As people in South Africa roll up their sleeves to get vaccinated against COVID-19 in the coming months, many will receive a jab made by the pharmaceutical companies Pfizer and BioNTech. This vaccine is not only highly effective but it is also at the cutting edge of vaccine science - being one of the first of a new type of vaccines called messenger RNA, or mRNA for short.
While scientists have been investigating and developing mRNA technology for decades, (see this 2018 review in Nature), research in this area has recently been propelled forward by unprecedented public financing in response to COVID-19. Apart from the Pfizer/BioNTech vaccine, the pharmaceutical company Moderna has also launched a highly effective mRNA vaccine. Both these mRNA vaccines were developed with substantial public funding, and both are already in wide use, particularly in wealthy countries.
The potential benefits of mRNA technology go far beyond COVID-19
mRNA vaccines are being investigated for their effectiveness in preventing a broad range of other illnesses, including malaria, flu, Zika, and HIV. They are also investigated as a potential new area of cancer treatment.
This new class of vaccines has also been central to debates on how vaccine production can be scaled up around the world. This is because setting up mRNA vaccine production is thought to be simpler and cheaper than it is for traditional vaccines. For now, though, mRNA manufacturing capacity is mostly in the United States and Europe - although Australia, Singapore, and South Korea have recently announced investments and partnerships to localise this capacity.
mRNA technologies have also attracted the attention of African leaders, including South Africa's President Cyril Ramaphosa and Rwanda's President Paul Kagame, who both called for building mRNA manufacturing capacity on the continent. The African CDC and African Union have made similar appeals, stressing the manufacturing advantages of the new technology over conventional vaccine manufacturing approaches.
But currently, there is extremely limited capacity in Africa to manufacture vaccines and what capacity there is, is largely restricted to vialing and packaging imported vaccines. This has had a devastating impact on access to COVID-19 vaccines on the continent, as wealthier countries have devoured available stock and manufacturing countries, like India, have restricted exports.
mRNA vaccine manufacturing versus conventional approaches
The advantages of manufacturing mRNA vaccines over conventional vaccines are essentially due to the novel vaccination approach used in mRNA vaccines.
For conventional vaccines, whole pathogens that are weakened or killed so that they cannot cause disease or part of a pathogen known as a protein are used as the active ingredient. Living cell systems, typically derived from animals, are used to grow the pathogens or their proteins for use in vaccines inside large stainless-steel bioreactors located in factories with carefully controlled conditions.
However, for mRNA vaccines, the active ingredient is the mRNA itself. mRNA is a piece of genetic material that instructs our cells to make specific proteins. In the case of COVID-19 vaccines, the mRNA contains instructions that teach and prompt our cells to make COVID-19's distinctive spike protein. On its own, the spike protein is harmless and cannot cause infection. Our immune systems recognise the spike protein made by our cells as a foreign threat and make antibodies that enable our immune system to identify and fight off SARS-CoV-2 infection should we be exposed to it.
The mRNA used in COVID-19 vaccines is chemically synthesised (made through chemical reactions using enzymes), rather than biologically grown. So instead of producing disease combating proteins inside animal cells in factories as done for conventional vaccines, mRNA vaccines harness our own body's ability to produce these proteins naturally.
As mRNA vaccines remove the need to grow pathogens or their proteins in living cell systems, they have several manufacturing advantages over conventional vaccines. The removal of the need to handle and grow infectious agents as part of the vaccine manufacturing process makes producing the vaccines safer, while the removal of living cell systems makes the process less vulnerable to contamination and easier to rapidly scale up.
Another advantage of mRNA vaccines is that, unlike conventional vaccines, they can be modified relatively easily and quickly. This means manufacturers can change and update vaccines to address new disease mutations - such as the new variants emerging for COVID-19. Moderna, for example, has developed a booster mRNA vaccine targeted against the variant B.1.351, which was first identified in South Africa, that is undergoing clinical trials.
A further benefit of mRNA manufacturing approaches is that the manufacturing platform, technologies, and processes developed for COVID-19 are expected to be useful for manufacturing mRNA vaccines against other diseases, as new mRNA products enter the market. Conventional vaccine manufacturing approaches are comparatively far more customised to specific pathogens.
Establishing mRNA vaccine manufacturing capacity on the continent remains complex and murky
While establishing mRNA manufacturing capacity may be easier than establishing conventional vaccine manufacturing capacity, and may have several benefits over traditional approaches, it will by no means be easy to establish. "None of that technology exists at this point and time on the continent," says Stavros Nicolaou, Senior Executive at Aspen.
Multiple different inputs and partners will need to come together and align to enable domestic manufacturing. The inputs include access to proprietary knowledge, technology transfer partnerships, as well as the availability of requisite skills, facilities, technology, and raw materials. Below we break down the process of mRNA vaccine manufacturing and what is required to establish vaccine manufacturing capacity on the continent.
