The Phase I clinical trial of ImmunityBio’s experimental COVID vaccine, designed to be effective against COVID variants, is about to be expanded to include different administration routes as well as effectiveness in people who previously had COVID.
Co-investigator Prof Graeme Meintjes, second chair in the Department of Medicine at UCT, said that the Phase I trial has started and is still ongoing at the Wellcome Centre for Infectious Diseases Research in Africa’s (CIDRI-Africa) Khayelitsha clinical research site.
He said that the first two cohorts of ten participants each both received two subcutaneous injections of the vaccine, three weeks apart, with one cohort receiving a higher dose.
“The purpose of that was to assess safety, so participants were followed up very carefully for side effects and for reactions to the vaccine. And the review of that suggests no major safety concerns,” he explained. He added that the Phase I trial design has since been adapted to include four more cohorts, which is going through the approval process.
These four additional cohorts will include people who have had COVID because the researchers want to look at the effect the vaccine will have on boosting existing immunity against COVID. Each cohort will have ten participants, bringing the expected total number of participants for Phase I to 60 people.
New administration routes
To see whether different administration routes produce a sufficient immune response, each participant in these new cohorts will receive one dose of the vaccine through one of four routes. These would be either a subcutaneous injection, a sublingual route, a combination of subcutaneous injection and sublingual method, or an intranasal route.
“We’ll be measuring the antibody responses as well as the T-cell responses to the vaccine, but we do not have results yet,” said Meintjes. He added that enrolment should be complete in the next two months, pending the outcome of the approval process.
Phase II/III trial plans
Phase II and Phase III trials in South Africa are being planned, which will be headed by the South African Medical Research Council (SAMRC), Mentjes confirmed.
Details will be made available once the trial has been approved by SAHPRA. It is unlikely that placebos will be used, now that vaccines are shown to be effective; rather different vaccines will be compared.
Broader immune response with two-pronged defence
The vaccine has been designed to potentially offer a broader, long-lasting immune response, Mentjes noted. In this way it should also provide improved protection against COVID variants.
Currently, most of the COVID vaccines are designed to produce an immune response against the spike protein of the virus, but it mutates rapidly, allowing certain variants to partially or fully escape vaccines.
The ImmunityBio vaccine aims to offer a two-pronged or dual defence, Meintjes said, with the vaccine containing two proteins from the SARS-CoV-2 virus: the spike protein along with the more stable nucleocapsid protein. The nucleocapsid is an RNA-binding protein which is critical for viral replication and genome packaging.
He explains that targeting nucleocapsid could potentially provide more durable and long-term protection against different variants of the SARS-CoV-2 virus because the immune system will recognise the nucleocapsid even when the spike protein changes.
“The hope is that by including the nucleocapsid you would generate a vaccine response that covers emerging variants, those that have emerged and those that might emerge in the future,” he says.
Human-adenovirus based vaccine carrier
The ImmunityBio vaccine will use an adenovirus vector to deliver the antigens. Director of the Africa Health Research Institute (AHRI), Professor Willem Hanekom, explained that a vector is needed in order to stimulate the immune system’s response, and a viral vector is effective since it is foreign to the immune system, helping provoke an immune response. The virus is designed to simply carry the antigens into the body.
The AstraZeneca vaccine uses a modified chimpanzee adenovirus while Johnson & Johnson’s uses the human adenovirus Ad26, which has been used before in a number of vaccines including HIV. ImmunityBio’s vaccine uses the human adenovirus hAd5, which was initially used in failed gene therapy trials — but which proved to be an excellent vaccine delivery system. However, its development over the past two decades has been halting.
According to Prof Hanekom, if there is previous immunity against the adenovirus being used in a vaccine, the immune system will destroy it before the antigens inside are released. This has been circumvented with the ImmunityBio vaccine so that the immune system doesn’t immediately recognise the hAd5 vector. There was concern that the Johnson & Johnson vaccine would have limited efficacy in sub-Saharan Africa due to the fact that about half the population have immunity to Ad26.
“They’ve modified the adenovirus so it will still work and still be seen by the immune system even if there is pre-existing immunity because they’ve taken out the parts that the pre-existing immunity sees,” Prof Hanekom said.
Enhanced T-cell response
The vaccine is specifically designed to elicit strong T-cell responses to the nucleocapsid, and this has been seen in animal studies, Mentjes noted.
“Obviously one purpose of these studies is to see whether this design element generates those strong T-cell responses in humans as well,” he says. “All COVID vaccines elicit T and B cell responses, it’s not one or the other. But this (vaccine) is specifically designed to enhance those T-cell responses.”
B-cells and T-cells form part of the body’s adaptive immune response. B-cells form the antibodies to respond to a pathogen, and when the virus is introduced again, memory B-cells provide the antibodies to respond quickly.
Vardas says that with the ImmunityBio vaccine, B-cells and memory B-Cells will be formed that will remember the spike protein and the nucleocapsid and how to attack it. She likens this to a sniper attack. She explains that when a memory B-cell detects the spike or nucleocapsid protein, it signals for the production of B-cell antibodies. These antibodies then coat the outside of the virus, which signals the T-cells to attack and essentially “eat up” the virus-infected cells.
There are two types of T-cells, explains Vardas – CD4 cells which attack the virus, and CD8 cells, which also form a memory cell as the B-cell does. “You’ll have groups of CD4 and CD8 cells that are spike protein-specific and groups that are nucleocapsid specific, so improving that kind of attack to two sides of the war,” said Vardas.
Source: University of Cape Town