Trial evaluates safety, tolerability, and immunogenicity of BBIBP-CorV in COVID-19

BBIBP-CorV, an inactivated coronavirus vaccine candidate (manufactured through whole-microbe approach which was isolated from human throat swabs and replicated in the media titer in China) , is safe, immunogenic, and has good tolerability in healthy people. Immunization with this vaccine rapidly induces immune responses against coronavirus and would be beneficial to prevent or limit the coronavirus pandemic.

According to the World Health Organization (WHO) coronavirus disease (COVID)-19 dashboard, the coronavirus pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to 35 million infections and more than 1,000,000 deaths.

Individuals aged 60 years and older and individuals having pre-existing cardiovascular or respiratory  disorder have an elevated risk of severe disease and mortality if infected with coronavirus. The SARS-CoV-2 virus appears to undergo more prompt transmission in comparison with other coronaviruses. This causes an urgent demand for a vaccine to control coronavirus infection.

According to WHO’s draft landscape of coronavirus candidate vaccines, about 42 candidate vaccines are in the clinical assessments and 151 candidate vaccines are in the preclinical assessments. DNA plasmid vaccines, adenovirus-vectored vaccines, virus-like particle vaccines, inactivated vaccines, RNA vaccines, and protein subunit vaccines are the various candidate vaccines in the clinical trials.

The efficacy and safety of some of these vaccine candidates have been illustrated in the preclinical trials, and the safety and immunogenicity have been displayed in clinical trials. Developing inactivated vaccines is a mature technology, that is extensively utilized for preventing and controlling emerging infectious diseases, including poliovirus and influenza virus. Till now, two inactivated vaccine candidates have been noted to safeguard non-human primates against SARS-CoV-2, with favorable safety in the preclinical trials.

Rationale behind research

A vaccine against SARS-CoV-2 is urgently required to prevent further waves of coronavirus pandemic. Therefore, this large study was performed.

Objective

A phase I/II, dose-escalation, randomized, double-blind, placebo-controlled trial was carried to explore the safety, immunogenicity, and tolerability of BBIBP-CorV in humans. 

Study outcomes

• The primary endpoint was safety  and tolerability
• The secondary endpoint was immunogenicity, evaluated as the neutralizing antibody responses against coronavirus

Outcomes

Baseline: There were no significant differences reported at baseline.

Study outcomes

• In phase I, at least one adverse reaction was noted within the first seven days of inoculation in 29% (42/144) vaccine recipients. Fever was the most frequent systematic side effect. All noxious reactions were moderate or mild in severity. No severe adverse event was reported within 28 days after vaccination.
• At day 42, the neutralizing antibody geometric mean titres were found to be elevated in the cohort aged 18–59 years (87·7 [95% CI 64·9–118·6], 2 μg cohort; 211·2 [158·9–280·6], 4 μg cohort; and 228·7 [186·1–281·1], 8 μg cohort) and the group aged 60 years and older (80·7 [65·4–99·6], 2 μg cohort; 131·5 [108·2–159·7], 4 μg cohort; and 170·87 [133·0–219·5], 8 μg cohort) in comparison with the placebo cohort (2·0 [2·0–2·0]). 
• In phase II, at least one side effect within the first seven days was noted in 23% (76 /336) vaccine-treated subjects. Notably, 1 placebo-treated subject in the 4 μg days 0 and 21 cohort witnessed grade 3 fever, but was self-limited and recovered. All the other noxious effects were mild or moderate in severity. The most frequent systematic side effect was fever.
• Vaccine-stimulated neutralizing antibody titres on day 28 were considerably higher in the 4 μg days 0 and 14 (169·5, 95% CI 132·2–217·1), days 0 and 21 (282·7, 221·2–361·4), and days 0 and 28 (218·0, 181·8–261·3) schedules in comparison with the 8 μg day 0 schedule.

The vaccine candidate, administered as a two-dose immunization displayed safety and good tolerability at all three doses in both the age groups in this study.  In 100% of vaccine-treated subjects, a robust humoral immune response was noted. In the preclinical assessments, immunization with the vaccine candidate was found to stimulate elevated levels of neutralizing antibody titres in rabbits, mice, pigs, rats, guinea pigs, and non-human primates to safeguard against this deadly virus.

