Safety and efficacy of the FAKHRAVAC compared with BBIBP-Corv2 against SARS-CoV-2 in adults: a non-inferiority multi-center trial.

BACKGROUND: We compared Fakhravac and BBIBP-Corv2 vaccines in a phase III trial. METHOD: We conducted a multicenter, parallel-group, active-control, non-inferiority clinical trial with pragmatic considerations assessing the safety and efficacy of Fakhravac and BBIBP-Corv2 vaccines. We started with two randomized double-blind arms and added two non-randomized open-label arms (based on participant preference) because of slow recruitment. The adult population received 0.5 ml (10 µg per dose) intramuscular injections of Fakhravac or BBIBP-Corv-2 vaccines 21 days apart. The primary outcome was the occurrence of PCR-positive symptomatic Covid-19 disease 14 days or more after the second injection. A 10% non-inferiority margin to the reported 72.8% efficacy of BBIBP-Corv2 was assumed. Cox proportional hazard modeling was used to estimate hazard ratios and their 95% confidence intervals. RESULT: We enrolled 24,056 adults in four groups (randomized-Fakhravac: 824, randomized-BBIBP-Corv2: 832; Non-randomized-Fakhravac: 19,429, Non-randomized-BBIBP-Corv2: 2971). All observed local and systemic adverse reactions were generally self-limited and resolved completely. We observed similar Serious Adverse Event (SAE) rates in the BBIBP-Corv2 (2.57, 95% CI 1.33-4.49) and Fakhravac (2.25, 95% CI 1.72-2.89) groups; none of which were related to the vaccines received. We recorded 9815 Medically Attendant Adverse Events (MAAE), 736 of which were categorized as somehow related. The rate of related MAAE in the Fakhravac was similar to the BBIBP-Corv2 groups (0.31 and 0.26 per 1000 person-day) in the randomized and considerably higher (0.24 and 0.07 per 1000 person-day) in the non-randomized arms. We observed 129 (35% of the 365 required by target sample size) events of PCR + symptomatic Covid-19 during four months of active follow-up in the randomized arm, demonstrating that those receiving the Fakhravac vaccine were significantly less likely (HR = 0.69; 95% CI 0.49-0.98) to be diagnosed with PCR + symptomatic Covid-19 compared with those receiving BBIBP-Corv2 vaccine. After adjusting for type I error using the O'Brien Fleming method, the Fakhravac vaccine was non-inferior to the BBIBP-Corv2 (assuming a 10% non-inferiority margin to the reported 72.8% BBIBP-Corv2 vaccine efficacy; HR < 1.35) (One-way test: HR = 0.66; 99.8% CI 0.38-1.15). In the non-randomized arm, the results were inconclusive (HR = 1.23; 95% CI 0.96-1.61). We observed 5 cases of hospitalized Covid-19 in the randomized arm, none of which occurred in the Fakhravac vaccine group. Those receiving the Fakhravac vaccine were four times less likely to go to the hospital because of a Covid-19 diagnosis (HR = 0.24; 95% CI 0.10-0.60). The vaccine efficacy of the Fakhravac vaccine is estimated to be 81.5% (95% CI 81-82.4%). CONCLUSION: Fakhravac inactivated SARS-CoV-2 vaccine has comparable safety and efficacy to the BBIBP-Corv2 vaccine. Trial registration This study was registered with the Iranian Registry of Clinical Trials ( www.irct.ir : IRCT20210206050259N3).

Phase II randomized, double blind, placebo controlled, clinical trial of safety and immunogenicity of an inactivated SARS-CoV-2 vaccine FAKHRAVAC in adults aged 18-70 years.

