Safety and immunogenicity clinical trial of an inactivated SARS-CoV-2 vaccine, BBV152 (a phase 2, double-blind, randomised controlled trial) and the persistence of immune responses from a phase 1 follow-up report

Abstract

BackgroundBBV152 is a whole-virion inactivated SARS-CoV-2 vaccine (3 µg or 6 µg) formulated with a Toll-like receptor 7/8 agonist molecule adsorbed to alum (Algel-IMDG). Earlier, we reported findings from a phase 1 (vaccination regimen on days 0 and 14) randomised, double-blind trial on the safety and immunogenicity of three different formulations of BBV152 and one control arm containing Algel (without antigen). Two formulations were selected for the phase 2 (days 0 and 28) study. Here, we report interim findings of a controlled, randomised, double-blind trial on the immunogenicity and safety of BBV152: 3 µg and 6 µg with Algel-IMDG.MethodsWe conducted a double-blind, randomised, multicentre, phase 2 clinical trial to evaluate the immunogenicity and safety of BBV152. A total of 380 healthy children and adults were randomised to receive two vaccine formulations (n=190 each) with 3 µg with Algel-IMDG and 6 µg with Algel-IMDG. Two intramuscular doses of vaccines were administered (four weeks apart). Participants, investigators, and laboratory staff were blinded to the treatment allocation. The primary outcome was seroconversion (≥4-fold above baseline) based on wild-type virus neutralisation (PRNT50). Secondary outcomes were reactogenicity and safety. Cell-mediated responses were evaluated. A follow-up blood draw was collected from phase 1 participants at day 104 (three months after the second dose).FindingsAmong 921 participants screened between Sep 7-13, 2020, 380 participants were randomised to the safety and immunogenicity population. The PRNT50 seroconversion rates of neutralising antibodies on day 56 were 92·9% (88·2, 96·2) and 98·3% (95·1, 99·6) in the 3 µg and 6 µg with Algel-IMDG groups, respectively. Higher neutralising titres (2-fold) were observed in the phase 2 study than in the phase 1 study (p<0.05). Both vaccine groups elicited more Th1 cytokines than Th2 cytokines. After two doses, the proportion (95% CI) of solicited local and systemic adverse reactions were 9.7% (6·9, 13·2) and 10.3% (7·4, 13·8) in the 3 µg and 6 µg with Algel-IMDG groups, respectively. No significant difference was observed between the groups. No serious adverse events were reported in this study. Phase 1 follow-up immunological samples at day 104 showed seroconversion in 73·5% (63·6, 81·9), 81·1% (71·4, 88·1), and 73·1% (62·9, 81·8) of individuals in the 3 µg with Algel-IMDG, 6 µg with Algel-IMDG, and 6 µg with Algel groups, respectively.InterpretationIn the phase 1 trial, BBV152 produced high levels of neutralising antibodies that remained elevated in all participants three months after the second vaccination. In the phase 2 trial, BBV152 led to tolerable safety outcomes and enhanced humoral and cell-mediated immune responses. The safety profile of BBV152 is noticeably lower than the rates for other SARS-CoV-2 vaccine platform candidates. The 6 µg Algel-IMDG formulation was selected for the phase 3 efficacy trial.FundingThis work was supported and funded by Bharat Biotech International Limited.Clinicaltrials.gov: NCT04471519

Target Product Profile Analysis of COVID-19 Vaccines in Phase III Clinical Trials and Beyond: An Early 2021 Perspective

“…Three Chinese conglomerates and one Indian company have used the tried-and-true method of viral inactivation by β-propriolactone treatment, along with various alum adjuvants for generation of their SARS-CoV-2 vaccine candidates [36][37][38][39][40][41][42]. Each is using the prime-boost regimen with 4-6 μg virus and 14-28 days separation between prime and booster injections.…”

“…Ad5 21 d.a.) [30] Post dose 1 Notes: The most common solicited local and systemic reactogenicity were pain at the injection site, and headache, and these have been reported in Table 2 Table 3 in reference [42].…”

“…For this reason, there is of interest to know if the immune response induced by the different vaccine platforms are Th1 or Th2 biased [17,22,26,54]. Bharat Biotech's COVAXIN has used the novel adjuvant Algel-IMDG, which is an imidazoquinoline adsorbed on alum [42]. The Th1/Th2 ratio for this vaccine shows a very strong Th1 bias (Table 3) with a good reactogenicity profile ( Table 2).…”

Neutralization of UK-variant VUI-202012/01 with COVAXIN vaccinated human serum

“…The sero-conversion rate with neutralizing antibodies (NAb) following vaccination with BBV152 was 99.6%. 5 Here, we present the NAb titers (PRNT 50 ) of sera collected from vaccine recipients, who had received BBV152 vaccine-candidate in phase-II trial 4 Andreano E et al reported an escape of the UK-variant with E484K substitution, which was followed by an 11-amino-acid insertion in the NTD N5 loop (248aKTRNKSTSRRE248k) from high NAb in convalescent plasma, which was a serious concern pertaining to the potential efficacy of the vaccines. 7 Our study evidently highlighted comparable neutralization activity of vaccinated individuals sera against variant as well as heterologous SARS-CoV-2 strains.…”

COVID-19 Reinfection in the Face of a Detectable Antibody Titer

“…They are done to retrospectively diagnose a case that could have been missed during its initial acute phase [3]. Actual reinfection from the same strain of coronavirus disease 2019 (COVID- 19) has often been questioned since many issues related to technical errors during sample collection, timing of collection, type of sample used, and false negative or positive results while performing the reverse transcription-polymerase chain reaction (RT-PCR) method [4]. In this case report, we discuss a reinfected case of COVID-19 despite having circulating antibodies.…”