In January 2022, Cape Town-based biotechnology company Afrigen Biologics announced that it has successfully produced a lab-scale batch of a Covid-19 vaccine that is similar to that made by pharmaceutical company Moderna. The achievement is particularly impressive since the vaccine uses the still relatively new mRNA vaccine technology.

The achievement, billed as the first successful “reverse engineering” of Moderna’s vaccine, has been hailed as an important milestone towards building capacity in low- and middle-income countries (LMICs) to manufacture Covid-19 vaccines.

But what has actually happened so far, and what else needs to happen before jabs developed at Afrigen can be used in vaccination programmes?

It started with the Hub

Recognising the rapidly emerging and widening inequality in access to Covid-19 vaccines globally, the World Health Organization (WHO) announced the establishment of an mRNA Technology Transfer Hub in June 2021. The aim of the Hub is to build mRNA vaccine manufacturing capacity in LMICs, with a focus first on Covid-19 vaccines. South Africa was selected to host the Hub, and Afrigen was tasked with developing an mRNA Covid-19 vaccine along with a technology transfer package that could be used to capacitate commercial manufacturers in LMICs to produce the vaccine.

When the Hub was initially launched it was hoped that, through engagement and pressure, one of the companies with a leading mRNA vaccine against Covid-19 – Moderna and/or Pfizer/BioNTech – would be swayed to cooperate with and support the work of the Hub through licensing their intellectual property and transferring their technology to the Hub.

This did not happen.

Both companies dug in their heels, as revenues from the sale of their respective Covid-19 vaccines ballooned and, to date, both have refused to share their technology with the Hub.

Without a technology transfer partner, Afrigen was forced to go it alone – albeit with significant support from international health agencies and technical experts from around the world.

In January 2022 – less than seven months after the Hub’s establishment – Afrigen announced that it had successfully made a lab-scale batch of an mRNA vaccine against Covid-19 that is similar to Moderna’s product.

So what has Afrigen actually made?

Afrigen has made a lab-size batch (a couple of litres) of mRNA vaccine drug substance using the publicly available genetic sequence that was used by Moderna to develop its vaccine.

Prof Petro Terblanche, CEO of Afrigen, told Reuters, “We haven’t copied Moderna, we’ve developed our own processes because Moderna didn’t give us any technology. We started with the Moderna sequence because that gives, in our view, the best starting material. But this is not Moderna’s vaccine; it is the Afrigen mRNA Hub vaccine,” she said.

The WHO has previously stated that the Hub would focus on developing a vaccine similar to Moderna’s, rather than Pfizer/BioNTech’s, because of the availability of relevant data in the public domain, the vaccine’s less stringent refrigeration requirements, and because of the company’s pledge not to enforce its patents during the pandemic.

Terblanche explained to Spotlight that developing a lab-scale batch of mRNA vaccine substance has involved multiple steps and that “the steps for the lab batch are exactly what it would be for full-scale”. What will change for full-scale production are the conditions under which the vaccine is produced.

Vaccines given to humans as part of clinical trials or through health programmes can only be produced in facilities certified for complying with Good Manufacturing Practices (cGMP) – which Afrigen is currently working toward.

According to Terblanche, producing the lab batch involved producing the sequence, making the plasmid – the DNA, linearising it, purifying the RNA strains, stabilising it, and encapsulating it. (You can read more about what these steps entail here).

Terblance says there are many raw materials used to develop Afrigen’s mRNA vaccine, and, “it’s exactly all the raw materials that are being used by Moderna and CureVac and some of the others. There are the IVT enzymes, there are the lipids… the four different nano lipid particles, there are all the enzymes, all the assays for the analytics, and they are sourced from Europe and the US.” 

Terblanche explains that the RNA (which is synthesised from DNA) used to develop Afrigen’s lab-batch of mRNA vaccines was made by Afrigen’s academic partner – the University of Witwatersrand (Wits), where they have the relevant platforms and have been working on RNA for six years.

Using the RNA produced at Wits, the formulation, production of the vaccine drug substance, stability testing, and validation were all done at Afrigen.

For all the excitement generated by the announcement of an mRNA vaccine hub being established in South Africa, the country is still going to need help making Covid jabs. (Photo: Aspen Pharmacare)

A key component in formulating mRNA vaccines is encapsulating the mRNA in an oily shell or fat bubble known as a lipid nanoparticle that prevents degradation of the mRNA and allows for its delivery to patients. While the complexity of this phase has been widely cited as a potential barrier to expanding manufacturing capacity for mRNA vaccines, particularly in LMICs, Afrigen has been able to successfully complete this process in the lab.

“Afrigen’s strength is in formulations … the scientists here, the PhDs here, that’s what they do really well,” says Terblanche. “The challenge is for us to scale, you know, to take this two litres … and there we are getting some technical support from international experts.

