Safety, tolerability, and immunogenicity of a SARS-CoV-2 recombinant spike protein vaccine: a randomised, double-blind, placebo-controlled, phase 1-2 clinical trial (ABDALA Study)

Abstract

AimTo evaluate the safety and immunogenicity of a SARS-CoV-2 recombinant spike protein vaccine (Abdala), administered intramuscularly in different strengths and vaccination schedules.MethodA phase 1-2, randomized, double-blind, placebo-controlled trial was done. Subjects were randomly distributed in 3 groups: placebo, 25 and 50µg RBD. The product was applied intramuscularly, 0.5 mL in the deltoid region. During the first phase, two immunization schedules were studied: short (0-14-28 days) and long (0-28-56 days). In phase 2, only the short scheme was evaluated. The main endpoints were: safety and proportion of subjects with seroconversion of anti-RBD IgG antibodies to SARS-CoV-2. Blood samples were collected in several points according to the corresponding vaccination schedule to determine the level of RBD-specific IgG antibodies (seroconversion rates and geometric mean of the titers), the percentage of inhibition of RBD-ACE-2 binding and levels of neutralizing antibodies.ResultsThe product was well tolerated. Severe adverse events were not reported. Adverse reactions were minimal, mostly mild and local (from the injection site), resolved in the first 24-48 hours without medication. In phase 1, at day 56 (28 days after the third dose of the short vaccination schedule, 0-14-28 days) seroconversion of anti-RBD IgG was seen in 95.2 % of the participants (20/21) for the 50μg group and 81 % of the participants (17/21) for the 25μg group, and none in the placebo group (0/22); whereas neutralizing antibodies to SARS-CoV-2 were seen in 80 % of the participants (8/10) for the 50μg group and 94.7% of the participants (18/19) for the 25μg group. For the long schedule, at day 70 (14 days after the third dose) seroconversion of anti-RBD IgG was seen in 100% of the participants (21/21) for the 50μg group and 94.7% of the participants (18/19) for the 25μg group, and none in the placebo group (0/22); whereas neutralizing antibodies to SARS-CoV-2 were seen in 95 % of the participants (19/20) for the 50μg group and 93.8% of the participants (15/16) for the 25μg group In phase 2, at day 56 seroconversion of anti-RBD IgG was seen in 89.2% of the participants (214/240) for the 50μg group, 77.7% of the participants (185/238) for the 25μg group, and 4.6% in the placebo group (11/239); whereas neutralizing antibodies to SARS-CoV-2 were seen in 97.3% of the participants (146/150) for the 50μg group and 95.1% of the participants (58/61) for the 25μg group.ConclusionAbdala vaccine against SARS-CoV-2 was safe, well tolerated and induced humoral immune responses against SARS-CoV-2 among adults from 19 to 80 years of age.Trial registration / Review protocolRPCEC00000346. Cuban Public Clinical Trial Registry (WHO accepted Primary Registry).Available from: https://rpcec.sld.cu/en/trials/RPCEC00000346-EnInformation about the ethical aspects and IRB approvalThe protocol was approved by the Ethic Committee of the participating hospital and by the Cuban Regulatory Authority (Center for State Control of Drugs, Medical Devices and Equipment).Summary boxCOVID-19 is a serious global health problem. Vaccines are urgently needed to protect humanity. Multiple vaccine candidates are currently being evaluated. The article shows promising safety and immunogenicity results for a vaccine candidate, based on the recombinant RBD subunit of the spike protein.

The Impact of COVID-19 and Vaccine on the Human Nervous System

“…Then, the literature was screened by the following criteria: (1) healthy participants older than 16 years; (2) a sample size of at least 100 participants; (3) randomized controlled design; and (4) the most recent study phase. A total of 33 studies met the inclusion criteria [ 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 ], and we extracted the vaccine platform, name, location, age, study phase, sample size, and safety data (especially the neurological AEs) from the included clinical trials (Table 2 ). Moreover, it must be noted that vaccine-unrelated AEs as specified in the articles have been excluded.…”

Reactogenic sleepiness after COVID-19 vaccination. A hypothesis involving orexinergic system linked to inflammatory signals

“…On the other hand, sleepiness or sleep disturbance as minor to moderate side effects after Pfizer-BioNTech COVID-19 vaccination have been reported [ 13 , 14 ]. Likewise, in some cases, after protein subunit candidates, a number of participants reported a desire to sleep or somnolence [ 12 ]. This fact could be a good sign that the vaccine is working because a more pronounced immune activation during an infection can induce a sleep response that in turn may support host defense and immunological memory formation [ 8 , 21 ].…”

“…But balancing the beneficial and detrimental effects of these inflammatory events is necessary to keep reactogenicity at clinically acceptable levels [ 4 ]. Current analysis of COVID-19 homologous and heterologous vaccination schedules has shown a manageable reactogenicity profile [ [10] , [11] , [12] ].…”

“…A brief outline of sleep response in the context of COVID-19 vaccination provides some information about the frequent occurrence of sleepiness after its administration [ [12] , [13] , [14] , [15] , [16] ]. Then, considering that orexin (Ox) hypothalamic neurons are the key brain substrate controlling wakefulness and mediate some aspects of sickness behavior, we hypothesize its implication in reactogenic sleepiness after peripheral activation of the innate immune system by some of the COVID-19 vaccines.…”

Interferon-Gamma profile of mice (Mus musculus L.) after complete SARS-CoV-2 vaccination

“…Immunogenicity test parameters include humoral immune cell testing (antibody titer), cellular (cytokines), and antibody protectiveness against natural viruses (PRNT). Testing the cellular immune response, one of which includes examining the IFN-γ profile, measuring the IFN-γ profile in the body can provide important information about the immune response mechanism of vaccination (Ashmawy et al, 2022;Banerjee et al, 2022;Hernández-Bernal et al, 2022;Vajo, 2022;Xu et al, 2021).…”