How are mRNA vaccines produced?
Manufacturing of mRNA vaccines is a multi-stage process often conducted across multiple facilities and countries. mRNA vaccines produced in the United States, for example, must travel across several states before production is complete. While vaccines produced in Europe include components from and production stages in several countries. Factories involved in the manufacturing of approved mRNA vaccines include factories owned by Moderna, Pfizer, and BioNTech, as well as many factories owned by other companies contracted to produce part of the vaccines - known as contract manufacturing organisations.
Raw materials or starting materials are manufactured in different locations. Key raw materials used in the production of mRNA vaccines include plasmids, enzymes, capping agents, and lipid solutions.
Plasmids are small DNA molecules that carry the gene sequence of the coronavirus. They are manufactured or grown in solutions of E. coli bacteria. While plasmids can be bought commercially, the availability of plasmid supply has been highlighted as a potential bottleneck to scaling up manufacturing of mRNA vaccines for COVID-19.
Enzymes are biological molecules that catalyse chemical reactions. Specific enzymes are used to convert plasmid into mRNA.
Capping agents which stabilise the mRNA may be in synthetic or enzyme format. One important synthetic capping agent, which has contributed to bottlenecks in scaling up mRNA vaccine manufacturing, is under patent and only supplied by a single U.S.-based company.
Lipid solutions are oily solutions that are mixed with the mRNA to create lipid nanoparticles. These are basically tiny fat droplets that encase and protect the mRNA for delivery to patients. Certain lipid solutions used for the production of mRNA vaccines remain under patent and are only produced by a small number of suppliers.
If an African company were to produce mRNA vaccines locally, it would need to assess what key raw materials can be produced locally, versus what would need to be imported - considering supply constraints on the global market. The company would also need to decide whether it would seek to establish the capacity to produce active ingredients - namely the mRNA - and other raw materials or focus on later stages of production, such as mixing the mRNA with lipid solutions. While it may make sense to focus on later stages of development, building backward on the continent's existing fill and finish capacity, the process of mixing mRNA with lipid solutions has been described as the most difficult stage in the mRNA vaccine manufacturing process.
Whether the Africa CDC, the African Union, the African Vaccine Manufacturing Initiative, and other stakeholders can effectively steer different companies in different African countries to develop complementary capacities for mRNA vaccine manufacturing on the continent remains to be seen.
What is needed to produce mRNA vaccines in Africa?
Developing sustainable mRNA production capacity in Africa is a complex challenge. There are at least five factors to consider.
The freedom to operate without the threat of legal challenge
Analyses of patents on mRNA vaccines have found that hundreds of patents have been granted or are being sought on different aspects of the vaccines, including their method of functioning, their method of production, their chemical structure, and their method of use. Patents have also been sought on the ingredients and technologies needed to produce these vaccines. Given the extensive web of patents that have been sought on these technologies, new companies seeking to enter this space face a high threat of legal challenge.
Because of the urgent need for more manufacturers to come to market to address critical shortages of COVID-19 vaccines, South Africa has spearheaded a call at the World Trade Organisation for the body to grant a waiver to allow countries to not grant or enforce patents on health technologies needed to respond to the pandemic. The waiver would give new companies to freedom to operate without legal challenge. While the proposal remains under deliberation, it has received significant support to date, including surprising backing by the United States who has requested "text-based negotiations" related to the waiver.
In the absence of the waiver or efforts by governments to override patents at a national level (known as compulsory licensing), African manufacturers are reliant on patent holders to grant them voluntary licenses to operate. This has not happened for the production of an mRNA vaccine on the continent to date.
The transfer of know-how to LMICs
Besides removing legal barriers impeding the use of knowledge related to mRNA vaccine manufacturing, companies in Africa seeking to develop this capacity will need help and training from the handful of companies who hold this knowledge. Moderna's CEO Stéphane Bancel recently said regarding the TRIPS waiver proposal "if someone wants to start from scratch, they would have to figure out how to make mRNA, which is not in our patents".
Companies such as Moderna, BioNTech, and Pfizer will need to share their carefully guarded trade secrets related to manufacturing processes and assist in training new experts in low- and middle-income countries (LMICs) to enable skills transfer for mRNA manufacturing. The rapid onboarding of contract manufacturing organisations by these companies suggests that this skill and knowledge transfer can be done where there are adequate incentives.
Recognising the need for skills transfer to enable companies in LMICs to manufacture mRNA vaccines, the World Health Organization (WHO) announced its intentions to establish a tech transfer hub to facilitate the transfer of know-how and technology between patent holders and LMIC manufacturers last month.
