Study evaluates safety, tolerability, and immunogenicity of CoronaVac in older healthy adults

CoronaVac was found to be safe and well-tolerated in older adults. The neutralizing antibody titres stimulated by the 3 μg dose were comparable with the 6 μg dose, and elevated compared to the 1·5 μg dose, favoring the usage of the 3 μg dose CoronaVac in phase III studies to determine protection against coronavirus.

The ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak has expeditiously spread across the world. It has been found that in comparison with younger people, individuals aged 60 years or older, and those with underlying chronic conditions, display a raised risk of mortality and serious illness. This risk elevates with age.

There is an urgent requisition of effective and safe coronavirus vaccines to minimize the burden of coronavirus disease (COVID-19) infection worldwide. Due to immune senescence and age-associated alterations that impact the cellular and molecular elements of both adaptive and innate immune systems, the response to vaccines is usually decreased in older adults. Thus, it is crucial to examine the efficacy of coronavirus vaccines in this specific population.

Since the outbreak began, various investigators have been racing to produce effective and safe coronavirus vaccines. As of 15 January 2021, more than 64 candidate vaccines are in the clinical assessment stage and another 173 vaccines are in the preclinical assessment stage. Numerous studies have demonstrated that with the aid of distinct vaccine platforms (including inactivated virus, mRNA, and adenovirus vectors), the neutralizing antibody responses can be induced in older adults.

The interim efficacy assessment from four phase III studies has demonstrated different vaccines to be highly efficacious against this deadly virus in individuals aged 16 years or older, including two adenovirus vectored vaccines with efficacies of 70% and 91%, and two mRNA vaccines with 95% efficacy. For developing vaccines, the purified inactivated viruses have been utilized traditionally. Currently, about 8 inactivated coronavirus candidate vaccines are in clinical assessment.

There is a paucity of results of efficacy against coronavirus. However, numerous studies have demonstrated that the inactivated vaccines have good safety profiles and can stimulate neutralizing antibody responses. According to the findings of a preclinical trial, CoronaVac (coronavirus vaccine candidate containing inactivated SARS-CoV-2) stimulated good neutralizing antibody responses in animals and partially or completely offered defense from severe interstitial pneumonia in macaques after coronavirus challenge. No antibody-dependent enhancement of infection was noted.

Rationale behind research:

A vaccine against coronavirus is quickly required for older adults, in whom infection-related mortality is elevated. In a previous phase I/II study of CoronaVac in subjects aged 18–59 years, the vaccine was found to stimulate humoral responses against the deadly virus and also displayed good tolerability.

Objective:

A randomized, phase I/II, double-blind, single-centre, placebo-controlled clinical study was carried out to explore the tolerability, safety, and immunogenicity of CoronaVac (an inactivated SARS-CoV-2 vaccine) in healthy subjects aged 60 years and older. 

Study outcomes

• Any vaccine-associated adverse event within 28 days after the administration of each dose of placebo or vaccine was the major safety endpoint
• Seroconversion rate of neutralizing antibodies to live virus on day 28 following the second dose was the major immunogenicity outcome
• Severe adverse events and geometric mean titre of neutralizing antibodies to live virus, as well as seropositive rates and geometric mean rise were the secondary outcome parameters
  

Outcomes

Baseline: There were no vital differences reported at baseline.

Study outcomes

• In the safety populations from both the phases, any side effect within 28 days after injection was found to occur in 20% (20/100) subjects in the 1·5 μg arm, 20% (25/125) in the 3 μg arm, 22% (27/123) in the 6 μg arm, and 21% (15/73) in the placebo arm
• All adverse reactions were mild/moderate in severity. The most commonly noted side effect was injection site pain (9% [39/421] participants)
• Notably, 8 severe adverse events (considered not associated with vaccination) have been witnessed by 2% (n=7) participants. In phase I, seroconversion after the second dose was noted in 100% (24/24) participants in the 3 μg arm and 95.7% (22/23) in the 6 μg arm
• In phase II, seroconversion was witnessed in 90.7% (88/97) participants in the 1·5 μg arm, 98% (96/98) in the 3 μg arm, and 99% (97/98) in the 6 μg arm
• No detectable antibody responses were noted in the subjects administered a placebo

In subjects (age 60 years and older), the two doses of the inactivated SARS-CoV-2 vaccine were found to be safe and also displayed good tolerability at doses of 1·5 μg, 3 μg, and 6 μg. The occurrence of side effects in different dose groups was found to be comparable. This indicated that there was no dose-associated aggravation concern regarding safety. Furthermore, most side effects were transient and mild. The most noted symptom was injection site pain. The findings demonstrated similarity to the trial of participants aged 18–59 years. The study findings were also comparable to the findings of other inactivated coronavirus vaccines in older and younger adults.