BACKGROUND: The FAKHRAVAC®, an inactivated SARS-CoV-2 vaccine, was assessed for safety and immunogenicity in a phase II trial. METHODS: We did a phase II, single-centered, randomized, double-blind, placebo-controlled clinical trial of the FAKHRAVAC inactivated SARS-CoV-2 vaccine on adults aged 18 to 70. The two parallel groups received two intramuscular injections of either a 10-µg vaccine or a placebo at 2-week intervals. The participants' immunogenicity responses and the occurrence of solicited and unsolicited adverse events were compared over the study period of up to 6 months. Immunogenicity outcomes include serum neutralizing antibody activity and specific IgG antibody levels. RESULTS: Five hundred eligible participants were randomly (1:1) assigned to vaccine or placebo groups. The median age of the participants was 36 years, and 75% were male. The most frequent local adverse reaction was tenderness (21.29% after the first dose and 8.52% after the second dose), and the most frequent systemic adverse reaction was headache (11.24% after the first dose and 8.94% after the second dose). Neutralizing antibody titers two and four weeks after the second injection in the vaccine group showed about 3 and 6 times increase compared to the placebo group (GMR = 2.69, 95% CI 2.32-3.12, N:309) and (GMR = 5.51, 95% CI 3.94-8.35, N:285). A four-fold increase in the neutralizing antibody titer was seen in 69.6% and 73.4% of the participants in the vaccine group two and four weeks after the second dose, respectively. Specific ELIZA antibody response against a combination of S1 and RBD antigens 4 weeks after the second injection increased more than three times in the vaccine compared to the placebo group (GMR = 3.34, 95% CI 2.5-4.47, N:142). CONCLUSIONS: FAKHRAVAC® is safe and induces a significant humoral immune response to the SARS-CoV-2 virus at 10-µg antigen dose in adults aged 18-70. A phase III trial is needed to assess the clinical efficacy. TRIAL REGISTRATION: Trial Registry Number: Ref., IRCT20210206050259N2 ( http://irct.ir ; registered on 08/06/2021).

Comparison of the Safety and Immunogenicity of FAKHRAVAC and BBIBP-CorV Vaccines when Administrated as Booster Dose: A Parallel Two Arms, Randomized, Double Blind Clinical Trial.

Purpose: This study was completed to assess the immunogenicity and safety of the FAKHRAVAC and BBIBP-CorV vaccines as a booster dose in the population with a history of receiving two doses of BBIBP-CorV vaccine. Methods: In this double-blind, parallel clinical trial, we randomly assigned healthy adults with a history of receiving two doses of the BBIBP-CorV vaccine, who then received either the FAKHRAVAC or BBIBP-CorV vaccine as a booster dose. The trial is registered in the Iranian Registry of Clinical Trial document depository (Code: IRCT20210206050259N4). Results: The outcomes that were monitored in this study were serum neutralizing antibody (Nab) activity, immunoglobulin G (IgG) level, local and systemic adverse reactions, serious adverse events, suspected unexpected serious adverse reactions, and medically attended adverse events. After administering vaccines to 435 participants, the most frequent local and systemic adverse reactions were tenderness and nausea in 23.7% and 1.4% of cases, respectively. All adverse events were mild, occurred at a similar incidence in the two groups, and were resolved within a few days. Conclusions: On the 14th day after the booster dose injection, the seroconversion rate (i.e., four-fold increase) of Nabs for seronegative participants were 87% and 84.6% in the FAKHRAVAC® and BBIBP-CorV groups, respectively. This study shows that the FAKHRAVAC® vaccine, as a booster dose, has a similar function to the BBIBP-CorV vaccine in terms of increasing the titer of virus-neutralizing antibodies, the amount of specific antibodies, and safety.

Development of Inactivated FAKHRAVAC® Vaccine against SARS-CoV-2 Virus: Preclinical Study in Animal Models.

The recent viral infection disease pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in a global public health crisis. Iran, as one of the countries that reported over five million infected cases by September 2021, has been concerned with the urgent development of effective vaccines against SARS-CoV-2. In this paper, we report the results of a study on potency and safety of an inactivated SARS-CoV-2 vaccine candidate (FAKHRAVAC) in a preclinical study so as to confirm its potential for further clinical evaluation. Here, we developed a pilot-scale production of FAKHRAVAC, a purified inactivated SARS-CoV-2 virus vaccine candidate that induces neutralizing antibodies in Balb/c mice, guinea pigs, rabbits, and non-human primates (Rhesus macaques-RM). After obtaining ethical code of IR.IUMS.REC.1399.566, immunizations of animals were conducted by using either of three different vaccine dilutions; High (H): 10 µg/dose, Medium (M): 5 µg/dose, and Low (L): 1 µg/dose, respectively. In the process of screening for viral seeds, viral strains that resulted in the most severe clinical manifestation in patients have been isolated for vaccine development. The viral seed produced the optimal immunity against SARS-CoV-2 virus, which suggests a possible broader neutralizing ability against SARS-CoV-2 strains. The seroconversion rate at the H-, M-, and L-dose groups of all tested animals reached 100% by 28 days after immunization. These data support the eligibility of FAKHRAVAC vaccine candidate for further evaluation in a clinical trial.

