First WHO/MPP mRNA Technology Transfer Programme Meeting

In June, 2021, WHO and the MPP announced the establishment of a technology transfer programme for mRNA vaccines in South Africa. This programme was to be hosted by Afrigen, the Biovac Institute, and the South African Medical Research Council, all from Cape Town, South Africa, and would share technology and expertise with another 14 biomanufacturing partners distributed among low-income and middle-income countries (LMICs). From April 17 to 21, 2023, the first WHO/Medicines Patent Pool (MPP) mRNA Technology Transfer Programme Meeting was held in Cape Town, South Africa. Martin Friede (WHO Initiative for Vaccine Research, Geneva, Switzerland) introduced the context and objectives for the meeting. Among the more than 200 delegates was a substantial number from partner institutions, making this an LMIC-dominated meeting. Rick Bright (Bright Global Health) described the lessons learned from the WHO's Technology Transfer Programme for influenza vaccines (2006–16), which assisted nine of the original 14 LMIC partners to develop or strengthen influenza vaccine manufacturing. There was then an overview of the programme by WHO/MPP, followed by a report on implementation at the Centre for mRNA Technology Development and Transfer at Afrigen, by the Chief Executive Officer, Petro Terblanche. The MPP gave a brief, but important, summary of the intellectual property landscape. They have simplified the process of due diligence by compiling VaxPal, an active database of the patent status of COVID-19 vaccines worldwide. This database also includes information on lipid nanoparticle formulation and modifications to RNA, such as use of modified nucleotides, capping enzymes, and RNA terminal sequences leading to improved expression. The 15 partner institutions then each described their actual or proposed implementation of mRNA vaccine technology. The most impressive aspect of several of these was their established biomanufacturing capacity: as well established vaccine and therapeutics or drug manufacturers, they could simply bolt on mRNA manufacture. African partner facilities that manufacture vaccines and biologics are the Instituts Pasteur de Dakar (IPD; Dakar, Senegal) and Instituts Pasteur de Tunis (IPT; Tunis, Tunisia), and BioGeneric Pharma (Cairo, Egypt). IPD was established in 1896 and has been a vaccine manufacturer (yellow fever) since 1937. They aim to establish mRNA vaccine manufacturing in the facility for Rift Valley fever virus and Crimean–Congo haemorrhagic fever virus. IPT, established in 1893, aims to replace some WHO Essential Programme on Immunization vaccines with mRNA. Aspirational partners are Biovaccines Nigeria, who want vaccines for outbreak viruses like Lassa, chikungunya, Rift Valley fever, and Ebola; Biovax Kenya, who will produce their first vials of polio vaccine by 2025 or 2026; BioGeneric Pharma, who are implementing mRNA production technology from Afrigen; and Biovac in Cape Town, which has good manufacturing practice (GMP) fill and finish capability, and is only starting to make drug substance. They will be involved in mRNA vaccine formulation and vialling with Afrigen. José Castillo (Quantoom Biosciences, Brussels, Belgium) described their modular laboratory to production scale mRNA synthesis and formulation technology, which has been adopted by Sinergium (Buenos Aires, Argentina) and IPT, and has just been installed at Afrigen.1AfrigenPRESS RELEASE: Quantoom Biosciences installs the first Ntensify™ system for mRNA manufacturing at Afrigen Biologics in Cape Town.https://www.afrigen.co.za/news-press-release-events/Date: May 3, 2023Date accessed: May 15, 2023Google Scholar Laboratory-scale production will be established at the University of Cape Town as a training and preclinical laboratory for Afrigen. Quantoom's machinery uses disposable 20 mL reaction vessels, can make mRNA at 5–6 g/L with more than 90% capping and polyA tailing, and at 8·1% of the cost of conventional manufacture. They claim to have met a Bill & Melinda Gates Foundation-specified target of US$0·25 per dose. Friede introduced the topic of mRNA vaccine targets. To aid in this targeting, his team developed vaccine value profiles and preferred product characteristics to inform decision making.2Hutubessy RCW Laure JA Giersing B et al.The full value of vaccine assessments (FVVA): a framework to assess and communicate the value of vaccines for investment and introduction decision making.SSRN. 2021; (published online May 19.) (preprint).https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3841999Crossref Google Scholar Drew Weissman (University of Pennsylvania, Philadelphia, PA, USA) gave a talk on what we know or do not know about mRNA technologies. There are 17 innate cellular sensors that recognise RNA as foreign, so RNA can be highly inflammatory. Uracil modifications reduce inflammation, whereas modifications of other bases do not, and modified mRNAs are better translated, for up to 10 days in transfected cells. mRNAs were much better than HIV-1 Env protein at eliciting T follicular helper cells (Tfh). CpG and other adjuvants all made responses worse, as these induced type 1 interferons, which block Tfh formation. Alan Barrett (The University of Texas Medical Branch [UTMB], Galveston, TX, USA) described how a major problem with flaviviruses was their serological cross-reactivity, and potentially antibody-dependent enhancement of infection in cell culture. Justin Richner's (University of Illinois at Chicago, Chicago, IL, USA) laboratory has made mRNA candidate vaccines for a wide range of flaviviruses, delivering the PrM-E polygene for natural self-cleavage and subsequent assembly into budded virus-like particles. These elicited protective antibody responses including neutralising antibodies, with titres close to those found in natural infections. Both CD4 and CD8 T-cell responses were also elicited for dengue virus and yellow