None of the severe side effects witnessed during the study was associated with vaccination. Notably, one case of pancreatitis was noted in the 3 μg arm and was deemed to be unassociated with the vaccine. After administering other vaccines like vaccines against hepatitis A and hepatitis B (combined), hepatitis A, human papillomavirus, measles, mumps, and rubella there have been reports of vaccine-associated pancreatitis.

The combined hepatitis A and B vaccine and the human papillomavirus vaccine consist of an aluminium adjuvant. A study indicated that in conjunction with an aluminium adjuvant, inducing immunity through molecular mimicry may culminate in the generation of cytotoxic autoantibodies having a specific affinity for pancreatic acinar cells.

Vaccine-stimulated pancreatitis seems to be an underdiagnosed condition. It can frequently be masked by the incidental presence of more frequently recognized causes, or it may be misdiagnosed as idiopathic pancreatitis. In future and ongoing assessments and through pharmacovigilance, the incidence of pancreatitis should be meticulously monitored.

In subjects aged 60 years and older, the CoronaVac was found to be immunogenic. The neutralizing antibody responses noted in the older adults who were given two vaccine doses (3 μg or 6 μg) were comparable and was found to considerably exceed the response to the 1·5 μg dose. As per the phase I data, the seroconversion rates and geometric mean titres of neutralizing antibodies were low prior to the second vaccination, which offers evidence for a two-dose immunization schedule.

In this assessment, the seroconversion rates in subjects treated with 3 μg or 6 μg doses were over 95% after the two-dose vaccination, with geometric mean titres ranging from 42·2 to 64·4-comparable to the responses in individuals aged 18–59 years who were given 3 μg (seroconversion 97%; geometric mean titre 44·1) or 6 μg doses (100%; 65·4) of vaccine with the similar immunization schedule. Thus, the preliminary findings indicated that the responses to CoronaVac are not lowered in older adults.

In an exploratory assessment stratified by age, no substantial differences were witnessed in the neutralizing antibody responses following the second vaccination between the age groups (60–64 years, 65–69 years, and ≥70 years) following administration of similar doses of vaccine. The geometric mean titres in phase I elevated with age in participants receiving the 3 μg dose. However, they declined with age in participants receiving the 6 μg dose, although these trends did not display statistical significance.

In phase II, opposite trends in geometric mean titres to those of phase I were noted. In all the age groups, the geometric mean titres did not considerably differ between subjects receiving the 3 μg and 6 μg doses following the second injection, except in the individuals aged 70 years and older in phase I and the individuals aged 60–64 years in phase II. The large differences in immune responses to vaccination across older individuals and the small sample sizes and might account for these differences. The association between the immune response to the inactivated SARS-CoV-2 vaccine and age will be investigated in the ongoing phase III trials.

The correlates of protection have not yet been successfully established for any coronavirus vaccines in development. However, the neutralizing antibodies are investigated in all the trials due to evidence of their link with protection against coronavirus in animal challenge experiments. The live virus  neutralization assays are time-consuming, laborious, and need biosafety level 3 conditions. Developing other assays to investigate the antibody titres is important. In this analysis, the neutralizing antibodies to live SARS-CoV-2 and anti-receptor-binding domain IgG antibodies were assessed in adults aged 18–59 years, and a powerful correlation was noted between neutralizing antibodies and anti- receptor-binding domain IgG antibodies.

The IFN-γ was detected as an indicator of T-cell responses after vaccination in this phase I trial in subjects aged 18–59 years, and the findings demonstrated that the responses evoked by the inactivated SARS-CoV-2 vaccine were low. In an ongoing phase III study, the responses of type 1 and type 2 T-helper cells by the CoronaVac will be investigated.

In conclusion, the CoronaVac displayed good tolerability and stimulated humoral responses in individuals aged 60 years and older, thus favoring the usage of this vaccine in the older population. The neutralizing antibody titres stimulated by the 3 μg dose were greater in comparison with the 1·5 μg dose and was found to be comparable with the 6 μg dose. Combined with the safety and production capacity, the 3 μg dose of CoronaVac with a two-dose immunization schedule is being utilized in the ongoing phase III trials to evaluate the defense against coronavirus.

In the ongoing phase III study, a prompt immunization schedule (with injections on days 0 and 14) is also being utilized in older individuals to explore CoronaVac's efficacy. Future investigations are needed to explore CoronaVac's effectiveness in various populations, including older individuals having chronic underlying disorders, and with geographical and ethnic diversity.