“We are now doing more batches and we will then start with some preclinical work,” she says. Using lab-scale batches, Afrigen can start undertaking preclinical research to gain insight into the quality and safety of their vaccine before moving to clinical trials with human subjects. At this stage, preclinical work includes conducting stability testing on the vaccine, validating production processes, and conducting preclinical safety evaluations.

When will Afrigen’s candidate vaccine be ready for clinical trials?

The next major milestone for Afrigen will be developing a clinical trial-size batch of mRNA vaccines. Currently, there are no facilities in South Africa that have the capacity to produce clinical trial-size batches of vaccines and so, historically, when South African researchers have sought to develop clinical trial stock of locally developed vaccines or biotherapeutics, they have had to commission manufacturing outside the country.

The scale at which clinical trial stock must be produced can be a challenge – typically thousands of doses, depending on what is required to demonstrate statistical significance in clinical trials. Apart from scale, a critical impediment to production is the lack of a local facility with the required GMP certifications.

Under South Africa’s Medicines Act, medicine and vaccine manufacturers must be licensed by the South African Health Products Regulatory Authority (Sahpra), and holding a manufacturing licence is contingent on demonstrating compliance with GMP standards.

Afrigen aims to be the first company in South Africa to have a manufacturing site certified to produce clinical-grade vaccines. (NantSA, which plans to produce a broader range of products than Afrigen, including vaccines using different platforms, did not respond to a request for comment – sent to a media contact listed on this media statement – on the company’s target date for receiving GMP certifications for its newly launched manufacturing campus in Cape Town).

Before Afrigen can apply for GMP certification from Sahpra, it must complete facility upgrades and installation of manufacturing equipment.

“Facility readiness is about 60% at the moment,” says Terblanche. She adds that Afrigen is aiming to finalise this process and gain cGMP approval by June 2022.

Facility upgrades under way include upgrading the facility’s electrical systems and installing a heating, ventilation, and air-conditioning system.

Changing role of Sahpra

Meanwhile, Sahpra is positioning itself to assess and certify Afrigen’s GMP compliance.

Sahpra, which must assess and certify whether Afrigen’s facility complies with good manufacturing practices, is currently working towards gaining Maturity Level 3 (ML3) status from the WHO. According to the WHO, countries with ML3 status have a “stable, well-functioning, and integrated regulatory system”.  

“[Sahpra] needs to be at an ML3 status and specifically, vaccine GMP accredited before they can inspect our own facility,” says Terblanche. She adds that “Sahpra is well on track to reach their ML3 status before June, before we need them to audit us.”

Sahpra’s Nthabi Moloi told Spotlight, “For a National Regulatory Authority to be able to rely on another regulator’s decision there needs to be an alignment in terms of the standards applied/work practices deployed, etc. The easiest mechanism for regulators to use to draw these parallels is to use an ML3 status or ML4 status as an indicator of the regulatory rigour.

The World Health Organization (WHO) announced the establishment of a mRNA Technology Transfer Hub in June 2021 to build mRNA vaccine manufacturing capacity in low and middle-income countries. South Africa was selected to host the Hub, and Afrigen was tasked with developing a mRNA COVID-19 vaccine. (Photo: Roger Bosch/MPP)

“Sahpra is currently engaged with the [WHO’s] initial assessment cycle. The assessment was initiated in November 2021 with an on-site and virtual team contributing to the assessment process. Sahpra is completing the response cycle and providing further documentation so that the WHO team can, during their May 2022 site visit, then complete our formal benchmarking assessment,” said Moloi.

Timeline for conducting clinical trials

Afrigen is aiming to gain GMP certification in June of this year, and to start Phase 1 clinical trials on its candidate vaccine by November. Terblanche explains that the product that will be used in Phase 1 trials will be formulated from end-to-end at Afrigen. This will include making the RNA, formulating the vaccine, inserting the vaccine into vials (known as fill and finish), and labelling the vials for trial use.

“We thought that Phase 1 will take us at least six months, including data analysis, and then, say, a two-month period to get approval for Phase 2. So, eight months since the start of Phase 1, we could move to Phase 2,” she says.

She says that Sahpra and the WHO are committed to fast-track the clinical development if the results warrant it. “Phase 2 will probably take about 12 months, and then we will go into Phase 3,” she says.

“We hope that it might not be necessary to do all three Phases, depending on our results, but what we said is the clinical development may be 36 months in all.”

Doing efficacy trials on Covid-19 vaccines has become more complicated as more and more people have already received vaccines and as the efficacy of existing vaccines has raised questions about the use of placebos in trials.

“At this point in time, we can’t tell how many patients we would require for clinical trials – we can’t even tell what the detailed clinical development programme would look like. Because this landscape is changing fairly fast … You’re not going to find naive patients … We’ll have to look at how to design this trial. How do we ensure that we get statistical significance? Are we going to do a case comparative trial with Moderna? So those details we would only be able to really unpack after we have some of the preclinical data,” says Terblanche.

