Results from the Phase I trial in humans of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a Synopsis

Clinical Trials Coronavirus Covid-19 Disease Control Emerging Infectious Diseases Global Pandemic SARS-CoV-2 vaccine safety

One of the vaccine candidates for COVID-19 at the Phase I stage is the non-replicating adenovirus type-5 (Ad5) vectored COVID-19 vaccine developed by the Beijing Institute of Biotechnology (Beijing, China) and CanSino Biologics (Tianjin, China).

Three days ago, the results of the Phase I trial of the vaccine in humans was published in the Lancet. (Zhu, Feng-Cai et al. Lancet Online. May 22, 2020).

The vaccine is very similar to the one being developed by the Oxford group. Both use adenoviruses as vectors. However, where the Oxford uses chimpanzee adenovirus, the CanSino team uses human adenovirus type 5 that has been treated so it cannot replicate. Into this adenovirus vector is then placed the portion of the genome of SARS-CoV-2 that codes for the spike protein. The adenovirus vector, now expressing the spike protein of the SARS-CoV-2 virus was then injected into volunteers as a vaccine candidate.

Between March 16 and March 27, 2020, 108 healthy participants in Wuhan, China, were recruited for the trial. They were between ages 18 and 60; 51% male, 49% female. Among other requirements, pharyngeal swabs or sputum and anal swabs from the participants had to be negative for SARS-CoV-2. Also, serology tests had to be negative for any SARS-CoV-2 antibodies.

The vaccine was dosed by how many particles of adenovirus were injected. Three doses were tested in this study – low, medium, and high doses.
The low dose contained 5 × (10 to the power 10), the medium dose 1 × (10 to the power 11), and the high dose 1·5 × (10 to the power 11) viral particles.
The cohort was divided into 3 groups of 36 for the different dose levels.
Those in the low and medium groups received the shots in one arm. The dose for the participants in the high dose group was divided between the shoulders.

The study aimed to assess adverse events at days 7 and 28 and safety up to 28 days post-vaccination. The team also planned to study the antibodies that would be generated from the vaccine. The hope was that the vaccine would be immunogenic and generate both binding and neutralizing antibodies in the participants.
Lastly, the ability of the vaccine to generate T-cell responses was also going to be assessed.

(Where neutralizing antibodies bind to pathogens and inactivate them biologically, binding antibodies bind to pathogens but lack the ability to kill them off. They however induce other immune cells to attack and inactivate these pathogens. Unfortunately, in some instances, binding antibodies, in attaching to pathogens enhance their ability to enter the cell. Sometimes the presence of binding antibodies from one virus enhances the virulence of a closely related virus..a phenomenon called antibody-dependent enhancement – ADE).

Results:

87 (81%) of 108 participants reported at least one adverse reaction within the first 7 days after the vaccination: 30 (83%) in the low dose group, 30 (83%) in the middle dose group, and 27 (75%) in the high dose group.
The most common adverse reaction was pain at the injection site.
The most commonly reported systematic adverse reactions overall were fever, fatigue, headache, and muscle pain. None of the systematic reactions lasted longer than 48 hours. No adverse reactions were reported after 28 days.

The vaccine was immunogenic. A positive antibody response (seroconversion) was defined as at least a four-fold increase in post-vaccination titer from baseline.

By Day 28 post-vaccination, at least a four-fold increase in rapid binding antibodies to the receptor binding domain (anti-RBD) was found in 97% of the participants in the low group, 94% in the middle group and 100% in the high group. The highest titer was in the high dose group. This was proven by testing blood samples of the participants with constructed receptor binding domain through the ELISA test.

Neutralizing antibodies were absent at Day 0, increased moderately by Day 14 and peaked by Day 28. Again, the highest titer was in the high dose group. 50% of the participants in the low dose group, 50% in the middle dose group, and 75% in the high dose group had at least a four-fold increase in neutralizing antibody titers by day 28.
This was proven by testing blood samples of the participants with live SARS-CoV-2 viruses.
Both antibodies from participants’ samples were also tested against a vesicular stomatitis virus that had been altered to express the spike glycoprotein of SARS-CoV-2. Again, the antibodies showed activity.

The vaccine also induced T-cell responses. Again, the response was highest in the high dose group and quite low in the low dose group. The expression of IFNγ and TNFα expression shows that CD4+ and CD8+ T cells were activated.

The vector used for the vaccine is the Adenovirus type 5 (Ad5). This virus is found in humans and causes the common cold. This means that there were participants who had neutralizing antibodies to Ad5. These participants showed a lower ability to generate neutralizing antibodies to the SARS-CoV-2 vaccine regardless of vaccine dose. Even though those in the high dose group showed slightly higher seroconversions, it was not statistically significant. The presence of anti-Ad5 antibodies also hindered the T-cell response. These inhibiting effects of the Ad5 antibodies were most observable in those between ages 45 – 60.
Interestingly, participants with prior anti-Ad5 antibodies saw an increase in its titer after receiving the vaccine.

Take-Aways:

The chances of getting a vector-based COVID-19 vaccine…one that actually induces immunogenicity… is a solid possibility and should make all excited.

The study is limited by the its small cohort size, the short duration of follow-up, and the absence of a randomized control group.

The ability to generate neutralizing antibodies that inactivate the SARS-CoV-2 virus in vitro does not necessarily translate to the same thing happening in the human body. However, in a study with ferrets, the antibodies were protective when they were vaccinated and later challenged with the SARs-CoV-2 virus. This suggests that these neutralizing antibodies may protect against Covid-19.

The use of Adenovirus type 5 which can infect humans may be a hindrance due to the presence of the anti-Ad5 antibody. This makes the Oxford version more interesting since it uses an adenovirus from the chimpanzee to avoid this problem.

Further studies are needed to know how long the neutralizing antibodies will last.

An effective dose still needs to be worked on.

More older people (> = 60) need to be studied to assess the degree of antibody production in this population. Their numbers in the present study were rather low.

In spite of all the unknowns, this development is still really encouraging and bodes well for the future use of vectors not only in vaccine production but also in targeted cancer therapies.

By Nana Dadzie Ghansah an anesthesiologist who lives and works in Lexington Kentucky

Also look into our post on the French Chloroquine Study

holisticphysician

A physician providing primary medical care to patients across the lifespan

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