Last week, South African healthcare received a double shot in the arm with the opening of a local vaccine manufacturing facility and the approval of a World Bank loan to bolster social safety nets and health systems.
On Wednesday, President Cyril Ramaphosa and health technology billionaire Dr Patrick Soon-Shiong officially opened a new vaccine manufacturing facility in Brackenfell, Western Cape.
The South African-born entrepreneur has been strongly supporting local healthcare, with R3 billion invested to help SA share vaccine technology with the rest of Africa. His company, ImmunityBio, is developing a T-cell based universal COVID vaccine, currently in Phase III trials in SA. The same adenovirus vector technology it uses is also being tested in cancer vaccines.
“It has been a dream of mine, since I left the country as a young physician, to bring state-of-the-art, 21st century medical care to SA and to enable the country to serve as a scientific hub for the continent,” Dr Shoon-Siong had previously said. The technology transfer will help “establish much-needed capacity and self-sufficiency.”
The hub will transfer technology, know-how and materials for DNA, RNA, adjuvant vaccine platforms and cell therapies to SA.
“There is no reason we couldn’t make 500 million doses a year,” said Dr Soon-Shiong, who is also a Wits alumnus. “Subject to the raw material being available.”
He said he wants to tap the country’s expertise on prevalent diseases such as HIV and cervical cancer. “There are fantastic scientists with deep knowledge about these diseases,” he said. “More so than in America because they see these patients every day.”
President Ramaphosa and Dr Soon-Shiong also launched the Coalition to Accelerate Africa’s Access to Advanced Healthcare, which aims to drive the development of innovative therapeutics and ensure the continent is prepared for future pandemics.
The coalition aims to manufacture a billion doses of the COVID vaccine by 2025 and to develop treatments for conditions including cancer, COVID, tuberculosis and HIV.
South Africa also received approval from the World Bank for a US$750 million COVID relief loan aimed at reducing the worst of the pandemic’s impact on the poor.
“The World Bank budget support is coming at a critical time for us and will contribute towards addressing the financing gap stemming from additional spending in response to the COVID crisis,” said Dondo Mogajane, Director General of the National Treasury. “It will assist in addressing the immediate challenge of financing critical health and social safety net programs whilst also continuing to develop our economic reform agenda to build back better.”
Meanwhile, Health Minister Dr Joe Phaahla warned that South Africa will likely enter a fifth wave when cold temperatures in May, though what COVID variants may drive it remain to be seen.
Immunotherapy company ImmunityBio has been authorised by the South Africa Health Products Regulatory Authority (SAHPRA) to proceed with the South Africa Sisonke T-Cell Universal Boost trial.
The Phase 1/2/3 study, starting in the second third quarter of 2021, is designed to evaluate hAd5 Spike + Nucleocapsid (S+N) as a boost for South African healthcare workers previously vaccinated with an S (Spike)-only vaccine.
“With the virus continuing to spread, moving forward with this boost trial is crucial,” said Leonard Sender, MD, Chief Operating Officer of ImmunityBio. “We are encouraged by the preliminary safety findings in our ongoing Phase 1 studies in both the U.S. and South Africa. In addition, our U.S. data show that just a single prime subcutaneous vaccination with our COVID-19 vaccine candidate induces a 10-fold increase in T cell response—equivalent to T cell responses from patients previously infected with SARS-CoV-2. We have also shown that the T-cell responses are maintained against variants, which is critical to providing protection against this ever-changing virus.”
In the trial, the effect of combining vaccination by subcutaneous (SC) and sublingual (SL) routes will be assessed. This combination has the potential to deliver protection from the virus with a single injection followed by droplets placed under the tongue. Methods that do not require injection such as SL, intranasal, and oral capsule offer potential advantages depending on the participant’s needs or situation. Sublingual administration offers the most rapid absorption, while nasal spray or oral capsule delivery have the potential to provide mucosal immunity, which could reduce both the chance of infection and potential spread of the virus via the respiratory tract. The three non-injection formulations do not need a trained healthcare worker to administer them and are easier to transport and store. The SL and nasal routes of administration are also currently being tested in a separate Phase 1 trial in South Africa.
“The number of new cases in South Africa is frightening, particularly when you consider recent data suggesting currently available COVID-19 vaccines may not provide the immune memory needed to fend off infection from future variants. This highlights an urgent need for a boost dose that confers long-term protection by activating both antibodies and T cells, ” said Patrick Soon-Shiong, MD, Founder and Executive Chairman of ImmunityBio.
“Several peer-reviewed studies demonstrate that patients who have recovered from SARS-CoV in the 2003 outbreak possess long lasting memory T cells reactive to the nucleocapsid protein of SARS-CoV 17 years after infection. While antibodies block infection when present, T cells are vital for long-term immune memory. We are excited to begin this controlled, randomized trial of boosting a previously administered DNA-based viral vector vaccine with our own Ad5 dual-antigen S plus N vaccine to see if it can augment protection in participants who have received the S-based vaccine alone,” added Dr Soon-Shiong.
In addition to traditional subcutaneous administration for the vaccine candidate, the trial will measure immune responses generated by sublingual and nasal administration routes. Photo by Gustavo Fring from Pexels
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.