Immunogenic Evaluation of Bivalent Vaccine Candidate against Enterohemorrhagic and Enterotoxigenic Escherichia coli.

BACKGROUND: Caused by bacterial, viral, and parasitic pathogens, diarrhea is the second leading cause of death among children under five. Two strains of E. coli, namely Enterotoxigenic, ETEC and Enterohemorrhagic EHEC are the most important causes of this disease in developing countries. EHEC is a major causative agent of bloody diarrhea and hemorrhagic uremic syndrome, while ETEC is the most important cause of diarrhea in neonates and travelers. OBJECTIVES: To evaluate the immunologic properties of a subunit vaccine candidate comprising the main immunogenic epitopes from these two bacterial strains. METHODS: The construct comprised of LTB and CfaB antigens from ETEC, and Intimin and Stx2B antigens from EHEC, was designed, analyzed and synthesized using bioinformatics methods. The chimeric gene was sub-cloned in the expression vector and expressed in E. coli host. The purified chimera protein was injected subcutaneously into the experimental animals. The production of specific antibodies was confirmed by immunological methods, and the protection capacity was evaluated by the challenge of immunized mice with the pathogenic bacteria. RESULTS: Chimeric recombinant protein was able to increase IgG titer. Neutralization assay indicated that the antibodies generated against LtB moiety were able to neutralize ETEC toxin. In animal challenge study, all non-immune mice died within 3 days after the injection of toxin, but all immunized mice survived from Stx toxin. CONCLUSIONS: The immunity to both ETEC and EHEC bacteria is significant, and this structure can be considered as a candidate for vaccine production against these bacterial strains.

Oral immunization with a plant-derived chimeric protein in mice: Toward the development of a multipotent edible vaccine against E. coli O157: H7 and ETEC.

The most bacterial cause of infectious diseases associated with diarrhea are enterotoxigenic and enterohemorrhagic Escherichia coli (ETEC and EHEC, respectively). These strains use colonization factors for the attachment to the human intestinal mucosa, followed by enterotoxins production that could induce more host damage. The Heat-labile enterotoxin (LT) and colonization factors (CFs) are momentous factors for the pathogenesis of ETEC. Also, Intimin and Shiga like toxin (STX) are the main pathogenic factors expressed by EHEC. Because of mucosal surfaces are the major entry site for these pathogens, oral immunization with providing the protective secretary IgA antibody (sIgA) responses in the mucosa, could prevent the bacterial adherence to the intestine. In this study oral immunogenicity of a synthetic recombinant protein containing StxB, Intimin, CfaB and LtB (SICL) was investigated. For specific expression in canola seeds, the optimized gene was cloned in to plant expression vector containing the Fatty Acid Elongase (FAE) promoter. The evaluation of the expression level in canola seeds was approximately 0.4% of total soluble protein (TSP). Following to oral immunization of mice, serum IgG and fecal IgA antibody responses induced. Caco-2 cell binding assay with ETEC shows that the sera from immunized mice could neutralize the attachment properties of toxigenic E. coli. The reduction of bacterial shedding after the challenge of immunized mice with E. coli O157:H7 was significant. The sera from immunized mice in the rabbit ileal loop experiment exhibited a significant decrease in the fluid accumulation compared to the control. The results indicate efficacy of the recombinant chimeric protein SICL in transgenic canola seed as an effective immunogen, which elicits both systemic and mucosal immune responses as well as protection against EHEC and ETEC adherence and toxicity.