fever vaccines. Use of mRNA avoided the severe adverse events associated with live attenuated vaccines, and one could engineer epitopes (eg, remove immunodominant fusion loop epitopes) to stop antibody-dependent enhancement. As for targets, Barrett observed that Japanese encephalitis virus was possibly the best candidate for a mRNA vaccine: only low levels of neutralising antibody were needed, and there were licenced vaccines against which to compare it. Richner proposed making a pentavalent dengue and Zika vaccine combination. Erin Staples (US Centers for Disease Control and Prevention) suggested that replacing the inactivated vaccines was a good idea to start with. Mélika Ben Ahmed (IPT) presented a strategy for a mRNA-based Leishmania vaccine involving the genes for one sand fly salivary protein and four Leishmania proteins, chosen to be conserved between different species of parasite and to elicit a Th1 response, as well as to be well presented by antigen presenting cells. Ali Mirazimi (Public Health Agency of Sweden, Solna, Sweden) gave a keynote talk on Crimean–Congo haemorrhagic fever virus. His strategy is to develop vaccines to prevent infection of animals, in turn preventing human infections. He noted that DNA vaccines encoding the Gn and N protein genes protect both mice and macaques from infection, indicating the feasibility of mRNA vaccines. Anita McElroy (University of Pittsburgh, Pittsburgh, PA, USA) stressed the importance of neutralising antibodies to Gn in protection. They would plan to use Gn and Gc genes in mRNA, even though there was evidence that N protein alone is partly protective. Alexander Bukreyev (UTMB) described their promising work on filovirus, Lassa virus, and hantavirus mRNA vaccines. An Ebola GP-based vaccine was protective in mice; so too GP genes from Marburg and Ravn marburgviruses—and use of both GP and VP40 genes allowed in vivo production of virus-like particles, and 100% protection at lower doses. Lassa virus GPC-encoding mRNA elicited good binding antibody, but poor neutralising antibody responses, but was protective for both prefusion-stabilised and native proteins. In a test of possible rapid response to Andes hantavirus, which emerged in 2019 in Argentina, they tested Gn and Gc protein genes in both modified and unmodified mRNAs: both were protective in mice against disease, but not infection. Mani Margolin (Afrigen) described how respiratory syncytial virus vaccines would be their next mRNA vaccine target after SARS-CoV-2. He said that, “We have been shown time and time again that we have to do this for ourselves,” and that Afrigen was well equipped to do this for Africa. Kanta Subbarao (The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia) noted that the whole process for selection of strains to update seasonal influenza vaccines would have to change with mRNA vaccines, and new assays and reagents would have to be developed, but that it would be possible to wait longer to make predictions because the process would be much faster, with no need for reassortment strains of virus. In discussion, it was suggested that neuraminidase could easily be added to mRNA vaccines, that better antigens could be designed, and that seasonal influenza vaccines might not be the ideal placeholder while waiting for a pandemic, but that respiratory syncytial virus might be. It was also noted that mixing mRNAs for different HA proteins could be a problem, as mixed trimers could result, which could jeopardise immune responses. The last day of the conference was a tuberculosis vaccine session, introduced by Friede saying that mRNA vaccines were a good opportunity to accelerate tuberculosis vaccine development. He said, in a few years there would be several countries able to make small volumes of GMP vaccines to test, and that it was crucial to identify other things that can be made to keep facilities going, as tuberculosis was the big one we needed to solve. A session highlight was Munya Musvosvi's (South African Tuberculosis Vaccine Initiative [SATVI], Cape Town, South Africa) description of new potential protein targets that could elicit robust T-cell responses, arrived at by analysis of bacterial peptides bound by major histocompatibility complexes in people who did not progress to disease. These were PE13 and CPT10, with Wbbl1 and PPE18 as possible additions, with all of these involved in various aspects of bacterial growth. SATVI were making polygenes for these antigens with Patrick Arbuthnot's laboratory at University of the Witwatersrand (Johannesburg, South Africa), for a new African mRNA vaccine candidate. Musvosvi mentioned that their platform could also readily be adapted for rational antigen or gene selection for vaccines for other difficult pathogens. The meeting was exciting and informative; the information presented will inform future thinking on the applicability of mRNA technology for different vaccines, and also on its applicability in the setting of LMICs. Negative aspects of mRNA technology that emerged were that the technology probably cannot be used for everything—pertussis was Friede's example of a bad target, given that the antigens are not proteins—and that mixing mRNAs to broaden responses could be a problem if it led to aberrant assembly of HIV or influenza virus Env or HA trimers, or of different HPVs, for example. The positives of mRNA technology were that even small facilities could produce many millions of doses of vaccines, and that the simplicity of the platform meant that problems encountered in conventional production platforms when switching products would not feature with mRNA manufacture. The surprising revelations of the number and sophistication of vaccine manufacturing centres in LMICs also boded well for application of the technology, as add-ons to existing facilities with established cGMP. I am a shareholder in Cape Bio Pharms (Cape Town, South Africa), which is not involved in this initiative.