, with GMTs of 11 (95%CI:8-15) versus 383 (95%CI:277-531) in younger adults (35.4-folds increase), and 6.5(95%CI: 5-8) versus 300(95%CI:142-631) in older adults (46.0-folds increase), respectively. We also observed a considerable and consistent increase of pseudovirus neutralizing titres against emerging VOCs from day 28 post second vaccination to day 14 post booster vaccination, with GMTs of 206 (95%CI:163-259) versus 607 (95%CI: 478-771) for Alpha strain, 54 (95%CI:38-77) versus 329 (95%CI: 255-425) for Beta strain, 219 (95%CI:157-306) versus 647 (95%CI: 484-865) for Delta strain. Our preliminary findings indicate a homogenous booster dose of V-01 was safe and well-tolerated, with overall adverse reactions being absent or mild-to-moderate in severity, and no grade 3 or worse AEs were related to booster vaccination. ConclusionsA homogenous booster immunization in participants receiving a primary series of two-dose V-01 elicited a substantial humoral immune response against wild-type SARS-CoV-2 and emerging VOCs, along with a favorable safety and reactogenicity profile. Our study provided promising data for a homogenous prime-boost strategy using recombinant protein vaccine to tackle the ongoing pandemic, potentially providing broad protection against emerging VOCs and overcoming waning immunity.
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Recently, the emerged and rapidly spreading SARS-CoV-2 variant of concern (VOC) 501Y.V2 with 10 amino acids in spike protein were found to escape host immunity induced by infection or vaccination. Global concerns have been raised for its potential to affect vaccine efficacy. Here, we evaluated the neutralization activities of two vaccines developed in China against 501Y.V2. One is licensed inactivated vaccine BBIBP-CorV and the other one is recombinant dimeric receptor-binding domain (RBD) vaccine ZF2001. Encouragingly, both vaccines largely preserved neutralizing titres, with slightly reduction, against 501Y.V2 authentic virus compare to their titres against both original SARS-CoV-2 and the currently circulating D614G virus. These data indicated that 501Y.V2 variant will not escape the immunity induced by vaccines targeting whole virus or RBD.
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BackgroundA safe and effective coronavirus disease 2019 (COVID-19) vaccine is urgently needed to control the ongoing pandemic. Although progress has been made recently with several candidates reporting positive efficacy results, COVID-19 vaccines developed so far cannot meet the global vaccine demand. We developed a protein subunit vaccine against COVID-19, using dimeric form of receptor-binding domain (RBD) as the antigen. We aimed to assess the safety and immunogenicity of this vaccine in humans and determine the appropriate dose and schedule for an efficacy study. MethodsWe did two randomized, double-blind, placebo-controlled, phase 1 and 2 trials for an RBD-based protein subunit vaccine, ZF2001. In phase 1 study, 50 healthy adults aged 18-59 years were enrolled and randomly allocated to three groups to receive three doses of vaccine (25 g or 50 g RBD-dimer, with adjuvant) or placebo (adjuvant-only) intramuscularly, 30 days apart. In phase 2 study, 900 healthy adults aged 18-59 years were enrolled and randomly allocated to six groups to receive vaccine (25 g or 50 g RBD-dimer, with adjuvant) or placebo (adjuvant-only) intramuscularly, with the former 3 groups given two doses and the latter 3 groups given three doses, 30 days apart. For phase 1 trial, the primary outcome was safety, as measured by the occurrence of adverse events and serious adverse events. The secondary outcome was immunogenicity as measured by the seroconversion rate and magnitude of antigen-binding antibodies, neutralizing antibodies and T-cell cytokine production. For phase 2 trial, the primary outcome included both safety and immunogenicity. These trials are registered with ClinicaTrials.gov, NCT04445194 and NCT04466085. FindingsBetween June 22 and September 15, 2020, 50 participants were enrolled to the phase 1 study (mean age 32.6 years) and 900 participants were enrolled to phase 2 study (mean age 43.5 years), to receive vaccine or placebo with a two-dose or three-dose schedule. For both trials, local and systemic adverse reactions were absent or mild in most participants. There were no serious adverse events related to vaccine in either trial. After three doses, neutralizing antibodies were detected in all participants receiving either 25 g or 50 g dose of vaccine in phase 1 study, and in 97% (the 25 g group) and 93% (the 50 g group) of participants, respectively, in phase 2 study. The SARS-CoV-2-neutralizing geometric mean titres (GMTs) were 94.5 for the 25 g group and 117.8 for the 50 g group in phase 1, and 102.5 for the 25 g group and 69.1 for the 50 g group in phase 2, exceeding the level of a panel of COVID-19 convalescent samples (GMT, 51). Vaccine induced balanced TH1 and TH2 responses. The 50 g group did not show enhanced immunogenicity compared with the 25 g group. InterpretationThe protein subunit vaccine ZF2001 is well-tolerated and immunogenic. The safety and immunogenicity data from phase 1 and 2 trials for ZF2001 support the use of 25 g vaccine dose with three-dose schedule to an ongoing phase 3 large-scale evaluation for safety and efficacy. FundingNational Program on Key Research Project of China, National Science and Technology Major Projects of Drug Discovery, Strategic Priority Research Program of the Chinese Academy of Sciences, and Anhui Zhifei Longcom Biopharmaceutical.