However, as the WHO's proposed tech transfer hub provides for voluntary participation by patent-holding companies, it may be similarly snubbed by companies as were earlier proposals by the WHO to share intellectual property and transfer know-how for COVID-19 health technologies. Medicine access advocates have argued that public funders such as the United States and the European Union missed a crucial opportunity to compel patent-holding companies to license their technologies and transfer their know-how to LMICs by not including these requirements as conditions for receipt of public financing.
The availability of raw ingredients, consumables, and technologies
Adequate availability of raw materials - including plasmids, enzymes, lipids, and consumables such as vials and single-use bioreactor bags - is necessary to initiate local production. Supply constraints and shortages have been reported for certain raw materials which remain under patent, as well as for single-use bioreactor bags. The granting of the WTO waiver may therefore also increase the availability of certain critical raw materials.
Besides the availability of raw materials, a local producer will need to procure specialised machinery needed for the production of mRNA vaccines. As this technology is new, the machinery needed for scaled production is still being developed and adapted.
While there may be a backlog on specialised machinery - Moderna's Bancel has said it takes six to nine months to add significant manufacturing capacity to a new site, including ordering, building, and installing required machinery. A benefit of mRNA manufacturing processes is that the technology is largely modular. This allows for the technologies used by patent-holding companies to be easily replicated and shipped around the world (if they can be convinced or compelled to share them).
Although customisations and differences between machinery and processes used by different mRNA-producing companies create complexities for African companies seeking to enter this space.
Biovac's CEO Morena Makhoana told Spotlight that "unfortunately mRNA is a new technology even to the vaccine manufacturing industry. It is an area that we are studying ourselves. Not all mRNA technologies appear the same and therefore what appears on the surface still needs a lot of navigation and investigation."
Appropriate production facilities
The availability or construction of manufacturing facilities that meet the strict regulatory standards required for the production of vaccines is another prerequisite for domestic manufacturing of mRNA vaccines. To receive regulatory approval, manufacturers must demonstrate the manufacturing can be done under sterile conditions and that air and water quality in the facility is highly controlled and specific. Besides regulatory approval of the manufacturing facility, regulatory approval of manufacturing processes is also required.
The availability of financing and sustainability of demand
A major challenge for any company seeking to establish mRNA vaccine manufacturing capacity is the high cost of establishing this capacity and the availability of financing. Establishing new facilities and procuring specialised machinery for manufacturing mRNA vaccines is expected to run into the billions of rands.
In wealthy countries, the rapid establishment and scaling up of mRNA vaccine manufacturing capacity has been supported by massive public financing contributions. Victoria, a state in Australia, for example, recently committed to invest fifty million Australian dollars (equivalent to around R500 million) to "kickstart" domestic manufacturing of mRNA vaccines in the country. Establishing mRNA vaccine manufacturing capacity in Africa will likely require a combination of public and philanthropic funding, as well as loans from multilateral development banks.
Finally, even if each of the prerequisites of local production is met and financing is secured, it may not be enough to build sustainable domestic manufacturing capacity.
"In the absence of proper localisation policy on the continent, you can't do anything. You can talk about patents, you can be donated a modular facility, but you cannot fund the running costs if you continue importing", says Nicolaou. "You will be out of business in a few years' time. You need to first have long-term contracts and guaranteed off-takes... unless you get that off the ground, you don't have a chance of succeeding... you might as well continue importing."
New manufacturers seeking to enter the mRNA vaccine manufacturing space will need to consider how their facilities will be used and how they will maintain debt payments in years when countries are not facing a pandemic. They will also need to consider how the conclusion of the TRIPS waiver (if granted) will impact their operations. The fact that the waiver is only proposed to last "until herd immunity is reached" for COVID-19 may disincentivise new entrants to the market who fear how the waiver's unclear timeline may impact the future sustainability of their operations.
Future unknowns must be considered
Finally, despite the promise of mRNA technology, some health experts have cautioned that policymakers and companies should not focus solely on building mRNA vaccine production capacity but rather focus on diversifying manufacturing capacity across companies and countries in Africa.
Former director of the Biomedical Advanced Research and Development Authority (BARDA) in the United States, Rick Bright said during a recent conference on vaccine manufacturing in Africa that "Messenger RNA vaccines are new and they are attractive, but that doesn't mean they are for everything, for every disease, or for every vaccine candidate out there".
"There are other vaccine platforms ... you must have a diversified portfolio because we don't know what is coming our way and we don't know if each platform can successfully make a vaccine for that particular pathogen or that threat, so diversification across the country and the continent I think is absolutely critical to be successful," said Bright.
Cold-chain requirements for mRNA also add significant complexity to delivering these vaccines to patients, and until cold chain requirements for mRNA vaccines are less stringent or new cold chain technology for use in LMICs is developed and easily accessible, conventional vaccines will continue to play a critical role in ensuring that people in Africa can access life-saving inoculations.