New interim results of a phase 1-2 clinical trial published in The Lancet Infectious Diseases tested the safety and effectiveness of an adjuvanted recombinant protein vaccine against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) called CoV2 preS dTM. Findings showed the vaccine was well-tolerated overall in human adults and produced antibodies against wild-type SARS-CoV-2 strains in vitro. However, the vaccine did not elicit a robust neutralizing response to the virus in older adults.
“The lower than expected immune responses, especially in the older age groups, and the high reactogenicity after dose two were probably due to higher than anticipated host-cell protein content and lower than planned antigen doses in the formulations tested, which was discovered during characterization studies on the final bulk drug substance.”
The researchers conducted the clinical trial across ten research centers in the United States and plan to complete the study a year after the last injection. The current results display trial progress after 43 days. Future work for this vaccine candidate includes optimizing the antigen formulation and dose before testing in phase 3 trials.
Trial design information
The currents study results took place between September 3 and September 29, 2020. A total of 269 participants — ranging from 18 to 49 years of age and 90 participants who were older than 50 — received two vaccine doses. About 170 participants were randomly assigned to receive only one dose of the vaccine.
The groups would be randomly assigned to receive either low-dose antigen with AF03 or AS03 adjuvant, high-dose antigen with AF03 or AS03 adjuvant, high-dose antigen with AF03 or AS03 adjuvant, or unadjuvanted high-dose antigen.
Because of trial enrollment numbers, the researchers note more younger individuals were assigned to the single-dose group. Also, people older than 50 did not receive the unadjuvanted high-dose antigen group, with the reasoning being prior work showing older adults had less immune response without the presence of an adjuvant. More people in the two-dose group were likely to receive AS-3-adjuvanted formulations than AF03-adjuvanted formulations.
Favorable vaccine safety profile
Adjuvanted two-dose vaccine groups received expected injection-site side-effects — pain, skin redness, and swelling — in the first seven days after vaccination. Grade 3 adverse events happened more after the second dose than the first.
The unadjuvanted high-dose group reported less unfavorable events around the injection site; their side effects were comparable to the placebo group. Grade 3 injection site reactions were the highest amongst the high dose plus AS03 group after receiving the second vaccine dose, with 24% reporting redness and 13% reporting swelling. Although, no grade 3 reactions were considered severe, and all had resolved after two days.
Amongst all groups, pain around the injection site was the most common side-effect. Although expected injection-site reactions were less common and severe in participants 50 years or older, participants who received the AF03-adjuvanted formulations and in participants who received the low two-dose formulation.
Systemic reactions were reported more often on the second day after receiving the second dose, with the most common being myalgia, malaise, and headache. These reactions were less severe and frequent amongst participants aged 50 years or older than those in the younger age group and participants who received AF03-adjuvanted formulations. Grade 3 systemic reactions happened more after the second dose among the vaccine group with the adjuvanted formulations — especially the low-dose plus AS03 group.
There were no vaccine-related unsolicited reactions observed until after the second dose.
Vaccine-induced immune response is dependent on age
There were no neutralizing antibody titers greater than the placebo group after a single dose of the vaccine at days 22 or 36.
After the second dose, people in the unadjuvanted high-dose formulation group had comparable antibody levels to the placebo group. In contrast, the adjuvanted groups — AF03- and AS03-adjuvanted high-dose formulations — had three-fold and four-fold more neutralizing antibody titers than their low-dose counterparts.
Further analysis considering age showed the four-fold increase in antibody titers was mainly from the immune responses of people lower than 50 years of age, especially amongst people 60 years and older. The age-related results were also the same for seroconversion.
While binding antibody responses were observed across vaccine groups, it was higher amongst the two-dose groups. Responses were higher in the AS03-adjuvanted groups than in the AF03-adjuvanted groups and in groups with higher vaccine doses.
The researchers also observed more robust increases of IFN-γ, IL-2, and TNFα cytokines from before vaccination to days 22 and 36, especially for the AS03-adjuvanted groups.