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The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) continues to infect people globally. The increased COVID-19 cases and no licensed vaccines highlight the need to develop safe and effective vaccines against SARS-CoV-2 infection. Multiple vaccines candidates are under pre-clinical or clinical trails with different strengths and weaknesses. Here we developed a pilot scale production of a recombinant subunit vaccine (RBD-Fc Vacc) with the Receptor Binding Domain of SARS-CoV-2 S protein fused with the Fc domain of human IgG1. RBD-Fc Vacc induced SARS-CoV-2 specific neutralizing antibodies in non-human primates and human ACE2 transgenic mice. The antibodies induced in macaca fascicularis neutralized three divergent SARS-CoV2 strains, suggesting a broader neutralizing ability. Three times immunizations protected Macaca fascicularis (20ug or 40ug per dose) and mice (10ug or 20ug per dose) from SARS-CoV-2 infection respectively. These data support clinical development of SARS-CoV-2 vaccines for humans. RBD-Fc Vacc is currently being assessed in randomized controlled phase 1/II human clinical trails. SummaryThis study confirms protective efficacy of a SARS-CoV-2 RBD-Fc subunit vaccine.
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ObjectiveTo evaluate the early cellular immune responses to three kinds of hepatitis B surface antigen (HBsAg) in the immunized mice.MethodsAt day 4,the levels of IFN-γand IL-2 secreted by CD4+ and CD8+T cells which selected from splenic mononuclear cells (MNC) of the vaccinated mice were detected by enzyme-linked immunospot methods (ELISPOT) after stimulation in vitro with HBsAg MHC class Ⅰ peptide S28-39 of HBsAg or recombinant hepatitis B surface antigen(rHBsAg).ResultsAfter selected by MACs,the purity of CD3+/CD4+ and CD3+/CD8+T cell was more than 90％.The positive rate of IFN-γsecreted by CD4+T cells induced by HBsAg derived from Hansenula polymorpha(rHP) was higher than that of HBsAg derived from CHO cell (rCHO).Levels of IFN-γ secreted by CD8+T cells and IL-2 secreted by CD4+T cells induced by rHP antigen were significantly higher than those of rCHO( P＜0.05 ).Meanwhile,levels of IFN-γsecreted by CD4+T cells and CD8+T cells induced by rHP were also significantly higher than those of plasma HBsAg(pHB) (P＜0.05).ConclusionAt day 4,the cellular immune responses induced by HBsAg could be detected.But the immune responses induced by the three kinds of HBsAg are different in levels.According to early cellular immune response intensity,the rHP HBsAg are superior to the rCHO and pHB,in accordance with the high protection rate interrupting the mother-infant transmission immunized by rHP vaccine in clinical trial.It provides scientific basis for necessity of timely birth dose of HB vaccine and kind of HB vaccine for high risk newborn infants vaccinated.
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Objective To analyze the laboratory testing data of 2009 pandemic influenza A (H1N1) vaccines during lot release procedure, thus to know the overall quality status of this vaccines.Methods National Institutes for Food and Drug Control(NIFDC) carried out the laboratory test according to the specifications of each manufacture, and the results was analyzed and compared between manufacturer and NIFDC. Results 99.8% of vaccines batches were released by NIFDC, haemagglutinin contents were between 90% to 103 % of labeled values, and testing results slightly differ between manufactures and NIFDC,other items related to safety were all meet specifications. Conclusion The quality of H1N1 vaccines in China were satisfying, the lot release and independent test by NIFDC play important roles to ensure the vaccines' quality.
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Objective To prepare and study the immunogenicity of hepatitis B virus surface anti-gen (HBsAg)-tetanus toxoid (TT) conjugate vaccine. Methods Tr was activated by cyangen bromide and reacted with adipic acid dihydrazide, then HBsAg-TT conjugate was prepared by carbediimide. Conjugate, HBsAg or hepatitis B vaccine was injected subcutaneously into mice. Anti-HBsAg and HBsAg-specific T cell response elicited by these immunogens were assayed. Results New HBsAg-TT conjugate elicited higher levels of anti-HBsAg and HBsAg positive conversion rates after the immunization than did HBsAg alone or hepatitis B vaccine. Conjugate induced mesdy antibodies of the IgG2a subclass, while HBsAg alone or hepa-titis B vaccine mainly elicited anti-HBsAg in the IgG1 subclass. The number of IFN-γand IL-2 secreting T cells induced by conjugate was also significantly higher than that did by HBsAg or hepatitis B vaccine. Con-clusion This study indicated new HBsAg-TT conjugate can induce both stronger humoral and TH1 type of cellular immune response.
