A phase II clinical trial of a candidate vaccine for COVID-19 consisting of an attenuated human adenovirus type 5 (Ad5) vector engineered to transfer coronavirus "spike protein" genetic coding into humans has found it was safe, and that it stimulated marked immune responses (Lancet 2020; doi: https://doi.org/10.1016/S0140-6736(20)31605-6).

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The researchers also found the vaccine stimulated production of antibodies that neutralized live coronavirus in laboratory tests. They concluded the data had validated the vaccine for phase III investigation of disease prevention in populations at risk of coronavirus infection.

Research Details

The double-blind, randomized phase II study with 508 healthy adults followed an earlier phase I trial of dose and toxicity that had detected antibody and T-cell responses to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the COVID-19 virus.

"The phase II trial adds further evidence on safety and immunogenicity in a large population. This is an important step in evaluating this early-stage experimental vaccine, and phase III trials are now underway," said co-first author Feng-Cai Zhu, MSc, from the NHC Key Laboratory of Enteric Pathogenic Microbiology, Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, China.

The study used an adenovirus typical of common cold viruses in humans that had been engineered to be non-replicating and hence not pathogenic. A similar study in the UK (reported in the same edition of The Lancet) used an adenovirus found naturally in chimpanzees as the vector. It also reported T-cell and antigen responses and virus neutralizing activity.

The Chinese and UK studies differed in design and vaccine dose groups. One of the coronavirus candidate vaccine arms in the Chinese study used a dose of 0.5 x 10¹¹ viral particles (the same as in the UK study). The other active vaccine arm (from a total of three study arms) doubled this to 1.0 x 10¹¹ viral particles-prompted by a hint (from the phase I findings) that the higher dose had greater efficacy with good safety.

The third arm of the Chinese study used a placebo that was physically identical to the active agent but lacked viral particles. (The UK study's control arm used injections of a meningitis vaccine.)

Another small difference between the two studies was that in the single-blinded UK trial the investigators knew which injection was being used. But in the double-blinded Chinese study the code was not broken until data analysis.

Phase II Study Design

The trial of the Ad5-vectored COVID-19 vaccine was conducted at a single center in Wuhan, China, among volunteers who were at least 18 years old (mean age 39.7 years, half of them male). Six out of 10 were younger than 44, but 13 of them were 55 or older. They did not have HIV and had never been infected with SARS-CoV-2.

All of the study subjects were given intramuscular injections and were randomly assigned to three groups: half (253 people) were injected with the higher dose of the candidate vaccine (1.0 x 10¹¹ virus particles). The remaining two groups were randomized to have outwardly identical injections with either the lower dose of vaccine (0.5 x 10¹¹ virus particles) or placebo.

Immunogenicity was a primary endpoint as assessed through assays of the geometric mean titers (GMTs) of specific ELISA antibody responses to the receptor binding domain (RBD). Another assessment was made by testing samples for neutralizing antibody responses at day 28. The co-primary endpoint-safety-was evaluated from the incidence of adverse reactions reported within 14 days.

The vaccine induced seroconversion of the neutralizing antibodies to SARS-CoV-2 in around half of the group vaccinated-with little difference between the two vaccine dose groups. (There was a mean GMT of 19.5 in subjects given the higher dose vaccine, 18.3 among those on the lower dose).

Seroconversion of binding antibody was high, with little dose dependency-96 percent and 97 percent in the two dosage arms. RBD-specific ELISA (binding) antibodies reached median peaks of 656.5 and 571.0 by day 28.

Positivity rates for specific T-cell responses (measured by interferon [gamma] ELISpot) were also high-90 percent and 88 percent.

Another way of viewing the immunological response was that 95 percent of all participants in the high-dose group, and 91 percent of those in the 5x10¹⁰ viral particles dose group, had shown either cellular (T-cell) or humoral (antibody) immune responses 28 days after vaccination.

Unsurprisingly, some subjects had pre-existing immunity to the Ad5 human virus vector. This factor, and older age, could have reduced specific immune responses to vaccination, the researchers noted-particularly humoral immune responses. Considering this possible dilution of vaccine effect, the finding of more than 90 percent response overall was a strong endorsement of the vaccine's immunogenicity.

Also, the investigators found (in contrast to their expectations) that the vaccine dose of 0.5 x 10¹¹ viral particles had comparable immunogenicity to the vaccine at 1 x 10¹¹ viral particles. And importantly it had a better safety profile.

Adverse reactions to the injections were reported by nearly three-quarters of all the subjects who received an active vaccine. They were mostly mild or moderate. But the study found a quarter of those taking the higher dose vaccine had severe reactions while in the lower dose group only a single participant had a severe reaction.

Phase III Investigation Validated

The researchers concluded that the findings validated the lower dose of vaccine to go forward into phase III studies to determine whether it effectively protected people against SARS-CoV-2 infection. It had induced "significant immune responses" in the majority of recipients after a single immunization.

"Our results suggest [that] a single-dose immunization schedule of Ad5-vectored COVID-19 vaccine at 5 x 10¹⁰ viral particles is an appropriate regimen for healthy adults," they wrote.

Participants 55 years or older had relative low antibody responses, particularly in terms of neutralizing antibodies. But the active vaccine still induced significantly higher neutralizing antibodies by day 28 than in the control group.

"We found older people to have a significantly lower immune response-but higher tolerability-to the Ad5-vectored COVID-19 vaccine," the researchers noted in the study. They planned to study the use of a booster vaccination in older people.

The study was planned to broaden to a multicenter, randomized, double-blind, controlled phase III trial, and the researchers acknowledged the need to continue international cooperation in vaccine testing.

"We are in the midst of a global COVID-19 pandemic. Timely sharing of the results of clinical trials with candidate vaccines is critical," they concluded.

Peter M. Goodwin is a contributing writer.