Fever and pain were the most commonly occurring adverse effects. These were reported in a small percentage of vaccine treated subjects and with no vital difference across the groups. All the adverse events were moderate or mild in severity. In the placebo arm, more systemic side effects were noted. However, during the follow-up monitoring of respiratory symptoms, there were no upper respiratory tract infections.  No clinically vital abnormal alterations in laboratory measurements were noted and the alterations were not linked to the vaccine.

The evidence indicating an antibody-dependent enhancement in coronavirus infection has emerged. But, no antibody-dependent enhancement was witnessed in rhesus macaques  in the preclinical studies of vaccine immunization and SARS-CoV-2 challenge. In the ongoing phase II study, the vaccine candidate was used at 2 μg, 4 μg, and 8 μg, in one-dose, two-dose, and three-dose immunization schedules to profile immunogenicity and safety of the vaccine in children and adolescents (aged 3–17 years), adults (18–59 years), and geriatrics (≥60 years).

The vaccine candidate was immunogenic and stimulated robust humoral responses promptly. For individuals aged 60 years and older, and individuals suffering from a pre-existing respiratory or cardiovascular disorder, the coronavirus infection presents a substantially elevated risk of severe disease and mortality. This study was carried out to determine BBIBP-CorV's  safety and tolerability  in individuals aged 60 years and older.

Compared to the cohort aged 60 years and older, the cohort aged 18–59 years rapidly attained a 100% seroconversion rate. After the initial vaccine dose (day 14), more than 75% of vaccine-treated subjects in the cohort aged 18–59 years seroconverted, and the remaining vaccine-treated subjects seroconverted on 28^th day. For the cohort aged 60 years and older, the seroconversion rate of  participants treated with the 4 μg and 8 μg dose attained 100% on day 28, and the 2 μg cohort was 100% seroconverted by 42^nd day. Compared to the cohort aged 18–59 years, the magnitude of neutralizing antibodies in the cohort aged 60 years and older was minimized.

BBIBP-CorV- elicited neutralizing antibodies have the ability to neutralize the multiple strains of SARS-CoV-2. This indicates that this vaccine candidate has immense potential to offer cross-protection against other strains of SARS-CoV-2. In the assessment of various immunization schedules, the neutralizing antibody titres of the 8 μg, day 0 single-dose immunization schedule were considerably reduced in comparison with those of all three two-dose immunization schedules.

Following the second inoculation, the neutralizing antibody titres in the 4 μg days 0 and 21 schedules were similar in comparison with those in the 4 μg days 0 and 28 schedules. However, it was considerably higher in comparison with that in the 4 μg days 0 and 14 schedules. These findings indicate that the boost inoculation is crucial to attain more efficient protection, offering valuable information for a phase III clinical trial.

The outcomes of a similar trial of coronavirus inactivated vaccine were noted. Although there were similar findings in immunogenicity and safety, the trial claimed no notable alterations in the lymphocyte subset or cytokines, that is consistent with the unpublished outcomes. Testing will not be initiated in individuals aged younger than 18 years until there is a finalization of the complete analysis of the adult groups. The younger ages will be investigated in the ongoing phase I clinical trial. This analysis was not designed to investigate vaccine efficacy.

In conclusion, BBIBP-CorV is immunogenic and tolerable in healthy people. Humoral responses against the virus were elicited in all vaccine-treated participants on day 42. After the first inoculation, prompt humoral responses against the deadly virus were witnessed from day 4 and 100% seroconversion was witnessed in all subjects on day 42. Two-dose immunization with 4 μg vaccine on days 0 and 21 or days 0 and 28 attained greater neutralizing antibody titres compared to the single 8 μg dose or 4 μg dose on days 0 and 14.

The days 0 and 21 and days 0 and 28 two-immunization schedules induced remarkably increased neutralizing antibody titres compared to the days 0 and 14 schedule and single-immunization schedule. To curb coronavirus infection, additional studies should investigate the potential of this vaccine candidate in clinical application. The ongoing phase I/II and phase II trials will offer more information on the immunogenicity and safety, dosage, and immunization schedule of this vaccine candidate.