She notes that both the WHO and local experts in clinical development will be involved in designing the trials.

When will manufacturing be transferred to commercial partners?

As a technology transfer Hub, Afrigen will be tasked with transferring technology to and training multiple international partners. The WHO has already announced 13 countries that will receive technology transfers from the Hub to enable their manufacture of Covid-19 mRNA vaccines. Although the WHO has not yet announced which companies in these countries will act as commercial partners, it is already known that, in South Africa, Afrigen’s commercial partner will be the partially state-owned entity, Biovac.

Terblanche adds that in addition to producing commercial stock, the Hub’s commercial partners may be responsible for producing some of the clinical trial stock, which can assist them with their later regulatory applications – but that this is still being worked out.

“The thinking,” she says, “was it makes sense that at the end of Phase 2, that the sponsor for Phase 3 should be the market authorisation entity and therefore, Biovac. I think the verdict on that decision is still out. It is not impossible that Afrigen will go to Phase 3 and have the market authorisation. It’s also not impossible that Biovac may come in at Phase 2.”

Dr Morena Makhoana, CEO of Biovac, told Spotlight that he expects Biovac will manufacture the vaccine for the Phase 3 trial. “If Phase 3 clinical trials are successful this will lead to market authorisation of the product through the regular regulatory approval process,” he says.

At the beginning of March 2022 Biovac announced that a consortium of development finance institutions would support Biovac in raising R2.3-billion to expand its vaccine manufacturing capacity – including for the Pfizer/BioNTech mRNA vaccine. “Biovac has an agreement with Pfizer/BioNTech where it will be producing Drug Product (Formulation-Fill Finish) on behalf of Pfizer,” says Makhoana.

In addition to the expanded capacity being developed at Biovac, Terblanche notes, “The capacity we’ve designed [at the Afrigen facility] for once it’s fully, fully commissioned, is 10 million vials, which is about 50 million doses. We are a tech developer and training facility,” she says. “We are not a commercial supply facility.” However, production capacity at Afrigen may be used to bridge or supplement that of its commercial partners.

SA training international manufacturers to produce mRNA vaccines

In addition to developing a technology transfer package, Afrigen will conduct hands-on training for commercial partners seeking to gain knowledge, capacity, and skills to produce mRNA vaccines. “Our training is tech transfer and training. It’s very specific. It is in the process and the product that will be made in those facilities. [It] is very, very focused,” says Terblanche. She adds that the training will happen on-site, off-site, and some of it also, to some extent, remotely, depending on the maturity levels of the partners.

Technology transfer recipients from Argentina and Brazil are arriving in the country in the second week of March “for the first hands-on training to make the lab-scale vaccine,” says Terblanche.

South Africa’s new role as a global trainer in mRNA vaccine development and manufacturing, less than a year since the establishment of the Hub’s first spoke in the country, is impressive. Terblance says credit is due to the South African scientific community for making a vaccine, in a short period, on a new platform for vaccine production. “It is really phenomenal,” she says.

Potential patent problem

Despite backing from international health agencies and funding of the Hub by multiple countries, patent protections held by the private company, Moderna, leave significant legal uncertainty on whether the Hub’s vaccine candidate will be able to be manufactured, marketed, and rolled out in LMICs, if demonstrated safe and effective in clinical trials.

“Under the Bolar exemption [a provision in South Africa’s and international trade law] we can operate up to Phase 3 clinical trials, but we cannot go commercial,” Terblanche told Spotlight.

Whether the Hub’s vaccine can be commercialised after clinical development will depend on its patent status in each country where it will be used.

“We are working on a number of strategies to ensure that we have freedom to operate for the Hub and spokes… remember, now it’s not only South Africa… it is going to be 20 other countries, low-and middle-income countries,” says Terblanche.

According to data compiled by the Medicines Patent Pool, 17 patent applications related to Moderna’s vaccine were filed through the World Intellectual Property Organization’s Patent Cooperation Treaty (which acts as a clearing house for filing applications to multiple countries at once) between 2006 and 2021. These protections could impede competitor products such as the Hub’s vaccine through 2041. Eight of these patent applications were filed in South Africa – four of which were granted – lasting through 2032.

While Moderna has pledged not to enforce its patents during the pandemic, it has retained discretion on when it will resume enforcement of these patents. Says Médecins Sans Frontières’ Candice Sehoma, “The patents granted to Moderna related to mRNA vaccines may jeopardise the success of the WHO’s mRNA Vaccine Technology Transfer Hub as well as the future of self-reliant vaccine production in South Africa.” DM/MC

*This article was published by Spotlight – health journalism in the public interest.