Ad5-vectored COVID-19 vaccine gets a boost with new data
Amidst the global race for a vaccine against COVID-19, the Ad5*-vectored COVID-19 (Ad5-nCoV) vaccine gets a boost with the release of encouraging data from the phase II trial, which provide further evidence supporting the safety and immunogenicity of this vaccine.
The novel Ad5-nCoV vaccine has been shown to be safe, well-tolerated, and induce rapid immune response against SARS-CoV-2 in healthy adults in the phase I trial. Specific T-cell response against SARS-CoV-2 was seen as early as 14 days after a single vaccine shot, while humoral immune response peaked at 28 days.
“These results represent an important milestone. The trial demonstrates that a single dose of the new Ad5-nCoV vaccine produces virus-specific antibodies and T cells in 14 days, making it a potential candidate for further investigation,” said principal investigator Professor Chen Wei from the Beijing Institute of Biotechnology, Beijing, China.
Unlike the phase I trial, the phase II trial enrolled a more diverse population (without the age cap) — thus expanding the population to individuals 55 years and older.
“Since elderly individuals face a high risk of serious illness and death associated with COVID-19 infection, they are an important target population for a COVID-19 vaccine,” Chen said.
Nonetheless, the researchers were cautiously optimistic on what the data mean for a working vaccine against SARS-CoV-2. “These results should be interpreted cautiously. The challenges in the development of a COVID-19 vaccine are unprecedented, and the ability to trigger these immune responses does not necessarily indicate that the vaccine will protect humans from COVID-19,” he cautioned.
Promising data from phase I
Ad5-nCoV vaccine, the first COVID-19 vaccine to enter a phase I trial, consists of an Ad5 vector carrying the genetic code of the SARS-CoV-2 spike glycoprotein.
The phase I trial is a dose-escalation study to determine the suitable doses for further investigation among three doses tested: high dose (5x10¹⁰ viral particles; n=36), middle dose (1x10¹¹ viral particles; n=36), and low dose (1.5x10¹¹ viral particles; n=36). Participants were 108 healthy adult volunteers aged 18–60 years (mean age 36.3 years, 51 percent male). [Lancet 2020;395:1845-1854]
Regardless of the dosage used, the vaccine was able to trigger both arms of the immune system: the humoral immunity, which entails the production of neutralising antibodies, and the cell-mediated immunity involving T cell response. Humoral immunity targets circulating virus in the blood and lymphatic system, while T cells directly attack infected cells.
“Onset of detectable immune responses was rapid, with T-cell responses peaking at day 14 after vaccination and antibodies peaking at day 28,” observed the researchers.
Immune responses were seen in most participants at the 14-day peak for T-cell response (83.3 percent, 97.2 percent, and 97.2 percent for low, medium, and high dose, respectively) and the 28-day peak for humoral response (97 percent, 94 percent, and 100 percent, respectively).
However, the high-dose vaccine was also associated with a greater incidence of severe adverse reactions such as severe fever, fatigue, dyspnoea, muscle pain, and joint pain. Hence, the low- and middle-dose were chosen for further evaluation in the phase II study.
Consistent findings in phase II
The double-blind phase II trial involved 508 participants randomized 2:1:1 to receive a high-dose (1x10¹¹ viral particles) or a low-dose vaccine (5x1010 viral particles) or placebo. Also included among the participants were 65 seniors (13 percent) aged ≥55 years. [Lancet 2020;doi:10.1016/S0140-6736(20)31605-6]
Consistent with the phase I data, both doses of vaccine induced an immune response (antibody or T cell-mediated responses) in the majority of participants at 28 days post-vaccination (95 percent and 91 percent in the high- and low-dose groups, respectively).
Specifically, neutralising antibody response to live SARS-CoV-2 was detected in 59 percent and 47 percent of participants receiving the high and low dose, respectively — with geometric mean titres (GMTs) of 19.5 and 18.3, respectively. Binding antibody response, on the other hand, was shown in 96 percent and 97 percent of participants and peaked at 656.5 ELISA units and 571 ELISA units, respectively.
For T cell-mediated immunity, 90 percent and 88 percent of participants in the high- and low-dose groups showed positive responses as measured by IFNγ-ELISpot — with a median of 11 and 10 spot-forming cells per 1×10⁵ peripheral blood mononuclear cells, respectively, at day 28.
There were no increases in antibody or T-cell responses from baseline in the placebo group.
“A single injection of the Ad5-vectored COVID-19 vaccine … induced comparable specific immune responses to the spike glycoprotein at day 28, with no significant differences noted between the two [doses],” Chen and co-authors reported.
Common adverse reactions post-vaccination included fever, fatigue, and pain at injection site, but were mostly mild to moderate, in line with the phase I data.
Insights on older people
“Compared with the younger population, we found older people have a significantly lower immune response, but higher tolerability, to the [vaccine],” said Chen.
As the researchers observed, older age — in addition to pre-existing immunity to the Ad5 vector (a vector also carried by the common cold virus) — could stifle the immune responses to vaccination. The reverse was observed with regard to tolerability, in which incidence of fever was associated with younger age and low pre-existing immunity to the Ad5 vector.
These findings are in line with the expectation that older people are more likely to have prior exposure to Ad5, the researchers explained.
“It is possible that an additional dose may be needed to induce a stronger immune response in the elderly population, and further research [in phase IIb trial] is underway to evaluate this,” said Chen.
The road ahead
“[The results] augur well for phase III trials … [and] the safety signals … are reassuring,” commented Drs Naor Bar-Zeev and William J Moss from Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, US, in a linked commentary. [Lancet 2020;doi:10.1016/S0140-6736(20)31611-1]
“But when things are urgent, we must proceed cautiously. The success of COVID-19 vaccines hinges on community trust in vaccine sciences,” they wrote.
Whether the specific immune response elicited confers an effective protection against infection is not yet known based on the early-phase results, noted Chen and co-authors.
Also, questions remained regarding the durability of immune response, the type of immune response required to drive protection, or whether immunogenicity differs by patient characteristics such as age, sex, or ethnicity.
“Our results suggest a single-dose immunization at 5×10¹⁰ viral particles is an appropriate regimen for healthy adults,” and this, according to the researchers, will be further investigated in the phase III trial.